Influencia del ambiente y la alimentación en la programación epigenética de la obesidad

El término epigenética hace referencia a los patrones hereditarios de la expresión de genes que se mantienen estables y que su- ceden sin que haya cambios en la secuencia de ADN. Los principales cambios en el patrón epigenético son: la metilación del ADN y la diferente organización de las histonas. Hay evidencias de que la metilación del genoma varía según los tejidos, los individuos o las condiciones de enfermedad, y se ha visto que la desorganización de la impronta genómica está relacionada con diferentes enfermeda- des en adultos, entre las que se encuentran la obesidad y/o el síndrome metabólico. El establecimiento de las marcas epigené- ticas durante el desarrollo puede estar in- fluenciado por factores ambientales como la dieta, principalmente por medio de nutrientes donantes de grupos metilo. Las alteraciones epigenéticas pueden ser debidas a la dieta parental (anterior al desarrollo intrauterino), al ambiente intrauterino y a la alimentación materna durante el embarazo, así como a las características de la alimentación peri y posnatal. Estas alteraciones epigenéticas INTRODUCCIÓN La programación de la obesidad puede darse por medio de al- teraciones permanentes de una o más vías relevantes durante el desarrollo embrionario y perinatal. Así, un tipo de alteraciones que afectan al desarrollo de obesidad y de síndrome metabólico en la edad adulta lo conforman los cambios en el patrón epige- nético. Dado que la obesidad es fundamentalmente un desor- den del balance energético, en el cual la energía ingerida excede pueden conservarse en el tiempo a través de sucesivas generaciones por su transmisión a la descendencia. A pesar de lo que ya se sabe, se necesitan nuevos trabajos que estudien los efectos de la alimentación en el estado epigenético del genoma y sus repercusiones fenotípicas a largo plazo para conocer mejor las posibles causas de la obesidad así como para diseñar nuevas estrategias para su prevenció

Genotypic and phenotypic diversity in the noncapsulated Haemophilus infl uenzae: adaptation and pathogenesis in the human airways

The human respiratory tract contains a highly adapted microbiota including commensal and opportunistic pathogens. Noncapsulated or nontypable Haemophilus infl uenzae (NTHi) is a human-restricted member of the normal airway microbiota in healthy carriers and an opportunistic pathogen in immunocompromised individuals. The duality of NTHi as a colonizer and as a symptomatic infectious agent is closely related to its adaptation to the host, which in turn greatly relies on the genetic plasticity of the bacterium and is facilitated by its condition as a natural competent. The variable genotype of NTHi accounts for its heterogeneous gene expression and variable phenotype, leading to differential host-pathogen interplay among isolates. Here we review our current knowledge of NTHi diversity in terms of genotype, gene expression, antigenic variation, and the phenotypesassociated with colonization and pathogenesis. The potential benefi ts of NTHi diversity studies discussed herein include the unraveling of pathogenicity clues, the generation of tools to predict virulence from genomic data, and the exploitation of a unique natural system for the continuous monitoring of long-term bacterial evolution in human airways exposed to noxious agents. Finally, we highlight the challenge of monitoring both the pathogen and the host in longitudinal studies, and of applying comparative genomics to clarify the meaning of the vast NTHi genetic diversity and its translation to virulence phenotypes. [Int Microbiol 2012; 15(4): 157-170

Genotypic and phenotypic diversity in the noncapsulated Haemophilus infl uenzae: adaptation and pathogenesis in the human airways

The human respiratory tract contains a highly adapted microbiota including commensal and opportunistic pathogens. Noncapsulated or nontypable Haemophilus infl uenzae (NTHi) is a human-restricted member of the normal airway microbiota in healthy carriers and an opportunistic pathogen in immunocompromised individuals. The duality of NTHi as a colonizer and as a symptomatic infectious agent is closely related to its adaptation to the host, which in turn greatly relies on the genetic plasticity of the bacterium and is facilitated by its condition as a natural competent. The variable genotype of NTHi accounts for its heterogeneous gene expression and variable phenotype, leading to differential host-pathogen interplay among isolates. Here we review our current knowledge of NTHi diversity in terms of genotype, gene expression, antigenic variation, and the phenotypesassociated with colonization and pathogenesis. The potential benefi ts of NTHi diversity studies discussed herein include the unraveling of pathogenicity clues, the generation of tools to predict virulence from genomic data, and the exploitation of a unique natural system for the continuous monitoring of long-term bacterial evolution in human airways exposed to noxious agents. Finally, we highlight the challenge of monitoring both the pathogen and the host in longitudinal studies, and of applying comparative genomics to clarify the meaning of the vast NTHi genetic diversity and its translation to virulence phenotypes. [Int Microbiol 2012; 15(4): 157-170

