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1.
Am J Hum Genet ; 89(5): 675-81, 2011 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-22077973

RESUMEN

Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS or Ohdo syndrome) is a multiple anomaly syndrome characterized by severe intellectual disability, blepharophimosis, and a mask-like facial appearance. A number of individuals with SBBYSS also have thyroid abnormalities and cleft palate. The condition usually occurs sporadically and is therefore presumed to be due in most cases to new dominant mutations. In individuals with SBBYSS, a whole-exome sequencing approach was used to demonstrate de novo protein-truncating mutations in the highly conserved histone acetyltransferase gene KAT6B (MYST4/MORF)) in three out of four individuals sequenced. Sanger sequencing was used to confirm truncating mutations of KAT6B, clustering in the final exon of the gene in all four individuals and in a further nine persons with typical SBBYSS. Where parental samples were available, the mutations were shown to have occurred de novo. During mammalian development KAT6B is upregulated specifically in the developing central nervous system, facial structures, and limb buds. The phenotypic features seen in the Qkf mouse, a hypomorphic Kat6b mutant, include small eyes, ventrally placed ears and long first digits that mirror the human phenotype. This is a further example of how perturbation of a protein involved in chromatin modification might give rise to a multisystem developmental disorder.


Asunto(s)
Codón sin Sentido/genética , Hipotiroidismo Congénito/genética , Exoma/genética , Histona Acetiltransferasas , Discapacidad Intelectual/genética , Anomalías Múltiples/genética , Adulto , Animales , Blefarofimosis/genética , Niño , Cromatina/metabolismo , Cromosomas Humanos Par 10/genética , Facies , Femenino , Regulación del Desarrollo de la Expresión Génica , Cardiopatías Congénitas , Histona Acetiltransferasas/deficiencia , Histona Acetiltransferasas/genética , Humanos , Mutación INDEL/genética , Inestabilidad de la Articulación , Masculino , Errores Innatos del Metabolismo/genética , Ratones , Ratones Transgénicos , Análisis por Micromatrices , Polimorfismo de Nucleótido Simple/genética
2.
Pain Med ; 15(1): 142-53, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24206362

RESUMEN

BACKGROUND: Pain management for patients in hospital is a major problem. There is significant variation in care provision. Evidence is needed about the ways in which acute pain services are organized in order to understand whether these are linked to important differences in patient outcomes. The National Inpatient Pain Study group is a voluntary collaborative venture of inpatient pain specialists in the United Kingdom who are working toward establishing a national prospective database of service provision and activity. OBJECTIVES: The objectives of this article are (1) to describe current pain service provision and activity (2) to define and monitor the quality and side effects of the primary analgesic techniques, such as central neuraxial block or systemic analgesia, and identify variations in practice. METHODS: Phase 1: Surveys were conducted in two phases during 2010-2011. Information about the organization of services was collected from 121 centers via a live Website. Phase 2: The pilot clinical dataset was collected from 13 hospitals in 2011. RESULTS: Results indicated that staffing varied widely from one to nine nurses per hospital site. Twelve percent of hospitals did not routinely collect data. The main workload was orthopedic and general surgery based on data from 13 hospitals and 29,080 patients in 2011. Thirty-seven percent of patients reported a pain score of moderate to severe pain on the first assessment by the specialist pain team, and 21% reported severe pain. Nausea and vomiting was the most frequent adverse event reported. Sixty-nine major adverse events were logged, of which 64 documented respiratory depression (N = 29,080, 0.22%). CONCLUSIONS: Prospective longitudinal data has the potential to improve our understanding of variation in process and outcome measures and establish future research priorities.


Asunto(s)
Dolor Agudo/tratamiento farmacológico , Clínicas de Dolor/estadística & datos numéricos , Manejo del Dolor/estadística & datos numéricos , Pautas de la Práctica en Medicina/estadística & datos numéricos , Dolor Agudo/epidemiología , Dolor Agudo/enfermería , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Analgésicos/efectos adversos , Analgésicos/uso terapéutico , Servicio de Anestesia en Hospital/estadística & datos numéricos , Niño , Preescolar , Estudios Transversales , Recolección de Datos , Utilización de Medicamentos , Femenino , Encuestas de Atención de la Salud , Humanos , Hipotensión/inducido químicamente , Hipotensión/epidemiología , Lactante , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Programas Nacionales de Salud/organización & administración , Clínicas de Dolor/organización & administración , Clínicas de Dolor/normas , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/epidemiología , Náusea y Vómito Posoperatorios/inducido químicamente , Náusea y Vómito Posoperatorios/epidemiología , Calidad de la Atención de Salud , Sistema de Registros , Trastornos Respiratorios/inducido químicamente , Trastornos Respiratorios/epidemiología , Encuestas y Cuestionarios , Resultado del Tratamiento , Reino Unido/epidemiología , Adulto Joven
3.
Hum Mutat ; 31(10): 1142-54, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20672375

