APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease.

BACKGROUND: Variants in APOE and PSEN1 (encoding apolipoprotein E and presenilin 1, respectively) alter the risk of Alzheimer's disease. We previously reported a delay of cognitive impairment in a person with autosomal dominant Alzheimer's disease caused by the PSEN1 E280A variant who also had two copies of the apolipoprotein E3 Christchurch variant (APOE3 Ch). Heterozygosity for the APOE3 Ch variant may influence the age at which the onset of cognitive impairment occurs. We assessed this hypothesis in a population in which the PSEN1 E280A variant is prevalent. METHODS: We analyzed data from 27 participants with one copy of the APOE3 Ch variant among 1077 carriers of the PSEN1 E280A variant in a kindred from Antioquia, Colombia, to estimate the age at the onset of cognitive impairment and dementia in this group as compared with persons without the APOE3 Ch variant. Two participants underwent brain imaging, and autopsy was performed in four participants. RESULTS: Among carriers of PSEN1 E280A who were heterozygous for the APOE3 Ch variant, the median age at the onset of cognitive impairment was 52 years (95% confidence interval [CI], 51 to 58), in contrast to a matched group of PSEN1 E280A carriers without the APOE3 Ch variant, among whom the median age at the onset was 47 years (95% CI, 47 to 49). In two participants with the APOE3 Ch and PSEN1 E280A variants who underwent brain imaging, 18F-fluorodeoxyglucose positron-emission tomographic (PET) imaging showed relatively preserved metabolic activity in areas typically involved in Alzheimer's disease. In one of these participants, who underwent 18F-flortaucipir PET imaging, tau findings were limited as compared with persons with PSEN1 E280A in whom cognitive impairment occurred at the typical age in this kindred. Four studies of autopsy material obtained from persons with the APOE3 Ch and PSEN1 E280A variants showed fewer vascular amyloid pathologic features than were seen in material obtained from persons who had the PSEN1 E280A variant but not the APOE3 Ch variant. CONCLUSIONS: Clinical data supported a delayed onset of cognitive impairment in persons who were heterozygous for the APOE3 Ch variant in a kindred with a high prevalence of autosomal dominant Alzheimer's disease. (Funded by Good Ventures and others.).

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects.

BACKGROUND: The Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries. METHODS: We characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer's disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes. RESULTS: We identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent. CONCLUSIONS: Colombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies.

[Association between polymorphism in uncoupling proteins and type 2 diabetes in a northwestern Colombian population]. / Asociación de variantes en genes de las proteínas desacoplantes con diabetes mellitus tipo 2 en una población del nordeste colombiano.

INTRODUCTION: The uncoupling proteins belong to the family of anion transporting proteins which uncouple the ATP production from the mitochondrial respiration, cause proton leakage through the inner mitochondrial membrane, and release energy as heat. Although uncoupling protein function has not been well established, specific polymorphisms in these proteins have been associated with type 2 diabetes mellitus, obesity and insulin resistance. OBJECTIVE: The association was assessed between the polymorphisms in uncoupling protein genes 1, 2 and 3 genes and type 2 diabetes mellitus. MATERIALS AND METHODS: In a northwestern Colombian population, 545 diabetes cases and 449 controls were investigated for presence of 14 polymorphisms in uncoupling protein genes (3826A/G, ID 45, 2723T/A, 1957G/A, 866G/A, and 55C/T) by PCR and PCR-RFLP. Single associations were evaluated by chi-square test, and bayesian logistic regression analysis was done including as covariates the individual admixture estimates obtained by 54 informative markers for European, African and Amerind ancestry. RESULTS: Association between type 2 diabetes mellitus and the polymorphisms 3826A (OR=0.78; 95% CI = 0.63-0.97; p = 0.02) and 55 C (OR = 1.41; 95% CI = 1.04-1.92; p = 0.03) and the haplotype D45, 866G, 1957G, 2723T, and 55C (OR = 1.26; 95% CI = 1.02-1.56; p = 0.03) were found. These associations remained after adjustment using individual genetic admixture estimates. CONCLUSION: Some alleles of uncoupling protein genes 1, 2 and 3, and their haplotypes confer risk to type 2 diabetes in a northwestern Colombian population.