Anatomical basis of sleep

El sueño es un estado biológico activo, periódico, en el que se distinguen las etapas NREM y REM, que se alternan sucesivamente durante la noche. Intervienen los relojes biológicos en la modulación del sistema, así como neurotransmisores específicos. Se trata de una red neuronal compleja, en la que intervienen diversas zonas del sistema nervioso central. Los procesos oníricos están controlados además de forma neural. Se resume la historia de las investigaciones sobre el tema, desde el siglo XIX hasta nuestra época. Hay que destacar los recientes descubrimientos de Lugaresi y su equipo, que, al describir el insomnio familiar grave, dieron importancia al núcleo dorsomedial del tálamo en la instauración de la fase de sueño profundo. Al grupo de Reinoso se debe el hallazgo de que el “director de orquesta” en la instauración del sueño REM es la zona ventral paramediana del núcleo reticular pontino ora

Dietary total antioxidant capacity is associated with leukocyte telomere length in a children and adolescent population

Background & Aims: Oxidative stress and inflammation seem to be potential underlying mechanisms for telomere attrition. A lack of specific antioxidants is believed to increase free radical damage and a greater risk for telomere shortening. Our aim was to evaluate the relationship between diet and leukocyte telomere length in a cross-sectional study of children and adolescents. We hypothesized that dietary total antioxidant capacity would be positively associated with telomere length. Methods: Telomere length was measured by quantitative real-time polymerase chain reaction in 287 participants (55% males, 6–18 years), who were randomly selected from the GENOI study. Results: A positive correlation between dietary total antioxidant capacity and telomere length (r=0.157, p=0.007) was found after adjustment for age and energy intake. However, higher white bread consumption was associated with shorter telomeres (β=-0.204, p=0.002) in fully-adjusted models. Interestingly, those individuals who had simultaneously higher dietary total antioxidant capacity and lower white bread consumption significantly presented the longest telomeres. Moreover, the multivariable-adjusted odds ratio for very short telomeres was 0.30 for dietary total antioxidant capacity (p=0.023) and 1.37 for white bread (p=0.025). Conclusion: It was concluded that longer telomeres were associated with higher dietary total antioxidant capacity and lower white bread consumption in S2panish children and adolescents. These findings might open a new line of investigation about the potential role of an antioxidant diet in maintaining telomere length

Il6 gene promoter polymorphism (-174G/C) influences the association between fat mass and cardiovascular risk factors

During the last decades, the prevalence of obesity has increased rapidly among young people. A polymorphism in the promoter region of the IL6 gene (-174G/C), has been previously reported to be involved in obesity and metabolic syndrome development. Therefore, the aim of the study was to examine whether the IL6 -174G/C polymorphism influence the association of body fat with low-grade inflammatory markers and blood lipids and lipoproteins in Spanish adolescents. 504 Spanish adolescents participating in the AVENA study were genotyped for the -174G/C polymorphism of the IL6 gene. Anthropometric and body composition measurements were taken and blood samples were collected for plasma molecules determinations. No differences between genotypes were observed in anthropometric values, body composition measurements and plasma markers concentration. Physical activity level differ between genotypes with subjects carrying the C allele of the polymorphism being significantly (p<0.05) more active than GG subjects. The association between body fat mass and plasma glucose was influenced by the -174G/C polymorphism of the IL6 gene. Subjects carrying the C allele of the mutation seem to have higher values of lipoprotein (a) and C-reactive protein as their percentage of body fat mass increase. Our results suggest that this promoter polymorphism influences the association between adiposity and some plasma markers

Assessment of trimethoprim-sulfamethoxazole susceptibility testing methods for fastidious Haemophilus spp.

