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INTRODUCTION: Many efforts have been made to stimulate clinical trials (CTs) in pediatrics but most of the drugs are still authorized only in adults and used off-label in the pediatric population. AIM: To assess how widespread is the off-label prescription in Italy and to identify areas of unmet medical need by applying a model for the systematic collection and analysis of data. METHODS: A study was performed using 2015 data from the Italian Medicines Utilization Monitoring Centre Health Database (OsMed). A study sample of 3,726,583 pediatric patients, was considered. Cardiovascular drugs were selected for this study. Assessment of the off-label use, the analysis of the pharmacovigilance signals, a bibliographic research and the analysis of ongoing CTs were carried out. RESULTS: In 2015, 8,544 pediatric patients received treatment with a cardiovascular drug. Angiotensin converting enzyme inhibitors (ACE-I) followed by beta blockers agents are the most prescribed molecules. Eight molecules were selected and an in-depth analysis conducted. The PhV network showed only one record of adverse reaction as off-label in 2015. The results show several therapeutic areas of use in pediatrics. CONCLUSION: Off-label in pediatrics is largely widespread in Europe and US and our results show it is also present in Italy. Molecules selected are used off-label for therapeutic areas such as oncologic, hematological and rare diseases. Results of pharmacovigilance suggests underreporting. The analysis carried out in this study could be an open track for a systematic monitoring activity and of interest for prescribers, pediatricians and other healthcare professionals during the clinical practice.
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Uso Fuera de lo Indicado , Pediatría , Adulto , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Niño , Atención a la Salud , Humanos , Pautas de la Práctica en Medicina , PrescripcionesRESUMEN
Down syndrome is the most common chromosomal condition, and average life expectancy has increased substantially, from 25 years in 1983 to 60 years in 2020. Despite the unique clinical comorbidities among adults with Down syndrome, there are no clinical guidelines for the care of these patients. To develop an evidence-based clinical practice guideline for adults with Down syndrome. The Global Down Syndrome Foundation Medical Care Guidelines for Adults with Down Syndrome Workgroup (n = 13) developed 10 Population/Intervention/ Comparison/Outcome (PICO) questions for adults with Down syndrome addressing multiple clinical areas including mental health (2 questions), dementia, screening or treatment of diabetes, cardiovascular disease, obesity, osteoporosis, atlantoaxial instability, thyroid disease, and celiac disease. These questions guided the literature search in MEDLINE, EMBASE, PubMed, PsychINFO, Cochrane Library, and the TRIP Database, searched from January 1, 2000, to February 26, 2018, with an updated search through August 6, 2020. Using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology and the Evidence-to-Decision framework, in January 2019, the 13-member Workgroup and 16 additional clinical and scientific experts, nurses, patient representatives, and a methodologist developed clinical recommendations. A statement of good practice was made when there was a high level of certainty that the recommendation would do more good than harm, but there was little direct evidence. From 11â¯295 literature citations associated with 10 PICO questions, 20 relevant studies were identified. An updated search identified 2 additional studies, for a total of 22 included studies (3 systematic reviews, 19 primary studies), which were reviewed and synthesized. Based on this analysis, 14 recommendations and 4 statements of good practice were developed. Overall, the evidence base was limited. Only 1 strong recommendation was formulated: screening for Alzheimer-type dementia starting at age 40 years. Four recommendations (managing risk factors for cardiovascular disease and stroke prevention, screening for obesity, and evaluation for secondary causes of osteoporosis) agreed with existing guidance for individuals without Down syndrome. Two recommendations for diabetes screening recommend earlier initiation of screening and at shorter intervals given the high prevalence and earlier onset in adults with Down syndrome. These evidence-based clinical guidelines provide recommendations to support primary care of adults with Down syndrome. The lack of high-quality evidence limits the strength of the recommendations and highlights the need for additional research.
