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OBJECTIVES: A few studies reported that both decrease and increase in body mass index (BMI) were associated with the development of dementia in later life. However, it is unclear what changes in body composition are associated with cognitive decline. This study investigated the longitudinal influences of changes in body composition on cognitive function among community-dwelling adults. DESIGN, SETTING AND PARTICIPANTS: This longitudinal study included older adults aged ≥60 years without cognitive impairment who participated in National Institute for Longevity Sciences - Longitudinal Study of Aging. MEASUREMENTS: Cognitive function was assessed using the MMSE. Body composition was measured by a dual-energy X-ray absorptiometry system. Then, BMI, fat mass index (FMI), fat-free mass index (FFMI), and muscle mass index (MMI) were calculated. The changes in body composition over 6 years (second wave to fifth wave) were calculated, and three groups were created: decreased group, decrease of >5%; stable group, change within 5%, and increased group, increase of >5%. In statistical analysis, a linear mixed model was applied by sex to investigate the influences of body composition changes on cognitive function over 4 years (fifth wave to seventh wave). RESULTS: This study analyzed 515 participants (mean age, 67.05 years; 53.4% men). Men with decreased group in FFMI and MMI exhibited faster declines in MMSE scores than those with stable group (ß [95% CI]: FFMI, -0.293 [-0.719 to -0.020]; MMI, -0.472 [-0.884 to -0.059]). In women, there was no significant association between body composition changes and cognitive functions. CONCLUSIONS: Decrease in fat-free mass and muscle mass is associated with faster cognitive declines in men. These results suggest the importance of continuous monitoring of muscle mass to prevent cognitive decline in later life.
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Envelhecimento , Composição Corporal , Masculino , Humanos , Feminino , Idoso , Estudos Longitudinais , Estudos Prospectivos , Composição Corporal/fisiologia , Índice de Massa Corporal , Cognição , MúsculosRESUMO
Anaphylactic reactions during the induction of general anaesthesia are rare. Anaesthetists should determine the pathogenesis of anaphylaxis in order to establish appropriate treatment and prevent recurrence. Very little clinical information has been published to date about anaphylaxis induced by the recently launched drug remimazolam. A 78-year-old man, scheduled for elective surgery for colon cancer, became profoundly hypotensive and hypoxic shortly following the induction of general anaesthesia with remimazolam, remifentanil and rocuronium. His physiological derangement was successfully managed with adrenaline, vasopressors and intravenous fluid resuscitation. His serum tryptase level was significantly elevated and an intradermal test with diluted remimazolam revealed a positive reaction, confirming the diagnosis of anaphylaxis. We believe this is the first case report of remimazolam-induced anaphylactic shock diagnosed with a serum tryptase elevation and positive skin test.
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BACKGROUND: The association of sarcopenia with cognitive function in its specific domains remains poorly understood. OBJECTIVES: To investigate the association of sarcopenia and its components with neuropsychological performance among patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). DESIGN: Cross-sectional design. SETTING: A memory clinic in Japan. PARTICIPANTS: The study included 497 MCI/684 AD patients aged 65-89 years. MEASUREMENTS: Patients were assessed for muscle mass by bioelectrical impedance analysis, muscle strength by hand grip strength (HGS), and physical performance by timed up and go test (TUG). Sarcopenia was defined as presence of both low muscle strength and low muscle mass. The patients underwent neuropsychological tests, including logical memory, frontal lobe assessment battery, word fluency test, Raven's colored progressive matrices, digit span, and the Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog). RESULTS: The prevalence of sarcopenia in men and women was 24.1% and 19.5%, respectively. In multiple regression analyses adjusting for confounders, unlike in men, sarcopenia was associated with memory function in women (ADAS-cog, memory domain, coefficient = 1.08, standard error (SE) = 0.36), which was thought likely due to the relationship between HGS and memory function (immediate recall of logical memory, coefficient = 0.07, SE = 0.03; ADAS-cog, memory domain, coefficient = -0.10, SE = 0.03). Of the components of sarcopenia in both sexes, HGS and TUG were associated with visuospatial function and frontal lobe function, respectively. CONCLUSIONS: The specific association of sarcopenia and its components with cognitive domains may provide the key to elucidating the muscle-brain interactions in AD.
