Exploring NK cell receptor dynamics in paediatric leukaemias: implications for immunotherapy and prognosis.

Objectives: Immunotherapies targeting natural killer (NK) cell receptors have shown promise against leukaemia. Unfortunately, cancer immunosuppressive mechanisms that alter NK cell phenotype prevent such approaches from being successful. The study utilises advanced cytometry to examine how cancer immunosuppressive pathways affect NK cell phenotypic changes in clinical samples. Methods: In this study, we conducted a high-dimensional examination of the cell surface expression of 16 NK cell receptors in paediatric patients with acute myeloid leukaemia and acute lymphoblastic leukaemia, as well as in samples of non-age matched adult peripheral blood (APB) and umbilical cord blood (UCB). An unsupervised analysis was carried out in order to identify NK cell populations present in paediatric leukaemias. Results: We observed that leukaemia NK cells clustered together with UCB NK cells and expressed relatively higher levels of the NKG2A receptor compared to APB NK cells. In addition, CD56dimCD16+CD57- NK cells lacking NKG2A expression were mainly absent in paediatric leukaemia patients. However, CD56br NK cell populations expressing high levels of NKG2A were highly represented in paediatric leukaemia patients. NKG2A expression on leukaemia NK cells was found to be positively correlated with the expression of its ligand, suggesting that the NKG2A-HLA-E interaction may play a role in modifying NK cell responses to leukaemia cells. Conclusion: We provide an in-depth analysis of NK cell populations in paediatric leukaemia patients. These results support the development of immunotherapies targeting immunosuppressive receptors, such as NKG2A, to enhance innate immunity against paediatric leukaemia.

Characterization of Human Engraftment and Hemophagocytic Lymphohistiocytosis in NSG-SGM3 Neonate Mice Engrafted with Purified CD34+ Hematopoietic Stem Cells.

Immunodeficient mice bearing human immune systems, or "humanized" chimeric mice, are widely used in basic research, along with the preclinical stages of drug development. Nonobese diabetic-severe combined immunodeficiency (NOD-SCID) IL2Rγnull (NSG) mice expressing human stem cell factor, granulocyte-macrophage colony stimulating factor, and interleukin-3 (NSG-SGM3) support robust development of human myeloid cells and T cells but have reduced longevity due to the development of fatal hemophagocytic lymphohistiocytosis (HLH). Here, we describe an optimized protocol for development of human immune chimerism in NSG-SGM3 mice. We demonstrate that efficient human CD45+ reconstitution can be achieved and HLH delayed by engraftment of neonatal NSG-SGM3 with low numbers of human umbilical cord-derived CD34+ hematopoietic stem cells in the absence of preconditioning irradiation.

Evaluación de la variabilidad de la práctica médica en la enfermedad isquémica coronaria / Evaluation of the variability of medical practice in coronary ischemic disease

RESUMEN Objetivo Determinar la variabilidad de práctica médica del uso de angioplastia y revascularización para tratamiento de la enfermedad isquémica coronaria en aseguradoras de salud. Materiales y Métodos Estudio descriptivo retrospectivo de tipo ecológico mixto del registro de tasa de uso de procedimientos cardiovasculares de angioplastia y revascularización empleados en el tratamiento de la enfermedad isquémica coronaria. Se realizó un análisis de regresión y un análisis de varianza (ANOVA) con los reportes de varias aseguradoras en un periodo de cinco años. Resultados La edad media de procedimientos fue 64,9 años, desviación estándar de 11,3. El procedimiento más usado fue angioplastia (75,6%) y se realizaron más procedimientos en hombres 2:1. Se encontraron diferencias estadísticamente significativas (p<0,05) en cada grupo etario para ambos procedimientos y variaciones en al menos dos aseguradoras. El análisis univariado por sexo encontró lo siguiente: variaciones de tasas de uso en angioplastia: pacientes de 40 a 49 años (p=0,017) y de 50 a 59 años (p=0,036); variaciones de tasas de uso de revascularización: pacientes de 30 a 39 años (p=0,036); de 40 a 49 años (p=0,013); de 50 a 59 años (p=0,002) y de 60 a 69 años (p<0,001). Conclusiones En las aseguradoras hay variaciones en la tasa de uso para procedimientos cardiovasculares (en todos los grupos etarios observados) después de los 30 años (también en tasa de uso por sexo). Se infirieron causas como el factor protector hormonal y terapias de reemplazo hormonal sin descartar otras causas de variación injustificadas como educación en salud a mujeres sobre detección de la enfermedad isquémica coronaria, factores culturales, sociales y económicos que limitan el uso de tecnologías.

ABSTRACT Objective To determine the variability of the medical practice of the use of angioplasty and revascularization for the treatment of Coronary Ischemic Disease in health insurers. Materials and Methods Retrospective descriptive study of mixed ecological type of the registry of the rate of use of cardiovascular procedures, angioplasty and revascularization, used in the treatment of coronary ischemic disease. Regression analysis and analysis of variance (ANOVA) were performed on five years of reports from various insurers. Results The mean age of procedures was 64.9 years, standard deviation of 11.3. The most widely used procedure was angioplasty (75.6%), and more procedures were performed in 2:1 men. Statistically significant differences (p<0.05) were found in each age group for both procedures, and variations in at least two insurers. Univariate analysis by sex, variations in angioplasty use rates 40 to 49 years (p=0.017) and 50 to 59 years (p=0.036) and revascularization 30 to 39 years (p=0.036), 40 to 49 years (p=0.013), 50 to 59 years (p=0.002) 60 to 69 years (p<0.001). Conclusions There are variations in the rate of use for cardiovascular procedures in all age groups observed after 30 years in insurers, also in rate of use by sex, causes such as the hormonal protective factor and hormone replacement therapies are inferred without ruling out other unjustified causes of modification such as health education for women on detection of coronary ischemic disease, cultural, social and economic factors that limit the use of technologies.

