Differential DNA methylation at birth associated with mental disorder in individuals with 22q11.2 deletion syndrome.

Individuals with 22q11.2 deletion syndrome (DS) have an increased risk of comorbid mental disorders including schizophrenia, attention deficit hyperactivity disorder, depression, as well as intellectual disability. Although most 22q11.2 deletion carriers have the long 3-Mb form of the hemizygous deletion, there remains a large variation in the development and progression of psychiatric disorders, which suggests that alternative factors contribute to the pathogenesis. In this study we investigated whether neonatal DNA methylation signatures in individuals with the 22q11.2 deletion associate with mental disorder later in life. DNA methylation was measured genome-wide from neonatal dried blood spots in a cohort of 164 individuals with 22q11.2DS, including 48 individuals diagnosed with a psychiatric disorder. Among several CpG sites with P-value<10-6, we identified cg23546855 (P-value=2.15 × 10-7) mapping to STK32C to be associated with a later psychiatric diagnosis. Pathway analysis of the top findings resulted in the identification of several Gene Ontology pathways to be significantly enriched (P-value<0.05 after Benjamini-Hochberg correction); among them are the following: neurogenesis, neuron development, neuron projection development, astrocyte development, axonogenesis and axon guidance. In addition, we identified differentially methylated CpG sites in LRP2BP (P-value=5.37 × 10-8) to be associated with intellectual disability (F70-79), in TOP1 (P-value=1.86 × 10-7) with behavioral disorders (F90-98), in NOSIP (P-value=5.12 × 10-8) with disorders of psychological development (F80-89) and in SEMA4B (P-value=4.02 × 10-7) with schizophrenia spectrum disorders (F20-29). In conclusion, our study suggests an association of DNA methylation differences at birth with development of mental disorder later in life in 22q11.2DS individuals.

Kangaroo supported diagonal flexion positioning: New insights into skin-to-skin contact for communication between mothers and very preterm infants.

OBJECTIVE: Skin-to-skin contact shows benefits in the relationship developed between a mother and her premature infant. In the skin-to-skin session, face-to-face exchanges are impossible in vertical infant positioning. We therefore undertook an observational, prospective, single-center study using kangaroo "supported diagonal flexion" (SDF) positioning. The first aim was to evaluate the safety of kangaroo SDF positioning compared to the usual vertical positioning. The second aim was to evaluate SDF positioning on early communication between the mother and her infant and to improve their well-being. PARTICIPANTS AND SETTING: Fifteen mothers and their very premature infants (birth 26<32 weeks' gestation) were assigned to one of the two kangaroo positioning modes, either the current vertical positioning (n=7) or SDF positioning (n=8). DESIGN: Physiological variables and critical events were recorded before, during, and after ten successive skin-to-skin contact sessions. The first and last sessions were videotaped to allow later behavioral measurements. Mothers' risk for depression and feelings about the way they experienced communication with their infant were assessed through questionnaires. RESULTS: In terms of the infant's physiology, no negative effects were associated with SDF positioning in comparison with the usual vertical positioning. SDF positioning led to fewer disorganized gestures, negative vocalizations, and drowsiness, in favor of more deep sleep. SDF led to more mother-infant eye-to-eye contact as well as maternal vocalizations, smiles, and caressing, although these differences did not reach significance. The score for the risk of postnatal depression decreased significantly between the first and the last session in the SDF group, whereas it did not change in the vertical positioning group. CONCLUSION: These results support the idea that the kangaroo SDF positioning technique is physiologically safe, has obvious immediate benefits on mothers' infant-directed communicative behaviors, and respects the baby's naturally flexed and asymmetrical tonic neck posture. It is an innovative, inexpensive, easy-to-use technique in daily practice, by all healthcare professionals working in a neonatal intensive care unit. These data suggest that the current kangaroo positioning technique could be improved. More studies are needed to confirm the benefits and safety of the kangaroo SDF positioning in larger groups of preterm infants.

Genetic determinants of plasma ß2-glycoprotein I levels: a genome-wide association study in extended pedigrees from Spain.