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Humanos , Adulto , Atención Primaria de Salud/organización & administración , Manejo de Atención al Paciente/organización & administración , Síndrome de DownRESUMEN
Otofaciocervical syndrome (OFCS) is a rare disorder characterized by facial anomalies, cup-shaped low-set ears, preauricular fistulas, hearing loss, branchial defects, skeletal anomalies, and mild intellectual disability. Autosomal dominant cases are caused by deletions or point mutations of EYA1. A single family with an autosomal recessive form of OFCS and a homozygous missense mutation in PAX1 gene has been described. We report whole exome sequencing of 4 members of a consanguineous family in which 2 children, showing features of OFCS, expired from severe combined immunodeficiency (SCID). To date, the co-occurrence of OFCS and SCID has never been reported. We found a nonsense homozygous mutation in PAX1 gene in the 2 affected children. In mice, Pax1 is required for the formation of specific skeletal structures as well as for the development of a fully functional thymus. The mouse model strongly supports the hypothesis that PAX1 depletion in our patients caused thymus aplasia responsible for SCID. This report provides evidence that bi-allelic null PAX1 mutations may lead to a multi-system autosomal recessive disorders, where SCID might represent the main feature.
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Síndrome Branquio Oto Renal/genética , Discapacidad Intelectual/genética , Mutación , Factores de Transcripción Paired Box/genética , Inmunodeficiencia Combinada Grave/genética , Animales , Secuencia de Bases , Síndrome Branquio Oto Renal/complicaciones , Síndrome Branquio Oto Renal/inmunología , Síndrome Branquio Oto Renal/patología , Niño , Consanguinidad , Modelos Animales de Enfermedad , Exoma , Familia , Femenino , Expresión Génica , Genes Recesivos , Humanos , Lactante , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/inmunología , Discapacidad Intelectual/patología , Masculino , Ratones , Marruecos , Factores de Transcripción Paired Box/inmunología , Linaje , Inmunodeficiencia Combinada Grave/complicaciones , Inmunodeficiencia Combinada Grave/inmunología , Inmunodeficiencia Combinada Grave/patología , Timo/anomalías , Timo/inmunología , Timo/metabolismoRESUMEN
PURPOSE: To identify potential antigenic targets for Porphyromonas gingivalis vaccine development. MATERIALS AND METHODS: In the present study, we analyzed the Porphyromonas gingivalis, fimA type II primary amino acid sequence and characterized the similarity to the human proteome at the pentapeptide level. RESULTS: We found that exact peptide-peptide profiling of the fimbrial antigen versus the human proteome shows that only 19 out of 344 fimA type II pentapeptides are uniquely owned by the bacterial protein. CONCLUSIONS: The concept that protein immunogenicity is allocated in rare peptide sequences and the search the Porphyromonas gingivalis fimA type II sequence for peptides unique to the bacterial protein and absent in the human host, might be used in new therapeutical approaches as a significant adjunct to current periodontal therapies.
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BACKGROUND: Executive function (EF) deficits are a recognised component of the cognitive phenotype of youth with Down Syndrome (DS). Recent research in this area emphasises the use of behaviour ratings, such as the Behavior Rating Inventory of Executive Functions-Preschool Version (BRIEF-P), to capture the real-world applications of executive functions. To account for the intellectual functioning of youth with DS, this measure is used out of age range; however, its psychometric properties when used in this fashion are unknown. The goals of this study are to evaluate psychometric characteristics of the BRIEF-P among youth with DS and to examine the pattern of EF strengths/weaknesses in children with DS and co-occurring psychiatric conditions. METHOD: A total of 188 clinically referred youth with DS, ages 3-13 were rated by their caregivers using the BRIEF-P. These youth were evaluated by a clinician with expertise in DS and were characterised as having no co-occurring behavioural disorder (Typical DS group), co-occurring Autism Spectrum Disorder (DS + ASD) or co-occurring Disruptive Behaviour Disorder (DS + DBD). RESULTS: An exploratory factor analysis of item-level BRIEF-P data from clinically referred youth with DS supported the theoretically derived three-factor structure originally proposed for the BRIEF-P (Emergent Metacognition, Flexibility and Inhibitory Self-Control); however, the item composition of each factor varied somewhat in comparison to the original structure of the measure. Group comparisons indicate that, while youth with typical DS evidence fewer executive function difficulties across all domains, youth with DS + ASD show the greatest weaknesses in Emergent Metacognition, and youth with DS + DBD show significant difficulties in both Emergent Metacognition and Inhibition. CONCLUSIONS: These findings offer preliminary support for use of the BRIEF-P with clinically referred youth with Down Syndrome. Some scoring modifications may be necessary if the theoretically derived index scores are to be used with this population. BRIEF-P scores may offer an empirical basis for differentiating DS youth with varying behavioural profiles.