Validation of an instrument to measure adherence to orthodontic treatment provided in dental clinics of dentistry schools / Validación de un instrumento para medir la adherencia al tratamiento de ortodoncia en servicios odontológicos de facultades de odontología

Abstract Introduction: Adherence to treatment is associated with the quality of health care given to the patient, especially in institutions with a high workload, such as dentistry schools. In these places, treatments are long and high adherence is required for them to be successful. Objective: To validate, by means of an exploratory factor analysis (EFA) and a confirmatory factor analysis (CFA), an instrument for measuring adherence to orthodontic treatment in dental clinics of dentistry schools, where a large number of patients are treated. Materials and methods: Quantitative study in which an instrument was validated by performing an EFA and a CFA. A 27-item questionnaire (adapted from the original 37-item instrument) was administered to 601 patients treated at a dentistry school of a Colombian university in two different periods: during the second semester of 2018 (n=202) and during the first semester of 2019 (n=399). The EFA and the CFA were performed using the SPSS and the LISREL software, respectively. Results: Factor analysis established that the instrument has six factors and 25 questions suitable for collecting information on adherence to treatment by obtaining the following adjustment values: x2 S B=420.09 with d.f.=260 and p<0.05; x2 S B divided by the degrees of freedom index (X2 SB/d.f.) = 1.62; CFI=0.99; RFI=0.98; NNFI= 0.99; RMSEA=0.039 (90%CI 0.032-0.046); and SRMR= 0.057. Conclusions: Based on the results obtained after performing the EFA and the CFA, it is possible to conclude that the instrument is valid and highly reliable to measure orthodontic treatment in this context. Consequently, its use in similar institutions will allow determining the levels of adherence in these patients accurately, and thus, when necessary, develop and implement actions that encourage greater engagement from this population to orthodontic treatment to obtain better outcomes.

Resumen Introducción. La adherencia al tratamiento está relacionada con la calidad de la atención en salud dada al paciente, especialmente en instituciones con un alto volumen de trabajo, como las facultades de odontología, donde los tratamientos son prolongados y se requiere de una alta adherencia para que estos sean exitosos. Objetivo. Validar, mediante un análisis factorial exploratorio (AFE) y un análisis factorial confirmatorio (AFC), un instrumento para medir la adherencia al tratamiento ortodóntico en clínicas odontológicas de facultades de odontología en las que se atiende un alto número de pacientes. Materiales y métodos. Estudio cuantitativo en el que se validó un instrumento mediante un AFE y un AFC. Se aplicó un cuestionario de 27 preguntas (adaptado del instrumento original de 37 preguntas) a 601 pacientes atendidos en una facultad de odontología de una universidad colombiana en dos periodos diferentes: el segundo semestre de 2018 y el primer semestre de 2019. El AFE y el AFC se realizaron mediante los programas SPSS y LISREL, respectivamente. Resultados. El análisis factorial permitió establecer un instrumento con 6 factores y 25 preguntas adecuado para recolectar información sobre la adherencia al tratamiento al obtener los siguientes valores de ajuste: B=420.09 con gl=260 y p<0.05; B/gl = 1.62; CFI=0.99; RFI=0.98; NNFI=0.99; RMSEA=0.039 (IC90%: 0.032-0.046), y SRMR=0.057. Conclusiones. El AFE y el AFC permitieron establecer un instrumento válido y con una alta con-fiabilidad para medir la adherencia al tratamiento ortodóntico en este escenario, por lo que su uso en instituciones similares permitirá determinar de manera confiable los niveles de adherencia en estos pacientes, y, de esta forma, cuando sea necesario, desarrollar e implementar acciones que fomenten un mayor compromiso de esta población con los tratamientos de ortodoncia para obtener mejores desenlaces.

Human CD141+ dendritic cells (cDC1) are impaired in patients with advanced melanoma but can be targeted to enhance anti-PD-1 in a humanized mouse model.

BACKGROUND: The conventional type 1 dendritic cell subset (cDC1) is indispensable for tumor immune responses and the efficacy of immune checkpoint inhibitor (ICI) therapies in animal models but little is known about the role of the human CD141+ DC cDC1 equivalent in patients with melanoma. METHODS: We developed a flow cytometry assay to quantify and characterize human blood DC subsets in healthy donors and patients with stage 3 and stage 4 metastatic melanoma. To examine whether harnessing CD141+ DCs could improve responses to ICIs in human melanoma, we developed a humanized mouse model by engrafting immunodeficient NSG-SGM3 mice with human CD34+ hematopoietic stem cells (HSCs) from umbilical cord blood followed by transplantation of a human melanoma cell line and treatment with anti-programmed cell death protein-1 (anti-PD-1). RESULTS: Blood CD141+ DC numbers were significantly reduced in patients with stage 4 melanoma compared with healthy controls. Moreover, CD141+ DCs in patients with melanoma were selectively impaired in their ability to upregulate CD83 expression after stimulation with toll-like receptor 3 (TLR3) and TLR7/8 agonists ex vivo. Although DC numbers did not correlate with responses to anti-PD-1 and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) ICIs, their numbers and capacity to upregulate CD83 declined further during treatment in non-responding patients. Treatment with anti-PD-1 was ineffective at controlling tumor growth in humanized mice but efficacy was enhanced by indirectly expanding and activating DCs in vivo with fms-like tyrosine kinase-3 ligand (Flt3L) and a TLR3 agonist. Moreover, intratumoral injections of CD141+ DCs resulted in reduced tumor growth when combined with anti-PD-1 treatment. CONCLUSIONS: These data illustrate quantitative and qualitative impairments in circulating CD141+ DCs in patients with advanced melanoma and that increasing CD141+ DC number and function is an attractive strategy to enhance immunogenicity and response rates to ICIs.

