RESUMO
BACKGROUND: Variants in APOE and PSEN1 (encoding apolipoprotein E and presenilin 1, respectively) alter the risk of Alzheimer's disease. We previously reported a delay of cognitive impairment in a person with autosomal dominant Alzheimer's disease caused by the PSEN1 E280A variant who also had two copies of the apolipoprotein E3 Christchurch variant (APOE3 Ch). Heterozygosity for the APOE3 Ch variant may influence the age at which the onset of cognitive impairment occurs. We assessed this hypothesis in a population in which the PSEN1 E280A variant is prevalent. METHODS: We analyzed data from 27 participants with one copy of the APOE3 Ch variant among 1077 carriers of the PSEN1 E280A variant in a kindred from Antioquia, Colombia, to estimate the age at the onset of cognitive impairment and dementia in this group as compared with persons without the APOE3 Ch variant. Two participants underwent brain imaging, and autopsy was performed in four participants. RESULTS: Among carriers of PSEN1 E280A who were heterozygous for the APOE3 Ch variant, the median age at the onset of cognitive impairment was 52 years (95% confidence interval [CI], 51 to 58), in contrast to a matched group of PSEN1 E280A carriers without the APOE3 Ch variant, among whom the median age at the onset was 47 years (95% CI, 47 to 49). In two participants with the APOE3 Ch and PSEN1 E280A variants who underwent brain imaging, 18F-fluorodeoxyglucose positron-emission tomographic (PET) imaging showed relatively preserved metabolic activity in areas typically involved in Alzheimer's disease. In one of these participants, who underwent 18F-flortaucipir PET imaging, tau findings were limited as compared with persons with PSEN1 E280A in whom cognitive impairment occurred at the typical age in this kindred. Four studies of autopsy material obtained from persons with the APOE3 Ch and PSEN1 E280A variants showed fewer vascular amyloid pathologic features than were seen in material obtained from persons who had the PSEN1 E280A variant but not the APOE3 Ch variant. CONCLUSIONS: Clinical data supported a delayed onset of cognitive impairment in persons who were heterozygous for the APOE3 Ch variant in a kindred with a high prevalence of autosomal dominant Alzheimer's disease. (Funded by Good Ventures and others.).
Assuntos
Doença de Alzheimer , Apolipoproteína E3 , Presenilina-1 , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Idade de Início , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Apolipoproteína E3/genética , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Colômbia , Família , Genes Dominantes , Heterozigoto , Tomografia por Emissão de Pósitrons , Presenilina-1/genética , Estudos RetrospectivosRESUMO
Highly penetrant autosomal dominant Alzheimer's disease (ADAD) comprises a distinct disease entity as compared to the far more prevalent form of AD in which common variants collectively contribute to risk. The downstream pathways that distinguish these AD forms in specific cell types have not been deeply explored. We compared single-nucleus transcriptomes among a set of 27 cases divided among PSEN1-E280A ADAD carriers, sporadic AD, and controls. Autophagy genes and chaperones clearly defined the PSEN1-E280A cases compared to sporadic AD. Spatial transcriptomics validated the activation of chaperone-mediated autophagy genes in PSEN1-E280A. The PSEN1-E280A case in which much of the brain was spared neurofibrillary pathology and harbored a homozygous APOE3-Christchurch variant revealed possible explanations for protection from AD pathology including overexpression of LRP1 in astrocytes, increased expression of FKBP1B, and decreased PSEN1 expression in neurons. The unique cellular responses in ADAD and sporadic AD require consideration when designing clinical trials.
Assuntos
Doença de Alzheimer , Presenilina-1 , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Humanos , Presenilina-1/genética , Masculino , Feminino , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Análise de Sequência de RNA/métodos , Autofagia/genética , Transcriptoma , Idoso , Neurônios/metabolismo , Neurônios/patologia , Pessoa de Meia-Idade , Astrócitos/metabolismo , Astrócitos/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Proteínas de Ligação a Tacrolimo/genética , Idoso de 80 Anos ou mais , Análise de Célula ÚnicaRESUMO
We characterized the world's second case with ascertained extreme resilience to autosomal dominant Alzheimer's disease (ADAD). Side-by-side comparisons of this male case and the previously reported female case with ADAD homozygote for the APOE3 Christchurch (APOECh) variant allowed us to discern common features. The male remained cognitively intact until 67 years of age despite carrying a PSEN1-E280A mutation. Like the APOECh carrier, he had extremely elevated amyloid plaque burden and limited entorhinal Tau tangle burden. He did not carry the APOECh variant but was heterozygous for a rare variant in RELN (H3447R, termed COLBOS after the Colombia-Boston biomarker research study), a ligand that like apolipoprotein E binds to the VLDLr and APOEr2 receptors. RELN-COLBOS is a gain-of-function variant showing stronger ability to activate its canonical protein target Dab1 and reduce human Tau phosphorylation in a knockin mouse. A genetic variant in a case protected from ADAD suggests a role for RELN signaling in resilience to dementia.