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Déficit de la Atención y Trastornos de Conducta Disruptiva/diagnóstico , Trastorno del Espectro Autista/diagnóstico , Síndrome de Down/diagnóstico , Función Ejecutiva/fisiología , Escalas de Valoración Psiquiátrica/normas , Psicometría/instrumentación , Adolescente , Déficit de la Atención y Trastornos de Conducta Disruptiva/epidemiología , Trastorno del Espectro Autista/epidemiología , Niño , Preescolar , Comorbilidad , Síndrome de Down/epidemiología , Humanos , MasculinoRESUMEN
UNLABELLED: The infratentorial supracerebellar approach is most widely used for pineal tumors. We report our own experience and technical considerations using this approach. MATERIAL: From 1982 to 2010, we operated on 232 patients with pineal region tumors. Of these, 201 patients were operated on using a suboccipital transtentorial approach while 31 patients were operated on using a supracerebellar infratentorial approach. The median age of the patients ranged between 8 months and 74 years. There were 19 children and 12 adults. All patients presented with elevated intracranial pressure. There were 6 pinealocytomas, 3 papillary tumors, 7 germinomas, 2 benign teratomas, 4 pineal cysts and 9 gliomas. Adjuvant post-surgical therapy consisted of chemo-radiotherapy in 4 patients, 2 with germinomas and 2 with a grade II/III gliomas. Radiotherapy was performed in the other twelve patients (5 germinomas and 7 gliomas). RESULTS AND COMPLICATIONS: All patients are still alive at a median follow-up of eight years. Twelve of the 19 children are attending normal school classes for their age, 5 are attending classes for special needs children and 2 are not yet of school age at the last follow-up. Seven of the 12 adults are working normally, three are working part-time at the same job and two have retired but are able to lead a normal life. Postoperative complications included symptomatic diffuse cerebellar edema (one patient) completely resolved with a mild residual cerebellar syndrome; double vision secondary to IV nerve palsy (one patient); transitory Parinaud's syndrome (2 patients) and cerebellar gait (2 patients) nearly completely recovered at respectively six and twelve months. CONCLUSION: The supracerebellar infratentorial approach seems to be a safe and effective choice in the treatment of pineal region tumors. In our experience, it permits complete tumor resections with acceptable morbidity and all neurosurgeons should master this approach in order to adapt their surgical choice according to size, extent and the relationship of the lesion with the surrounding anatomical structures.
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Neoplasias Encefálicas/cirugía , Cerebelo/cirugía , Glioma/cirugía , Glándula Pineal/patología , Pinealoma/cirugía , Adolescente , Adulto , Anciano , Neoplasias Encefálicas/patología , Niño , Preescolar , Terapia Combinada/métodos , Femenino , Glioma/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Procedimientos Neuroquirúrgicos , Pinealoma/patología , Resultado del Tratamiento , Adulto JovenRESUMEN
Down syndrome (DS) is caused by an extra copy of all or part of the long arm of human chromosome 21 (HSA21). While the complete phenotype is both complex, involving most organs and organ systems, and variable in severity among individuals, intellectual disability (ID) is seen in all people with DS and may have the most significant impact on quality of life. Because the worldwide incidence of DS remains at approximately 1 in 1,000 live births, DS is the most common genetic cause of ID. In recent years, there have been important advances in our understanding of the functions of genes encoded by HSA21 and in the number and utility of in vitro and in vivo systems for modeling DS. Of particular importance, several pharmacological treatments have been shown to rescue learning and memory deficits in one mouse model of DS, the Ts65Dn. Because adult mice were used in the majority of these experiments, there is considerable interest in extending the studies to human clinical trials, and a number of trials have been completed, are in progress or are being planned. A recent conference brought together researchers with a diverse array of expertise and interests to discuss (1) the functions of HSA21 genes with relevance to ID in DS, (2) the utility of model systems including Caenorhabditis elegans, zebrafish and mouse, as well as human neural stem cells and induced pluripotent stems cells, for studies relevant to ID in DS, (3) outcome measures used in pharmacological treatment of mouse models of DS and (4) outcome measures suitable for clinical trials for cognition in adults and children with DS.