Human CLEC9A antibodies deliver NY-ESO-1 antigen to CD141+ dendritic cells to activate naïve and memory NY-ESO-1-specific CD8+ T cells.

BACKGROUND: Dendritic cells (DCs) are crucial for the efficacy of cancer vaccines, but current vaccines do not harness the key cDC1 subtype required for effective CD8+ T-cell-mediated tumor immune responses. Vaccine immunogenicity could be enhanced by specific delivery of immunogenic tumor antigens to CD141+ DCs, the human cDC1 equivalent. CD141+ DCs exclusively express the C-type-lectin-like receptor CLEC9A, which is important for the regulation of CD8+ T cell responses. This study developed a new vaccine that harnesses a human anti-CLEC9A antibody to specifically deliver the immunogenic tumor antigen, NY-ESO-1 (New York esophageal squamous cell carcinoma 1), to human CD141+ DCs. The ability of the CLEC9A-NY-ESO-1 antibody to activate NY-ESO-1-specific naïve and memory CD8+ T cells was examined and compared with a vaccine comprised of a human DEC-205-NY-ESO-1 antibody that targets all human DCs. METHODS: Human anti-CLEC9A, anti-DEC-205 and isotype control IgG4 antibodies were genetically fused to NY-ESO-1 polypeptide. Cross-presentation to NY-ESO-1-epitope-specific CD8+ T cells and reactivity of T cell responses in patients with melanoma were assessed by interferon γ (IFNγ) production following incubation of CD141+ DCs and patient peripheral blood mononuclear cells with targeting antibodies. Humanized mice containing human DC subsets and a repertoire of naïve NY-ESO-1-specific CD8+ T cells were used to investigate naïve T cell priming. T cell effector function was measured by expression of IFNγ, MIP-1ß, tumor necrosis factor and CD107a and by lysis of target tumor cells. RESULTS: CLEC9A-NY-ESO-1 antibodies (Abs) were effective at mediating delivery and cross-presentation of multiple NY-ESO-1 epitopes by CD141+ DCs for activation of NY-ESO-1-specific CD8+ T cells. When benchmarked to NY-ESO-1 conjugated to an untargeted control antibody or to anti-human DEC-205, CLEC9A-NY-ESO-1 was superior at ex vivo reactivation of NY-ESO-1-specific T cell responses in patients with melanoma. Moreover, CLEC9A-NY-ESO-1 induced priming of naïve NY-ESO-1-specific CD8+ T cells with polyclonal effector function and potent tumor killing capacity in vitro. CONCLUSIONS: These data advocate human CLEC9A-NY-ESO-1 Ab as an attractive strategy for specific targeting of CD141+ DCs to enhance tumor immunogenicity in NY-ESO-1-expressing malignancies.

Human CLEC9A antibodies deliver Wilms' tumor 1 (WT1) antigen to CD141+ dendritic cells to activate naïve and memory WT1-specific CD8+ T cells.

OBJECTIVES: Vaccines that prime Wilms' tumor 1 (WT1)-specific CD8+ T cells are attractive cancer immunotherapies. However, immunogenicity and clinical response rates may be enhanced by delivering WT1 to CD141+ dendritic cells (DCs). The C-type lectin-like receptor CLEC9A is expressed exclusively by CD141+ DCs and regulates CD8+ T-cell responses. We developed a new vaccine comprising a human anti-CLEC9A antibody fused to WT1 and investigated its capacity to target human CD141+ DCs and activate naïve and memory WT1-specific CD8+ T cells. METHODS: WT1 was genetically fused to antibodies specific for human CLEC9A, DEC-205 or ß-galactosidase (untargeted control). Activation of WT1-specific CD8+ T-cell lines following cross-presentation by CD141+ DCs was quantified by IFNγ ELISPOT. Humanised mice reconstituted with human immune cell subsets, including a repertoire of naïve WT1-specific CD8+ T cells, were used to investigate naïve WT1-specific CD8+ T-cell priming. RESULTS: The CLEC9A-WT1 vaccine promoted cross-presentation of WT1 epitopes to CD8+ T cells and mediated priming of naïve CD8+ T cells more effectively than the DEC-205-WT1 and untargeted control-WT1 vaccines. CONCLUSIONS: Delivery of WT1 to CD141+ DCs via CLEC9A stimulates CD8+ T cells more potently than either untargeted delivery or widespread delivery to all Ag-presenting cells via DEC-205, suggesting that cross-presentation by CD141+ DCs is sufficient for effective CD8+ T-cell priming in humans. The CLEC9A-WT1 vaccine is a promising candidate immunotherapy for malignancies that express WT1.

Activation of human CD141+ and CD1c+ dendritic cells in vivo with combined TLR3 and TLR7/8 ligation.

