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.

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 < .005). CFA showed that the ASA-R Three Factor Model fit well to the data, showing satisfactory fit indices, with S-Bχ2 > 0.05 (0.436), RMSEA closer to 0 (0.006), SRMR < 0.08 (0.065), GFI and AGFI close to 1 (0.924 and 0.921), and CFI and NNFI > 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 (AU)

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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.

Mecanismo de acción de la guanfacina: un abordaje postsináptico diferencial del tratamiento del trastorno por deficit de atención e hiperactividad (TDAH) / Mechanism of action of guanfacine: a postsynaptic differential approach to the treatment of attention deficit hyperactivity disorder (ADHD)

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Catatonía periódica o síndrome neuroléptico maligno: claves para un reto diagnóstico / Periodic catatonia or neuroleptic malign syndrom: diagnostic clues

Introducción: Los pacientes institucionalizados con enfermedad mental grave y alteraciones motoras plantean frecuentes dudas diagnósticas. La catatonía periódica se manifiesta por alteraciones motoras y signos orgánicos por lo que debe incluirse en el diagnóstico diferencial ante un cuadro sugestivo de síndrome neuroléptico maligno. Caso clínico: Varón de 45 años institucionalizado por trastorno del desarrollo intelectual. Durante 3 primaversas consecutivas presenta insomnio, alteraciones conductuales persistentes, seguidas de catatonías acinéticas y síndrome neurovegetativo: rigidez, estereotipias, sudoración, taquicardia, febrícula y pérdida ponderal. Se le diagnostica de síndrome neuroléptico maligno retirándose los antipsicóticos. Reingresa sin solución de continuidad con importantes alteraciones conductuales que ceden tras reintroducción de los antipsicóticos. Emitido el diagnóstico de catatonía periódica se añade litio, sin recaídas hasta la fecha. Discusión: Los cuadros psiquiátricos primarios graves, habituales antes de la introducción de los antipsicóticos todavía se observan en instituciones con difícil acceso a los servicios de salud mental. Debe contemplarse su diagnóstico en sujetos en los que concurren trastornos del neurodesarrollo con cambios bruscos de su funcionamiento(AU)

Introduction: Psychiatric institutionalized patients suffering severe learning disabilities and coincidental motor symptoms usually represent a challenge in their diagnostic and therapeutic processes. Periodic catatonia may produce neurovegetative and motor symptoms, the first being essential findings for an accurate diagnosis. Otherwise, these constellations of symptoms manifested in patients undergoing antipsychotic therapy might be misidentified as a neuroleptic malignant syndrome. Case report: An institutionalized 45 year-old male with severe learning disability presented for 3 years seasonal behavioural changes: During the last winter weeks he experienced a purposeless excessive motor activity. Every springtime the patient associated insomnia and treatment-resistant hyperkinetic behavioural disturbances as a prelude of akinetic catatonia episodes with intercurrent neurovegetative syndrome (stereotyped movements, sweating, tachycardia, slight fever and severe weight loss). A diagnosis of malignant neuroleptic syndrome was made during his third episode zenith, and antipsychotic treatment removed; the patient must be readmitted to the hospital after severe behaviour disturbances, which remitted after antipsychotics reintroduction. The patient was subsequently diagnosed of periodical catatonia (bipolar disorder with catatonic features) and put on lithium carbonate-based therapy, presenting no relapses in the three next years. Discussion: Some severe mental disorders characteristic from the pre-antipsychotic era can be still diagnosed affecting institutionalized patients commit in residential resources. So in spite of the tendency of considering psychotropic drugs and infections as the sole cause for this disorders, a primary psychiatric disturbance should also be considered in this kind of patients(AU)

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.

