Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 545
Filtrar
1.
bioRxiv ; 2023 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-37163057

RESUMO

The abundance of Lp(a) protein holds significant implications for the risk of cardiovascular disease (CVD), which is directly impacted by the copy number (CN) of KIV-2, a 5.5 kbp sub-region. KIV-2 is highly polymorphic in the population and accurate analysis is challenging. In this study, we present the DRAGEN KIV-2 CN caller, which utilizes short reads. Data across 166 WGS show that the caller has high accuracy, compared to optical mapping and can further phase ~50% of the samples. We compared KIV-2 CN numbers to 24 previously postulated KIV-2 relevant SNVs, revealing that many are ineffective predictors of KIV-2 copy number. Population studies, including USA-based cohorts, showed distinct KIV-2 CN, distributions for European-, African-, and Hispanic-American populations and further underscored the limitations of SNV predictors. We demonstrate that the CN estimates correlate significantly with the available Lp(a) protein levels and that phasing is highly important.

2.
Int J Cardiol ; 360: 83-90, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35609714

RESUMO

BACKGROUND: We assessed trends in aortic dissection (AD) death rates in 23 countries from 2000 to 2017. METHODS: We extracted AD mortality data for countries with high usability data from the World Health Organization (WHO) Mortality Database and from the Center for Disease Control (CDC) WONDER Database for the United States of America (USA). Age Standardized Death Rates (ASDRs) per 100,000 population were computed. Trends were assessed by locally weighted scatter plot smoother (LOWESS) regression. RESULTS: Between 2000 and 2017, ASDRs from AD decreased in Australia, Belgium, Croatia, Denmark, France, Italy, New Zealand, Norway, Sweden, the United Kingdom, and the USA for both sexes. Increasing AD mortality was observed in Austria, Czech Republic, Germany, Hungary, Israel, and Japan for both sexes. The largest absolute increases in ASDR were in Japan for men (+1.59) and women (+1.11). The largest percentage decreases were in Norway for men (-0.91) and in New Zealand (-0.6) for women. In 2017, the highest mortality rates were in Japan for both sexes (3.22 and 2.09, respectively). The lowest ASDR was in Kyrgyzstan for both sexes (0.16 and 0.10, respectively). ASDRs for AD in 2017 were higher for men than women in all countries included. Spain had the greatest difference between the gender's mortality rates with a 2.71-fold higher mortality average rate in men. CONCLUSION: We identified an overall decrease in AD mortality in most included countries, while an increase was noted in other countries including Israel and Japan.


Assuntos
Dissecção Aórtica , Dissecção Aórtica/diagnóstico , República Tcheca , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Mortalidade , Noruega , Reino Unido/epidemiologia , Estados Unidos , Organização Mundial da Saúde
4.
Life Sci ; 256: 117975, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32565251

RESUMO

Our goal is to understand how loss of circulating estrogens and estrogen replacement affect brain physiology and function, particularly in brain regions involved in cognitive processes. We recently conducted a large metabolomics study characterizing the effects of rodent models of menopause and treatment with estrogen receptor (ER) agonists on neurochemical targets in hippocampus, frontal cortex, and striatum. Here we characterize effects on levels of several key enzymes involved in glucose utilization and energy production, specifically phosphofructokinase, glyceraldehyde 3-phosphate dehydrogenase, and pyruvate dehydrogenase. We also evaluated effects on levels of ß-actin and α-tubulin, choline acetyltransferase (ChAT) activity, and levels of ATP citrate lyase. All experiments were conducted in young adult rats. Experiment 1 compared the effects of ovariectomy (OVX), a model of surgical menopause, and 4-vinylcyclohexene diepoxide (VCD)-treatments, a model of transitional menopause, with tissues collected at proestrus and at diestrus. Experiment 2 used a separate cohort of rats to evaluate the same targets in OVX and VCD-treated rats treated with estradiol or with selective ER agonists. Differences in the expression of metabolic enzymes between cycling animals and models of surgical and transitional menopause were detected. These differences were model-, region- and time- dependent, and were modulated by selective ER agonists. Collectively, the findings demonstrate that loss of ovarian function and ER agonist treatments have differing effects in OVX vs. VCD-treated rats. Differences may help to explain differences in the effects of estrogen treatments on brain function and cognition in women who have experienced surgical vs. transitional menopause.