Efecto de la hiperglucemia en el síndrome coronario agudo y sus implicaciones en el tratamiento antiagregante plaquetario / Effect of hyperglycemia on acute coronary syndrome and the implications of antiplatelet therapy

RESUMEN La enfermedad cardiovascular representa, según los datos de la Organización Mundial de la Salud, la principal causa de muerte asociada con factores de riesgo como el tabaquismo, el sedentarismo, la hipertensión, la dislipidemia y la diabetes mellitus. Precisamente, esta última enfermedad es una de las que más se relaciona con la aparición, la progresión y las complicaciones de un evento coronario. La hiperglucemia potencia diferentes vías bioquímicas y celulares como la del sorbitol, el factor nuclear kβ, la formación de productos finales de glicación avanzada, la vía de la proteína cinasa C y el estrés oxidativo, que terminan favoreciendo en el paciente coronario un estado proinflamatorio y procoagulante, que se asocia con un peor pronóstico y agrava la lesión miocárdica; además, inhibe y compite con la acción de los antiagregantes plaquetarios, generando resistencia no solo a estos sino también a la terapia trombolítica. Por lo anterior, se hace necesario generar una actualización del tema, para sensibilizar a la comunidad médica sobre la importancia del control glucémico, sobre todo en pacientes con cardiopatía isquémica, y así mejorar las estrategias de control. Se realizó la búsqueda bibliográfica en PubMed, de una forma estructurada, no sistemática. Se incluyeron artículos publicados en inglés y español, sin restricción por fecha de publicación.

SUMMARY According to data from the World Health Organization, cardiovascular disease is the main cause of death associated with risk factors such as smoking, sedentary lifestyle, hypertension, dyslipidemia and diabetes mellitus. Precisely, this last disease is one of the most related to the appearance, progression, and complications of a coronary event. Hyperglycemia potentiates different biochemical and cellular pathways such as sorbitol, the nuclear factor kβ, the formation of advanced glycation end products, the protein kinase C pathway and oxidative stress, which end up favoring in the coronary patient a proinflammatory state and procoagulant, which is associated with a worse prognosis and aggravates myocardial injury; in addition, it inhibits and competes with the action of platelet antiaggregants, generating resistance not only to these but also to thrombolytic therapy. Therefore, it is necessary to generate an update of the topic, to sensitize the medical community about the importance of glycemic control, especially in patients with ischemic heart disease and thus improve control strategies. The bibliographic search was carried out in PubMed, in a structured, non-systematic way. Articles published in English and Spanish were included, without restriction by publication date.

Planificación familiar en mujeres en condiciones de vulnerabilidad social / Family planning for women in vulnerable social

Introducción: La planificación familiar es un componente esencial en el cuidado de la salud primaria y reproductiva desatendida en poblaciones socialmente vulnerables. Objetivo: Evaluar los conocimientos básicos sobre planificación familiar y su aplicación con mujeres en edad reproductiva que viven en condiciones de pobreza y vulnerabilidad en un barrio de la ciudad de Medellín, Colombia. Metodología: Estudio descriptivo de corte transversal, en donde se aplicó una entrevista personal semi-estructurada a 100 mujeres elegidas por muestreo abierto. Resultados: Las mujeres encuestadas tenían conocimientos básicos sobre la existencia de diferentes métodos de planificación familiar. El 93% de las mujeres no deseaba concebir más hijos, de estas el 38,7% no planificaba en el momento de la entrevista. El 42% tenía un nivel bajo de escolaridad; se halló relación entre este hecho y el número de hijos, donde el 31% de las madres tenía entre 3 y 7 hijos (p<0,001; O.R: 5,8). El 68% de las mujeres tenía vida sexual activa; de estas 69,1% planificaba. El 33% de las mujeres inició su vida sexual antes de los 15 años, además, esto se suma con la no utilización de métodos anticonceptivos, el número de hijos y la no planeación de los embarazos; (p<0,02). Conclusión: El nivel de conocimientos de los métodos de planificación familiar es aceptable, sin embargo, esto no se ve reflejado en el uso. La edad de inicio de relaciones sexuales temprana es un factor determinante de vulnerabilidad, dado que está influenciado por la condición de pobreza de estas mujeres. Salud UIS 2011; 43 (3): 241-248.