Objectives: To compare the determinants of trimethoprim-sulfamethoxazole resistance with established susceptibility values for fastidious Haemophilus spp., to provide recommendations for optimal trimethoprim-sulfamethoxazole measurement. Methods: We collected 50 strains each of Haemophilus influenzae and Haemophilus parainfluenzae at Bellvitge University Hospital. Trimethoprim-sulfamethoxazole susceptibility was tested by microdilution, E-test and disc diffusion using both Mueller-Hinton fastidious (MH-F) medium and Haemophilus test medium (HTM) following EUCAST and CLSI criteria, respectively. Mutations in folA, folP and additional determinants of resistance were identified in whole-genome-sequenced isolates. Results: Strains presented generally higher rates of trimethoprim-sulfamethoxazole resistance when grown on HTM than on MH-F, independent of the methodology used (average MIC 2.6-fold higher in H. influenzae and 1.2-fold higher in H. parainfluenzae). The main resistance-related determinants were as follows: I95L and F154S/V in folA; 3- and 15-bp insertions and substitutions in folP; acquisition of sul genes; and FolA overproduction potentially linked to mutations in -35 and -10 promoter motifs. Of note, 2 of 19 H. influenzae strains (10.5%) and 9 of 33 H. parainfluenzae strains (27.3%) with mutations and assigned as resistant by microdilution were inaccurately considered susceptible by disc diffusion. This misinterpretation was resolved by raising the clinical resistance breakpoint of the EUCAST guidelines to ≤30 mm. Conclusions: Given the routine use of disc diffusion, a significant number of strains could potentially be miscategorized as susceptible to trimethoprim-sulfamethoxazole despite having resistance-related mutations. A simple modification to the current clinical resistance breakpoint given by the EUCAST guideline for MH-F ensures correct interpretation and correlation with the reference standard method of microdilution

Design of the nutritional therapy for overweight and obese Spanish adolescents conducted by registered dieticians: the EVASYON study

Background: Dietary treatment for obese adolescents should aim to ensure adequate growth and development, by reducing excessive fat mass accumulation, avoiding loss of lean body mass, improving well-being and selfesteem and preventing cyclical weight regain. The aim of this article is to describe the dietary intervention design and the methods used to evaluate nutritional knowledge and behavior in the EVASYON study (Development, implementation and evaluation of the efficacy of a therapeutic programme for overweight/obese adolescents). Methods/design: EVASYON is a multi-centre study conducted in 5 Spanish hospital settings (Granada, Madrid, Pamplona, Santander and Zaragoza), where 204 overweight/obese Spanish adolescents were treated in groups of 9 to 11 subjects over 20 visits. The study was implemented in two stages: an intensive, calorie-restricted period for the first 9 weeks, and an extensive body-weight follow-up period for the last 11 months. A moderate energy intake restriction was applied in the intensive period according to the degree of obesity, on the basis of a balanced diet supplying 50-55% of daily energy as carbohydrates; 30-35% as fats and 10-15% as proteins. In the intensive period, adolescents were prescribed both a fixed full-day meal plan for the first three weeks and a full day meal plan with different food-choices for 6 weeks. Later, adolescents received a flexible meal plan based on food exchanges for the follow-up period until the end of the trial. Data on food intake, dietary and meal-related habits and behavior were collected by means of dietary questionnaires. To analyse nutritional knowledge, adolescents were examined regarding nutrient concepts and food items for a healthy diet with the appropriate tools. Participants were given nutritional information with complementary teaching material, which was available on the EVASYON website (www.estudioevasyon.com). Discussion: The dietary intervention of the EVASYON programme with a moderate calorie restriction for a limi - ted period of time could be a good strategy in treating overweight and obese adolescents and that will be tested further. Moreover, combining fixed plan with free-choice menus may help adolescents and their families to make right decisions for every day meals

Phase Variation in HMW1A Controls a Phenotypic Switch in Haemophilus influenzae Associated with Pathoadaptation during Persistent Infection