BACKGROUND: ß2 -Glycoprotein I (ß2 -GPI), also designated apolipoprotein H, is a 50-kDa protein that circulates in blood at high concentrations, playing important roles in autoimmune diseases, hemostasis, atherogenesis, and angiogenesis, as well as in host defense against bacteria and in protein/cellular waste removal. Plasma ß2 -GPI levels have a significant genetic component (heritability of ~ 80%). OBJECTIVES: To present the results of a genome-wide association study for plasma ß2 -GPI levels in a set of extended pedigrees from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project. PATIENTS/METHODS: A total of 306 individuals for whom ß2 -GPI plasma measurements were available were typed for 307,984 single-nucleotide polymorphisms (SNPs) with the Infinium 317k Beadchip (Illumina). Association with the ß2 -GPI phenotype was investigated through variance component analysis, and the most significant results were followed up for association with coronary artery disease (CAD) in an independent in silico analysis involving 5765 CAD cases from the PROCARDIS Project and 7264 controls from the PROCARDIS Project and the Wellcome Trust Case Control Consortium (WTCCC) collection. RESULTS: After correction for multiple testing, three SNPs located in/around two genes (ELF5 and SCUBE2) reached genome-wide significance. Moreover, an SNP in the APOH gene showed suggestive association with the ß2 -GPI phenotype. Some of the identified genes are plausible biological candidates, as they are actually or potentially involved in inflammatory processes. CONCLUSIONS: Our results represent a first step towards identifying common variants reflecting the genetic architecture influencing plasma ß2 -GPI levels, and warrant further validation by functional experiments, as the functions of some of the discovered loci are still unknown.

Vitamina B12 y dieta vegetariana / No disponible

La dieta vegetariana es cada vez más frecuente en nuestrospacientes. La alimentación está basada únicamente en productosvegetales; algunos menos estrictos aceptan el consumode huevo y/o leche. Se asocia a menor prevalecia deobesidad, enfermedad cardiovascular, diabetes y cáncer, perotienen menor aporte energético y proteico, y podemosencontrar déficit de vitamina B12, entre otras. La vitaminaB12 únicamente podemos obtenerla a través del consumo deproductos animales. Su déficit puede provocar anemia, trastornosneuropsiquiátricos y alteración de la función cognitiva.La carencia de vitamina B12 es el principal riesgo de losvegetarianos. Para evitarlo podrían optar por ingerir alimentosenriquecidos con vitamina B12, suplementos de vitaminaB12 o el consumo de leche o huevos. Las dietas vegetarianasbien planificadas son seguras y saludables, pero si son inadecuadaspueden producir déficits nutricionales, entre ellos elde vitamina B12 (AU)

The vegetarian diet is becoming more frequent in our patients.The food intake is based exclusively on plant products, with some less strict diets including the consumption of egg and/or milk. It is associated to a lower rate of obesity, cardiovascular disease, diabetes and cáncer, however, it provides a lower contribution of energy and protein, it being possible to find vitamin B12 deficit, among others. VitaminB12 can only be obtained through the consumption of animal products. Its deficit can provoke anemia, neurological and psychiatrics disorders, and cognitive function alterations. Lack of vitamin B12 is the principal risk for vegetarians. To avoid it, they should eat vitamin B12 enriched foods, take vitamin B12 supplements or eat milk or eggs. Well-planned vegetarian diets are sure and healthy, but if they are inadequate they can produce nutritional deficits, among them that of vitamin B12 (AU)

SNP sets selection under mutual information criterion, application to F7/FVII dataset.

One of the main goals of human genetics is to find genetic markers related to complex diseases. In blood coagulation process, it is known that genetic variability in F7 gene is the most responsible for observed variations in FVII levels in blood. In this work, we propose a method for selecting sets of Single Nucleotide Polymorphisms (SNPs) significantly correlated with a phenotype (FVII levels). This method employs a feature selection algorithm (variant of Sequential Forward Selection, SFS) based on a criterion of statistical significance of a mutual information functional. This algorithm is applied to a sample of independent individuals from the GAIT project. Main SNPs found by the algorithm are in correspondence with previous results published using family-based techniques.

Genetic determinants of normal variation in coagulation factor (F) IX levels: genome-wide scan and examination of the FIX structural gene.

