Transcriptional reprogramming during human osteoclast differentiation identifies regulators of osteoclast activity.

Enhanced osteoclastogenesis and osteoclast activity contribute to the development of osteoporosis, which is characterized by increased bone resorption and inadequate bone formation. As novel antiosteoporotic therapeutics are needed, understanding the genetic regulation of human osteoclastogenesis could help identify potential treatment targets. This study aimed to provide an overview of transcriptional reprogramming during human osteoclast differentiation. Osteoclasts were differentiated from CD14+ monocytes from eight female donors. RNA sequencing during differentiation revealed 8 980 differentially expressed genes grouped into eight temporal patterns conserved across donors. These patterns revealed distinct molecular functions associated with postmenopausal osteoporosis susceptibility genes based on RNA from iliac crest biopsies and bone mineral density SNPs. Network analyses revealed mutual dependencies between temporal expression patterns and provided insight into subtype-specific transcriptional networks. The donor-specific expression patterns revealed genes at the monocyte stage, such as filamin B (FLNB) and oxidized low-density lipoprotein receptor 1 (OLR1, encoding LOX-1), that are predictive of the resorptive activity of mature osteoclasts. The expression of differentially expressed G-protein coupled receptors was strong during osteoclast differentiation, and these receptors are associated with bone mineral density SNPs, suggesting that they play a pivotal role in osteoclast differentiation and activity. The regulatory effects of three differentially expressed G-protein coupled receptors were exemplified by in vitro pharmacological modulation of complement 5 A receptor 1 (C5AR1), somatostatin receptor 2 (SSTR2), and free fatty acid receptor 4 (FFAR4/GPR120). Activating C5AR1 enhanced osteoclast formation, while activating SSTR2 decreased the resorptive activity of mature osteoclasts, and activating FFAR4 decreased both the number and resorptive activity of mature osteoclasts. In conclusion, we report the occurrence of transcriptional reprogramming during human osteoclast differentiation and identified SSTR2 and FFAR4 as antiresorptive G-protein coupled receptors and FLNB and LOX-1 as potential molecular markers of osteoclast activity. These data can help future investigations identify molecular regulators of osteoclast differentiation and activity and provide the basis for novel antiosteoporotic targets.

11ß-Hydroxysteroid Dehydrogenase Type 1 within Osteoclasts Mediates the Bone Protective Properties of Therapeutic Corticosteroids in Chronic Inflammation.

Therapeutic glucocorticoids (GCs) are powerful anti-inflammatory tools in the management of chronic inflammatory diseases such as rheumatoid arthritis (RA). However, their actions on bone in this context are complex. The enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is a mediator of the anti-inflammatory actions of therapeutic glucocorticoids (GCs) in vivo. In this study we delineate the role of 11ß-HSD1 in the effects of GC on bone during inflammatory polyarthritis. Its function was assessed in bone biopsies from patients with RA and osteoarthritis, and in primary osteoblasts and osteoclasts. Bone metabolism was assessed in the TNF-tg model of polyarthritis treated with oral GC (corticosterone), in animals with global (TNF-tg11ßKO), mesenchymal (including osteoblast) (TNF-tg11ßflx/tw2cre) and myeloid (including osteoclast) (TNF-tg11ßflx/LysMcre) deletion. Bone parameters were assessed by micro-CT, static histomorphometry and serum metabolism markers. We observed a marked increase in 11ß-HSD1 activity in bone in RA relative to osteoarthritis bone, whilst the pro-inflammatory cytokine TNFα upregulated 11ß-HSD1 within osteoblasts and osteoclasts. In osteoclasts, 11ß-HSD1 mediated the suppression of bone resorption by GCs. Whilst corticosterone prevented the inflammatory loss of trabecular bone in TNF-tg animals, counterparts with global deletion of 11ß-HSD1 were resistant to these protective actions, characterised by increased osteoclastic bone resorption. Targeted deletion of 11ß-HSD1 within osteoclasts and myeloid derived cells partially reproduced the GC resistant phenotype. These data reveal the critical role of 11ß-HSD1 within bone and osteoclasts in mediating the suppression of inflammatory bone loss in response to therapeutic GCs in chronic inflammatory disease.

The emerging role of heterodimerisation and interacting proteins in ghrelin receptor function.