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Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/genética , Discapacidad Intelectual/tratamiento farmacológico , Discapacidad Intelectual/genética , Animales , Cromosomas Humanos Par 21 , Cognición/efectos de los fármacos , Modelos Animales de Enfermedad , Síndrome de Down/tratamiento farmacológico , Síndrome de Down/genética , Humanos , Ratones , Células-Madre Neurales/efectos de los fármacosRESUMEN
PURPOSE: Epidural blood patch (EBP) represents one of the best nonsurgical treatment for intracranial hypotension syndrome. Orthostatic headache caused by reduced intracranial cerebrospinal fluid (CSF) pressure, like in "spontaneous" intracranial hypotension or as consequence of lumbar puncture or anesthesiological procedure, can be managed with the injection of autologous blood on the epidural space with a successful rate of 89%, increased to 97% after a second application. MATERIALS AND METHODS: This 9-year-old girl was admitted to our department because of a suboccipital pseudomeningocele. She was previously operated on for a Chiari type I malformation by suboccipital craniectomy, C1 laminectomy and duraplasty. At the admission, she complained for nucal pain. Brain MRI showed a large suboccipital fluid collection that persisted even after the revision of the duraplasty and the placement of an external lumbar drainage. The child underwent a first injection of a mixture of blood (10 ml) and fibrin glue (10 ml) within the subcutaneous space after needle-aspiration of the collection. The same treatment was repeated 3 weeks later. RESULTS: The procedures were well tolerated and no local or systemic complications occurred. The fluid collection was significantly reduced after the first injection and it was completely effaced following the second one. Such a result remained stable after 3 months, as demonstrated by MRI. No recurrence of the pseudomeningocele was detected at the last clinical control (8-month follow-up). CONCLUSION: Subcutaneous blood patch could represent a safe and effective option for the treatment of CSF fistula, especially in case of failure of the traditional management.
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Parche de Sangre Epidural , Craniectomía Descompresiva/efectos adversos , Fístula/cirugía , Enfermedad Iatrogénica , Malformación de Arnold-Chiari/cirugía , Niño , Descompresión Quirúrgica/efectos adversos , Femenino , Fístula/etiología , HumanosRESUMEN
BACKGROUND: The diagnostic validity of autism spectrum disorder (ASD) based on Diagnostic and Statistical Manual of Mental Disorders (DSM) has been challenged in Down syndrome (DS), because of the high prevalence of cognitive impairments in this population. Therefore, we attempted to validate DSM-based diagnoses via an unbiased categorisation of participants with a DSM-independent behavioural instrument. METHODS: Based on scores on the Aberrant Behaviour Checklist - Community, we performed sequential factor (four DS-relevant factors: Autism-Like Behaviour, Disruptive Behaviour, Hyperactivity, Self-Injury) and cluster analyses on a 293-participant paediatric DS clinic cohort. The four resulting clusters were compared with DSM-delineated groups: DS + ASD, DS + None (no DSM diagnosis), DS + DBD (disruptive behaviour disorder) and DS + SMD (stereotypic movement disorder), the latter two as comparison groups. RESULTS: Two clusters were identified with DS + ASD: Cluster 1 (35.1%) with higher disruptive behaviour and Cluster 4 (48.2%) with more severe autistic behaviour and higher percentage of late onset ASD. The majority of participants in DS + None (71.9%) and DS + DBD (87.5%) were classified into Cluster 2 and 3, respectively, while participants in DS + SMD were relatively evenly distributed throughout the four clusters. CONCLUSIONS: Our unbiased, DSM-independent analyses, using a rating scale specifically designed for individuals with severe intellectual disability, demonstrated that DSM-based criteria of ASD are applicable to DS individuals despite their cognitive impairments. Two DS + ASD clusters were identified and supported the existence of at least two subtypes of ASD in DS, which deserve further characterisation. Despite the prominence of stereotypic behaviour in DS, the SMD diagnosis was not identified by cluster analysis, suggesting that high-level stereotypy is distributed throughout DS. Further supporting DSM diagnoses, typically behaving DS participants were easily distinguished as a group from those with maladaptive behaviours.
