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INTRODUCTION: Heart rate (HR) is often elevated in cats with cardiomyopathies (CMPs). Pharmacologic modulation of HR may reduce cardiac morbidity and mortality. OBJECTIVES: To investigate the effects of cilobradine vs. placebo, regarding time to cardiac mortality or morbidity in cats with first episode of congestive heart failure (CHF) due to primary CMP. ANIMALS: Three hundred and sixty-seven client-owned cats with primary CMP that had presented with a first episode of CHF at 50 centers in Europe. Per-protocol population comprised 193 cats (n = 89 cilobradine, n = 104 placebo). An interim analysis for futility was planned. METHODS: Prospective, randomized, placebo-controlled, double-blinded, multicenter clinical trial. Primary outcome variable was the time to a composite of cardiac mortality or cardiac morbidity. RESULTS: Median time to primary outcome was 84 days (95% confidence interval [CI]: 63-219 days) in the cilobradine group (CG) and 203 days in the placebo group (95% CI: 145-377 days) with observed hazard ratio of 1.44, indicating a higher hazard for the CG (P = 0.057). Mean HR was 28 beats per minute (bpm) lower at Day 7 (P < 0.0001) and remained 29 bpm lower at Day 360 (P = 0.026) in the CG than that in the placebo group. Although the number of adverse events did not differ, there were more serious adverse events in the CG. CONCLUSIONS: Heart rate reduction by cilobradine in cats with a first episode of CHF due to primary CMP did not reduce cardiac mortality and morbidity.
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Cardiomiopatías , Enfermedades de los Gatos , Insuficiencia Cardíaca , Animales , Gatos , Benzazepinas , Cardiomiopatías/complicaciones , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/veterinaria , Enfermedades de los Gatos/tratamiento farmacológico , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/veterinaria , Piperidinas , Estudios ProspectivosRESUMEN
BACKGROUND: Inhaled corticosteroids are effective for the treatment of equine asthma but they induce cortisol suppression with potential side effects. OBJECTIVES: To study the efficacy of ciclesonide, an inhaled corticosteroid with an improved safety profile, on lung function, clinical signs related to airway obstruction, and serum cortisol levels in asthmatic horses exposed to a mouldy hay challenge. STUDY DESIGN: Cross-over placebo controlled, blinded, randomised experiment. METHODS: Sixteen horses were enrolled in three subsequent dose-titration studies (8 horses/study) to investigate the effects of inhaled ciclesonide administered for 2 weeks at doses ranging from 450 to 2700 µg twice daily or 3712.5 µg once daily. Systemic dexamethasone (0.066 mg/kg per os) was our positive control. A placebo group was also studied. Lung function and clinical scores were blindly performed before and after 7 and 14 days of treatment. Serum cortisol was measured before and after 3, 5, 7, 10, 14 days of treatment as well as 3 and 7 days post treatment. RESULTS: After 7 days, dexamethasone induced a significant reduction in pulmonary resistance (from 2.5 ± 0.6 at day 0 to 1.1 ± 0.7 cm H2 O/L/s), pulmonary elastance (5.0 ± 2.6 to 1.2 ± 1.0 cm H2 O/L), and of the weighted clinical score (14.8 ± 4.7 to 8.0 ± 4.4). Similarly, ciclesonide 1687.5 µg twice daily significantly improved pulmonary resistance (2.7 ± 1.1 to 1.6 ± 0.8 cm H2 O/L/s), pulmonary elastance (5.2 ± 3.1 to 2.2 ± 1.3 cm H2 O/L), and weighted clinical score (13 ± 2.9 to 10.8 ± 4.2). Serum cortisol suppression (<50 nmol/L) systematically occurred with dexamethasone from day 3 of treatment up to day 3 post treatment, but not with ciclesonide at any tested doses. Placebo did not exert any significant beneficial effect. MAIN LIMITATIONS: Experimentally induced asthma exacerbations in horses might respond differently to treatment than naturally occurring exacerbations. CONCLUSIONS: Inhaled ciclesonide is an effective treatment for horses with equine asthma. Serum cortisol was unaffected by treatment.