Genetic variants arising from within-patient evolution shed light on bacterial adaptation during chronic infection. Contingency loci generate high levels of genetic variation in bacterial genomes, enabling adaptation to the stringent selective pressures exerted by the host. A significant gap in our understanding of phase-variable contingency loci is the extent of their contribution to natural infections. The human-adapted pathogen nontypeable Haemophilus influenzae (NTHi) causes persistent infections, which contribute to underlying disease progression. The phase-variable high-molecular-weight (HMW) adhesins located on the NTHi surface mediate adherence to respiratory epithelial cells and, depending on the allelic variant, can also confer high epithelial invasiveness or hyperinvasion. In this study, we characterize the dynamics of HMW-mediated hyperinvasion in living cells and identify a specific HMW binding domain shared by hyperinvasive NTHi isolates of distinct pathological origins. Moreover, we observed that HMW expression decreased over time by using a longitudinal set of persistent NTHi strains collected from chronic obstructive pulmonary disease (COPD) patients, resulting from increased numbers of simple-sequence repeats (SSRs) downstream of the functional P2hmw1A promoter, which is the one primarily driving HMW expression. Notably, the increased SSR numbers at the hmw1 promoter region also control a phenotypic switch toward lower bacterial intracellular invasion and higher biofilm formation, likely conferring adaptive advantages during chronic airway infection by NTHi. Overall, we reveal novel molecular mechanisms of NTHi pathoadaptation based on within-patient lifestyle switching controlled by phase variation. IMPORTANCE Human-adapted bacterial pathogens have evolved specific mechanisms to colonize their host niche. Phase variation is a contingency strategy to allow adaptation to changing conditions, as phase-variable bacterial loci rapidly and reversibly switch their expression. Several NTHi adhesins are phase variable. These adhesins are required for colonization but also immunogenic, in such a way that bacteria with lower adhesin levels are better equipped to survive an immune response, making their contribution to natural infections unclear. We show here that the major NTHi adhesin HMW1A displays allelic variation, which can drive a phase-variable epithelial hyperinvasion phenotype. Over time, hmw1A phase variation lowers adhesin expression, which controls an NTHi lifestyle switch from high epithelial invasiveness to lower invasion and higher biofilm formation. This reversible loss of function aligns with the previously stated notion that epithelial infection is essential for NTHi infection establishment, but once established, persistence favors gene inactivation, in this case facilitating biofilm growth

Common variants in genes related to lipid and energy metabolism are associated with weight loss after an intervention in overweight/obese adolescents

Background: Some SNPs related to lipid and energy metabolism may be implicated not only in the development of obesity and associated comorbidities, but also in the weight loss response after a nutritional intervention. Objective: In this context, the present study analyzed four SNPs located within four genes known to be associated with obesity and other obesity-related complications, and their putative role in a weight-loss intervention in overweight/obese adolescents. Methods: The study population consisted of 199 overweight/obese adolescents (13-16 yr old) undergoing 10 weeks of a weight loss multidisciplinary intervention: the EVASYON programme (www.estudioevasyon.org). Adolescents were genotyped for 4 SNPs, and anthropometric measurements and biochemical markers were analyzed at the beginning and after the intervention. Results: Interestingly, APOA5(rs662799) was associated with the baseline anthropometric and biochemical outcomes, whereas FTO (rs9939609) seemed to be related with the change of these values after the 10-week intervention. The other two SNPs, located in the CETP (rs1800777) and the APOA1 (rs670) genes, showed important relationships with adiposity markers. Specifically, a combined model including both SNPs turned up to explain up to 24% of BMI-SDS change after 10 weeks of the multidisciplinary intervention, which may contribute to under - stand the weight loss response. Conclusion: Common variants in genes related to lipid and energy metabolism may influence not only biochemical outcomes but also weight loss response after a multidisciplinary intervention carried out in obese/overweight adolescents..Antecedentes: Algunas variantes genéticas relacionadas con el metabolismo lipídico y energético pueden estar implicadas en la respuesta a una intervención nutricional además de estar asociadas con el desarrollo de obesidad y comorbilidades asociadas. Objetivo: En este sentido, este artículo analiza cuatro polimorfismos situados en cuatro genes que han sido previamente asociados con la obesidad u otras complicaciones asociadas a la misma, así como su posible papel en la respuesta a una intervención para la pérdida de peso en adolescentes con sobrepeso u obesidad. Métodos: La población en estudio está formada por 199 adolescentes con sobrepeso u obesidad (13-16 años) llevando a cabo una intervención multidisciplinar de 10 semanas para la pérdida de peso: programa EVASYON (www.estudioevasyon.org). Los adolescentes fueron genotipados para los 4 SNPs y tanto al comienzo como al final de la intervención se analizaron marcadores bioquímicos y se tomaron medidas antropométricas. Resultados: Rs662799 del gen APOA5 se asoció al inicio con parámetros antropométricos y bioquímicos, mientras que el rs9939609 del gen FTO parecía estar asociado con el cambio de estas variables tras 10 semanas de intervención. Las variantes rs1800777 del gen CETP y rs670 del gen APOA1 mostraron una importante asociación con marcadores de adiposidad. Concretamente, un modelo combinado incluyendo los dos polimorfismos logró explicar hasta un 24% del cambio en el IMC-SDS tras 10 semanas de intervención. Conclusión: Variantes genéticas previamente relacionadas con el metabolismo lipídico y energético, pueden repercutir no solamente en valores bioquímicos sino también en la respuesta a una intervención multidisciplinar para la pérdida de peso en adolescentes con sobrepeso u obesidad