Assuntos
Acetilcoenzima A/metabolismo , Encéfalo/metabolismo , Colina O-Acetiltransferase/metabolismo , Estrogênios/farmacologia , Menopausa/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Cicloexenos/toxicidade , Estradiol/sangue , Feminino , Menopausa/efeitos dos fármacos , Ovariectomia/efeitos adversos , Ratos , Ratos Sprague-Dawley , Compostos de Vinila/toxicidade
5.
Science ; 367(6477): 569-573, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32001654

RESUMO

Africa, the ancestral home of all modern humans, is the most informative continent for understanding the human genome and its contribution to complex disease. To better understand the genetics of schizophrenia, we studied the illness in the Xhosa population of South Africa, recruiting 909 cases and 917 age-, gender-, and residence-matched controls. Individuals with schizophrenia were significantly more likely than controls to harbor private, severely damaging mutations in genes that are critical to synaptic function, including neural circuitry mediated by the neurotransmitters glutamine, γ-aminobutyric acid, and dopamine. Schizophrenia is genetically highly heterogeneous, involving severe ultrarare mutations in genes that are critical to synaptic plasticity. The depth of genetic variation in Africa revealed this relationship with a moderate sample size and informed our understanding of the genetics of schizophrenia worldwide.


Assuntos
Esquizofrenia/etnologia , Esquizofrenia/genética , Transmissão Sináptica/genética , Fatores Etários , Transtorno Autístico/genética , Transtorno Bipolar/genética , Dopamina/fisiologia , Feminino , Variação Genética , Glutamina/fisiologia , Humanos , Masculino , Mutação , Vias Neurais/fisiopatologia , Esquizofrenia/fisiopatologia , Fatores Sexuais , África do Sul/etnologia , Sinapses/fisiologia , Ácido gama-Aminobutírico/fisiologia
6.
Br J Surg ; 105(4): 366-378, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29431856

RESUMO

BACKGROUND: Silent cerebral infarction is brain injury detected incidentally on imaging; it can be associated with cognitive decline and future stroke. This study investigated cerebral embolization, silent cerebral infarction and neurocognitive decline following thoracic endovascular aortic repair (TEVAR). METHODS: Patients undergoing elective or emergency TEVAR at Imperial College Healthcare NHS Trust and Guy's and St Thomas' NHS Foundation Trust between January 2012 and April 2015 were recruited. Aortic atheroma graded from 1 (normal) to 5 (mobile atheroma) was evaluated by preoperative CT. Patients underwent intraoperative transcranial Doppler imaging (TCD), preoperative and postoperative cerebral MRI, and neurocognitive assessment. RESULTS: Fifty-two patients underwent TEVAR. Higher rates of TCD-detected embolization were observed with greater aortic atheroma (median 207 for grade 4-5 versus 100 for grade 1-3; P = 0·042), more proximal landing zones (median 450 for zone 0-1 versus 72 for zone 3-4; P = 0·001), and during stent-graft deployment and contrast injection (P = 0·001). In univariable analysis, left subclavian artery bypass (ß coefficient 0·423, s.e. 132·62, P = 0·005), proximal landing zone 0-1 (ß coefficient 0·504, s.e. 170·57, P = 0·001) and arch hybrid procedure (ß coefficient 0·514, s.e. 182·96, P < 0·001) were predictors of cerebral emboli. Cerebral infarction was detected in 25 of 31 patients (81 per cent) who underwent MRI: 21 (68 per cent) silent and four (13 per cent) clinical strokes. Neurocognitive decline was seen in six of seven domains assessed in 15 patients with silent cerebral infarction, with age a significant predictor of decline. CONCLUSION: This study demonstrates a high rate of cerebral embolization and neurocognitive decline affecting patients following TEVAR. Brain injury after TEVAR is more common than previously recognized, with cerebral infarction in more than 80 per cent of patients.


Assuntos
Aorta Torácica/cirurgia , Infarto Cerebral/etiologia , Procedimentos Endovasculares , Embolia Intracraniana/etiologia , Transtornos Neurocognitivos/etiologia , Placa Aterosclerótica/cirurgia , Complicações Pós-Operatórias/etiologia , Idoso , Idoso de 80 Anos ou mais , Infarto Cerebral/diagnóstico , Infarto Cerebral/epidemiologia , Feminino , Seguimentos , Humanos , Incidência , Embolia Intracraniana/diagnóstico , Embolia Intracraniana/epidemiologia , Modelos Lineares , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Transtornos Neurocognitivos/diagnóstico , Transtornos Neurocognitivos/epidemiologia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Fatores de Risco
7.
Mol Cell Endocrinol ; 473: 156-165, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-29396126