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Glucocorticoides/uso terapéutico , Enfermedades de los Caballos/tratamiento farmacológico , Hidrocortisona/sangre , Enfermedades Pulmonares Obstructivas/veterinaria , Pregnenodionas/uso terapéutico , Administración por Inhalación , Animales , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Glucocorticoides/administración & dosificación , Caballos , Enfermedades Pulmonares Obstructivas/inducido químicamente , Enfermedades Pulmonares Obstructivas/tratamiento farmacológico , Pregnenodionas/administración & dosificaciónRESUMEN
Despite sizeable short-term effects of neurofeedback (NF) therapy on attention-deficit and hyperactivity disorder (ADHD), longer-term clinical, comorbidity and self-regulation outcomes are less systematically studied. The aim of this largest NF follow-up to date was to evaluate these outcomes 6 months after NF compared to a semi-active control to disentangle specific from unspecific sustained effects. We performed a multicenter, randomized, parallel, controlled, clinical, superiority trial in five German university outpatient departments. Participants were eligible if they fulfilled DSM-IV-TR criteria for ADHD and were aged from 7 to 9 years. Participants were randomly assigned (1:1-ratio) to 25 sessions of slow cortical potential (SCP)-NF or electromyogram biofeedback (EMG-BF). Participants were not blinded, since they received instructions according to each treatment setting. Primary outcomes were parent ratings of ADHD. The trial was registered, number ISRCTN761871859. Both groups showed improvement of ADHD symptoms compared to baseline at 6-months follow-up with large effect sizes for SCP-NF (d = 1.04) and EMG-BF (d = 0.85), but without group differences. When analyzing all assessments (pre-test, post-test-1, post-test-2 and follow-up), a group-by-time interaction emerged (p = 0.0062), with SCP-NF showing stable improvement following treatment but EMG-BF showing a relapse from post-test-1 to post-test-2, and subsequent remission at follow-up. Six months after the end of treatment, improvement after SCP-NF remained large and stable. However, the lack of group differences at follow-up suggests shared specific and unspecific effects contributing to this clinical outcome. Our correlational results indicate specificity of SCP-NF for selected subscales after training, but not at follow-up.
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Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Neurorretroalimentación/métodos , Niño , Comorbilidad , Femenino , Humanos , Masculino , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Corticosteroids are the most potent drugs for the control of severe equine asthma, but adverse effects limit their chronic systemic administration. Inhaled medications allow for drug delivery directly into the airways, reducing the harmful effects of these drugs. OBJECTIVES: To evaluate the efficacy of inhaled budesonide specifically formulated for the equine use and administered by a novel inhalation device in horses with severe asthma. STUDY DESIGN: Experimental studies in horses with naturally occurring asthma with cross-over, randomised, blinded experimental designs. METHODS: In Study 1, budesonide (1800 µg twice daily) administered using a novel Respimat® based inhaler was compared to i.v. dexamethasone (0.04 mg/kg). In Study 2, 3 doses of budesonide (450, 900, and 1800 µg) were compared to oral dexamethasone (0.066 mg/kg). Lung function, bronchoalveolar fluid cytology (Study 1), CBC, serum chemistry, and serum cortisol and adrenocorticotropic hormone (ACTH) values were evaluated. RESULTS: In Study 1, there was a marked and significant improvement in the lung function of all horses treated with budesonide and dexamethasone. Neutrophil percentages in bronchoalveolar fluid decreased in all horses treated with dexamethasone and in four of six horses treated with budesonide. Serum cortisol and blood ACTH concentrations decreased with both treatments. In Study 2, there was a significant improvement in the lung function with all dosages of budesonide, and the effects of higher dosages were comparable to those of dexamethasone. Dexamethasone and budesonide at the two higher dosages induced a significant decrease of cortisol concentrations. MAIN LIMITATIONS: The Respimat® based inhaler is not currently commercially available. CONCLUSIONS: Administration of budesonide with the Respimat® based inhaler provided dose-dependent relief of airway obstruction in horses with severe asthma, but also a suppression of serum cortisol.