Introduction: Family planning is an essential component of primary health care and reproductive, unattended in socially vulnerable populations. Objective: To evaluate the basic knowledge about family planning and its implementation, in women of reproductive age living in poverty and vulnerability in a neighborhood of the city of Medellín, Colombia in 2010. Materials and methods: It was performed a cross sectional study, which applied a semi-structured interview to 100 women elected by open sampling. Results: The women surveyed had basic knowledge about the existence of different methods of family planning. 93% of women did not want to conceive more children, the 38.7% of these, did not plan at the time of the interview. 42% had low level of schooling relation was found between this and the number of children, where 31% of the mothers had children between 3 and 7 (p <0.001, OR: 5.8). 68% of the women were sexually active, 69.1% of these planned. 33% began sex before age 15 year old, relating to failure to use contraception, the number of children and not planning pregnancies; (p <0.02). From the women using some form of planning 82% received medical advice for their use, however only 14% belong to the family planning program. Conclusion: The level of knowledge of family planning methods is acceptable, however this is not reflected in their use. The age of first sexual intercourse early, is a determinant of vulnerability, because it is influenced by the poverty status of these women. Salud UIS 2011; 43 (3): 241-248.

Introdução: A planificação familiar é um componente essencial no cuidado da saúde primaria e reprodutiva desconsiderada em populações socialmente vulneráveis. Objetivo: Avaliar os conhecimentos básicos sobre o planejamento familiar e a sua aplicação em mulheres na idade reprodutiva que estejam em situação de pobreza e vulnerabilidade num bairro da cidade de Medellín, Colômbia; 2010. Métodos: Foi realizado um estudo descritivo de corte transversal, onde foi aplicada uma entrevista pessoal semi-estruturada em cem mulheres eleitas por amostragem aberta. Resultados: As mulheres entrevistadas tinham conhecimentos básicos sobre a existência de diferentes métodos de planejamento familiar. O 93% das mulheres não desejavam conceber mais filhos, destas o 38,7% não usava métodos de planejamento familiar no momento da entrevista. O 42% tinha baixo nível de escolaridade; encontrou-se relação entre este dado e o número de filhos, onde o 31% das mães tinham entre três e sete filhos (p<0,001; O.R: 5,8). O 68% das mulheres tinham vida sexual ativa; destas 69,1% usavam métodos de planejamento familiar. O 33% iniciou a sua vida sexual antes dos 15 anos, tendo relação com o não uso de métodos de planejamento familiar, o número de filhos e o não planejamento da gravidez; (p<0,02). Das mulheres que usavam algum método de planejamento familiar, o 82% recebeu conselho porem somente o 14% pertencem ao programa de planejamento familiar. Conclusão: O nível de conhecimentos dos métodos de planejamento familiar é aceitável, porem isto não esta se refletindo no seu uso. A idade de inicio das relações sexuais de forma prematura é um fator determinante de vulnerabilidade, devido a que isto esta influenciado pela situação de pobreza destas mulheres.

Asociación de variantes en genes de las proteínas desacoplantes con diabetes mellitus tipo 2 en una población del nordeste colombiano / Association between polymorphism in uncoupling proteins and type 2 diabetes in a northwestern Colombian population

Introducción. Las proteínas desacoplantes pertenecen a la familia de proteínas transportadoras de aniones que desacoplan la producción de ATP de la respiración mitocondrial, causando pérdida de protones a través de la membrana mitocondrial interna y disipando la energía en forma de calor. Aunque su función no ha sido bien establecida, algunos polimorfismos en estas proteínas se han asociado con diabetes mellitus tipo 2, obesidad y resistencia a la insulina. Objetivo. Evaluar la asociación entre las variantes -3826A/G, ID 45, -2723T/A, -1957G/A, -866G/A, -55C/T de los genes de las proteínas desacoplantes 1, 2 y 3 con diabetes mellitus tipo 2 en una población del nordeste colombiano. Materiales y métodos. Se tipificaron 545 casos y 449 controles para 14 variantes de los genes de las proteínas desacoplantes por medio de PCR y PCR-RFLP. Se hicieron pruebas de asociación simples con ji al cuadrado y se corrigieron en un análisis de regresión logística bayesiana, incluyendo los estimados de mezcla individual obtenidos mediante 54 marcadores informativos de ascendencia europea, africana y amerindia. Resultados. Las variantes -3826A (OR=0,78; IC95% 0,63-0,97; p=0,02), -55C (OR=1,41; IC95% 1,04-1,92; p=0,03) de las proteínas desacoplantes 1 y 3, respectivamente, y el haplotipo D45, -866G, -1957G, -2723T, -55C (OR=1,26; IC95% 1,02-1,56; p=0,03) se asociaron con diabetes tipo 2. Estas asociaciones se conservaron después de ajustar por la mezcla genética individual. Conclusión. Algunas variantes de las proteínas desacoplantes 1, 2 y 3, y sus haplotipos, confieren riesgo para diabetes mellitus tipo 2 en una población del nordeste colombiano.