Assuntos
Doença de Alzheimer , Animais , Feminino , Humanos , Masculino , Camundongos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Heterozigoto , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Transdução de SinaisRESUMO
Resumen Se presenta el caso de una mujer de 67 años, con antecedentes de hipertensión arterial y obesidad, que acudió a urgencias por tos, fatiga, fiebre y disnea. Durante la monitorización se documentó elevación del segmento ST anterolateral e inferior y elevación de troponina; la arteriografía coronaria no evidenció lesiones significativas; en el ventriculograma y en el ecocardiograma transtorácico se documentó acinesia apical. Se confirmó RT-PCR positiva para SARS-CoV-2; se consideró como diagnóstico síndrome de takotsubo.
Abstract A 67-years-old woman with hypertension, obesity as previous diseases, presented to the emergency department due to cough, fatigue, fever, and dyspnea. ST-segment elevation was visualized during monitoring, troponin was positive, the coronary angiography was negative; the ventriculogram and transthoracic echocardiogram documented apical akinesia. The RT-PCR was positive for SARS CoV-2; the diagnosis was takotsubo-syndrome.
RESUMO
Hypertrophic cardiomyopathy is the more commonly (60 to 70 percent) genetically determined disease of the heart muscle caused by mutations in one of several sarcomere genes that encode components of the heart's contractile apparatus. It is characterized by disproportionate hypertrophy in the absence of a secondary cause. The clinical presentation is variable, ranging from asymptomatic to heart failure or sudden cardiac death. Hypertrophy and abnormal ventricular configuration can result in dynamic left ventricular outflow obstruction in most cases. The goal of therapeutic interventions is largely to reduce dynamic obstruction, with different therapeutic options encompassing risk stratification for sudden death, genetic screening, lifestyle modifications, and drugs. A case of hypertrophic septal cardiomyopathy, a fairly frequent and under-diagnosed entity, is discussed below.
RESUMO
BACKGROUND: Chromosomal region 7q21.3 comprises approximately 5.2 mega base pairs that include genes DLX5/6, SHFM1, and DYNC1I1 associated with split hand/split foot malformation 1. So far, there are reports of eight families with deletion of DYNC1I1 and preserved DLX5/6 associated with ectrodactyly. From these families, only three patients did not present ectrodactyly and, unlike our patient, no other cases have been described as having craniofacial dysmorphology, mitral valve prolapse, kyphoscoliosis, inguinal herniae, or personality disorder. There is no designation described in the literature for patients with syndromic manifestations without ectrodactyly, which hinders diagnosis. CASE PRESENTATION: We report the case of a 44-year-old mestizo (combined European and Amerindian descent) man with a 3191 kilo base pairs deletion and International System for Human Cytogenetic Nomenclature array 7q21.3 (93,389,222-96,579,845)x1. Clinical manifestations included micrognathia, retrognathia, wormian bones, auditory canal stenosis, depressed nasal bridge, epicanthal fold, fullness of upper eyelid, long philtrum, low-set ears, sensorineural hearing loss, kyphoscoliosis, bilateral inguinal herniae, mild mitral valve prolapse, and paranoid personality disorder. His isolated DNA was analyzed using a CytoScan HD Microarray system. Chromosome Analysis Suite software was utilized for the microarray analysis. All copy number changes were determined using the human genome build 19 (hg19/NCBI build 37). CONCLUSIONS: Cases of deletions within chromosome 7q21.3 that include the split hand/split foot malformation 1 region represent a diagnostic challenge when not presenting ectrodactyly despite being syndromic. Due to the heterogeneity of the region, a better method to group and classify these patients is needed to facilitate their clinical diagnosis. For this purpose, we suggest that patients with 7q21.3 deletion including DYNC1I1 and preserved DLX5/6 without ectrodactyly, accompanied by craniofacial dysmorphology, personality disorder, hearing loss, musculoskeletal disorder, inguinal herniae and/or mitral valve prolapse be referred to by the eponym Ramos-Martínez syndrome.