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Antiinflamatorios/uso terapéutico , Asma/veterinaria , Budesonida/uso terapéutico , Enfermedades de los Caballos/tratamiento farmacológico , Animales , Antiinflamatorios/administración & dosificación , Asma/tratamiento farmacológico , Budesonida/administración & dosificación , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Caballos , Distribución AleatoriaRESUMEN
Temple syndrome (TS14, #616222) is a rare imprinting disorder characterised by phenotypic features including pre- and postnatal growth retardation, muscular hypotonia and feeding difficulties in infancy, early puberty and short stature with small hands and feet and often truncal obesity. It is caused by maternal uniparental disomies, paternal deletions and primary imprinting defects that affect the chromosomal region 14q32 and lead to a disturbed expression of imprinted genes in this region. Here, we present detailed clinical data of 8 patients with Temple syndrome, 4 with an imprinting defect, 2 with an imprinting defect in a mosaic state as well as 1 complete and 1 segmental maternal uniparental disomy of chromosome 14.
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Anomalías Múltiples/genética , Anomalías Múltiples/patología , Cromosomas Humanos Par 14/genética , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Polimorfismo de Nucleótido Simple/genética , Síndrome , Disomía Uniparental/genéticaRESUMEN
The ubiquitin pathway is an enzymatic cascade including activating E1, conjugating E2, and ligating E3 enzymes, which governs protein degradation and sorting. It is crucial for many physiological processes. Compromised function of members of the ubiquitin pathway leads to a wide range of human diseases, such as cancer, neurodegenerative diseases, and neurodevelopmental disorders. Mutations in the thyroid hormone receptor interactor 12 (TRIP12) gene (OMIM 604506), which encodes an E3 ligase in the ubiquitin pathway, have been associated with autism spectrum disorder (ASD). In addition to autistic features, TRIP12 mutation carriers showed intellectual disability (ID). More recently, TRIP12 was postulated as a novel candidate gene for intellectual disability in a meta-analysis of published ID cohorts. However, detailed clinical information characterizing the phenotype of these individuals was not provided. In this study, we present seven novel individuals with private TRIP12 mutations including two splice site mutations, one nonsense mutation, three missense mutations, and one translocation case with a breakpoint in intron 1 of the TRIP12 gene and clinically review four previously published cases. The TRIP12 mutation-positive individuals presented with mild to moderate ID (10/11) or learning disability [intelligence quotient (IQ) 76 in one individual], ASD (8/11) and some of them with unspecific craniofacial dysmorphism and other anomalies. In this study, we provide detailed clinical information of 11 TRIP12 mutation-positive individuals and thereby expand the clinical spectrum of the TRIP12 gene in non-syndromic intellectual disability with or without ASD.
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Trastorno Autístico/genética , Proteínas Portadoras/genética , Variación Genética , Discapacidad Intelectual/genética , Ubiquitina-Proteína Ligasas/genética , Adolescente , Trastorno Autístico/diagnóstico , Secuencia de Bases , Niño , Estudios de Cohortes , Femenino , Genoma Humano , Humanos , Discapacidad Intelectual/diagnóstico , Cariotipificación , Masculino , Mutación Missense , Fenotipo , Proteolisis , Empalme del ARN , Análisis de Secuencia de ADNRESUMEN
The spin of light in subwavelength-diameter waveguides can be orthogonal to the propagation direction of the photons because of the strong transverse confinement. This transverse spin changes sign when the direction of propagation is reversed. Using this effect, we demonstrate the directional spontaneous emission of photons by laser-trapped caesium atoms into an optical nanofibre and control their propagation direction by the excited state of the atomic emitters. In particular, we tune the spontaneous emission into the counter-propagating guided modes from symmetric to strongly asymmetric, where more than % of the optical power is launched into one or the other direction. We expect our results to have important implications for research in quantum nanophotonics and for implementations of integrated optical signal processing in the quantum regime.