Ghrelin is a peptide hormone secreted primarily by the stomach that acts upon the growth hormone secretagogue receptor (GHSR1), a G protein-coupled receptor whose functions include growth hormone secretion, appetite regulation, energy expenditure, regulation of adiposity, and insulin release. Following the discovery that GHSR1a stimulates food intake, receptor antagonists were developed as potential therapies to regulate appetite. However, despite reductions in signalling, the desired effects on appetite were absent. Studies in the past 15 years have demonstrated GHSR1a can interact with other transmembrane proteins, either by direct binding (i.e. heteromerisation) or via signalling cross-talk. These interactions have various effects on GHSR1a signalling including preferential coupling to one pathway (i.e. biased signalling), coupling to a unique G protein (G protein switching), suppression of GHSR1a signalling, and enhancement of signalling by both receptors. While many of these interactions have been shown in cells overexpressing the proteins of interest and remain to be verified in tissues, substantial evidence exists showing that GHSR1a and the dopamine receptor D1 (DRD1) form heteromers, which promote synaptic plasticity and formation of hippocampal memory. Additionally, a reduction in GHSR1a-DRD1 complexes in favour of establishment of GHSR1a-Aß complexes correlates with Alzheimer's disease, indicating that GHSR1a heteromers may have pathological functions. Herein, we summarise the evidence published to date describing interactions between GHSR1a and transmembrane proteins, discuss the experimental strengths and limitations of these studies, describe the physiological evidence for each interaction, and address their potential as novel drug targets for appetite regulation, Alzheimer's disease, insulin secretion, and inflammation.

La hipotenusa de pitágoras como índice de ametropía

Objetivo general. Crear un índice con base en la hipotenusa de Pitágoras para representar cualquier estado refractivo y facilitar los análisis estadísticos de los pacientes amétropes. Métodos. 3964 pacientes de una base de datos de Optiláser (Centro de cirugía refractiva en Bogotá, Colombia) del año 2014 fueron seleccionados para demostrar la aplicabilidad del índice de ametropía propuesto. Los pacientes no habían sido sometidos a ningún tipo de procedimiento quirúrgico. Otro ejemplo para ilustrar la aplicabilidad del índice de ametropía viene de la investigación Madre Canguro Integral llevada a cabo entre 2013 y 2014 en el Hospital de San Ignacio, Bogotá, en la cual 311 bebés nacidos prematuramente y en buen estado de salud fueron evaluados. Los meridanos principales de las ametropías se tomaron como catetos de un triángulo rectángulo para calcular la hipotenusa que fue tomada como índice de ametropía. Seguidamente, se determinó la correlación de Spearman entre el índice de ametropía y el ángulo visual expresado con mínimo ángulo de resolución (MAR). Resultados. La correlación de Spearman entre el índice de ametropía y el mínimo ángulo de resolución es 0,834. Por tanto, es estadísticamente significativa (p:< 0,001) y suficiente para validar el índice propuesto. Conclusiones. El índice de ametropía es un instrumento válido para la evaluación, manejo y análisis estadístico de las ametropías.

Objetivo geral. Criar um índice, baseado na hipotenusa de Pitágoras, para representar qualquer estado refrativo e facilitar a análise estatística de pacientes com ametropia. Métodos. 3964 pacientes de um banco de dados do OPTILASER (Centro de Cirurgia Refrativa de Bogotá, Colômbia) em 2014, foram selecionados para demonstrar a aplicabilidade do Índice de Ametropia proposto. Os pacientes não tinham sido submetidos a nenhum tipo de procedimento cirúrgico. Outro exemplo para ilustrar a aplicabilidade do Índice de Ametropia, vem da pesquisa "Mãe Canguru Integral", realizada entre 2013 e 2014, no Hospital de San Ignacio, Bogotá, onde 311 bebês nascidos prematuramente e com boa saúde foram avaliados. Os meridianos principais da ametropia são tomados como catetos de um triângulo retângulo para calcular a hipotenusa que será tomada como o índice de ametropia. Em seguida, foi determinada a correlação de Spearman entre o Índice de Ametropia e o Ângulo Visual expresso com o Ângulo Mínimo de Resolução (Mínimo Ángulo de Resolución, MAR). Resultados. A correlação de Spearman entre o Índice de Ametropia e o Ângulo Mínimo de Resolução é de 0,834, o que é estatisticamente significativo (p <0,001) e suficiente para validar o Índice proposto. Conclusões. O índice de ametropia é um instrumento válido para a avaliação, manejo e análise estatística das ametropia.

