Exploring the biological role of postzygotic and germinal de novo mutations in ASD.

De novo mutations (DNMs), including germinal and postzygotic mutations (PZMs), are a strong source of causality for Autism Spectrum Disorder (ASD). However, the biological processes involved behind them remain unexplored. Our aim was to detect DNMs (germinal and PZMs) in a Spanish ASD cohort (360 trios) and to explore their role across different biological hierarchies (gene, biological pathway, cell and brain areas) using bioinformatic approaches. For the majority of the analysis, a combined ASD cohort (N = 2171 trios) was created using previously published data by the Autism Sequencing Consortium (ASC). New plausible candidate genes for ASD such as FMR1 and NFIA were found. In addition, genes harboring PZMs were significantly enriched for miR-137 targets in comparison with germinal DNMs that were enriched in GO terms related to synaptic transmission. The expression pattern of genes with PZMs was restricted to early mid-fetal cortex. In contrast, the analysis of genes with germinal DNMs revealed a spatio-temporal window from early to mid-fetal development stages, with expression in the amygdala, cerebellum, cortex and striatum. These results provide evidence of the pathogenic role of PZMs and suggest the existence of distinct mechanisms between PZMs and germinal DNMs that are influencing ASD risk.

Alfabetización en salud en pacientes con diabetes tipo 2: un estudio transversal con el cuestionario HLS-EU-Q47 / Health literacy in patients with type 2 diabetes: A cross-sectional study using the HLS-EU-Q47 questionnaire

OBJETIVO: Determinar el grado de alfabetización en salud de pacientes diabéticos de Ourense, de 50 a 75 años de edad, y su relación con la concentración de hemoglobina glicada y el riesgo cardiovascular. MATERIALES Y MÉTODOS: Estudio transversal mediante cuestionario autocumplimentado. A partir de muestreo polietápico fueron incluidos aleatorizadamente pacientes diabéticos de tipo 2 pertenecientes a cupos urbanos de la ciudad de Ourense. Se analizó a un total de 103 pacientes. Se determinaron: grado de alfabetización en salud utilizando el cuestionario HLS-EU-Q47, último valor de hemoglobina glicada y el riesgo cardiovascular se calculó con el algoritmo UKPDS. Edad, sexo, nivel educativo, grado de apoyo social, clase social y comorbilidad se utilizaron como covariables. RESULTADOS: El 81,5% (84) tenía un nivel de alfabetización en salud inconveniente (el 29,1% nivel inadecuado y el 52,4% nivel problemático). Se observó asociación entre mayores grados de alfabetización en salud y niveles más altos de educación (p < 0,001). El nivel de hemoglobina glicada estaba relacionado de forma negativa con el grado de alfabetización en salud, de tal forma que un mayor grado de alfabetización implicaba un menor valor de hemoglobina glicada (p = 0,03). No se encontró asociación con el riesgo cardiovascular (p = 0,3). CONCLUSIONES: El grado de alfabetización en salud de la población analizada fue insuficiente y su incremento podría suponer mejores resultados clínicos en el tratamiento de los pacientes diabéticos

OBJECTIVE: The aim of this study was to determine the level of health literacy of diabetic patients aged 50 to 75 years, from Ourense, Spain, as well as its relationship with the glycated haemoglobin (HbA1c) concentration and cardiovascular risk of the patient. MATERIAL AND METHODS: Cross-sectional study using a self-completed questionnaire. From a multi-stage sampling, urban, type 2 diabetic patients were randomly included. The level of health literacy, using the HLS-EU-Q47 questionnaire, the last concentration of HbA1c, and both total and fatal cardiovascular risk at 10 year follow-up, measured using the UKPDS (U.K. Prospective Diabetes Study) algorithm, were determined. The age, gender, level of education, level of social support, social class, and comorbidities were used as covariates. RESULTS: A total of 103 patients were analysed. Out of all the patients, 81.5% (84) had an unsuitable health literacy level (29.1% had an inadequate level and 52.4% had a problematic level). A clear association was seen between a higher level of health literacy and higher levels of education. Moreover, the level of health literacy was seen to be inversely related to the level of control of the patients' diabetes measured on the basis of their HbA1c (P = .03) concentration. However, no such association was found with the cardiovascular risk (P = .3). CONCLUSIONS: The results of the present study show that the level of literacy of the analysed population was insufficient, and that its improvement could result in a better outcome in the treatment of diabetic patients

[Health literacy in patients with type 2 diabetes: A cross-sectional study using the HLS-EU-Q47 questionnaire]. / Alfabetización en salud en pacientes con diabetes tipo 2: un estudio transversal con el cuestionario HLS-EU-Q47.