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Trastornos de la Conducta Infantil/diagnóstico , Trastornos de la Conducta Infantil/epidemiología , Trastornos Generalizados del Desarrollo Infantil/diagnóstico , Trastornos Generalizados del Desarrollo Infantil/epidemiología , Síndrome de Down/diagnóstico , Síndrome de Down/epidemiología , Adolescente , Lista de Verificación/estadística & datos numéricos , Niño , Preescolar , Análisis por Conglomerados , Comorbilidad , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Prevalencia , Agitación Psicomotora/diagnóstico , Agitación Psicomotora/epidemiología , Conducta Autodestructiva/diagnóstico , Conducta Autodestructiva/epidemiología , Trastorno de Movimiento Estereotipado/diagnóstico , Trastorno de Movimiento Estereotipado/epidemiología , Adulto JovenRESUMEN
We describe immune-proteome structures using libraries of protein fragments that define a structural immunological alphabet. We propose and validate such an alphabet as i) composed of letters of five consecutive amino acids, pentapeptide units being sufficient minimal antigenic determinants in a protein, and ii) characterized by low-similarity to human proteins, so representing structures unknown to the host and potentially able to evoke an immune response. In this context, we have thoroughly sifted through the entire human proteome searching for non-redundant protein motifs. Here, for the first time, a complete sequence redundancy dissection of the human proteome has been conducted. The non-redundant peptide islands in the human proteome have been quantified and catalogued according to the amino acid length. The library of uniquely occurring n-peptide sequences that was obtained is characterized by a logarithmic decrease of the number of non-redundant peptides as a function of the peptide length. This library represents a highly specific catalogue of molecular protein signatures, the possible use of which in cancer/autoimmunity research is discussed, with a major focus on non-redundant dodecamer sequences.
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Antígenos/genética , Péptidos/genética , Proteoma/genética , Análisis de Secuencia de Proteína , Secuencias de Aminoácidos/genética , Secuencias de Aminoácidos/inmunología , Antígenos/inmunología , Humanos , Péptidos/inmunología , Proteoma/inmunología , Análisis de Secuencia de Proteína/métodosRESUMEN
The objective of this study was to test whether postnatal chronic inflammation resulted in altered reactivity to pain later in life when reexposed to the same inflammatory agent and whether this alteration correlated with brain-region-specific patterns of N-methyl-D-aspartate (NMDA) receptor subtype gene expression. Neonatal mouse pups received a single injection of complete Freund's adjuvant (CFA) or saline into the left hind paw on postnatal day 1 or 14. At 12 weeks of age, both neonatal CFA- and saline-treated animals received a unilateral injection of CFA in the left hind paw. Adult behavioral responsiveness of the left paw to a radiant heat source was determined in mice treated neonatally with saline or CFA before and after receiving CFA as adults. Twenty-four hours later, brains were dissected and NMDA receptor subunit gene expression was determined in four different brain areas by using an RNase protection assay. The results indicated that NMDA receptor subtype gene expression in adult mice exposed to persistent neonatal peripheral inflammation was brain region specific and that NMDA gene expression and pain reactivity differed according to the day of neonatal CFA exposure. Similarly, adult behavioral responsiveness to a noxious radiant heat source differed according to the age of neonatal exposure to CFA. The data suggest a possible molecular basis for the hypothesis that chronic persistent inflammation experienced early during development may permanently alter the future behavior and the sensitivity to pain later in life, especially in response to subsequent or recurrent inflammatory events.