RESUMO

Western blot is routinely used to quantify differences in the levels of target proteins in tissues. Standard methods typically use measurements of housekeeping proteins to control for variations in loading and protein transfer. This is problematic, however, when housekeeping proteins also are affected by experimental conditions such as injury, disease, and/or gonadal hormone manipulations. Our goal was to evaluate an alternative and perhaps superior method for conducting Western blot analysis of brain tissue homogenates from rats with distinct physiologically relevant gonadal hormone states. Tissues were collected from the hippocampus, frontal cortex, and striatum of young adult female rats that either were ovariectomized to model surgical menopause, or were treated with the ovatotoxin 4-vinylcyclohexene diepoxide (VCD) to model transitional menopause. Tissues also were collected from rats with a normal estrous cycle killed at proestrus when estradiol levels are high, and at diestrus when estradiol levels are low. Western blot detection of α-tubulin, ß-actin, and GAPDH was performed and were compared for sensitivity and reliability with a fluorescent total protein stain (REVERT®). Results show that the total protein stain was much less variable across samples and had a greater linear range than α-tubulin, ß-actin, or GAPDH. The stain was stable and easy to use, and did not interfere with the immunodetection or multiplexed detection of the housekeeping proteins. In addition, we show that normalization of our data to total protein, but not to GAPDH, revealed significant differences in α-tubulin expression in the hippocampus as a function of treatment, and that gel-to-gel consistency in measuring differences between paired samples run on multiple gels was significantly better when data were normalized to total protein than when normalized to GAPDH. These results demonstrate that the REVERT® total protein stain can be used in Western blot analysis of brain tissue homogenates to control for variations in loading and protein transfer, and provides significant advantages over the use of housekeeping proteins for quantifying changes in the levels of multiple target proteins.


Assuntos
Western Blotting/métodos , Encéfalo/metabolismo , Genes Essenciais , Gônadas/metabolismo , Hormônios/metabolismo , Proteínas/metabolismo , Coloração e Rotulagem/métodos , Animais , Eletroforese em Gel de Poliacrilamida , Feminino , Hormônios/sangue , Peso Molecular , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
8.
Diagn Microbiol Infect Dis ; 90(4): 241-247, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29329757

RESUMO

The accumulation of sequenced Francisella strains has made it increasingly apparent that the 16S rRNA gene alone is not enough to stratify the Francisella genus into precise and clinically useful classifications. Continued whole-genome sequencing of isolates will provide a larger base of knowledge for targeted approaches with broad applicability. Additionally, examination of genomic information on a case-by-case basis will help resolve outstanding questions regarding strain stratification. We report the complete genome sequence of a clinical isolate, designated here as F. novicida-like strain TCH2015, acquired from the lymph node of a 6-year-old male. Two features were atypical for F. novicida: exhibition of functional oxidase activity and additional gene content, including proposed virulence determinants. These differences, which could potentially impact virulence and clinical diagnosis, emphasize the need for more comprehensive methods to profile Francisella isolates. This study highlights the value of whole-genome sequencing, which will lead to a more robust database of environmental and clinical genomes and inform strategies to improve detection and classification of Francisella strains.


Assuntos
Francisella/classificação , Francisella/isolamento & purificação , Genótipo , Linfonodos/microbiologia , Tularemia/diagnóstico , Criança , DNA Bacteriano/química , DNA Bacteriano/genética , Francisella/genética , Genes Bacterianos , Variação Genética , Genoma Bacteriano , Humanos , Masculino , Oxirredutases/genética , Análise de Sequência de DNA , Fatores de Virulência/genética , Sequenciamento Completo do Genoma
9.
J Dent Res ; 97(1): 49-59, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28813618

RESUMO

Tooth agenesis is a common craniofacial abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been reported as contributing to the etiology. Here, we combined whole-exome sequencing, array-based genotyping, and linkage analysis to identify putative pathogenic variants in candidate disease genes for tooth agenesis in 10 multiplex Turkish families. Novel homozygous and heterozygous variants in LRP6, DKK1, LAMA3, and COL17A1 genes, as well as known variants in WNT10A, were identified as likely pathogenic in isolated tooth agenesis. Novel variants in KREMEN1 were identified as likely pathogenic in 2 families with suspected syndromic tooth agenesis. Variants in more than 1 gene were identified segregating with tooth agenesis in 2 families, suggesting oligogenic inheritance. Structural modeling of missense variants suggests deleterious effects to the encoded proteins. Functional analysis of an indel variant (c.3607+3_6del) in LRP6 suggested that the predicted resulting mRNA is subject to nonsense-mediated decay. Our results support a major role for WNT pathways genes in the etiology of tooth agenesis while revealing new candidate genes. Moreover, oligogenic cosegregation was suggestive for complex inheritance and potentially complex gene product interactions during development, contributing to improved understanding of the genetic etiology of familial tooth agenesis.