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REASONS FOR PERFORMING STUDY: Bronchospasm results in airway obstruction in horses with heaves. Atropine is the most potent bronchodilator drug currently available for horses, but is associated with side effects that limit its use. Like atropine, N-butylscopolammonium bromide (NBB) is an anticholinergic agent with bronchodilatory properties. OBJECTIVES: To compare the bronchodilating effects and side effects of atropine and NBB in horses with heaves. STUDY DESIGN: Cross-over experiment using horses with heaves. METHODS: Eight horses with heaves were administered atropine and NBB, using a cross-over design. Heart rate, pupillary dilatation, transrectal palpation, lung mechanics (maximal changes in transpulmonary pressure, pulmonary resistance and elastance) and arterial blood gases were assessed before and 10 and 30 min after drug administration. RESULTS: One horse treated with atropine developed colic. Significant pupillary dilatation was observed only with atropine. Tachycardia developed in all horses, but was more marked with atropine. Lung function improved with both drugs, but elastance values had returned to baseline at 30 min with NBB. There was no improvement in arterial hypoxaemia with either drug. CONCLUSIONS: The study indicated that the bronchodilatory properties of NBB were not statistically different from those of atropine, but were of shorter duration. N-butylscopolammonium bromide was associated with fewer systemic side effects, and therefore NBB should be preferred over atropine when assessing the reversibility of airway obstruction in horses.
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Atropina/efectos adversos , Broncoconstricción/efectos de los fármacos , Bromuro de Butilescopolamonio/efectos adversos , Enfermedades de los Caballos/tratamiento farmacológico , Enfermedades Pulmonares Obstructivas/veterinaria , Parasimpatolíticos/efectos adversos , Animales , Atropina/uso terapéutico , Bromuro de Butilescopolamonio/uso terapéutico , Estudios Cruzados , Femenino , Caballos , Enfermedades Pulmonares Obstructivas/tratamiento farmacológico , Masculino , Parasimpatolíticos/uso terapéuticoRESUMEN
Twenty-nine as yet unreported ring chromosomes were characterized in detail by cytogenetic and molecular techniques. For FISH (fluorescence in situ hybridization) previously published high resolution approaches such as multicolor banding (MCB), subcentromere-specific multi-color-FISH (cenM-FISH) and two to three-color-FISH applying locus-specific probes were used. Overall, ring chromosome derived from chromosomes 4 (one case), 10 (one case), 13 (five cases), 14, (three cases), 18 (two cases), 21 (eight cases), 22 (three cases), X (five cases) and Y (one case) were studied. Eight cases were detected prenatally, eight due developmental delay and dysmorphic signs, and nine in connection with infertility and/or Turner syndrome. In general, this report together with data from the literature, supports the idea that ring chromosome patients fall into two groups: group one with (severe) clinical signs and symptoms due to the ring chromosome and group two with no obvious clinical problems apart from infertility.
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Nager syndrome (MIM #154400) is the best-known preaxial acrofacial dysostosis, mainly characterized by craniofacial and preaxial limb anomalies. The craniofacial abnormalities mainly consist of downslanting palpebral fissures, malar hypoplasia, micrognathia, external ear anomalies, and cleft palate. The preaxial limb defects are characterized by radial and thumb hypoplasia or aplasia, duplication of thumbs and proximal radioulnar synostosis. Haploinsufficiency of SF3B4 (MIM *605593), which encodes SAP49, a component of the pre-mRNA spliceosomal complex, has recently been identified as the underlying cause of Nager syndrome. In our study, we performed exome sequencing in two and Sanger sequencing of SF3B4 in further ten previously unreported patients with the clinical diagnosis of Nager syndrome, including one familial case. We identified heterozygous SF3B4 mutations in seven out of twelve patients. Four of the seven mutations were shown to be de novo; in three individuals, DNA of both parents was not available. No familial mutations were discovered. Three mutations were nonsense, three were frameshift mutations and one T > C transition destroyed the translation start signal. In three of four SF3B4 negative families, EFTUD2 was analyzed, but no pathogenic variants were identified. Our results indicate that the SF3B4 gene is mutated in about half of the patients with the clinical diagnosis of Nager syndrome and further support genetic heterogeneity for this condition.