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Sistema Nervioso Central , Regulación del Desarrollo de la Expresión Génica/fisiología , Inflamación/complicaciones , Dolor/etiología , Receptores de N-Metil-D-Aspartato/metabolismo , Factores de Edad , Animales , Animales Recién Nacidos , Conducta Animal , Sistema Nervioso Central/crecimiento & desarrollo , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Femenino , Adyuvante de Freund , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Ratones , Dolor/metabolismo , Dimensión del Dolor , Subunidades de Proteína/metabolismo , Tiempo de Reacción/fisiología , Ribonucleasas/farmacología , Factores de TiempoRESUMEN
This study aimed to test the hypothesis that the tuberoinfundibular dopaminergic neurons of the arcuate nucleus and/or the lactotroph cells of the anterior pituitary gland are key targets for the programming effects of perinatal glucocorticoids (GCs). Dexamethasone was administered noninvasively to fetal or neonatal rats via the mothers' drinking water (1 mug/ml) on embryonic d 16-19 or neonatal d 1-7, and control animals received normal drinking water. At 68 d of age, the numbers of tyrosine hydroxylase-positive (TH+) cells in the arcuate nucleus and morphometric parameters of pituitary lactotrophs were analyzed. In control animals, striking sex differences in TH+ cell numbers, lactotroph cell size, and pituitary prolactin content were observed. Both pre- and neonatal GC treatment regimens were without effect in adult male rats, but in females, the overriding effect was to abolish the sex differences by reducing arcuate TH+ cell numbers (pre- and neonatal treatments) and reducing lactotroph cell size and pituitary prolactin content (prenatal treatment only) without changing lactotroph cell numbers. Changes in circulating prolactin levels represented a net effect of hypothalamic and pituitary alterations that exhibited independent critical windows of susceptibility to perinatal GC treatments. The dopaminergic neurons of the hypothalamic periventricular nucleus and the pituitary somatotroph populations were not significantly affected by either treatment regimen in either sex. These data show that the adult female hypothalamo-lactotroph axis is profoundly affected by perinatal exposure to GCs, which disrupts the tonic inhibitory tuberoinfundibular dopaminergic pathway and changes lactotroph morphology and prolactin levels in the pituitary and circulation. These findings provide new evidence for a long-term disruption in prolactin-dependent homeostasis in females, but not males, after inappropriate GC exposure in perinatal life.
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Dexametasona/toxicidad , Feto/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Prolactina/metabolismo , Animales , Núcleo Arqueado del Hipotálamo/patología , Dopamina/análisis , Femenino , Hormona del Crecimiento/análisis , Hormona del Crecimiento/metabolismo , Sistema Hipotálamo-Hipofisario/fisiología , Masculino , Hipófisis/patología , Embarazo , Prolactina/análisis , Prolactina/sangre , Ratas , Ratas Sprague-Dawley , Caracteres Sexuales , Tirosina 3-Monooxigenasa/análisisRESUMEN
OBJECTIVE: Down's syndrome, the most common genetic cause of mental retardation, results in characteristic physical and neuropsychological findings, including mental retardation and deficits in language and memory. This study was undertaken to confirm previously reported abnormalities of regional brain volumes in Down's syndrome by using high-resolution magnetic resonance imaging (MRI), determine whether these volumetric abnormalities are present from childhood, and consider the relationship between neuroanatomic abnormalities and the cognitive profile of Down's syndrome. METHOD: Sixteen children and young adults with Down's syndrome (age range=5-23 years) were matched for age and gender with 15 normal comparison subjects. High-resolution MRI scans were quantitatively analyzed for measures of overall and regional brain volumes and by tissue composition. RESULTS: Consistent with prior imaging studies, subjects with Down's syndrome had smaller overall brain volumes, with disproportionately smaller cerebellar volumes and relatively larger subcortical gray matter volumes. Also noted was relative preservation of parietal lobe gray and temporal lobe white matter in subjects with Down's syndrome versus comparison subjects. No abnormalities in pattern of brain asymmetry were noted in Down's syndrome subjects. CONCLUSIONS: The results largely confirm findings of previous studies with respect to overall patterns of brain volumes in Down's syndrome and also provide new evidence for abnormal volumes of specific regional tissue components. The presence of these abnormalities from an early age suggests that fetal or early postnatal developmental differences may underlie the observed pattern of neuroanatomic abnormalities and contribute to the specific cognitive and developmental deficits seen in individuals with Down's syndrome.