Assuntos
Anormalidades Múltiplas/genética , Dineínas do Citoplasma/genética , Transtornos Paranoides/genética , Complexo de Endopeptidases do Proteassoma/genética , Anormalidades Múltiplas/fisiopatologia , Anormalidades Múltiplas/psicologia , Adulto , Aberrações Cromossômicas , Deleção Cromossômica , Cromossomos Humanos Par 7 , Surdez , Humanos , Masculino , Transtornos Paranoides/psicologiaRESUMO
El diagnóstico de infarto agudo de miocardio en presencia de bloqueo de rama izquierda constituye un reto y hasta ahora los criterios de Sgarbossa eran la única herramienta disponible a pesar de las limitaciones conocidas. Una nueva regla diagnóstica puede disminuir la incertidumbre y con ello mejorar la selección de pacientes candidatos a reperfusión temprana, aunque se requiere más investigación para validarla.
The diagnosis of acute myocardial infarction in presence of left bundle branch block is a challenging one, and so far Sgarbossa criteria are the only tool available despite the known limitations. A new diagnostic rule can reduce our diagnostic uncertainty and thereby improve patient selection candidates for an early reperfusion, but so far research is needed to validate.
Assuntos
Bloqueio de Ramo , Diagnóstico , Infarto do MiocárdioRESUMO
Hace más de cuarenta años se describió el posible daño relacionado con la reperfusión, el cual podría explicar hasta el 50% del área total infartada. A finales de los ochenta se describió un mecanismo innato de protección frente a la lesión por isquemia-reperfusión, que se denominó acondicionamiento isquémico. En las últimas décadas, no sólo se han descrito diversos tipos de acondicionamiento sino que se han llevado a cabo experimentos clínicos en humanos, con resultados iniciales alentadores en cuanto a reducción del área infartada. Sin embargo, aún falta por demostrar si la reducción de la lesión por reperfusión tiene impacto en la mortalidad; las investigaciones actuales permitirán aclarar este interrogante en un futuro cercano.
The potential damage associated with reperfusion, which could explain up to 50% of the total area infarcted was described over fourty years ago. An innate mechanism of protection against ischemia-reperfusion injury was described in the late 80's which was called ischemic conditioning. Not just various types of conditioning have been described in the last decades, but also human clinical experiments with encouraging initial results in the reduction of the infarcted area have been conducted. However, it is not still demonstrated whether the reduction of reperfusion injury has an impact on mortality. The current research will allow to clarify this unanswered question in the near future.
Assuntos
Traumatismo por Reperfusão , Isquemia , Ferimentos e Lesões , MortalidadeRESUMO
El objetivo del presente estudio fue detectar la presencia de Salmonella sp. en 30 tortugas motelo (Geochelone denticulata) de un zoocriadero de la zona de Iquitos, Perú. Las muestras de heces se obtuvieron por hisopado rectal y se procesaron mediante pruebas de cultivo bacteriológico y bioquímicas. El 6.7% de las muestras fueron positivas a Salmonellasp., donde de la tipificación dio como resultado Salmonella enterica subespecie enterica serotipo typhimurium.
The objective of the present study was to detect the presence of Salmonella spp. in 30 motelo turtles (Geochelone denticulata) in a zoo of the Iquitos region, Peru. Fecal samples were obtained by rectal swaps and processed by bacteriological and biochemical cultivation tests. The results showed that 6.7% of the samples were positive to Salmonella spp. and the typing indicated Salmonella enterica subspecies enterica serotype typhimurium.
Assuntos
Animais , Criação de Animais Domésticos , Enterobacteriaceae , Salmonella , Tartarugas , Técnicas de Tipagem Bacteriana , PeruRESUMO
El síndrome de buried bumper es una complicación mayor de la gastrostomía endoscópica, rara vez descrita. Dentro de la fisiopatología se encuentra la isquemia de la mucosa gástrica por una excesiva presión por los topes que fijan la gastrostomía. Sus manifestaciones clínicas que dependen de la profundidad de migración del tope van desde la ausencia de síntomas, extravasación de la nutrición enteral siendo el más frecuente hasta cuadros de peritonitis. Las diversas modalidades de tratamiento descritas se basan en la profundidad de migración del tope valorado endoscópicamente. Se describe el uso exitoso de la ecoendosonografia para la estimación de la profundidad de la migración, cuando no se puede visualizar el tope interno endoscópicamente y se propone un algoritmo de manejo basado en esta técnica