OBJECTIVE: The aim of this study was to determine the level of health literacy of diabetic patients aged 50 to 75 years, from Ourense, Spain, as well as its relationship with the glycated haemoglobin (HbA1c) concentration and cardiovascular risk of the patient. MATERIAL AND METHODS: Cross-sectional study using a self-completed questionnaire. From a multi-stage sampling, urban, type 2 diabetic patients were randomly included. The level of health literacy, using the HLS-EU-Q47 questionnaire, the last concentration of HbA1c, and both total and fatal cardiovascular risk at 10 year follow-up, measured using the UKPDS (U.K. Prospective Diabetes Study) algorithm, were determined. The age, gender, level of education, level of social support, social class, and comorbidities were used as covariates. RESULTS: A total of 103 patients were analysed. Out of all the patients, 81.5% (84) had an unsuitable health literacy level (29.1% had an inadequate level and 52.4% had a problematic level). A clear association was seen between a higher level of health literacy and higher levels of education. Moreover, the level of health literacy was seen to be inversely related to the level of control of the patients' diabetes measured on the basis of their HbA1c (P=.03) concentration. However, no such association was found with the cardiovascular risk (P=.3). CONCLUSIONS: The results of the present study show that the level of literacy of the analysed population was insufficient, and that its improvement could result in a better outcome in the treatment of diabetic patients.

Dosage programming of phenobarbital in neonatal seizures.

Owing to the changes occurring in the organism as a result of biological maturation, disposition kinetics of phenobarbital in newborns is significantly different to that observed in the paediatric and adult populations. Moreover, the disposition parameters change constantly during the first days of life. The data on the serum levels of phenobarbital in 17 newborns were analysed to quantify the changes in the elimination half-life of phenobarbital during the first weeks of life. The half-life of the drug was estimated to be (mean +/- SD) 114.2 +/- 43.0 h, 73.19 +/- 24.17 h and 41.23 +/- 13.95 h in patients 1-10, 11-30 and 31-70 days old, respectively. According to these values and assuming phenobarbital serum levels of 20 mg/l to be safe and effective in neonatal seizures, the initial dosing recommended is 2.9, 4.8 and 6.0 mg/kg/day in newborns 1-10, 11-30 and 31-70 days old, respectively.

Plasma protein binding kinetics of valproic acid over a broad dosage range: therapeutic implications.

The aim of the study was to characterize, from the relationship between total and free serum levels of valproic acid obtained over a broad dosage range (10-50 mg/kg), the parameters defining the in-vivo kinetic behaviour of the binding of valproic acid to plasma proteins, their pharmacokinetic and clinical repercussions, and their application to therapeutic drug monitoring (TDM). The study was performed in nine healthy adults (20-35 years) who were given doses of 1000 (group A), 2000 (group B) and 3000 mg (group C) of sodium valproate according to a compensated cross-over design, simultaneously determining the total and free serum levels of valproic acid over a 24-h period. The mean free fraction increases with dose, although this increase is only significant (P < 0.05) for the highest dose (3000 mg). The variation in the free fraction of valproic acid begins to become significant (P < 0.05) at a total drug concentration above 100 mg/l. The mean values of the dissociation constant (K) and binding sites (n) were 460 mumol/l and 1.79, respectively, showing a variability of 86.6 and 38.7%, respectively, and a residual variability of 13.0%. Significant differences (P < 0.05) were found for the total plasma clearance (Cl) but not for the intrinsic plasma clearance (Clu) values, despite their tendency to decrease with the dose. If TDM is to be used for valproic acid, it is the free serum levels that should be determined, especially if high doses are administered, because the total serum levels are not a true reflection of the free ones, as is the case of other anti-epileptic drugs.

Influence of length of treatment on the interaction between phenobarbital and phenytoin.