General Objective. To create a suitable Index, based on Pythagoras' hypotenuse, to represent any refractive state and to facilitate statistical analyses of ametropic patients. Methods. 3964 patients from a database of OPTILASER (Refractive Surgery Center in Bogotá, Colombia) for the year 2014 were selected to demonstrate the applicability of the proposed Index of Ametropia. The patients had not been previously subjected to any kind of surgical procedure. Another example to illustrate the applicability of the proposed Index of Refraction comes from a database of an investigation "Madre Canguro Integral" (Integral Kangaroo Mother), carried out between 2013 and 2014 at Hospital San Ignacio, Bogotá in which 311 healthy prematurely-born babies were evaluated Principal meridians of ametropias are taken as catheti of a right triangle in order to calculate the Hypotenuse which will be taken as the Index of Ametropia. Spearman Correlation, between the Index of Ametropia and the Visual Acuity expressed as the Minimum Angle of Resolution (MAR), are determined. Results. Spearman Correlation between the Index of Ametropia and the Minimum Angle of Resolution is 0,834 statistically significant (p: < 0,001) ample enough to validate the proposed Index of Ametropia. Conclusions. The Index of Ametropia is a valid instrument for the assessment, management and statistical analysis of ametropias.

αEß7 Integrin Identifies Subsets of Pro-Inflammatory Colonic CD4+ T Lymphocytes in Ulcerative Colitis.

BACKGROUND AND AIMS: The αEß7 integrin is crucial for retention of T lymphocytes at mucosal surfaces through its interaction with E-cadherin. Pathogenic or protective functions of these cells during human intestinal inflammation, such as ulcerative colitis [UC], have not previously been defined, with understanding largely derived from animal model data. Defining this phenotype in human samples is important for understanding UC pathogenesis and is of translational importance for therapeutic targeting of αEß7-E-cadherin interactions. METHODS: αEß7+ and αEß7- colonic T cell localization, inflammatory cytokine production and expression of regulatory T cell-associated markers were evaluated in cohorts of control subjects and patients with active UC by immunohistochemistry, flow cytometry and real-time PCR of FACS-purified cell populations. RESULTS: CD4+αEß7+ T lymphocytes from both healthy controls and UC patients had lower expression of regulatory T cell-associated genes, including FOXP3, IL-10, CTLA-4 and ICOS in comparison with CD4+αEß7- T lymphocytes. In UC, CD4+αEß7+ lymphocytes expressed higher levels of IFNγ and TNFα in comparison with CD4+αEß7- lymphocytes. Additionally the CD4+αEß7+ subset was enriched for Th17 cells and the recently described Th17/Th1 subset co-expressing both IL-17A and IFNγ, both of which were found at higher frequencies in UC compared to control. CONCLUSION: αEß7 integrin expression on human colonic CD4+ T cells was associated with increased production of pro-inflammatory Th1, Th17 and Th17/Th1 cytokines, with reduced expression of regulatory T cell-associated markers. These data suggest colonic CD4+αEß7+ T cells are pro-inflammatory and may play a role in UC pathobiology.

Estudio retrospectivo del estado refractivo en niños prematuros detres a cuatro meses de edad corregida, realizado en el programa Madre Canguro Integral, Hospital San Ignacio, Bogotá / Retrospective study of corrected refractive status in premature infants of three to four months of age, performed in the Madre Canguro Integral Program at Hospital San Ignacio in Bogota

El estado refractivo en los niños al nacer está dado por la asociación entre los parámetros ópticos y la longitud axial del globo ocular, que van cambiando con el desarrollo del niño hasta conseguir la emetropización. Objetivo: determinar el estado refractivo de niños prematuros de tres a cuatro meses de edad, corregido en el Programa Madre Canguro del Hospital San Ignacio. Materiales y métodos: se revisaron 4908 historias clínicas de pacientes atendidos entre el 1º de julio del 2004 y el 31 de junio del 2009. Resultados: 1731 historias clínicas cumplieron los criterios de inclusión(52,3 % hombres y 47,7 % mujeres). La mediana de la edad gestacional fue de 34 semanas (Q 4);la mediana del peso al nacer, 1880 gramos con (Q 570). El estado refractivo fue del 67,26 % para astigmatismo hipermetrópico, y cuando se clasificó en 64 categorías, este defecto representó el 8,55 % (categoría 14 con esferas de +3,00 a +3,75, con cilindros de -1,00 a -1.75). No se encontró asociación estadísticamente significativa entre el defecto refractivo y el peso al nacer (p = 0,08), la edad gestacional (p = 0,582), la clasificación de Luchenco (p = 0,968) y el suministro de oxígeno(p = 0,568). Conclusiones: el defecto refractivo más frecuente en los prematuros es el astigmatismo hipermetrópico, que coincide con el proceso de emetropización; no hay correlación entre la maduración del niño al nacer y el grado de hipermetropía y no se encontró correlación entre el nivel de oxígeno y el grado de ametropía.