RESUMEN

A range of phenotypes including Greig cephalopolysyndactyly and Pallister-Hall syndromes (GCPS, PHS) are caused by pathogenic mutation of the GLI3 gene. To characterize the clinical variability of GLI3 mutations, we present a subset of a cohort of 174 probands referred for GLI3 analysis. Eighty-one probands with typical GCPS or PHS were previously reported, and we report the remaining 93 probands here. This includes 19 probands (12 mutations) who fulfilled clinical criteria for GCPS or PHS, 48 probands (16 mutations) with features of GCPS or PHS but who did not meet the clinical criteria (sub-GCPS and sub-PHS), 21 probands (6 mutations) with features of PHS or GCPS and oral-facial-digital syndrome, and 5 probands (1 mutation) with nonsyndromic polydactyly. These data support previously identified genotype-phenotype correlations and demonstrate a more variable degree of severity than previously recognized. The finding of GLI3 mutations in patients with features of oral-facial-digital syndrome supports the observation that GLI3 interacts with cilia. We conclude that the phenotypic spectrum of GLI3 mutations is broader than that encompassed by the clinical diagnostic criteria, but the genotype-phenotype correlation persists. Individuals with features of either GCPS or PHS should be screened for mutations in GLI3 even if they do not fulfill clinical criteria.


Asunto(s)
Anomalías Múltiples/genética , Factores de Transcripción de Tipo Kruppel/genética , Mutación , Proteínas del Tejido Nervioso/genética , Síndrome de Pallister-Hall/patología , Polidactilia/patología , Sindactilia/patología , Anomalías Craneofaciales/genética , Genotipo , Humanos , Anomalías de la Boca/genética , Síndrome de Pallister-Hall/genética , Fenotipo , Polidactilia/genética , Sindactilia/genética , Proteína Gli3 con Dedos de Zinc
4.
Bioorg Med Chem Lett ; 19(24): 6902-6, 2009 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-19879752

RESUMEN

We report the identification of novel small molecule agonists of integrin CD11b/CD18, which increased, in a dose-dependent manner, the adhesion of the integrin CD11b/CD18 expressing cells to two physiologically relevant ligands: Fibrinogen and iC3b. Compound 6 showed an ex vivo EC(50) of 10.5 microM and in vitro selectivity for binding to the recombinant alphaA-domain of CD11b/CD18. In silico docking experiments suggest that the compounds recognized a hydrophobic cleft in the ligand-binding alphaA-domain, implying an allosteric mechanism of modulation of integrin affinity by this novel compound.


Asunto(s)
Antiinflamatorios no Esteroideos/química , Antígeno CD11b/efectos de los fármacos , Antígenos CD18/efectos de los fármacos , Furanos/química , Tiazolidinedionas/química , Antiinflamatorios no Esteroideos/farmacología , Antígeno CD11b/química , Antígeno CD11b/metabolismo , Antígenos CD18/química , Antígenos CD18/metabolismo , Células CACO-2 , Adhesión Celular/efectos de los fármacos , Furanos/farmacología , Humanos , Conformación Proteica , Relación Estructura-Actividad , Tiazolidinedionas/farmacología
5.
Orphanet J Rare Dis ; 14(1): 180, 2019 07 19.
Artículo en Inglés | MEDLINE | ID: mdl-31324220