Mice reconstituted with human hematopoietic stem cells are valuable models to study aspects of the human immune system in vivo. We describe a humanized mouse model (hu mice) in which fully functional human CD141+ and CD1c+ myeloid and CD123+ plasmacytoid dendritic cells (DC) develop from human cord blood CD34+ cells in immunodeficient mice. CD141+ DC are the human equivalents of murine CD8+ /CD103+ DC which are essential for the induction of tumor-inhibitory cytotoxic T lymphocyte responses, making them attractive targets to exploit for the development of new cancer immunotherapies. We used CD34+ -engrafted NSG-A2 mice to investigate activation of DC subsets by synthetic dsRNA or ssRNA analogs polyinosinic-polycytidylic acid/poly I:C and Resiquimod/R848, agonists for TLR3 and TLR8, respectively, both of which are expressed by CD141+ DC. Injection of hu mice with these agonists resulted in upregulation of costimulatory molecules CD80, CD83 and CD86 by CD141+ and CD1c+ DC alike, and their combination further enhanced expression of these molecules by both subsets. When combined, poly I:C and R848 enhanced serum levels of key cytokines associated with cross-presentation and the induction of cytotoxic T lymphocyte responses including IFN-α, IFN-ß, IL-12 and CXCL10. These data advocate a combination of poly I:C and R848 TLR agonists as means of activating human DC for immunotherapy.

Human CD141+ Dendritic Cell and CD1c+ Dendritic Cell Undergo Concordant Early Genetic Programming after Activation in Humanized Mice In Vivo.

Human immune cell subsets develop in immunodeficient mice following reconstitution with human CD34+ hematopoietic stem cells. These "humanized" mice are useful models to study human immunology and human-tropic infections, autoimmunity, and cancer. However, some human immune cell subsets are unable to fully develop or acquire full functional capacity due to a lack of cross-reactivity of many growth factors and cytokines between species. Conventional dendritic cells (cDCs) in mice are categorized into cDC1, which mediate T helper (Th)1 and CD8+ T cell responses, and cDC2, which mediate Th2 and Th17 responses. The likely human equivalents are CD141+ DC and CD1c+ DC subsets for mouse cDC1 and cDC2, respectively, but the extent of any interspecies differences is poorly characterized. Here, we exploit the fact that human CD141+ DC and CD1c+ DC develop in humanized mice, to further explore their equivalency in vivo. Global transcriptome analysis of CD141+ DC and CD1c+ DC isolated from humanized mice demonstrated that they closely resemble those in human blood. Activation of DC subsets in vivo, with the TLR3 ligand poly I:C, and the TLR7/8 ligand R848 revealed that a core panel of genes consistent with DC maturation status were upregulated by both subsets. R848 specifically upregulated genes associated with Th17 responses by CD1c+ DC, while poly I:C upregulated IFN-λ genes specifically by CD141+ DC. MYCL expression, known to be essential for CD8+ T cell priming by mouse DC, was specifically induced in CD141+ DC after activation. Concomitantly, CD141+ DC were superior to CD1c+ DC in their ability to prime naïve antigen-specific CD8+ T cells. Thus, CD141+ DC and CD1c+ DC share a similar activation profiles in vivo but also have induce unique signatures that support specialized roles in CD8+ T cell priming and Th17 responses, respectively. In combination, these data demonstrate that humanized mice provide an attractive and tractable model to study human DC in vitro and in vivo.

Targeting CLEC9A delivers antigen to human CD141+ DC for CD4+ and CD8+T cell recognition.

DC-based vaccines that initiate T cell responses are well tolerated and have demonstrated efficacy for tumor immunotherapy, with the potential to be combined with other therapies. Targeting vaccine antigens (Ag) directly to the DCs in vivo is more effective than cell-based therapies in mouse models and is therefore a promising strategy to translate to humans. The human CD141+ DCs are considered the most clinically relevant for initiating CD8+ T cell responses critical for killing tumors or infected cells, and they specifically express the C-type lectin-like receptor CLEC9A that facilitates presentation of Ag by these DCs. We have therefore developed a human chimeric Ab that specifically targets CLEC9A on CD141+ DCs in vitro and in vivo. These human chimeric Abs are highly effective at delivering Ag to DCs for recognition by both CD4+ and CD8+ T cells. Given the importance of these cellular responses for antitumor or antiviral immunity, and the superior specificity of anti-CLEC9A Abs for this DC subset, this approach warrants further development for vaccines.

Rendimiento pronóstico de reglas de decisión clínica en síncope Un estudio piloto / Prognostic performance of clinical decision rules in syncope A pilot study

Objetivo: desarrollar un estudio piloto de factibilidad de comparación del rendimiento pronóstico de las reglas de decisión clínica en pacientes con síncope. Objetivo secundario: evaluar el rendimiento pronóstico de las reglas de decisión OESIL (Osservatorio Epidemiologico sulla Síncope nel Lazio), EGSYS (European Guidelines in Syncope Study), SFSR (San Francisco Syncope Rule) y su aplicación con los Ottawa Electrocardiographic Criteria (SFSR+Ottawa), en predicción de mortalidad por cualquier causa y desenlaces cardiovasculares y no cardiovasculares mayores a siete y 30 días. Métodos: estudio observacional, analítico, prospectivo, tipo longitudinal, de no intervención, con muestreo por conveniencia. Se incluyeron pacientes >18 años de edad admitidos a urgencias con síncope menor o igual a 48 horas de evolución. Se compararon las reglas mediante curvas ROC y sensibilidad, especificidad, VPP y VPN para mortalidad y desenlaces mayores a siete y 30 días. Resultados: se incluyeron 44 pacientes durante un periodo de siete meses, hospitalizándose el100%. El análisis ROC mostró una AUC para SFSR+Ottawa para mortalidad y/o desenlaces mayores a siete días de 0.76 (IC 95% 0.49-0.82) y 30 días 0.76 (IC 95% 0.49-0.82), con sensibilidad de 86 y 84% y especificidad de 45 y 47% a siete y 30 días respectivamente. Conclusiones: es factible realizar un estudio de comparación de rendimiento pronóstico de reglas de decisión clínica de síncope en Colombia. La comparación realizada, sugiere un mejor desempeño de SFSR si se aplica con los criterios electrocardiográficos de Ottawa (SFSR+Ottawa) para la predicción de desenlaces a corto plazo. (Acta Med Colomb 2015; 40: 36-44).