BACKGROUND: High-normal and elevated plasma FIX activity (FIX:C) levels are associated with increased risk for venous- and possibly arterial-thrombosis. OBJECTIVE: Because the broad normal range for FIX:C involves a substantial unknown genetic component, we sought to identify quantitative-trait loci (QTLs) for this medically important hemostasis trait. METHODS: We performed a genome-wide screen and a resequencing-based variation scan of the known functional regions of every distinct FIX gene (F9) in the genetic analysis of idiopathic thrombophilia project (GAIT), a collection of 398 Spanish-Caucasians from 21 pedigrees. RESULTS: We found no evidence for linkage (LOD scores <1.5) despite genotyping more than 540 uniformly-spaced microsatellites. We identified 27 candidate F9 polymorphisms, including three in cis-elements responsible for the increase in FIX:C that occurs with aging, but found no significant genotype-specific differences in mean FIX:C levels (P-values > or = 0.11) despite evaluating every polymorphism in GAIT by marginal multicovariate measured-genotype association analysis. CONCLUSIONS: The heritable component of interindividual FIX:C variability likely involves a collection of QTLs with modest effects that may reside in genes other than F9. Nevertheless, because the alleles of these 27 polymorphisms exhibited a low overall degree of linkage disequilibrium, we are currently defining their haplotypes to interrogate several highly-conserved non-exonic sequences and other F9 segments not examined here.

A locus on chromosome 2 influences levels of tissue factor pathway inhibitor: results from the GAIT study.

OBJECTIVE: Levels of tissue factor pathway inhibitor (TFPI) have been associated with arteriosclerosis and thrombotic disease. Although a genetic component to variation in TFPI levels is well-documented, no systematic genome-wide screens have been conducted to localize genes influencing levels of TFPI. METHODS AND RESULTS: We studied TFPI levels in 397 individuals in 21 Spanish families participating in the Genetic Analysis of Idiopathic Thrombosis (GAIT) study. Twelve families were selected through a proband with idiopathic thrombosis and 9 were ascertained without regard to phenotype. A genome scan was performed using microsatellite markers spaced at approximately 10 cM intervals. Standard multipoint variance component linkage methods were used. The heritability of TFPI levels was 0.52 (P<0.0001), with no evidence for shared household effects. In the genome screen, only 1 LOD score >2 was observed. On chromosome 2q, the maximum multipoint LOD score was 3.52 near marker D2S1384. This is near the structural gene for TFPI, which is located at 2q32. In follow-up association analyses, marginal evidence of association (P=0.04) was observed with the TFPI promoter variant C-399T. CONCLUSIONS: These results suggest that polymorphisms in and around the TFPI structural gene may be the major genetic determinants of variation in TFPI levels.

Optimización de la cita para maximizar el tiempo por visita

El objetivo principal de la asistencia sanitaria es llevar a cabo una buena atención que sea aceptable para la población. El médico de familia es el profesional responsable de proporcionar una atención integral y continuada a todo individuo que solicite asistencia médica. La buena organización de la consulta requiere gestionar adecuadamente las 2 herramientas fundamentales: los circuitos organizativos (gestión de la demanda) y la agenda (gestión del tiempo). El aumento de la presión asistencial en las consultas de medicina de familia está generando una enorme preocupación por los riesgos que comporta para la calidad asistencial. El aumento de la accesibilidad es un componente importante de la calidad de la atención y, claramente, produce un aumento de la utilización. El tiempo de visita está relacionado con el tipo de asistencia que recibe el paciente en atención primaria. El objetivo de la gestión de la agenda es la priorización en la gestión del tiempo. Es muy difícil que los médicos puedan establecer un tiempo idóneo para una visita; para ello, desde el punto de vista de la gestión, se estiman tiempos aproximados únicamente para la programación de pacientes. En este artículo se realiza una revisión sobre las características que debe tener una agenda de las consultas de atención primaria, y cómo gestionarla para poder optimizar el tiempo dedicado a cada paciente, con el objetivo de establecer al máximo el tiempo disponible y ofrecer una cartera de servicios de gran calidad asistencial. La accesibilidad, la flexibilidad, la autogestión de la agenda y la informatización de la consulta son las bases para obtener los mejores resultados (AU)

[Difficult patients in primary care: a quantitative and qualitative study]. / Pacientes de trato difícil en atención primaria: una aproximación cuantitativa y cualitativa.