RESUMEN

BACKGROUND: A pattern of major and minor congenital anomalies, facial dysmorphic features, and neurodevelopmental difficulties, including cognitive and social impairments has been reported in some children exposed to sodium valproate (VPA) during pregnancy. Recognition of the increased risks of in utero exposure to VPA for congenital malformations, and for the neurodevelopmental effects in particular, has taken many years but these are now acknowledged following the publication of the outcomes of several prospective studies and registries. As with other teratogens, exposure to VPA can have variable effects, ranging from a characteristic pattern of major malformations and significant intellectual disability to the other end of the continuum, characterised by facial dysmorphism which is often difficult to discern and a more moderate effect on neurodevelopment and general health. It has become clear that some individuals with FVSD have complex needs requiring multidisciplinary care but information regarding management is currently lacking in the medical literature. METHODS: An expert group was convened by ERN-ITHACA, the European Reference Network for Congenital Malformations and Intellectual Disability comprised of professionals involved in the care of individuals with FVSD and with patient representation. Review of published and unpublished literature concerning management of FVSD was undertaken and the level of evidence from these sources graded. Management recommendations were made based on strength of evidence and consensus expert opinion, in the setting of an expert consensus meeting. These were then refined using an iterative process and wider consultation. RESULTS: Whilst there was strong evidence regarding the increase in risk for major congenital malformations and neurodevelopmental difficulties there was a lack of high level evidence in other areas and in particular in terms of optimal clinical management.. The expert consensus approach facilitated the formulation of management recommendations, based on literature evidence and best practice. The outcome of the review and group discussions leads us to propose the term Fetal Valproate Spectrum Disorder (FVSD) as we feel this better encompasses the broad range of effects seen following VPA exposure in utero. CONCLUSION: The expert consensus approach can be used to define the best available clinical guidance for the diagnosis and management of rare disorders such as FVSD. FVSD can have medical, developmental and neuropsychological impacts with life-long consequences and affected individuals benefit from the input of a number of different health professionals.


Asunto(s)
Discapacidad Intelectual/diagnóstico , Ácido Valproico/uso terapéutico , Anticonvulsivantes/efectos adversos , Consenso , Femenino , Humanos , Embarazo , Complicaciones del Embarazo , Estudios Prospectivos , Teratógenos/toxicidad , Útero/efectos de los fármacos
6.
J Clin Pharmacol ; 58(12): 1655-1665, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30144093

RESUMEN

Potential drug interactions with hormonal contraceptives are an important public health concern. A public meeting on "Drug Interactions With Hormonal Contraceptives: Public Health and Drug Development Implication" was hosted by the United States Food and Drug Administration (FDA). The meeting endeavored to provide an opportunity for the FDA to seek input from experts on the public health concerns associated with the use of hormonal contraceptives and interacting drugs that might affect efficacy and safety, including pharmacokinetic/pharmacodynamic considerations, in the design of drug interaction studies of hormonal contraceptives for drug development and approaches to translating the results of drug interaction information into informative labeling and communication. The input received could be used to refine FDA's thinking on hormonal contraceptives drug interaction study design and interpretation and labeling communication of drug interaction risk. This meeting benefited from strong and diverse participation from the Center for Drug Evaluation and Research at the FDA, Centers for Disease Control and Prevention, National Institutes of Health, Swedish Medical Products Agency, pharmaceutical industry, and representatives of academia. This report provides a summary of the key discussion based on the presentations and panel discussion.


Asunto(s)
Anticonceptivos Femeninos/administración & dosificación , Anticonceptivos Femeninos/farmacocinética , Desarrollo de Medicamentos , Salud Pública , United States Food and Drug Administration , Interacciones Farmacológicas , Humanos , Estados Unidos
7.
J Biomed Inform ; 39(5): 532-40, 2006 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16464644

RESUMEN

Researchers are generally trained to administer informed consent by studying approved guidelines, but still can fail to satisfactorily answer questions from potential participants. An application using a virtual character allowed novice participants to practice administering informed consent. This character was designed to behave as a potential participant for a study and asked many of the questions research participants typically ask, such as queries about the study itself, the sponsor, timing, selection procedures, confidentiality, voluntariness, benefits and risks, and contact information. The user responded to the character's queries as if speaking with a true potential research participant. The application was effective even after only brief usage. In a laboratory experiment, novice participants who practiced with the virtual character were later more effective in conducting informed consent interviews with a human interviewee than those who were trained only with written materials. Thus, simulated learning-by-doing improved informed consent skills. Implications for related health dialog applications are discussed.


Asunto(s)
Comunicación , Instrucción por Computador/métodos , Consentimiento Informado , Investigación Biomédica , Humanos
8.
Clin Dysmorphol ; 14(1): 35-36, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15602092

RESUMEN

Simpson-Golabi-Behmel syndrome (SGBS) is an X linked recessive overgrowth disorder in which digital abnormalities are a well-described aspect of the phenotype. We report a case with marked index finger hypoplasia and a congenital abnormality of the proximal phalanx and review the literature detailing index finger abnormalities in this condition.