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Doença de Alzheimer , Disfunção Cognitiva , Sarcopenia , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/epidemiologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/epidemiologia , Estudos Transversais , Feminino , Força da Mão/fisiologia , Humanos , Masculino , Equilíbrio Postural , Sarcopenia/complicações , Sarcopenia/diagnóstico , Sarcopenia/epidemiologia , Estudos de Tempo e MovimentoRESUMO
AIM: To clarify the utility of contrast-enhanced ultrasonography (CEUS) for interim evaluation of response to chemotherapy in lymphoma treatment. MATERIALS AND METHODS: CEUS was performed both before (day 0) and after the treatment (7 and/or 14 days), and a time-intensity curve was obtained. The patients were divided into two groups (complete remission [CR] group and non-CR group) according to the results of conventional response evaluation, and peak enhancement (PE), time to peak enhancement, perfusion index (PI), the total area under the curve during wash-in (AUC-in), and the total AUC were compared between the groups. RESULTS: Among 27 patients with various types of lymphoma, the median change ratio of PE and PI at day 7 evaluation were significantly different between the CR group and the non-CR group (0.81 versus 1.39, p=0.017 for PE and 0.92 versus 2.09, p=0.010 for PI). The change ratio of PE < 1.09 (specificity: 86%; sensitivity, 88%) and PI < 1.65 (specificity: 86%; sensitivity: 94%) distinguished CR from non-CR. Patients who achieved a PE change ratio <1.09 or a PI change ratio <1.65 had significantly better estimated progression-free survival (p<0.001). CONCLUSION: The present study demonstrated that changes in tumour perfusion parameters evaluated with CEUS at 1 week after the treatment initiation were significantly different between lymphoma patients in CR group and non-CR group. Alterations in perfusion parameters evaluated via CEUS could impact the prognosis of lymphoma patients.
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Quimioterapia de Indução , Linfoma/diagnóstico por imagem , Linfoma/tratamento farmacológico , Neovascularização Patológica/diagnóstico por imagem , Ultrassonografia/métodos , Idoso , Meios de Contraste , Feminino , Fluorocarbonos , Humanos , Interpretação de Imagem Assistida por Computador , Masculino , Projetos Piloto , Prognóstico , Estudos ProspectivosRESUMO
During behavioral states of immobility, sleep, and anesthesia, the hippocampus generates high-frequency oscillations called ripples. Ripples occur simultaneously with synchronous neuronal activity in the neocortex, known as slow waves, and contribute to memory consolidation. During these ripples, various neocortical regions exhibit modulations in spike rates and local field activity irrespective of whether they receive direct synaptic inputs from the hippocampus. However, little is known about the subthreshold dynamics of the membrane potentials of neocortical neurons during ripples. We patch-clamped layer 2/3 pyramidal cells in the posterior parietal cortex (PPC), a neocortical region that is involved in allocentric spatial representation of behavioral exploration and sequential series of relevant action potentials during ripples. We simultaneously monitored the membrane potentials of post hoc-identified PPC neurons and the local field potentials of the hippocampus in anesthetized mice. More than 50% of the recorded PPC neurons exhibited significant depolarizations and/or hyperpolarizations during ripples. Histological inspections of the recorded neurons revealed that the ripple-modulated PPC neurons were distributed in the PPC in a spatially non-biased fashion. These results suggest that hippocampal ripples are widely but selectively associated with the subthreshold dynamics of the membrane potentials of PPC neurons even though there is no monosynaptic connectivity between the hippocampus and the PPC.
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SETD1B is a component of a histone methyltransferase complex that specifically methylates Lys-4 of histone H3 (H3K4) and is responsible for the epigenetic control of chromatin structure and gene expression. De novo microdeletions encompassing this gene as well as de novo missense mutations were previously linked to syndromic intellectual disability (ID). Here, we identify a specific hypermethylation signature associated with loss of function mutations in the SETD1B gene which may be used as an epigenetic marker supporting the diagnosis of syndromic SETD1B-related diseases. We demonstrate the clinical utility of this unique epi-signature by reclassifying previously identified SETD1B VUS (variant of uncertain significance) in two patients.