Objective: to develop a feasibility pilot study comparing the prognostic performance of clinical decision rules in patients with syncope. Secondary objective: To assess the prognostic performance of OESIL (Osservatorio sulla Epidemiologico Sincope nel Lazio) decision rules, EGSYS (European Guidelines in Syncope Study), SFSR (San Francisco Syncope Rule) and its application to the Ottawa Electrocardiographic Criteria (SFSR + Ottawa) in predicting all-cause mortality and cardiovascular and non-cardiovascular outcomes longer than seven and 30 days. Methods: an observational, analytical, prospective, longitudinal, non-interventional study with convenience sampling. Patients >18 years of age admitted to the emergency room less than or equal to 48 hours after onset of syncope were included. Rules were compared by using ROC curves and sensitivity, specificity, PPV and NPV for mortality and major outcomes to seven and 30 days. Results: 44 patients were included over a period of seven months. 100% were hospitalized. ROC analysis showed an AUC for SFSR + Ottawa for mortality and / or major outcomes to 7 days of 0.76 (95% CI 0.49 to 0.82) and 30 days 0.76 (95% CI 0.49-0.82) with sensitivity of 86 and 84% and specificity of 45 and 47% for seven and 30 days respectively. Conclusions: it is feasible to conduct a comparison study of prognostic performance of clinical decision rules of syncope in Colombia. The comparison realized suggests a better performance of SFSR if applied with electrocardiographic criteria of Ottawa (SFSR + Ottawa) for predicting outcomes in the short term. (Acta Med Colomb 2015; 40: 36-44).

Diagnóstico fractal del ventriculograma cardiaco izquierdo: geometría fractal del ventriculograma durante la dinámica cardiaca / Fractal diagnosis of left heart ventriculograms: fractal geometry of ventriculogram during cardiac dynamics

Antecedentes y objetivos: la geometría fractal permite describir y caracterizar los objetos irregulares, lo que resulta adecuado para medir estructuras del cuerpo humano. El propósito de este trabajo es caracterizar el ventrículo izquierdo durante la dinámica cardiaca con dimensiones fractales para desarrollar un diagnóstico matemático objetivo y reproducible de la ventriculografía izquierda. Método: este es un estudio de concordancia diagnóstica donde se calcularon las dimensiones fractales del ventrículo en sístole, en diástole y en un total de 36 ventriculogramas evaluados como normales, y anormales en leves, moderados y severos de acuerdo con la fracción de eyección según el diagnóstico clínico convencional; posteriormente se determinaron los grados de similitud de las dimensiones fractales entre los tres objetos componentes. Resultados: los grados de similitud estuvieron entre 1 y 9.000, y al organizar estos valores en conjuntos, se encontró una progresión a partir de los normales hasta los anormales severos. Se establecieron los grados de similitud característicos que permiten diferenciar normalidad de enfermedad y evolución entre éstas, evidenciando que la clasificación de la clínica convencional presenta dificultades al evaluar de forma precisa y objetiva la evolución de un ventriculograma hacia la normalidad o la enfermedad. Conclusiones: se desarrolló una nueva metodología diagnóstica objetiva y reproducible de aplicación clínica basada en evaluaciones geométricas independiente de la clasificación clínica.

Background and Objectives: fractal geometry allows to describe and characterize irregular objects, which is appropriate for measuring human body structures. The purpose of this study is to characterize the left ventricle during cardiac dynamics by means of fractal dimensions to develop an objective, mathematical and reproducible diagnosis of left ventriculography. Method: this is a diagnostic concordance study in which we calculated the fractal dimensions of the ventricle in systole, in diastole and in a total of 36 ventriculograms evaluated as normal, mild, moderate and severe according to the ejection fraction in accordance with the conventional clinical diagnosis ; subsequently, the degree of similarity of the fractal dimensions between the three components were determined. Results: the degrees of similarity were between 1 and 9,000, and when arranging these values into sets, there was a progression from normal to severe. We established the characteristic degrees of similarity that allow to distinguish normality from disease and the evolution between them, showing that the conventional clinical classification presents difficulties to assess accurately and objectively the evolution of a ventriculogram towards normality or disease. Conclusions: we developed a new objective and reproducible diagnostic methodology of clinical application based on geometric assessments that is independent from the clinical classification.