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Exoma/genética , Disostosis Mandibulofacial/genética , Mutación/genética , Precursores del ARN/genética , Proteínas de Unión al ARN/genética , Empalmosomas/genética , Adolescente , Adulto , Preescolar , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Masculino , Disostosis Mandibulofacial/diagnóstico , Factores de Empalme de ARNRESUMEN
BACKGROUND: Patients with attention deficit-hyperactivity disorder (ADHD) exhibit difficulties in multiple attentional functions. Although high heritability rates suggest a strong genetic impact, aetiological pathways from genes and environmental factors to the ADHD phenotype are not well understood. Tracking the time course of deviant task processing using event-related electrophysiological brain activity should characterize the impact of familiality on the sequence of cognitive functions from preparation to response control in ADHD. Method Preparation and response control were assessed using behavioural and electrophysiological parameters of two versions of a cued continuous performance test with varying attentional load in boys with ADHD combined type (n = 97), their non-affected siblings (n = 27) and control children without a family history of ADHD (n = 43). RESULTS: Children with ADHD and non-affected siblings showed more variable performance and made more omission errors than controls. The preparatory Cue-P3 and contingent negative variation (CNV) following cues were reduced in both ADHD children and their non-affected siblings compared with controls. The NoGo-P3 was diminished in ADHD compared with controls whilst non-affected siblings were located intermediate but did not differ from both other groups. No clear familiality effects were found for the Go-P3. Better task performance was further associated with higher CNV and P3 amplitudes. CONCLUSIONS: Impairments in performance and electrophysiological parameters reflecting preparatory processes and to some extend also for inhibitory response control, especially under high attentional load, appeared to be familially driven in ADHD and may thus constitute functionally relevant endophenotypes for the disorder.
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Trastorno por Déficit de Atención con Hiperactividad/genética , Potenciales Relacionados con Evento P300/genética , Hermanos , Adolescente , Atención/fisiología , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Encéfalo/fisiopatología , Estudios de Casos y Controles , Niño , Variación Contingente Negativa/genética , Variación Contingente Negativa/fisiología , Señales (Psicología) , Electroencefalografía , Potenciales Relacionados con Evento P300/fisiología , Potenciales Evocados/genética , Potenciales Evocados/fisiología , Humanos , Masculino , Tiempo de ReacciónRESUMEN
Primary microcephaly MCPH1 is an extremely rare autosomal recessive disorder associated with congenital microcephaly, mental retardation and a distinctive cellular phenotype of misregulated chromosome condensation. The MCPH1 gene encodes an 835-amino acid protein, microcephalin, which contains 1 N-terminal and 2 C-terminal BRCT (BRCA1 C-terminus) domains. BRCT domains are predominantly found in proteins involved in cell cycle control and DNA repair. Here we describe 1 novel and 1 previously reported MCPH1 missense mutation, p.Trp75Arg and p.Ser72Leu, respectively, in the N-terminal BRCT domain of microcephalin associated with severe congenital microcephaly. Both residues are entirely conserved in the MCPH1 orthologs of all vertebrate species and Drosophila. Proliferating lymphocytes of the patients with p.Trp75Arg and p.Ser72Leu show the unique cellular MCPH1 phenotype of misregulated chromosome condensation, indicating that these missense alterations disrupt the function of the N-terminal BRCT domain of the protein. Interestingly, both residues are strictly conserved in BRCT domains of BRCA1. ClustalW alignments show that the residue p.Ser72 of microcephalin corresponds to p.Ser1715 of the N-terminal BRCT domain of BRCA1, while the microcephalin residue p.Trp75 is analogous to p.Trp1718 in the N-terminal BRCT and to p.Trp1837 in C-terminal BRCT domains of BRCA1. Missense alterations for all 3 corresponding BRCA1 residues were described and are predicted to be deleterious resulting in the destabilization of the BRCA1 protein. Our data on the 2 MCPH1 missense alterations provide further evidence for the functional significance of these residues in BRCT domains.
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Microcephalic osteodysplastic primordial dwarfism type I (MOPD I) is a rare autosomal recessive developmental disorder characterized by extreme intrauterine growth retardation, severe microcephaly, central nervous system abnormalities, dysmorphic facial features, skin abnormalities, skeletal changes, limb deformations, and early death. Recently, mutations in the RNU4ATAC gene, which encodes U4atac, a small nuclear RNA that is a crucial component of the minor spliceosome, were found to cause MOPD I. MOPD I is the first disease known to be associated with a defect in small nuclear RNAs. We describe here the clinical and molecular data for 17 cases of MOPD I, including 15 previously unreported cases, all carrying biallelic mutations in the RNU4ATAC gene.