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Ansiedade/genética , Transtorno do Espectro Autista/genética , Metilação de DNA , Epilepsia/genética , Histona-Lisina N-Metiltransferase/genética , Deficiência Intelectual/genética , Mutação com Perda de Função , Adolescente , Adulto , Criança , Pré-Escolar , Ilhas de CpG , Epigênese Genética , Proteínas F-Box/genética , Feminino , Marcadores Genéticos , Humanos , Recém-Nascido , Histona Desmetilases com o Domínio Jumonji/genética , MasculinoAssuntos
Portador Sadio/virologia , Pneumonia em Organização Criptogênica/tratamento farmacológico , Glucocorticoides/uso terapêutico , Infecções por HTLV-I/complicações , Vírus Linfotrópico T Tipo 1 Humano , Prednisolona/uso terapêutico , Idoso , Pneumonia em Organização Criptogênica/virologia , Humanos , MasculinoAssuntos
Neoplasias Brônquicas/diagnóstico , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Bendamustina/administração & dosagem , Neoplasias Brônquicas/tratamento farmacológico , Broncoscopia , Feminino , Humanos , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Mucosa , Rituximab/administração & dosagem , Tomografia Computadorizada por Raios XRESUMO
The human WW Domain Containing Oxidoreductase (WWOX) gene was originally described as a tumor suppressor gene. However, recent reports have demonstrated its cardinal role in the pathogenesis of central nervous systems disorders such as epileptic encephalopathy, intellectual disability, and spinocerebellar ataxia. We report on six patients from three unrelated families of full or partial Yemenite Jewish ancestry exhibiting early infantile epileptic encephalopathy and profound developmental delay. Importantly, four patients demonstrated facial dysmorphism. Exome sequencing revealed that four of the patients were homozygous for a novel WWOX c.517-2A > G splice-site variant and two were compound heterozygous for this variant and a novel c.689A > C, p.Gln230Pro missense variant. Complementary DNA sequencing demonstrated that the WWOX c.517-2A > G splice-site variant causes skipping of exon six. A carrier rate of 1:177 was found among Yemenite Jews. We provide the first detailed description of patients harboring a splice-site variant in the WWOX gene and propose that the clinical synopsis of WWOX related epileptic encephalopathy should be broadened to include facial dysmorphism. The increased frequency of the c.517-2A > G splice-site variant among Yemenite Jews coupled with the severity of the phenotype makes it a candidate for inclusion in expanded preconception screening programs.
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Face/anormalidades , Deficiência Intelectual/genética , Espasmos Infantis/genética , Proteínas Supressoras de Tumor/genética , Oxidorredutase com Domínios WW/genética , Feminino , Estudos de Associação Genética , Humanos , Judeus/genética , Masculino , Mutação , Linhagem , IêmenRESUMO
LAMB1 gene analysis should be considered for intellectually disabled patients with cerebellar cysts, white matter signal change, and cortical malformation. Muscular involvement is absent, in contrast to the α-dystroglycanopathy types of congenital muscular dystrophies.
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Doenças Cerebelares/diagnóstico por imagem , Doenças Cerebelares/genética , Córtex Cerebral/patologia , Cistos/diagnóstico por imagem , Cistos/genética , Laminina/genética , Fenótipo , Substância Branca/patologia , Adolescente , Criança , Feminino , Humanos , MasculinoRESUMO
Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA) (OMIM #617481) is an autosomal recessive disease characterized by progressive microcephaly, plagiocephaly, hypotonia, spastic quadriparesis, global developmental delay, intellectual disability, optic features and abnormal brain magnetic resonance imaging (MRI). NMIHBA was recently reported to be caused by PRUNE1 mutations. Eight mutations have been reported in 13 unrelated families. Here, we report 3 PRUNE1 mutations in 1 Caucasian and 3 Japanese families. One recurrent missense mutation (p.Asp106Asn) was previously reported in Turkish and Italian families, while the other 2 mutations (p.Leu18Serfs*8 and p.Cys180*) are novel. We also show that mutant PRUNE1 mRNA can be subject to nonsense-mediated mRNA decay. The patients presented in this study showed atypical NMIHBA phenotypes with no progressive microcephaly. Furthermore, one Caucasian case had significant macrocephaly; therefore, patients with PRUNE1 mutations can exhibit a broad and heterogeneous spectrum of phenotypes.