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Encéfalo/anatomía & histología , Síndrome de Down/diagnóstico , Imagen por Resonancia Magnética/estadística & datos numéricos , Adolescente , Adulto , Factores de Edad , Cerebelo/anatomía & histología , Niño , Preescolar , Femenino , Lóbulo Frontal/anatomía & histología , Humanos , Masculino , Lóbulo Parietal/anatomía & histología , Lóbulo Temporal/anatomía & histologíaRESUMEN
The objective of this study was to use high-resolution MRI techniques to determine whether children with Down syndrome exhibit decreases in hippocampal and amygdala volumes similar to those demonstrated in recent studies of adults with this condition. When corrected for overall brain volumes, amygdala volumes did not differ between groups but hippocampal volumes were significantly smaller in the Down syndrome group. These findings suggest that the hippocampal volume reduction seen in adults with Down syndrome may be primarily due to early developmental differences rather than neurodegenerative changes.
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Amígdala del Cerebelo/patología , Síndrome de Down/patología , Hipocampo/patología , Niño , Femenino , Humanos , Imagen por Resonancia Magnética , MasculinoRESUMEN
The entire DNA sequence for human chromosome 21 is now complete, and it is predicted to contain only about 225 genes, which is approximately three-fold fewer than the number initially predicted just 10 years ago. Despite this remarkable achievement, very little is known about the mechanism(s) whereby increased gene copy number (gene dosage) results in the characteristic phenotype of Down syndrome. Although many of the phenotypic traits show large individual variation, neuromotor dysfunction and cognitive and language impairment are observed in virtually all individuals. Currently, there are no efficacious biomedical treatments for these central nervous system-associated impairments. To develop novel therapeutic strategies, the effects of gene dosage imbalance need to be understood within the framework of those critical biological events that regulate brain organization and function.
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Síndrome de Down/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Apolipoproteínas E/metabolismo , Encéfalo/anomalías , Mapeo Cromosómico/métodos , Cromosomas Humanos Par 21/genética , Trastornos del Conocimiento/genética , Citogenética/métodos , Síndrome de Down/metabolismo , Síndrome de Down/psicología , Expresión Génica , Humanos , Imagen por Resonancia Magnética , Estrés Oxidativo/fisiologíaRESUMEN
Behavior problems of 44 children with Down syndrome between the ages of 6 and 15 and 44 controls without mental retardation matched for age, sex, and socioeconomic status were compared on the basis of mother and teacher ratings. Ratings from both sources indicated that children with Down syndrome had more behavior problems, in particular attention deficit, noncompliance, thought disorder, and social withdrawal. Life events from the past year were significantly associated with mother but not teacher ratings of Down syndrome behavior problems.