Menopausia: panorama actual de manejo / Menopause: an overview of current assessment and management / Menopausa: panorama atual de abordagem

Aún existe, desde 2002, una marcada disminución en el uso de terapia hormonal clásica (TH), para el manejo de la menopausia, debido a los riesgos determinados en el estudio Iniciativa de salud para las mujeres (WHI: Women's Health Initiative). No obstante, revisiones del WHI y evidencias actuales determinan que la TH: (a) es la terapia más efectiva de los síntomas vasomotores, de sus potenciales consecuencias (disminución en calidad del sueño, irritabilidad, reducción en calidad de vida), y para tratar la atrofia urogenital. (b) Previene la osteoporosis y en pacientes con endotelios sanos, reduce el riesgo de hipertensión arterial, diabetes II y enfermedad coronaria, siendo el cociente beneficio/ riesgo mayor cuando se inicia tempranamente al sucederse el hipoestrogenismo. (c) Existe la tendencia a utilizar dosis mínimas, estrógenos no orales y progestágenos puros, para disminuir sus riesgos. (d) Tibolona y paroxetina son las mejores alternativas para tratar los síntomas vasomotores. (e) Finalmente, los cambios a estilo de vida saludable son coadyuvantes excelentes de la TH en el manejo de los síntomas menopaúsicos y en la prevención de las enfermedades crónicas de la postmenopausia, las cuales ameritan tratamientos específicos...

There has been a marked decline in hormonal therapy (HT) for menopausal symptoms, since 2002, due the understanding of the benefits and risks as described in the Women's Health Initiative (WHI). Nevertheless, revisions of the WHI and current evidences determine that the HT: (a) is the most effective treatment for menopause vasomotor symptoms and their potential consequences (diminished sleep quality, irritability, and reduced quality of life), and to treat urogenital atrophy. (b) prevents the osteoporosis and, in women with healthy endothelial arteries, it reduces the risk of hypertension, diabetes II and coronary heart disease; but, the benefit-risk ratio is favorable for women who initiate HT close to ovarian failure or menopause. (c) There is the tendency to minimize dose, give no oral estrogens and pure progestagens, in order to diminish its potential risks. (d) Tibolona and Paroxetine are good alternatives to treat menopausal vasomotor symptoms. (e) Finally, the changes in the lifestyle are excellent HT adittional aids to prevent postmenopausal chronic diseases; but these diseases deserve specific treatments...

Ainda permanece, desde 2002, uma diminuição acentuada no uso de terapia hormonal clássica (TH) para a abordagem da menopausa, devido aos riscos identificados no estudo Iniciativa de saúde para mulheres (WHI: Women's Health Initiative). No entanto, revisiões WHI e as evidências atuais determinam que o TH: (a) é a terapia mais eficaz para os sintomas vasomotores, as suas possíveis conseqüências (diminuição da qualidade de sono, irritabilidade, redução da qualidade de vida), e tratamento de atrofia urogenital. (b) Previne a osteoporose, e em pacientes com endotélio saudável, reduz o risco de hipertensão, diabetes tipo II e doença arterial coronariana, com a relação risco / benefício maior quando o inicio do hipoestrogenismo é cedo. (c) Há uma tendência a utilizar pequenas doses, de estrógenos não-orais e progestágenos puros, para reduzir seus riscos. (d) Tibolona e paroxetina são as melhores alternativas para o tratamento de sintomas vasomotores. (e) Finalmente, as alterações a estilos de vida saudável são excelentes auxiliares da HT na abordagem dos sintomas da menopausa e prevenção de doenças crônicas na pós-menopausa, que merecem um tratamento específico...

Effectiveness of switching from antipsychotic polypharmacy to monotherapy.

OBJECTIVE: This randomized trial addressed the risks and benefits of staying on antipsychotic polypharmacy or switching to monotherapy. METHOD: Adult outpatients with schizophrenia taking two antipsychotics (127 participants across 19 sites) were randomly assigned to stay on polypharmacy or switch to monotherapy by discontinuing one antipsychotic. The trial lasted 6 months, with a 6-month naturalistic follow-up. Kaplan-Meier and Cox regression analyses examined time to discontinuation of assigned antipsychotic treatment, and random regression models examined additional outcomes over time. RESULTS: Patients assigned to switch to monotherapy had shorter times to all-cause treatment discontinuation than those assigned to stay on polypharmacy. By month 6, 86% (N=48) of those assigned to stay on polypharmacy were still taking both medications, whereas 69% (N=40) of those assigned to switch to monotherapy were still taking the same medication. Most monotherapy discontinuations entailed returning to the original polypharmacy. The two groups did not differ with respect to psychiatric symptoms or hospitalizations. On average, the monotherapy group lost weight, whereas the polypharmacy group gained weight. CONCLUSIONS: Discontinuing one of two antipsychotics was followed by treatment discontinuation more often and more quickly than when both antipsychotics were continued. However, two-thirds of participants successfully switched, the groups did not differ with respect to symptom control, and switching to monotherapy resulted in weight loss. These results support the reasonableness of prescribing guidelines encouraging trials of antipsychotic monotherapy for individuals receiving antipsychotic polypharmacy, with the caveat that patients should be free to return to polypharmacy if an adequate trial on antipsychotic monotherapy proves unsatisfactory.

Dinámica probabilista temporal de la epidemia de dengue en Colombia / Temporary probabilistic dynamics of the dengue's epidemic in Colombia

En el estudio de las enfermedades epidémicas se han aplicado diferentes modelos, tanto matemáticos como epidemiológicos, orientados hacia la comprensión y predicción de la dinámica de estos fenómenos. Dichas aproximaciones se fundamentan en la búsqueda de relaciones causales, tales como el clima, la precipitación pluvial, los movimientos poblacionales, entre otros, lo cual dificulta la generalización de dichas predicciones. Partiendo de la construcción de dos espacios de probabilidad que cuantifican el número anual de infectados de dengue en Colombia en rangos de 5 000 y 10 000 infectados y del comportamiento probabilista de casos durante rangos de años consecutivos, se realizó una predicción temporal del número de casos de dengue en Colombia.El número de casos de dengue predicho para el 2007 se encontró en el rango de 35 000-45 000 y de 37 500-42 500, valores calculados con los rangos de 10 000 y 5 000 respectivamente. Estos valores fueron corroborados con los datos del Instituto Nacional de Salud que corresponde, en la semana epidemiológica 52, a 43 564 casos en Colombia, lo que evidenció una autoorganización matemática de la dinámica de aparición de casos de la epidemia de dengue de carácter predictivo. El estudio de las probabilidades durante la dinámica de la epidemia permite predecir la cantidad de infectados para el 2007 con predicciones simples, directamente comprobables y aplicables, lo cual evita el problema causal de los modelos matemáticos y establece predicciones más fáciles que economizan tiempo y recursos.

