RESUMO
Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549 692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual's cognitive changes were constructed. One SNP--rs2075650, located in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog)--had a genome-wide significant association with cognitive ageing (P=2.5 × 10(-8)). This result was replicated in a meta-analysis of three independent Swedish cohorts (P=2.41 × 10(-6)). An Apolipoprotein E (APOE) haplotype (adjacent to TOMM40), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (P=2.18 × 10(-8); females, P=1.66 × 10(-11); males, P=0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P=3.66 × 10(-11)) and TOMM40 (rs11556505; P=2.45 × 10(-8)) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear.
Assuntos
Envelhecimento/genética , Apolipoproteínas E/genética , Cognição/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Estudos de Coortes , Inglaterra , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , EscóciaRESUMO
Underactivity of the glutamatergic system is an attractive model for the pathophysiology of several major mental illnesses. We previously described a chromosome abnormality disrupting the kainate class ionotropic glutamate receptor gene, GRIK4/KA1, in an individual with schizophrenia and learning disability (mental retardation). We also demonstrated in a case-control study that two physically separated haplotypes within this gene were significantly associated with increased risk of schizophrenia and decreased risk of bipolar disorder, respectively. The latter protective haplotype was located at the 3' end of the gene. We now report the identification from carriers of the protective haplotype of a deletion variant within the 3' untranslated region of the gene. The deletion allele also was found to be negatively associated with bipolar disorder in both initial (P = 0.00000019) and replication (P = 0.0107) case-control studies. Expression studies indicated that deletion-carrying mRNA transcripts were relatively more abundant. We postulate that this may be a direct consequence of the differences in the RNA secondary structures predicted for the insertion and deletion alleles. These data suggest a mechanism whereby the genetic protective effect is mediated through increased kainate receptor expression.
Assuntos
Regiões 3' não Traduzidas/genética , Transtorno Bipolar/genética , Mutação INDEL , Receptores de Ácido Caínico/genética , Transcrição Gênica , Regiões 3' não Traduzidas/química , Alelos , Sequência de Aminoácidos , Haplótipos , Heterozigoto , Humanos , Dados de Sequência Molecular , Conformação de Ácido Nucleico , Polimorfismo de Nucleotídeo Único , Deleção de SequênciaRESUMO
A case of proximal female hypospadias with urethral atresia is reported, and a nosological definition of this rare congenital anomaly is proposed. An attempt to clarify the difference between a urogenital sinus and a proximal or distal female hypospadias is made by examining the embryology of the urogenital tract.
Assuntos
Hipospadia/diagnóstico por imagem , Uretra/anormalidades , Pré-Escolar , Cistostomia , Diagnóstico Diferencial , Feminino , Humanos , Hipospadia/embriologia , Hipospadia/cirurgia , Masculino , Urografia , Fístula Vesicovaginal/congênito , Fístula Vesicovaginal/diagnóstico por imagem , Fístula Vesicovaginal/embriologia , Fístula Vesicovaginal/cirurgiaRESUMO
PURPOSE: Local anaesthesia for vitreoretinal surgery is little used as these procedures are deemed to be too long and uncomfortable for patients to tolerate. In this unit anterior intraconal local anaesthesia is used for most routine surgery. We undertook an audit to ensure that surgical standards and patient acceptability were not compromised. METHODS: A prospective observational audit was performed. Audit data included: Grade of anaesthetist and surgeon; details of anaesthetic and operation; compliance of patient; operating conditions and pain scores. Anaesthesia was provided with a combined peribulbar and intraconal anaesthetic, using bicarbonate buffered lignocaine and bupivacaine 50:50 mixture. RESULTS: 135 (76%) had local anaesthesia alone, 13 (7%) had local anaesthesia with sedation and 29 (16%) had general anaesthesia. 96.4% of patients were compliant and 98.8% of operating conditions were good or excellent. The mean perioperative pain score was 0.1 (range of 0-1), 97% said they would choose local anaesthesia again. CONCLUSIONS: LA for vitreoretinal surgery is a useful and flexible method of anaesthesia, which has been shown to have excellent patient tolerance.