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Trastornos de la Conducta Infantil/etiología , Síndrome de Down/complicaciones , Acontecimientos que Cambian la Vida , Adaptación Psicológica , Adolescente , Análisis de Varianza , Niño , Educación Especial , Femenino , Humanos , Masculino , Madres , Variaciones Dependientes del Observador , Escalas de Valoración Psiquiátrica , Factores de Riesgo , Encuestas y CuestionariosRESUMEN
The gene coding for preprosomatostatin (ppSom), the molecular precursor of somatostatin (Som), is regulated at the level of transcription by calcium ions and cyclic-AMP [F. Baldino, S. Fitzpatrick-McElligott, T. O'Kane, I. Gozes, Hormonal regulation of somatostatin, Synapse 2 (1988) 317-325; M.R. Montminy, M.J. Low, L. Tapia-Arancibia, Cyclic AMP regulates somatostatin mRNA accumulation in primary diencephalic cultures and in transfected fibroblast cells, J. Neurosci. 6 (1986) 1171-1176.], or by agents which increase intracellular levels of cAMP directly, such as forskolin [M.R. Montminy, M.J. Low, L. Tapia-Arancibia, Cyclic AMP regulates somatostatin mRNA accumulation in primary diencephalic cultures and in transfected fibroblast cells, J. Neurosci. 6 (1986) 1171-1176.]. Transcriptional induction of the ppSom gene as examined in PC12 cells, transfected fibroblasts and primary diencephalic cultures, requires the highly conserved cAMP response element (CRE), which confers gene responsiveness to cAMP [M. Comb, N. Mermod, S.E. Hyman, Proteins bound at adjacent DNA elements act synergistically to regulate human proenkephalin cAMP inducible transcription, EMBO J. 7 (1988) 3793-3805; T. Tsukada, J.S. Fink, G. Mandel, Identification of a region in the human vasoactive intestinal polypeptide gene responsible for regulation by cyclic AMP, J. Biol. Chem. 262 (1987) 8743-8747.]. The ppSom gene is subject to stringent regulation during cerebrocortical development in vivo; however, little information is available regarding ppSom gene regulation by neurotransmitters or second-messengers in cortical neurons. We used primary cerebrocortical cell cultures from fetal mice to examine the dose-response and time-course of ppSom gene expression in response to the cyclic-AMP analogs, dibutyrl-cAMP (dbcAMP), and 8-bromo-cAMP (8-BrcAMP). We report a dose-response for both analogs in the range of 0.1-10 mM. Dose-response studies using agents which directly stimulate intracellular cAMP synthesis (forskolin) or inhibit its breakdown (3-isobutyl 1-methyl xanthine) were also performed. We observed an apparent synergistic effect on ppSom expression when used in combination. An increase in ppSom mRNA levels was observed by 4 h, with a maximal response at 12-24 h. No change in ppSom mRNA levels was observed in response to phorbol myristate acetate (PMA). Our findings confirm the specificity of ppSom gene regulation by cAMP and Ca2+ ions, and demonstrate the utility of using primary cerebrocortical cultures for the study of somatostatin gene expression by neurotransmitters and second-messengers as a model of human neurologic disorders.
Asunto(s)
Corteza Cerebral/metabolismo , AMP Cíclico/fisiología , Diencéfalo/metabolismo , Regulación de la Expresión Génica/fisiología , Neuronas/metabolismo , Precursores de Proteínas/genética , Somatostatina/genética , 8-Bromo Monofosfato de Adenosina Cíclica/farmacología , Animales , Bucladesina/farmacología , Calcio/metabolismo , Células Cultivadas , Colforsina/farmacología , Feto , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Ratones Endogámicos C57BL , Células PC12 , Precursores de Proteínas/biosíntesis , Ratas , Proteínas Recombinantes/biosíntesis , Somatostatina/biosíntesis , TransfecciónRESUMEN
We describe a family carrying a direct duplication of an interstitial segment of the distal long arm of chromosome 4(q31.1q32.3) with a mild clinical phenotype. Affected family members include a 27-year-old woman and 2 of her 4 children, 1 of whom also has Klinefelter syndrome. Although 8 cases of simple duplications or insertions of 4q material have been described, only 3 include bands q31-q32, and these involve additional adjacent material. Affected members of the pedigree reported here have some of the manifestations of previously described cases of duplication 4q, but are less severely affected, suggesting that the genetic material in this region is well tolerated as a partial trisomy.