Studying some epidemical diseases have been applied different models also mathematical like epidemiological, towards understand and predict the dynamical of this phenomena. These methodologies are founded in search for acausal relations, like climate, pluvial precipitation, demographic movements and more, which difficult to generalize these predictions. Starting from the construction of two sample spaces for probability, which quantify the annual infected number of dengue in Colombia in ranges of 5.000 and 10.000 infected, and from the probabilistic behaviour along consecutive group of years, it was made a temporal prediction about cases number of dengue in Colombia. The prediction for infected people for 2007 year was founded in the ranges 35000-45000 and 37500-42500, values calculated with the ranges of 10000 and 5000 respectively. These values ware corroborated with the National Health Institute data, for the accumulate value in the epidemiological week number 52, equals to 43564 cases in Colombia, it was evident a mathematical self-organization for the dynamics of infected people for dengue epidemics of predictive way. To study the probabilities along the epidemic dynamics led to predict the infected people for 2007, in a simple way, directly probed and useful, avoiding the causal problem for some mathematical models and establishing predictions in a more easy way, economizing sources and time.

Generalización fractal de células preneoplásicas y cancerígenas del epitelio escamoso cervical: una nueva metodología de aplicación clínica / Fractal generalization of pre-neoplasic cervical epithelial cells for clinical application / Generalização fractal de célula pré-neoplásicas e cancer do epitélio escamoso cervical: uma nova metodologia de aplicação clínica

A partir de la evaluación de las dimensiones fractales y aplicando el concepto de variabilidad y armonía matemática intrínseca celular (AMI), se desarrolló un método matemático de aplicación clínica para el diagnóstico de células preneoplásicas y neoplásicas del epitelio escamoso cervical, el cual supera el diagnóstico de ASCUS (células escamosas atípicas de significado no determinado). A partir de un método desarrollado previamente para el diagnóstico de células normales, ASCUS y L-SIL, se realizaron permutaciones estructurales fractales con los valores generales de la AMI y de variabilidad fractal para normalidad y enfermedad, buscando los prototipos generales de células normales, preneoplásicas y neoplásicas. Se midieron cinco células ASCUS y cinco cancerígenas del epitelio escamoso del cuello uterino y se encontró que para la normalidad hay 18 prototipos, mientras que para la anormalidad 44, incluyendo todos los estados de evolución hasta carcinoma. Estos resultados fueron confirmados al comparar los resultados obtenidos por las técnicas convencionales con los obtenidos por esta metodología; lo que hace pensar que se desarrolló una nueva metodología que permite diferenciar los distintos tipos de células del epitelio escamoso del cuello uterino (normales o cancerígenas)...

Beginning with the evaluation of fractal dimensions, and applying the concept of variability and Cellular Intrinsic Mathematical Harmony, a mathematical method for clinical application was developed, about the diagnosis of preneoplastic and neoplastic squamous epithelial cervix cells, which improves the ASCUS (Atypical Squamous Cells of Undetermined Significance) diagnosis. Beginning with a method previously developed for the diagnosis of normal, ASCUS and L-SIL cells, fractal structural permutations with the general Intrinsic Mathematical Harmony (IMH) and variability values for normality and disease were made, looking for the general prototypes of normal cells, premalignant and carcinogen. 5 ASCUS and 5 carcinogen cells of the squamous epithelial cervix were measured. It was found that there are 18 normal prototypes, while there were obtained 44 prototypes for the abnormality, including all stages of evolution to carcinoma. These results were confirmed by comparing the obtained results by the conventional techniques with the results obtained by this methodology; making thinking that it was developed a new methodology that allows to differentiate the distinct types of the squamous epithelial cervix cells (normal or carcinogen)...

A partir da avaliaçúo da dimensúo fractal e aplicação do conceito de variabilidade e harmonia matemática subjacente celular (IAM), desenvolveu-se um método matemático para a aplicação clínica o diagnóstico de células pré-neoplásicas e neoplásicas do epitélio escamoso cervical, o que excede o diagnóstico ASCUS (células escamosas atípicas de significado indeterminado). Baseado em um método desenvolvido anteriormente para o diagnóstico de células normais, ASCUS e LSIL, foram realizadas permutações estruturais fractais com os valores gerais da AMI e variabilidade fractal para o normal e doença, procurando protótipos gerais de células normais, pré-neoplásicas e neoplásicas. Foram medidos cinco células ASCUS e cinco de câncer de epitélio escamoso cervical e encontrou-se que existem para o normal 18 protótipos, enquanto que para a alteração 44, incluindo todas as fases de evoluçúo para carcinoma. Estes resultados foram confirmados através da comparação dos resultados obtidos por técnicas convencionais com aqueles obtidos por este modelo matemático, sugerindo que desenvolveu-se uma nova metodologia para diferenciar diferentes tipos de células do epitélio escamoso cervical (normais ou cancerosos)...