TDAH y síndrome de Klinefelter: la importancia pronóstica de la detección precoz / ADHD and klinefelter syndrome: the importance of early diagnosis

Se presenta el caso clínico de un varón de 19 años deedad, con conductas delictivas y consumos tóxicos quefueron considerados como secundarios a un trastornoantisocial de personalidad, en el que la buena respuestaal metilfenidato y un patrón de hiperactividad eimpulsividad persistentes hizo sospechar la existenciade un TDAH del adulto, no detectado en la infancia. Sumorfotipo peculiar y algunos de sus síntomas llevaron aun diagnóstico genético tardío de Síndrome de Klinefelter.La concurrencia de estas condiciones biológicas ignoradasy no tratadas, con unas circunstancias psicosocialesadversas en la infancia configuró un cuadroabigarrado, con conductas antisociales de repercusiónpara sí y para otros. La base genética del TDAH, sucorrecto tratamiento farmacológico en la infancia y sucontrovertido diagnóstico en la forma del adulto tieneconsiderable interés por su relación con los consumostóxicos y las conductas disruptivas para el individuo ypara la sociedad

We present a 19 years old man who presented delictivebehaviour and illicit drugs abuse considered as secondaryto an antisocial personality disorder. Good response tomethilphenidate and persistent hiperactivity andimpulsivity led to diagnose an ADHD in the adult, notdiagnosed in the childhood. His strange habit and othersymptoms allowed to diagnosed genetically a Klinefelter´sSyndrome. The comorbidity of these unknown anduntreated biological conditions with adverse psychosocialcircumstances during the childhood drawn a bizarrepicture, with disruptive behaviour against himself andothers. Genetical origin of ADHD, its correctphamacological treatment during the first years of lifeand the controversial diagnosis of the adult type has greatinterest because of its link with drugs abuse and disruptivebehaviour

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.

Tendencias en los patrones de prescripción entre psiquiatras en formación: "la mano que mece la cuna..." / Pattern trends of prescription among psychiatrist in training

Introducción: La irrupción de nuevos antipsicóticos (APN), antidepresivos (ADN) y estabilizadores del ánimo (EAN) ha modificado los hábitos de prescripción de los profesionales que aprendieron a manejar fármacos antiguos eficaces en sus períodos de formación. En contraposición, los MIR actuales podrían asistir al progresivo desuso de fármacos antiguos, y desestimar su aplicación por no sentirse familiarizados con su uso. Objetivo: Determinar y comparar el conocimiento farmacológico y los patrones de prescripción en psiquiatras en formación del territorio estatal español. Métodos: 64/100 seleccionados cumplimentaron un cuestionario sobre el número de prescripciones de distintos fármacos clásicos y nuevos realizadas; se inquiría la principal indicación, rango de dosis para dicha indicación, y las razones de no utilización practicándose comparaciones entre grupos. Resultados: Cerca del 95 por ciento de los residentes no había realizado prescripciones de novo de fármacos clásicos. En contraposición, habían prescrito ADN y APN cerca del 90 por ciento. Hasta un 30 por ciento conocía las características de fármacos de prevista introducción, pero entre el 50 y el 100 por ciento no podían identificar los principios activos de algunos fármacos clásicos. En contraste el 90 por ciento usaba los fármacos nuevos a dosis recomendadas. Los encuestados presentaban un conocimiento significativamente mayor de los fármacos nuevos que de los clásicos (p<0,0001). Discusión: Nuestros datos señalan que los residentes actuales desestiman las opciones clásicas de tratamiento en favor de los fármacos nuevos. Esta relegación se asocia a un importante desconocimiento del manejo de los fármacos clásicos. Existe por consiguiente un riesgo de un futuro reduccionismo farmacológico de incierta repercusión política, económica, médica y ética. (AU)

Reducción de concentraciones elevadas de homocisteína con ácido fólico y vitaminas b en pacientes con tromboembolia venosa: relación entre respuesta y genotipo c677t de la metilén tetrahidrofólico reductasa (mthfr) / Lowering high levels of fasting total homocysteine with folic acid and vitamins B in patients with venous thromboembolism: relationship between response and the C677T methylenetetrahydrofolate reductase (MTHFR) genotype