A combination of anti-epileptic drugs gives rise to interactions that modify their disposition kinetics. To discover the clinical relevance of such interactions it is necessary to establish their direction and magnitude. Phenytoin may interact with phenobarbital either as an inducer or an inhibitor of metabolism, depending on the length of treatment with the combination of both drugs. Data obtained in six, adult, epileptic patients treated with phenobarbital alone, and later with a phenobarbital -phenytoin combination, showed that the serum levels of the barbiturate undergo an increase during the first year of treatment with the combination therapy. From this point onwards a decrease is observed in the levels of phenobarbital, to return after about 2 years to values similar to those observed with monotherapy.

Comparison of methods for the prediction of phenytoin concentrations.

A comparison was made of different methods for the prediction of the serum concentrations of phenytoin (PHT) at steady-state with a view to determining which of them had the best predictive performance. The methods employed calculated the predicted concentrations based on a dose steady-state concentration pair. Two of the methods used involved solving the Michaelis-Menten equation, determination of a single parameter in each individual and maintaining the Km (Method A) or Vmax (Method B) values at a constant. Methods C and D were Bayesian techniques that used population parameters determined in a population studied by us (Method C) and parameters drawn from the literature (Method D). Calculation of bias and precision suggests that Method C is the most suitable of those studied, with a mean prediction error (ME) of 0.56 +/- 2.16 mg/litre, a mean absolute error (MAE) of 1.76 +/- 1.31 mg/litre and a root mean squared prediction error (RMSE) of 2.17 mg/litre. Method C was also the method that showed the lowest percentage of underestimation (5.26%) and overestimation (10.53%).

Contribution of serum level monitoring in the individualization of carbamazepine dosage regimens.

The aim of the present work was to assess the forecasting efficiency of methods of dosage individualization for carbamazepine according to mean population pharmacokinetic parameters (method 1) and from information relating to one (method 2) or more (method 3) measured steady-state serum drug levels in 344 epileptic patients. All the individuals studied were outpatients on a multiple dosage regimen with carbamazepine. Carbamazepine serum levels were analyzed by an enzyme multiplied immunoassay technique (EMIT). The accuracy and precision of methods 1, 2 and 3 were judged by the mean prediction error (m.e.) and the root mean squared error (m.s.e.) that had values of -1.1 +/- 3.5 and 2.8 +/- 2.3; 0.3 +/- 2.0 and 1.4 +/- 1.5 and -0.15 +/- 1.9 and 1.4 +/- 1.2 for methods 1, 2 and 3, respectively. From the statistical analysis of the experimental data and those predicted by the three methods studied, it may be inferred that the availability of data referring to the drug serum levels contributes decisively to the establishment of a correct dosage regimen.

Distribution of cephalothin and ceftriaxone into experimental interstitial tissue fluid in rabbits.

A study was carried out on the access and residence of cephalothin and ceftriaxone in interstitial tissue fluid (ITF) produced experimentally by subcutaneous implantation of spiral steel cages after administration of 30 mg/kg of the two antibiotics to rabbits. The levels reached by the drug in serum and ITF were determined by a microbiological plate diffusion method. The elimination half-lives of cephalothin and ceftriaxone showed mean values of 0.23 and 1.77 h, respectively. Both these values were lower than those found for the disappearance half-lives from ITF. Cephalothin reached a maximum concentration in ITF of 4.37 micrograms/ml at 0.52 h, while ceftriaxone showed a maximum concentration of 24.94 micrograms/ml at 2.09 h. The area under the curve of tissue concentrations of ceftriaxone was approximately 20-fold greater than that of cephalothin at the same dose and using same administration route. The index of the penetration capacity expressed as the quotient of the respective AUC's in ITF and in the systemic circulation gave a value for ceftriaxone which was approximately double that obtained for cephalothin.

Effect of sodium valproate on phenobarbital serum levels in children and adults.

The influence of sodium valproate on serum levels of phenobarbital during combination treatment was studied in 29 children and 50 adults with epilepsy. Steady-state drug levels in serum were determined immediately prior to drug administration using immunoenzymatic analysis. The serum level/dose ratio of phenobarbital increased significantly (p less than 0.001) when sodium valproate was added to the treatment. The increase had a mean value of 50.9% in adults and 112.5% in children, suggesting marked interindividual variability in the intensity of the interaction. Almost half of the patients required a decrease in the dose of phenobarbital prescribed. The interaction was more pronounced in patients with high serum levels of phenobarbital, while the dose of phenobarbital and the serum levels and dose of sodium valproate did not seem to affect the extent of the interaction. Close monitoring of the serum levels of phenobarbital is recommended during simultaneous treatment with sodium valproate.