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Encéfalo/anormalidades , Microcefalia/genética , Hipotonia Muscular/genética , Monoéster Fosfórico Hidrolases/genética , Encéfalo/diagnóstico por imagem , Criança , Feminino , Humanos , Itália , Imageamento por Ressonância Magnética , Masculino , Mutação de Sentido Incorreto , Linhagem , RNA Mensageiro/genética , TurquiaAssuntos
Neuropatia Hereditária Motora e Sensorial/genética , Atrofia Muscular Espinal/genética , Simportadores/genética , Feminino , Neuropatia Hereditária Motora e Sensorial/fisiopatologia , Humanos , Japão , Mutação com Perda de Função/genética , Masculino , Pessoa de Meia-Idade , Atrofia Muscular Espinal/fisiopatologia , Linhagem , País de GalesRESUMO
Leukoencephalopathies encompass all clinical syndromes that predominantly affect brain white matter. Genetic diagnosis informs clinical management of these patients, but a large part of the genetic contribution to adult leukoencephalopathy remains unresolved. To examine this genetic contribution, we analyzed genomic DNA from 60 Japanese patients with adult leukoencephalopathy of unknown cause by next generation sequencing using a custom-designed gene panel. We selected 55 leukoencephalopathy-related genes for the gene panel. We identified pathogenic mutations in 8 of the 60 adult leukoencephalopathy patients (13.3%): NOTCH3 mutations were detected in 5 patients, and EIF2B2, CSF1R, and POLR3A mutations were found independently in 1 patient each. These results indicate that cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 mutations is the most frequent adult leukoencephalopathy in our cohort. Moreover, brain imaging analysis indicates that CADASIL patients who do not present typical phenotypes may be underdiagnosed if not examined genetically.
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CADASIL/genética , Predisposição Genética para Doença , Leucoencefalopatias/genética , Receptor Notch3/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , CADASIL/diagnóstico por imagem , CADASIL/fisiopatologia , Estudos de Coortes , Fator de Iniciação 2B em Eucariotos/genética , Testes Genéticos , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/fisiopatologia , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Mutação , Fenótipo , RNA Polimerase III/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Sequenciamento do ExomaRESUMO
Epilepsies are common neurological disorders and genetic factors contribute to their pathogenesis. Copy number variations (CNVs) are increasingly recognized as an important etiology of many human diseases including epilepsy. Whole-exome sequencing (WES) is becoming a standard tool for detecting pathogenic mutations and has recently been applied to detecting CNVs. Here, we analyzed 294 families with epilepsy using WES, and focused on 168 families with no causative single nucleotide variants in known epilepsy-associated genes to further validate CNVs using 2 different CNV detection tools using WES data. We confirmed 18 pathogenic CNVs, and 2 deletions and 2 duplications at chr15q11.2 of clinically unknown significance. Of note, we were able to identify small CNVs less than 10 kb in size, which might be difficult to detect by conventional microarray. We revealed 2 cases with pathogenic CNVs that one of the 2 CNV detection tools failed to find, suggesting that using different CNV tools is recommended to increase diagnostic yield. Considering a relatively high discovery rate of CNVs (18 out of 168 families, 10.7%) and successful detection of CNV with <10 kb in size, CNV detection by WES may be able to surrogate, or at least complement, conventional microarray analysis.
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Variações do Número de Cópias de DNA , Epilepsia/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Biologia Computacional/métodos , Epilepsia/diagnóstico , Exoma , Feminino , Estudos de Associação Genética/métodos , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Sequenciamento do Exoma , Adulto JovemRESUMO
A novel causative variant (c.608G>A, p.Arg203Gln) in PACS1.
