Exploring genetic testing requests, genetic alterations and clinical associations in a cohort of children with autism spectrum disorder.

Several studies show great heterogeneity in the type of genetic test requested and in the clinicopathological characteristics of patients with ASD. The following study aims, firstly, to explore the factors that might influence professionals' decisions about the appropriateness of requesting genetic testing for their patients with ASD and, secondly, to determine the prevalence of genetic alterations in a representative sample of children with a diagnosis of ASD. Methods: We studied the clinical factors associated with the request for genetic testing in a sample of 440 children with ASD and the clinical factors of present genetic alterations. Even though the main guidelines recommend genetic testing all children with an ASD diagnosis, only 56% of children with an ASD diagnosis were genetically tested. The prevalence of genetic alterations was 17.5%. These alterations were more often associated with intellectual disability and dysmorphic features. There are no objective data to explicitly justify the request for genetic testing, nor are there objective data to justify requesting one genetic study versus multiple studies. Remarkably, only 28% of males were genetically tested with the recommended tests (fragile X and CMA). Children with dysmorphic features and organic comorbidities were more likely to be genetic tested than those without. Previous diagnosis of ASD (family history of ASD) and attendance at specialist services were also associated with Genetically tested Autism Spectrum Disorder GTASD. Our findings emphasize the importance of establishing algorithms to facilitate targeted genetic consultation for individuals with ASD who are likely to benefit, considering clinical phenotypes, efficiency, ethics, and benefits.

A formal analysis of inconsistent decisions in intertemporal choice through subjective time perception.

The framework of this paper is subjective time perception in the context of intertemporal choice, that is to say, the process of making decisions on dated outcomes (monetary or not) by an individual or a group of individuals. In this setting, the Discounted Utility model and, more specifically, the exponential discounting have been the paradigmatic methodology used to measure the preferences on delayed outcomes. However, this model can only be applied to consistent choices in which individuals do not change their preferences when the involved rewards are delayed the same time interval. Unfortunately, this is not the case of several decision scenarios where time is viewed as a subjective variable. The objective of this paper is to formally analyze the consistency of intertemporal choices governed by a discount function, derived from the exponential, where time has been distorted according to certain psychological traits of the subjects involved in the decision-making. More specifically, the different types of decreasing impatience will be characterized by focusing on the distortion derived from the subjective perspective of time. The findings of this research are very relevant in order to explain the time-related behavior of decision-makers in some noteworthy fields such as finance, psychology, marketing or sociology.

Sleep-related hypermotor epilepsy with genetic diagnosis: description of a case series in a tertiary referral hospital.

INTRODUCTION: Sleep-related hypermotor epilepsy (SHE) is characterized by asymmetric tonic/dystonic posturing and/or complex hyperkinetic seizures occurring mostly during sleep. Experts agree that SHE should be considered a unique syndrome. PURPOSE: We present 8 cases of SHE for which a genetic diagnosis was carried out using a multigene epilepsy panel. METHODS: We retrospectively screened familial and isolated cases of SHE in current follow-ups in our center. RESULTS: We included 8 (5F/3M) patients, 5 of whom had a positive familial history of epilepsy. We identified a pathogenic mutation in CHRNA4, CHRNB2, and 3 different pathogenic changes in DEPDC5. CONCLUSIONS: Awareness of SHE needs to be raised, given its implications for finding an appropriate treatment, its relationship to cognitive and psychiatric comorbidities, and the opportunity to prevent the disorder in the descendants. We present our series with their clinical, radiological, electroencephalographic, and genetic characteristics, in which we found 3 pathogenic mutations in the DEPDC5 gene but not previously reported in the literature. Identifying new pathogenic mutations or new genes responsible for SHE will facilitate a better understanding of the disease and a correct genetic counseling.

Effectiveness and safety of rivaroxaban in a cohort of 142 patients with nonvalvular atrial fibrillation treated with rivaroxaban for the prevention of stroke.

AIM: To evaluate the clinical profile and effectiveness/safety of patients taking rivaroxaban in clinical practice. METHODS: Retrospective study that included patients with nonvalvular atrial fibrillation treated with rivaroxaban for the prevention of stroke between January 2012 and December 2016 in a tertiary hospital in Spain. RESULTS: A total of 142 patients (median age 78 years, 40.1% men, 32.4% creatinine clearance <50 ml/min; 96.5% CHA2DS2-VASc ≥2; 44.3% HAS-BLED ≥3) were included. Only two patients had a thromboembolic event (in both cases ischemic stroke) and three patients had major bleeding (rates of 1.3 and 1.9 events/100 patient years, respectively). CONCLUSION: Data regarding effectiveness and safety in our cohort were consistent with previous studies, showing that rivaroxaban can be effective and safely used in our setting.

The Appraisal of Self-Care Agency Scale - Revised (ASA-R): Adaptation and Validation in a Sample of Spanish Older Adults.

Self-care agency is an important determinant of healthy aging. The Appraisal of Self-care Agency Scale (ASA-R) (Sousa et al., 2010) is one of the main instrument to assess self-care capacity. The objectives of the study were: 1) to adapt and validate ASA-R scale for use in Spanish population; 2) to examine the dimensionality, validity and reliability; 3) and to establish the convergent validity of ASA-R using a self-reported health measure. The ASA-R Scale and the 12-item Short Form Health Survey (SF-12) were administered to 488 Spanish seniors aged 65 and over. Confirmatory Factor Analysis (CFA) was used to analyze the dimensionality, validity and reliability. Convergent validity was tested by correlating the ASA-R factors with the SF-12 subscales; correlations were significant (p 0.05 (0.436), RMSEA closer to 0 (0.006), SRMR 0.95 (0.996 and 0.995). The results also demonstrated that ASA-R is a reliable and valid instrument. The ASA-R has demonstrated to be a reliable (CR indices > 0.7) and valid (AVE > 0.5) instrument in measuring self-care agency among Spanish older population.