The association between the optical parameters and the axial length of the eyeball gives the refractive status in children at birth, which changes with the child’s development until emmetropization. Objective: To determine the corrected refractive status in premature infants of three to four months of age in the Madre Canguro Integral Program at Hospital San Ignacio. Materials and Methods: Medical records of 4908 patients seen between July 1, 2004 and June 31, 2009 were reviewed. Results: 1731 records met the inclusion criteria (52.3 % men, and 47.7 % women). The average gestational age was 34 weeks (Q 4); the average weight at birth was 1880 grams with (Q 570). The refractive state was of 67.26 % for hyperopic astigmatism, and when classified into 64 categories, this defect represented 8.55 % (category 14 with +3.00 to +3.75 spheres, with -1.00 to -1.75 cylinders). No statistically significant association was found between the refractive error and weight at birth (p = 0.08), gestational age (p = 0.582), Luchenco classification (p = 0.968) and oxygen delivery (p = 0.568). Conclusions: The most frequent refractive error in premature babies is hyperopic astigmatism, which coincides with the emmetropization process; there is no correlation between the child’s maturity at birth and the degree of hypermetropy and no correlation was found between oxygen level and degree of ametropia.

Influencia de la percepción visual en el aprendizaje / Influence of visual perception on learning

La percepción es el proceso activo de localización y extracción de la información obtenida del medio externo que se organiza en sistemas perceptuales, los cuales realizan el proceso de búsqueda y obtención de la información. Las habilidades perceptuales visuales son las encargadas de la organización y el procesamiento de la información a nivel visual formando parte de la percepción visual y colaborando en el desarrollo cognitivo. El entrenamiento de las habilidades perceptuales visuales y su integracion con dispositivos básicos de aprendizaje es una forma de mejorar el aprendizaje viso-perceptual y por ende la adaptación al medio, aun cuando todavía no se conocen completamente los mecanismos neuronales que dan el sustrato de la integración visoperceptual.

Perception is the active process of locating and extracting data from the outer environment. It is organized in perceptual systems in charge of searching and acquiring information. Visual perceptual skills are responsible for organizing and processing information on a visual level as part of visual perception and supporting cognitive development. Training of visual perceptual skills and its integration to basic learning devices is a way to improve visual perception learning and thusthe adaptation to the environment, despite not knowing the neuronal mechanisms that generate visual perception.

Agudeza visual de Snellen versus frecuencia espacial del test de mirada preferencial / Snellen visual acuity versus spatial frequency

La agudeza visual medida con la cartilla de Snellen y el test de mirada preferencial son utilizados para determinar cuantitativamente la capacidad que tiene el sistema visual para discriminar los detalles desde temprana edad hasta la adultez. Aunque matemáticamente los ciclos por grado del test de mirada preferencial y la fracción Snellen sean comparables, también se deben tener en cuenta otros factores propios de la persona como los perceptuales y del desarrollode las estructuras oculares del individuo, así como otros correspondientes a factores físico-ambientales donde se realizan los test, tal como la iluminación.

Preferential looking test is used to determine quantitatively the ability of the visual system to discriminate the details from an early age to adulthood. Although mathematically cycles per degree of preferential looking test and Snellen fraction are comparable, must also be taken into account other factors in the personas perceptual, and the development of ocular structures of the individual as well as other relevant factors where physical and environmental tests are performed, such as lighting.

Introduction to United States Department of Agriculture VetNet: status of Salmonella and Campylobacter databases from 2004 through 2005.

In 2003 the United States Department of Agriculture established USDA VetNet. It was modeled after PulseNet USA, the national molecular subtyping network for foodborne disease surveillance. The objectives of USDA VetNet are: to use pulsed-field gel electrophoresis (PFGE) to subtype zoonotic pathogens submitted to the animal arm of the National Antimicrobial Resistance Monitoring System (NARMS); examine VetNet and PulseNet PFGE patterns; and use the data for surveillance and investigation of suspected foodborne illness outbreaks. Whereas PulseNet subtypes 7 foodborne disease-causing bacteria- Escherichia coli O157:H7, Salmonella, Shigella, Listeria monocytogenes, Campylobacter, Yersinia pestis, and Vibrio cholerae-VetNet at present subtypes nontyphoidal Salmonella serotypes and Campylobacter from animals, including diagnostic specimens, healthy farm animals, and carcasses of food-producing animals at slaughter. By the end of 2005, VetNet had two functioning databases: the NARMS Salmonella and the NARMS Campylobacter databases. The Salmonella database contained 6763 Salmonella isolates and 2514 unique XbaI patterns, while the Campylobacter database contained 58 Campylobacter isolates and 53 unique SmaI patterns. Both databases contain the PFGE tagged image file format (TIFF) images, demographic information, and the antimicrobial resistance profiles assigned by NARMS. In the future, veterinary diagnostic laboratories will be invited to participate in VetNet. The establishment of USDA VetNet enhances the mission of the agriculture and public health communities in the surveillance and investigation of foodborne illness outbreaks.