Fundamento: Las concentraciones plasmáticas elevadas de homocisteína total (tHcy) se asocian con enfermedad trombótica arterial o venosa. Dependen principalmente del estado nutricional para el ácido fólico y vitaminas B12 o B6 pero también de la actividad enzimática desarrollada por la metilén tetrahidrofólico reductasa (MTHFR). Evaluamos el grado de respuesta de la hiperhomocisteinemia (HHcy) a un sencillo esquema de suplementación vitamínica respecto al genotipo de MTHFR. Pacientes y métodos: Se seleccionaron 227 pacientes, diagnosticados de tromboembolia venosa (TEV) y que fueron analizados para tHcy (ayunas) y para el polimorfismo genético MTHFR-C677T. Cuando la tHcy excedió el límite normal (varones = 16 y mujeres = 15 µmol/l), los pacientes recibieron el equivalente a 1 mg de ácido fólico, 0,2 mg de vitamina B12 y 100 mg de vitamina B6, diariamente durante 6 semanas. Posteriormente fueron reanalizados y la reducción fue comparada por genotipos MTHFR, buscando cualquier diferencia en el grado de respuesta. Resultados: La tHcy media fue de 12,3 µmol/l (DE = 8). Los 51 pacientes hiperhomocisteinémicos (22 por ciento) tenían edad superior (65,1 años) a los no-HHcy (55,0 años) (p = 0,0001). La cumplimentación del tratamiento fue apropiada en 46 pacientes (90 por ciento). La tHcy media pretratamiento fue de 23,2 µmol/l (DE = 10,5), y se redujo a 13,0 (DE = 5,9), el 42,1 por ciento (p = 0,0001). Por genotipos, los pacientes C/C de 21,0 a 13,2 µmol/l (37 por ciento) (n = 18), los C/T de 25,0 a 12,6 µmol/l (46 por ciento) (n = 24), y los homozigotos anormales T/T de 22,7 a 14,5 µmol/l (39 por ciento) (n = 4), aunque sin evidenciarse diferencias estadísticamente significativas. La respuesta fue completa (normalizándose la tHcy) en el 80 por ciento de los casos (37/46). Se observó una correlación negativa (r = -0.471) (p = 0,005) entre edad y respuesta. Conclusiones: El tratamiento con AF/B6/B12 reduce en forma sencilla, rápida y eficaz (> 40 por ciento en 6 semanas) los valores patológicos de tHcy sin ninguna influencia del genotipo MTHFR. Dado que la HHcy parece relacionarse con las recidivas de trombosis venosa, parece prudente determinar la tHcy sistemáticamente en pacientes con TEV, para intentar su reducción en casos seleccionados (AU)

Background: High levels of plasma total homocysteine (tHcy) are involved in arterial or venous occlusive diseases. It esentially depends on the nutritional status of folic acid (FA) and vitamins B12 or B6, but also on the methylenetetrahydrofolate reductase (MTHFR) enzymatic activity. We aim to evaluate the response of the hyperhomocysteinemia (HHcy) to a standard schedule of vitamin supplementation, according with the MTHFR genotype. Patients and methods: 227 patients, diagnosed with venous thromboembolism (VTE) were analysed for tHcy (in fasting conditions), and for the MTHFR-C677T gene polymorphism. When the tHcy exceeded the cut-off point (men = 16, women = 15 µmol/l), the patients were supplemented with a dose equivalent to 1 mg FA, 0.2 mg B12 and 100 mg of B6, daily by 6 weeks. Afterwards they were reanalysed and the reduction was stratified by MTHFR genotype, looking for any difference in the response. Results: The mean fasting tHcy was 12.3 µmol/l (SD = 8). The 51 hyperhomocysteinemic patients (22%) were older (65.1 y) than the normal ones (55.0 y) (p = 0.0001). The treatment was carried out properly in 46 patients (90%). The pre-treatment mean Hcy was 23.2 (SD = 10.5) µmol/l, and it was reduced to 13.0 (SD = 5.9) (p = 0.0001) (mean reduction = 42.1%). By genotype, the C/C reduced from 21.0 to 13.2 µmol/l (37%) (n = 18), the C/T from 25.0 to 12.6 µmol/l (46%) (n = 24), and the abnormal homozygotes T/T from 22.7 to 14.5 µmol/l (39%) (n = 4), although no statistical significant differences were found. In 80% of cases (37/46), tHcy values normalised. A negative correlation (r = ­0.471) (p = 0.005) was observed between age and response. Conclu sions: The FA/B6/B12 based therapy reduces in a simple, quick and effective way (> 40% in 6 weeks) the pathologic tHcy levels on a VTE population and this is not influenced by the MTHFR genotype. As HHcy seems related with recurrences of venous thrombosis, we could speculate if it would be useful to analyse routinely the tHcy, attempting reduction in selected cases (AU)