Mechanism of action of guanfacine: a postsynaptic differential approach to the treatment of attention deficit hyperactivity disorder (adhd).

The treatment of ADHD has focused on the use of psychostimulants drugs such as methylphenidate or amphetamine and derivatives, or not stimulants agents, such as atomoxetine. These agents act mainly on catecholaminergic presynaptic mechanisms. Recently the European Medicines Agency (EMA) has approved another not psychostimulant drug, guanfacine extended release (ER), as a new option to the treatment of ADHD, which acts at postsynaptic level. Guanfacine stimulates postsynaptic alfa-2A adrenergic receptors so it inhibits the production of cAMP and closes HCN channels enhancing the effectiveness of the signal of the pyramidal neurons of the prefrontal cortex (PFC), thus improving working memory and attention. In addition, stimulation of the alpha-2A receptors promotes growth and maturation of the dendritic spines of pyramidal neurons of the medial PFc, that are associated with brain function such as learning and memory. In contrast with psychostimulants or atomoxetine, guanfacine mimics noradrenaline stimulation of postsynaptic receptors alfa-2A on the PFC.

Intradermal immunization in the ear with cholera toxin and its non-toxic ß subunit promotes efficient Th1 and Th17 differentiation dependent on migrating DCs.

The nature of CD4(+) T-cell responses after skin immunization and the role of migrating DCs in the presence of adjuvants in the elicited response are interesting issues to be investigated. Here, we evaluated the priming of CD4(+) T cells following ear immunization with low doses of model antigens in combination with either cholera toxin (CT) or the non-toxic ß CT subunit (CTB) as an adjuvant. Following immunization with CT, we found efficient antigen presentation that is reflected in the production of IFN-γ and IL-17 by CD4(+) T cells over IL-4 or IL-5 production. The CTB-induced activation of DCs in the ear occurred without visible inflammation, which reflects a similar type of CD4(+) T-cell differentiation. In both cases, the elicited response was dependent on the presence of migrating skin cells. Remarkably, immunization with CT or with CTB led to the induction of a delayed-type hypersensitivity (DTH) response in the ear. The DTH response that was induced by CT immunization was dependent on IL-17 and partially dependent on IFN-γ activity. These results indicate that both CT and CTB induce an efficient CD4(+) T-cell response to a co-administered antigen following ear immunization that is dependent on migrating DCs.

Functional mapping of the fission yeast DNA polymerase delta B-subunit Cdc1 by site-directed and random pentapeptide insertion mutagenesis.

BACKGROUND: DNA polymerase delta plays an essential role in chromosomal DNA replication in eukaryotic cells, being responsible for synthesising the bulk of the lagging strand. In fission yeast, Pol delta is a heterotetrameric enzyme comprising four evolutionarily well-conserved proteins: the catalytic subunit Pol3 and three smaller subunits Cdc1, Cdc27 and Cdm1. Pol3 binds directly to the B-subunit, Cdc1, which in turn binds the C-subunit, Cdc27. Human Pol delta comprises the same four subunits, and the crystal structure was recently reported of a complex of human p50 and the N-terminal domain of p66, the human orthologues of Cdc1 and Cdc27, respectively. RESULTS: To gain insights into the structure and function of Cdc1, random and directed mutagenesis techniques were used to create a collection of thirty alleles encoding mutant Cdc1 proteins. Each allele was tested for function in fission yeast and for binding of the altered protein to Pol3 and Cdc27 using the two-hybrid system. Additionally, the locations of the amino acid changes in each protein were mapped onto the three-dimensional structure of human p50. The results obtained from these studies identify amino acid residues and regions within the Cdc1 protein that are essential for interaction with Pol3 and Cdc27 and for in vivo function. Mutations specifically defective in Pol3-Cdc1 interactions allow the identification of a possible Pol3 binding surface on Cdc1. CONCLUSION: In the absence of a three-dimensional structure of the entire Pol delta complex, the results of this study highlight regions in Cdc1 that are vital for protein function in vivo and provide valuable clues to possible protein-protein interaction surfaces on the Cdc1 protein that will be important targets for further study.

The C-terminal zinc finger of the catalytic subunit of DNA polymerase delta is responsible for direct interaction with the B-subunit.

DNA polymerase delta (Pol delta) plays a central role in eukaryotic chromosomal DNA replication, repair and recombination. In fission yeast, Pol delta is a tetrameric enzyme, comprising the catalytic subunit Pol3 and three smaller subunits, Cdc1, Cdc27 and Cdm1. Previous studies have demonstrated a direct interaction between Pol3 and Cdc1, the B-subunit of the complex. Here it is shown that removal of the tandem zinc finger modules located at the C-terminus of Pol3 by targeted proteolysis renders the Pol3 protein non-functional in vivo, and that the C-terminal zinc finger module ZnF2 is both necessary and sufficient for binding to the B-subunit in vivo and in vitro. Extensive mutagenesis of the ZnF2 module identifies important residues for B-subunit binding. In particular, disruption of the ZnF2 module by substitution of the putative metal-coordinating cysteines with alanine abolishes B-subunit binding and in vivo function. Finally, evidence is presented suggesting that the ZnF region is post-translationally modified in fission yeast cells.