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Alelos , Enanismo/genética , Retardo del Crecimiento Fetal/genética , Microcefalia/genética , Mutación , Osteocondrodisplasias/genética , ARN Nuclear Pequeño/genética , Encéfalo/patología , Enanismo/diagnóstico , Facies , Femenino , Retardo del Crecimiento Fetal/diagnóstico , Humanos , Lactante , Esperanza de Vida , Imagen por Resonancia Magnética , Masculino , Microcefalia/diagnóstico , Osteocondrodisplasias/diagnóstico , FenotipoRESUMEN
We report on the pre- and postnatal cytogenetic, molecular genetic and clinical findings in monochorionic-diamniotic twins discordant for trisomy 18. Structural anomalies were identified in one of the twins on prenatal ultrasound examination at 20 weeks' gestation and sampling of amniotic fluid from both sacs was performed for karyotyping. This revealed trisomy 18 in the twin with abnormalities and a normal karyotype in the other twin. Elective Cesarean section was performed at 31 + 5 weeks and the aneuploid twin died shortly after delivery. The surviving twin showed low-grade mosaicism for trisomy 18 on postnatal analysis but has shown normal development. For prenatal diagnosis in monochorionic-diamniotic twin pregnancy the sampling of both amniotic sacs is recommended, especially if one twin has structural anomalies on ultrasound scan.
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Amniocentesis/métodos , Cromosomas Humanos Par 18/genética , Enfermedades en Gemelos/genética , Mosaicismo , Cesárea , Enfermedades en Gemelos/diagnóstico , Enfermedades en Gemelos/embriología , Femenino , Humanos , Recién Nacido , Cariotipificación , Masculino , Mosaicismo/embriología , Embarazo , Resultado del Embarazo , Diagnóstico Prenatal , Gemelos Monocigóticos/genéticaRESUMEN
BACKGROUND: Twin and sibling studies have identified specific cognitive phenotypes that may mediate the association between genes and the clinical symptoms of attention deficit hyperactivity disorder (ADHD). ADHD is also associated with lower IQ scores. We aimed to investigate whether the familial association between measures of cognitive performance and the clinical diagnosis of ADHD is mediated through shared familial influences with IQ. METHOD: Multivariate familial models were run on data from 1265 individuals aged 6-18 years, comprising 920 participants from ADHD sibling pairs and 345 control participants. Cognitive assessments included a four-choice reaction time (RT) task, a go/no-go task, a choice-delay task and an IQ assessment. The analyses focused on the cognitive variables of mean RT (MRT), RT variability (RTV), commission errors (CE), omission errors (OE) and choice impulsivity (CI). RESULTS: Significant familial association (rF) was confirmed between cognitive performance and both ADHD (rF=0.41-0.71) and IQ (rF=-0.25 to -0.49). The association between ADHD and cognitive performance was largely independent (80-87%) of any contribution from etiological factors shared with IQ. The exception was for CI, where 49% of the overlap could be accounted for by the familial variance underlying IQ. CONCLUSIONS: The aetiological factors underlying lower IQ in ADHD seem to be distinct from those between ADHD and RT/error measures. This suggests that lower IQ does not account for the key cognitive impairments observed in ADHD. The results have implications for molecular genetic studies designed to identify genes involved in ADHD.
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Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno por Déficit de Atención con Hiperactividad/psicología , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/psicología , Inteligencia/genética , Pruebas Neuropsicológicas/estadística & datos numéricos , Fenotipo , Adolescente , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Niño , Conducta de Elección , Trastornos del Conocimiento/diagnóstico , Europa (Continente) , Femenino , Humanos , Inhibición Psicológica , Control Interno-Externo , Masculino , Análisis Multivariante , Determinación de la Personalidad/estadística & datos numéricos , Psicometría , Tiempo de Reacción/genética , RecompensaRESUMEN
Hallermann-Streiff syndrome (HSS) is a rare inherited disorder characterized by malformations of the cranium and facial bones, congenital cataracts, microphthalmia, skin atrophy, hypotrichosis, proportionate short stature, teeth abnormalities, and a typical facial appearance with prominent forehead, small pointed nose, and micrognathia. The genetic cause of this developmental disorder is presently unknown. Here we describe 8 new patients with a phenotype of HSS. Individuals with HSS present with clinical features overlapping with some progeroid syndromes that belong to the laminopathies, such as Hutchinson-Gilford progeria syndrome (HGPS) and mandibuloacral dysplasia (MAD). HGPS is caused by de novo point mutations in the LMNA gene, coding for the nuclear lamina proteins lamin A and C. MAD with type A and B lipodystrophy are recessive disorders resulting from mutations in LMNA and ZMPSTE24, respectively. ZMPSTE24 in addition to ICMT encode proteins involved in posttranslational processing of lamin A. We hypothesized that HSS is an allelic disorder to HGPS and MAD. As the nuclear shape is often irregular in patients with LMNA mutations, we first analyzed the nuclear morphology in skin fibroblasts of patients with HSS, but could not identify any abnormality. Sequencing of the genes LMNA, ZMPSTE24 and ICMT in the 8 patients with HSS revealed the heterozygous missense mutation c.1930C>T (p.R644C) in LMNA in 1 female. Extreme phenotypic diversity and low penetrance have been associated with the p.R644C mutation. In ZMPSTE24 and ICMT, no pathogenic sequence change was detected in patients with HSS. Together, we found no evidence that HSS is another laminopathy.