Introduction. The uncoupling proteins belong to the family of anion transporting proteins which uncouple the ATP production from the mitochondrial respiration, cause proton leakage through the inner mitochondrial membrane, and release energy as heat. Although uncoupling protein function has not been well established, specific polymorphisms in these proteins have been associated with type 2 diabetes mellitus, obesity and insulin resistance. Objective. The association was assessed between the polymorphisms in uncoupling protein genes 1, 2 and 3 genes and type 2 diabetes mellitus. Materials and methods. In a northwestern Colombian population, 545 diabetes cases and 449 controls were investigated for presence of 14 polymorphisms in uncoupling protein genes (3826A/G, ID 45, 2723T/A, 1957G/A, 866G/A, and 55C/T) by PCR and PCR-RFLP. Single associations were evaluated by chi-square test, and bayesian logistic regression analysis was done including as covariates the individual admixture estimates obtained by 54 informative markers for European, African and Amerind ancestry. Results. Association between type 2 diabetes mellitus and the polymorphisms 3826A (OR=0.78; 95%CI=0.63-0.97; p=0.02) and 55C (OR=1.41; 95%CI=1.04-1.92; p=0.03) and the haplotype D45, 866G, 1957G, 2723T, and 55C (OR=1.26; 95%CI=1.02-1.56; p=0.03) were found. These associations remained after adjustment using individual genetic admixture estimates. Conclusion. Some alleles of uncoupling protein genes 1, 2 and 3, and their haplotypes confer risk to type 2 diabetes in a northwestern Colombian population.

Propiedades linüüísticas de los trastornos específicos del desarrollo del lenguaje / Linguistic prperrties of specific language impairmnnt

This study reviews the main approaches of the functional alterations that may explain language alterations in children with Specific Language Impairment (SLI). It is estimated that at least 7.4% of the children have difficulties in their language development and most of them do not have other developmental delay. Although the linguistic difficulties could apparently be resolved in children with SLI, there is a group of children for whom the impairment persists across time and throughout their school age, mostly related with reading and writing difficulties; as a consequence, several barriers in their social and academic achievement may appear. Two theoretical positions pretend to explain functional alterations in the language of children who suffer the Specific Language Impairment: the processing and the linguistic approaches. The processing view suggests that the core disturbance is related to the working memory, while the lingüistic view proposes that the inherited grammar abilities explain the language difficulties. Lastly it is possible to conclude that children with Specific Language Impairment may show difficulties as in non word repetition tests as in grammatical language abilities that may explain the processing and the linguistic marker views, respectively. The understanding of the functional alterations in Specific Language Impairment may lead to design the therapeutic and educational strategies in this group of children.

Este estudio revisa los principales enfoques de las alteraciones que pueden explicar las alteraciones del lenguaje en los niños con Trastornos Específicos del Desarrollo del Lenguaje (TEDL). Se estima que en por lo menos en un 7.4% de los niños tienen dificultades en su desarrollo del lenguaje y la mayoría de ellos no tienen otro retraso en el desarrollo. Aunque las dificultades lingüísticas aparentemente podrían ser resultas en niños con TEDL, hay un grupo de niños en los que el daño persiste a través del tiempo y a través de la edad escolar y la mayoría está relacionado con las dificultades de la lectura y la escritura; como consecuencia, pueden aparecer algunas barreras en su logro social y académico. Dos posiciones teóricas pretenden explicar las alteraciones funcionales del lenguaje de los niños que sufren Trastornos Específicos del Desarrollo del Lenguaje: el enfoque de procesamiento y el lingüístico. La visión del procesamiento sugiere que el principal problema está relacionado con la memoria operativa, mientras la visión lingüística propone que las habilidades gramaticales heredadas explican las dificultades del lenguaje. Por último, es posible concluir que los niños con Trastornos Específicos del Desarrollo del Lenguaje pueden mostrar dificultades tanto en las pruebas de repetición tanto en las habilidades gramaticales del lenguaje que puedan explicar los marcadores de las visiones del procesamiento y lingüísticas, respectivamente. La comprensión de las alteraciones en los Trastornos Específicos del Desarrollo del Lenguaje puede llevar al diseño de Estrategias Terapéuticas y educativas en los grupos de niños.