Aplicación del MINI como orientación diagnóstica psiquiátrica en estudiantes de medicina de la Universidad Peruana Cayetano Heredia: informe preliminar epidemiológico / Aplication of the MINI as a psiquiatric diagnostic orientation for university students of the University Peruvian Cayetano Heredia: preliminary epidemiological report

La MINI (Mini Entrevista Neuropsiquiátrica Internacional) es una entrevista breve y altamente estructurada de los principales trastornos psiquiátricos de la CIE-10 y DSM-IV para ser empleado por psiquiatras y médicos no psiquiatras después de un corto tiempo de entrenamiento. Fue elaborada por Y. Lecrubier y col. de la "salpétrére" de París y D. Scheehan y col. de la universidad de Florida en Tampa en los años 1992, 1994 y 1998. Objetivo del presente trabajo (teniendo como base la CIE - 10) fue determinar la prevalencia de punto fijo de los trastorno mentales más frecuentes en alumnos de medicina de cuarto, quinto y sexto año. Material y métodos: Se aplicó el MINI a 250 estudiantes de medicina de 4º, 5º y 6º años. resultados: Se encontró una prevalencia alta de trastorno mentales (45.60 por ciento) sobresaliendo la depresión (31.60 por ciento) y la ansiedad (22.40 por ciento) siendo estos valores mayores que en la población general. Conclusión: Las altas cifras encontradas sugieren un problema grave de salud mental en nuestra juventud por lo que se recomienda que en otros niveles universitarios, institutos y ambiente laboral de la población entre los 20 y 30 años sea estudiada para confirmar este informe preliminar.

Odontología bioenergética conceptos, teoría y características de los odontólogos que la ejercen / Bioenergetic dentistry

La odontología bioenergética es un campo nuevo que algunos profesionales estan investigando e integrando en su práctica cotidiana. Se estudiaron por medio de unas entrevistas personales y dirigidas, las variables según sexo, Universidad de donde son egresados, donde se estudió la bioenergética, los métodos de diagnóstico utilizados, métodos de interconsulta, tiempo que se ha ejercido la bioenergética y resultados terapéuticos en una población de 28 odontólogos. La muestra constó de 12 (43 por ciento) hombres y 16 (57 por ciento) mujeres. Los profesionales eran egressados de varias facultades de odontología de Colombia distribuídos de la siguiente manera: Universidad Nacional de Colombia 14 (50 por ciento); Pontificia Universidad Javeriana 5 (18 por ciento); Universidad de Antioquia 3 (11 por ciento); Escuela Colombiana de Medicina 2 (7 por ciento) ; Colegio Odontológico Colombiano 2 (7); Fundación Universitaria San Martín 2 (7 por ciento). 100 por ciento de los odontólogos son autodidácticos en la bioenergética, los métodos utilizados para diagnóstico fueron: Filtros 12 (43 por ciento) ; terapia de Huneke 10 (36 por ciento); Mioquinética 6 (22 por ciento); Dermaton 3 (11 por ciento); Electroacupuntura de Voll 3 (11 por ciento) Cámara Kirlian 2 (7 por ciento); Lápiz de nitrato de uranio 1 (3.5 por ciento); Radiestesia 4 (14.2 por ciento). 100 por ciento de los odontólogos utilizan la interconsulta médica en todos sus casos con compromiso sistémico. El tiempo que llevaban ejerciendo la bioenergética fué de un promedio de 6 años y cinco meses (6.5 años más o menos 1.8 años D.E.) con un rango desde 6 meses hasta 25 años. 100 por ciento de los odontólogos describieron los resultados terapéuticos con palabras como "exelentes y positivos"

Interleuquina 1 en niños desnutridos / Interleukin 1 in undernutrition children

La interleuquina-1 (IL-1) es un medidor soluble con propíedades inmunoreguladoras, inflamatorias, anorexígenas y antianabólicas, secretado principalmente por macrófagos activados. Evaluamos los niveles séricos de IL-1alfa en 54 lactantes y preescolares con desnutrición leve, moderada o grave con o sin infección clínica asociada y en 40 cintroles eutróficos de edad, sexo, raza y condición socioeconómica comparables, mediante ensayo inmunoenzimático con un nivel inferior de detección de 37.5 pg/ml. El porcentaje de sueros con niveles detectables de la citoquina fue similar en el grupo total de niños desnutridos y en los eutróficos. Sin embargo, cuando se analizaron los valores promedio de IL-1 alfa en los sueros con niveles detectables de la citoquina se observó que: 1) El nivel de IL-1 alfa fué significativamente mayor en los desnutridos totales que en los eutróficos. 2) Cuando el grupo de niños desnutridos se subdividió de acuerdo a la severidad del déficit nutricional, cada subgrupo (desnutridos leves, moderados o graves) mostró una media de IL-1 alfa mayor a la del grupo control. No hubo diferencias en los nivles promedios de IL-1 alfa en sueros de desnutridos con infección clínica asociada o sin infección aparente. Se concluye que en la desnutrición primaria persiste la capacidad para sintetizar IL-1 alfa y 2) que los valores aumentados de IL-1 alfa observados en desnutridos serías causados por la alta prevalencia de infecciones clínicas asociadas. A su vez, los niveles elevados de IL-1 alfa en los desnutridos sin infección clínica asociada serían determinados por infecciones latentes, y/o traslocación de bacterias y endotoxina través de la mucosa intestinal atrófica