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Sequência de Aminoácidos/genética , Deficiências do Desenvolvimento/genética , Exoma/genética , Proteínas de Transporte Vesicular/genética , Pré-Escolar , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Humanos , Masculino , FenótipoRESUMO
BCL11A encodes a zinc finger protein that is highly expressed in hematopoietic tissues and the brain, and that is known to function as a transcriptional repressor of fetal hemoglobin (HbF). Recently, de novo variants in BCL11A have been reported in individuals with intellectual disability syndrome without epilepsy. In this study, we performed whole-exome sequencing of 302 patients with epileptic encephalopathies (EEs), and identified 2 novel BCL11A variants, c.577delC (p.His193Metfs*3) and c.2351A>C (p.Lys784Thr). Both the patients shared major physical features characteristic of BCL11A-related intellectual disability syndrome, suggesting that characteristic physical features and the persistence of HbF should lead clinicians to suspect EEs caused by BCL11A pathogenic variants. Patient 1, with a frameshift variant, presented with Lennox-Gastaut syndrome, which expands the phenotypic spectrum of BCL11A haploinsufficiency. Patient 2, with a p.Lys784Thr variant, presented with West syndrome followed by drug-resistant focal seizures and more severe developmental disability. These 2 newly described patients contribute to delineating the associated, yet uncertain phenotypic characteristics of BCL11A disease-causing variants.
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Encefalopatias/genética , Proteínas de Transporte/genética , Epilepsia/genética , Deficiência Intelectual/genética , Proteínas Nucleares/genética , Adolescente , Encefalopatias/fisiopatologia , Criança , Epilepsia/fisiopatologia , Feminino , Mutação da Fase de Leitura/genética , Humanos , Recém-Nascido , Deficiência Intelectual/fisiopatologia , Síndrome de Lennox-Gastaut/genética , Síndrome de Lennox-Gastaut/fisiopatologia , Masculino , Proteínas Repressoras , Espasmos Infantis/genética , Espasmos Infantis/fisiopatologia , Sequenciamento do ExomaRESUMO
The seizure threshold 2 (SZT2) gene encodes a large, highly conserved protein that is associated with epileptogenesis. In mice, Szt2 is abundantly expressed in the central nervous system. Recently, biallelic SZT2 mutations were found in 7 patients (from 5 families) presenting with epileptic encephalopathy with dysmorphic features and/or non-syndromic intellectual disabilities. In this study, we identified by whole-exome sequencing compound heterozygous SZT2 mutations in 3 patients with early-onset epileptic encephalopathies. Six novel SZT2 mutations were found, including 3 truncating, 1 splice site and 2 missense mutations. The splice-site mutation resulted in skipping of exon 20 and was associated with a premature stop codon. All individuals presented with seizures, severe developmental delay and intellectual disabilities with high variability. Brain MRIs revealed a characteristic thick and short corpus callosum or a persistent cavum septum pellucidum in each of the 2 cases. Interestingly, in the third case, born to consanguineous parents, had unexpected compound heterozygous missense mutations. She showed microcephaly despite the other case and previous ones presenting with macrocephaly, suggesting that SZT2 mutations might affect head size.
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Epilepsia Generalizada/genética , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Espasmos Infantis/genética , Pré-Escolar , Epilepsia Generalizada/diagnóstico por imagem , Epilepsia Generalizada/patologia , Feminino , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia , Imageamento por Ressonância Magnética , Masculino , Mutação de Sentido Incorreto/genética , Linhagem , Sítios de Splice de RNA/genética , Espasmos Infantis/diagnóstico por imagem , Espasmos Infantis/patologia , Sequenciamento do ExomaRESUMO
The skeletal ciliopathies are a heterogeneous group of disorders with a significant clinical and genetic variability and the main clinical features are thoracic hypoplasia and short tubular bones. To date, 25 genes have been identified in association with skeletal ciliopathies. Mutations in the KIAA0753 gene have recently been associated with Joubert syndrome (JBTS) and orofaciodigital (OFD) syndrome. We report biallelic pathogenic variants in KIAA0753 in four patients with short-rib type skeletal dysplasia. The manifestations in our patients are variable and ranging from fetal lethal to viable and moderate skeletal dysplasia with narrow thorax and abnormal metaphyses. We demonstrate that KIAA0753 is expressed in normal fetal human growth plate and show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone. The importance of KIAA0753 for normal skeletal development is further confirmed by our findings that zebrafish embryos homozygous for a nonsense mutation in kiaa0753 display altered cartilage patterning.