Asunto(s)
Dedos/anomalías , Enfermedades Genéticas Ligadas al Cromosoma X , Preescolar , Genes Recesivos , Humanos , Masculino
9.
Eur J Hum Genet ; 23(9): 1165-70, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25424711

RESUMEN

KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B. Of those where parental samples could be tested, all occurred de novo. Thirty out of thirty-four had truncating variants, one had a missense variant and the remaining three had the same synonymous change predicted to affect splicing. Variants in GPS tended to occur more proximally to those in SBBS patients, and genotype/phenotype analysis demonstrated significant clinical overlap between SBBS and GPS. The de novo synonymous change seen in three patients with features of SBBS occurred more proximally in exon 16. Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients. The few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS. We report the findings in a previously unreported patient with a deletion of the KAT6B gene to further delineate the haploinsufficiency phenotype. The molecular mechanisms giving rise to the SBBS and GPS phenotypes are discussed.


Asunto(s)
Blefarofimosis/genética , Hipotiroidismo Congénito/genética , Anomalías Craneofaciales/genética , Exones , Cardiopatías Congénitas/genética , Histona Acetiltransferasas/genética , Discapacidad Intelectual/genética , Inestabilidad de la Articulación/genética , Riñón/anomalías , Mutación , Rótula/anomalías , Trastornos Psicomotores/genética , Escroto/anomalías , Anomalías Urogenitales/genética , Blefarofimosis/diagnóstico , Blefarofimosis/patología , Preescolar , Hipotiroidismo Congénito/diagnóstico , Hipotiroidismo Congénito/patología , Anomalías Craneofaciales/diagnóstico , Anomalías Craneofaciales/patología , Análisis Mutacional de ADN , Diagnóstico Diferencial , Exoma , Facies , Femenino , Expresión Génica , Estudios de Asociación Genética , Genotipo , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/patología , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/patología , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/patología , Riñón/patología , Masculino , Rótula/patología , Fenotipo , Trastornos Psicomotores/diagnóstico , Trastornos Psicomotores/patología , Escroto/patología , Índice de Severidad de la Enfermedad , Anomalías Urogenitales/diagnóstico , Anomalías Urogenitales/patología
10.
Clin Dysmorphol ; 12(4): 277-8, 2003 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-14564219

RESUMEN

We report on two cases (male twins), and a female sib terminated at 20 weeks, whose autopsy revealed features of spondylothoracic dysplasia (STD) and also a diaphragmatic hernia and preaxial polydactyly. We present the findings and review STD and the closely related spondylocostal dysostosis. On the basis of the discussion we suggest that our cases are possibly the first report of preaxial polydactyly in spondylothoracic dysplasia and that STD and spondylocostal dysostosis may be allelic.


Asunto(s)
Anomalías Múltiples/patología , Dedos/anomalías , Hernia Diafragmática/patología , Osteocondrodisplasias/patología , Vértebras Torácicas/anomalías , Resultado Fatal , Humanos , Recién Nacido , Masculino , Osteocondrodisplasias/diagnóstico por imagen , Radiografía , Vértebras Torácicas/diagnóstico por imagen , Gemelos Monocigóticos
11.
Clin Dysmorphol ; 13(1): 17-9, 2004 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15127758

RESUMEN

We report a new case of Ohdo syndrome with bilateral patella dislocations where surgical intervention has been indicated. A review of the skeletal manifestations reported in the literature on Ohdo syndrome reveals that joint laxity and skeletal deformities are important aspects of the phenotype.


Asunto(s)
Huesos/anomalías , Discapacidad Intelectual/diagnóstico , Rótula/anomalías , Rótula/patología , Anomalías Múltiples , Blefarofimosis/diagnóstico , Preescolar , Cara , Humanos , Lactante , Inestabilidad de la Articulación , Rodilla/anomalías , Masculino , Fenotipo , Síndrome
12.
Prof Nurse ; 19(1): 45-7, 2003 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-14515823

RESUMEN

Pain relief during labour is problematic. The expectations of the mother have to be balanced against compromising the baby. A new drug that has been used in labour is remifentanil. This paper examines the indications for its use and the possible place it may find in providing another pain-relieving option for labouring women.


Asunto(s)
Analgesia Obstétrica , Analgesia Controlada por el Paciente , Analgésicos Opioides/administración & dosificación , Piperidinas/administración & dosificación , Adulto , Femenino , Humanos , Embarazo , Complicaciones del Embarazo , Remifentanilo , Disrafia Espinal
13.
J Clin Endocrinol Metab ; 97(2): E257-67, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22162478