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BACKGROUND: Out-of-hospital (OOH) pediatric emergencies have a relatively low prevalence. In Germany the vast majority of cases are attended by non-specialized emergency physicians (EPs) for whom these are not routine procedures. This may lead to insecurity and fear. However, it is unknown how EPs perceive and assess pediatric emergencies and how they could be better prepared for them. METHODS: All active EPs (n=50) of the Department of Anaesthesiology, Emergency and Intensive Care Medicine at the University Medical Centre of Göttingen were presented with a structured questionnaire in order to evaluate their perception and assessment of OOH pediatric emergencies. RESULTS: The 43 participating EPs made highly detailed statements on the expected characteristics of OOH pediatric emergencies. Their confidence level grew with the children's age (p<0.03) and with their own experience (p<0.01). The EPs felt particular deficits in the fields of cardiopulmonary resuscitation (n=18) and trauma management (n=8). The preferred educational strategies included simulator-based training (n=24) as well as more exposure to pediatric intensive care and pediatric anesthesia (n=12). CONCLUSIONS: Despite their own limited experience EPs can realistically assess the incidence and severity of pediatric emergencies. They felt the greatest deficits were in the care of infrequent but life-threatening emergencies. Three educational groups can be differentiated: knowledge and skills to be gained with children in hospital, clinical experience from adult care also applicable in children and rare diagnoses and interventions to be trained with manikins or simulators.
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Servicios Médicos de Urgencia , Médicos , Adulto , Actitud del Personal de Salud , Reanimación Cardiopulmonar , Niño , Competencia Clínica , Recolección de Datos , Auxiliares de Urgencia , Medicina de Emergencia , Femenino , Alemania , Conocimientos, Actitudes y Práctica en Salud , Humanos , Masculino , Encuestas y Cuestionarios , Heridas y Lesiones/terapiaRESUMEN
BACKGROUND: Detecting genetic factors involved in attention deficit hyperactivity disorder (ADHD) is complicated because of their small effect sizes and complex interactions. The endophenotype approach eases this by coming closer to the relevant genes. Different aspects of temporal information processing are known to be affected in ADHD. Thus, some of these aspects could represent candidate endophenotypes for ADHD. METHOD: Fifty-four sib-pairs with at least one child with ADHD and 40 control children aged 6-18 years were recruited and asked to perform two duration discrimination tasks, one with a base duration of 50 ms on automatic timing and one with a base duration of 1000 ms on cognitively controlled timing. RESULTS: Whereas children with ADHD, but not their unaffected siblings, were impaired in discrimination of longer intervals, both groups were impaired in discriminating brief intervals. Furthermore, a significant within-family correlation was found for discrimination of brief intervals. Task performances of subjects of the control group correlated with individual levels of hyperactivity/impulsivity for discrimination of brief intervals, but not of longer intervals. CONCLUSIONS: Cognitively controlled and also automatic processes of temporal information processing are impaired in children with ADHD. Discrimination of longer intervals appears as a typical 'disease marker' whereas discrimination of brief intervals shows up as a 'vulnerability marker'. Discrimination of brief intervals was found to be familial and linked to levels of hyperactivity/impulsivity. Taken together, discrimination of brief intervals represents a candidate endophenotype of ADHD.