AIM: To identify difficult (heartsink) patients (DP), describe their profile, and report the opinions and experiences they evoke in physicians who see them. DESIGN: Descriptive, cross-sectional study based on quantitative and qualitative methods. SETTING: Urban health care center. PARTICIPANTS: Difficult patients were selected daily from among all patients seen in six primary care practices during the period from March to May 2001. Patients were identified according to the diagnostic criteria of Ellis (patients who cause a knot in the stomach when their name appears on the list of patients with an appointment that day) and O'Dowd (patients who cause distress or discomfort). METHOD: Information was obtained on the number of DP seen, number of visits made by DP, age, sex, type of DP, level of education, occupation, family structure and comorbidity. Type of DP was determined with a modification of the Groves classification (dependent clinger, entitled demander, manipulative help-rejecter, self-destructive denier, somatizer, emotive seducer). We analyzed the opinions DP generated by examining the discourse produced during a discussion group session with 9 physicians from the participating health center and a moderator. RESULTS: A total of 82 DP were identified (prevalence.7%, i.e., 2.3% of all visits). Most (67.1%) were women. Mean age was 57.8 years (standard deviation 15.2 years). Dependent clinger patients predominated (41%). Most patients had primary-level education (62%), about one-third were retired (35%), and about one-third were married and had children (35%). Most had two or more medical diagnoses (74.4%), and many had at least one psychiatric diagnosis (40.2%).The feelings these patients evoked most often in physicians were irritability and frustration. Most physicians agreed that these patients are rare but have a severe emotional impact. Physicians believe that the skills and strategies they have to help them manage these patients are limited, and consider specific training necessary to improve them. CONCLUSIONS: Although DP are not a relevant problem in quantitative terms, they cause considerable emotional distress. Specific training in clinical interviewing is felt to be necessary given the difficulties in managing these patients.

Pacientes de trato difícil en atención primaria: una aproximación cuantitativa y cualitativa / Difficult patients in primary care: a quantitative and qualitative study

Objetivo. Identificar a los pacientes "de trato difícil" (PD), describir su perfil y las opiniones y vivencias que generan en los médicos que los atienden. Diseño. Estudio descriptivo transversal. Metodología cuantitativa-cualitativa. Emplazamiento. Centro de salud urbano. Participantes. Los PD seleccionados diariamente del total de pacientes atendidos en 6 consultas de atención primaria, entre marzo y mayo de 2001. Se identificaron mediante los criterios diagnósticos de Ellis (pacientes que provocan nudo en el estómago al leer su nombre en el listado) y O'Dowd (pacientes capaces de producir distrés, malestar).Método. Se recogió información sobre los PD visitados, número de visitas realizadas por PD, edad, sexo, clasificación, estudios, ocupación, estructura familiar y comorbilidad. Se utilizó la clasificación de Groves modificada (pasivo dependiente, exigente-agresivo, manipulador masoquista, negador-autodestructivo, somatizador, emotivo-seductor). Analizamos las opiniones que generan a partir del discurso producido en un grupo de discusión (9 médicos del centro y un moderador).Diseño. Se seleccionó a 82 pacientes (prevalencia del 0,7 por ciento [el 2,3 por ciento de las consultas realizadas]), de los que el 67,1 por ciento eran mujeres. La edad media era de 57,8 años (DE, 15,2). Predominó la paciente pasiva-dependiente (41 por ciento), con estudios primarios (62 por ciento), jubilada (35 por ciento), casada y con hijos (35 por ciento), con dos o más patologías médicas (74,4 por ciento) y al menos una psiquiátrica (40,2 por ciento).Los sentimientos que predominantemente generan en los médicos son irritabilidad y frustración. La mayoría coincide en que estos pacientes son escasos pero ocasionan un impacto emocional intenso, cree que sus habilidades y estrategias para manejarlos son limitadas y considera necesaria formación específica para mejorarlas. Conclusiones. Aunque cuantitativamente los PD no se consideran un problema relevante, provocan un gran desgaste emocional. Se consideran necesarios formación/entrenamiento específicos en entrevista clínica dadas las dificultades que presenta su manejo (AU)

[Value of exchange transfusion in the treatment of severe malaria (apropos of 5 cases)]. / Intérêt de l'exsanguinotransfusion dans le traitement du paludisme grave (à propos de 5 observations).

Five imported falciparum malaria cases with severe evolution are reported. Treatment associated a blood exchange transfusion and an antimalaria chemotherapy (mefloquine in three patients and quinine in two patients). All patients were successfully cured despite of serious visceral complications occurring in two patients (pulmonary and cerebral oedema). Technical management of treatment is detailed. Exchange transfusion should be considered in falciparum malaria when parasitaemia overcomes 20% and when serious visceral impairment, hemolysis or consumption coagulopathy are occurring.