RESUMEN

CONTEXT: P450 oxidoreductase deficiency (PORD) is a unique congenital adrenal hyperplasia variant that manifests with glucocorticoid deficiency, disordered sex development (DSD), and skeletal malformations. No comprehensive data on genotype-phenotype correlations in Caucasian patients are available. OBJECTIVE: The objective of the study was to establish genotype-phenotype correlations in a large PORD cohort. DESIGN: The design of the study was the clinical, biochemical, and genetic assessment including multiplex ligation-dependent probe amplification (MLPA) in 30 PORD patients from 11 countries. RESULTS: We identified 23 P450 oxidoreductase (POR) mutations (14 novel) including an exonic deletion and a partial duplication detected by MLPA. Only 22% of unrelated patients carried homozygous POR mutations. p.A287P was the most common mutation (43% of unrelated alleles); no other hot spot was identified. Urinary steroid profiling showed characteristic PORD metabolomes with variable impairment of 17α-hydroxylase and 21-hydroxylase. Short cosyntropin testing revealed adrenal insufficiency in 89%. DSD was present in 15 of 18 46,XX and seven of 12 46,XY individuals. Homozygosity for p.A287P was invariably associated with 46,XX DSD but normal genitalia in 46,XY individuals. The majority of patients with mild to moderate skeletal malformations, assessed by a novel scoring system, were compound heterozygous for missense mutations, whereas nearly all patients with severe malformations carried a major loss-of-function defect on one of the affected alleles. CONCLUSIONS: We report clinical, biochemical, and genetic findings in a large PORD cohort and show that MLPA is a useful addition to POR mutation analysis. Homozygosity for the most frequent mutation in Caucasians, p.A287P, allows for prediction of genital phenotype and moderate malformations. Adrenal insufficiency is frequent, easily overlooked, but readily detected by cosyntropin testing.


Asunto(s)
Hiperplasia Suprarrenal Congénita/genética , NADPH-Ferrihemoproteína Reductasa/genética , Adolescente , Hiperplasia Suprarrenal Congénita/orina , Insuficiencia Suprarrenal/genética , Insuficiencia Suprarrenal/metabolismo , Insuficiencia Suprarrenal/orina , Adulto , Niño , Estudios de Cohortes , Análisis Mutacional de ADN/métodos , Trastornos del Desarrollo Sexual , Femenino , Estudios de Asociación Genética , Genitales/anomalías , Hormonas Esteroides Gonadales/orina , Humanos , Masculino , Metaboloma , Modelos Biológicos , Modelos Moleculares , Reacción en Cadena de la Polimerasa Multiplex/métodos , NADPH-Ferrihemoproteína Reductasa/deficiencia , NADPH-Ferrihemoproteína Reductasa/fisiología , Adulto Joven
14.
Prof Nurse ; 19(1): 43, 2003 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-14515822
16.
Epilepsia ; 47(6): 1029-34, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16822249

RESUMEN

PURPOSE: Benign familial infantile seizures (BFIS) is a genetically heterogeneous condition characterized by partial seizures, onset age from 3 to 9 months, and favorable outcome. BFIS loci were identified on chromosomes 19q12-13.1 and 16p12-q12, allelic to infantile convulsions and choreathetosis. The identification of SCN2A mutations in families with only infantile seizures indicated that BFNIS and BFIS may show overlapping clinical features. Infantile seizures also were in a family with familial hemiplegic migraine and mutations in the ATP1A2 gene. We have examined the heterogeneous genetics of BFIS by means of linkage analysis. METHODS: Sixteen families were examined. Probands underwent neurologic examination, at least one EEG recording, and, when possible, brain CT and MRI. Clinical information about relatives was collected. Families with SCN2A or ATP1A2 mutations were excluded from the study. Chromosome 16p and 19q loci were examined by linkage analysis using two models that differed in penetrance rate. Genetic heterogeneity was evaluated with both models. RESULTS: Clinical information was available for 124 members of affected families. BFIS was diagnosed in 69 subjects. One patient without BFIS had a single febrile seizure, and another had rare episodes of paroxysmal dystonia. Evidence of linkage was obtained only for chromosome 16. Moreover, the high penetrance allowed the identification of genetic heterogeneity. CONCLUSIONS: Our data confirm the relevance of the chromosome 16 locus in BFIS and suggest the presence of an additional locus. This study shows that the genetic model used affects the outcome of linkage analysis.


Asunto(s)
Cromosomas Humanos Par 16/genética , Epilepsia Benigna Neonatal/genética , Familia , Ligamiento Genético , Modelos Genéticos , Mutación/genética , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Mapeo Cromosómico , Cromosomas Humanos Par 19/genética , Electroencefalografía/estadística & datos numéricos , Epilepsia Benigna Neonatal/diagnóstico , Femenino , Heterogeneidad Genética , Haplotipos , Humanos , Imagen por Resonancia Magnética , Masculino , Examen Neurológico , Linaje , Penetrancia , Tomografía Computarizada por Rayos X
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