Assuntos
Anodontia/genética , Feminino , Ligação Genética/genética , Variação Genética/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Laminina/genética , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Masculino , Proteínas de Membrana/genética , Mutação de Sentido Incorreto/genética , Linhagem , Reação em Cadeia da Polimerase em Tempo Real , Turquia , Sequenciamento do Exoma/métodos , Proteínas Wnt/genética
11.
Eur J Vasc Endovasc Surg ; 53(3): 362-369, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28214128

RESUMO

OBJECTIVE: Stroke caused by cerebral embolization constitutes a principal risk during arch manipulation and thoracic endovascular aortic repair (TEVAR). This study investigates the incidence of cerebral embolization during catheter placement in the aortic arch, and compares robotic and manual techniques. METHODS: Intra-operative transcranial Doppler (TCD) was performed in 11 patients undergoing TEVAR. Wire and catheter placement in the arch was performed by two experienced operators. Manual and robotic catheter placement and removal were compared for each patient; 44 manoeuvres were studied in total. A conventional 5Fr pigtail catheter was used for manual cannulation via a 5Fr access sheath. The 6Fr/9Fr co-axial Magellan endovascular robotic system was used for robotic navigation operated from a remote workstation. The number of high intensity transient signals (HITS) detected by TCD during different stages of TEVAR was recorded. RESULTS: The median procedural embolization rate was 173 (interquartile range 97-240). There were significantly fewer HITS detected during robotic catheter placement with six in total (median 0, IQR 0-1), compared with 38 HITS (median 2, IQR 1-5) during manual catheter placement (p = .018). There were no HITS detected during robotic catheter removal by auto-retraction as per manufacturer instructions. On two occasions, however, when the robotic catheter system was removed manually without correcting for articulation, it resulted in one HIT in one case and 11 HITS in the second case. CONCLUSIONS: Robotic catheter placement is feasible during TEVAR, and results in significantly less cerebral embolization compared with manual techniques. The active manoeuvrability, control, and stability of the robotic system is likely to reduce contact with an atheromatous aortic arch wall, and thereby reduce dislodgement of particulate matter and result in less embolization. The importance of adhering to manufacturer instructions during use and removal of the robotic catheter is also highlighted.


Assuntos
Aorta Torácica/cirurgia , Implante de Prótese Vascular/instrumentação , Procedimentos Endovasculares/instrumentação , Embolia Intracraniana/prevenção & controle , Procedimentos Cirúrgicos Robóticos/instrumentação , Dispositivos de Acesso Vascular , Idoso , Aorta Torácica/diagnóstico por imagem , Aortografia/métodos , Prótese Vascular , Implante de Prótese Vascular/efeitos adversos , Angiografia por Tomografia Computadorizada , Procedimentos Endovasculares/efeitos adversos , Estudos de Viabilidade , Feminino , Humanos , Embolia Intracraniana/diagnóstico por imagem , Embolia Intracraniana/etiologia , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada Multidetectores , Fatores de Risco , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Stents , Fatores de Tempo , Resultado do Tratamento , Ultrassonografia Doppler Transcraniana
12.
Vascular ; 25(3): 266-271, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27688294

RESUMO

Purpose The aim of this paper is to report our experience of type II endoleak treatment after endovascular aneurysm repair with intra-arterial injection of the embolizing liquid material, Onyx liquid embolic system. Methods From 2005 to 2012, we performed a retrospective review of 600 patients, who underwent endovascular repair of an abdominal aortic aneurysm. During this period, 18 patients were treated with Onyx for type II endoleaks. Principal findings The source of the endoleak was the internal iliac artery in seven cases, inferior mesenteric artery in seven cases and lumbar arteries in four cases. Immediate technical success was achieved in all patients and no endoleak from the treated vessel recurred. During a mean follow-up of 19 months, no major morbidity or mortality occurred, and one-year survival was 100%. Conclusions Treatment of type II endoleaks with Onyx is safe and effective over a significant time period.


Assuntos
Aneurisma da Aorta Abdominal/cirurgia , Implante de Prótese Vascular/efeitos adversos , Dimetil Sulfóxido/administração & dosagem , Embolização Terapêutica/métodos , Endoleak/terapia , Procedimentos Endovasculares/efeitos adversos , Artéria Ilíaca , Vértebras Lombares/irrigação sanguínea , Artéria Mesentérica Inferior , Polivinil/administração & dosagem , Tantálio/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Angiografia Digital , Angiografia por Tomografia Computadorizada , Dimetil Sulfóxido/efeitos adversos , Combinação de Medicamentos , Embolização Terapêutica/efeitos adversos , Endoleak/diagnóstico por imagem , Endoleak/etiologia , Feminino , Humanos , Artéria Ilíaca/diagnóstico por imagem , Injeções Intra-Arteriais , Masculino , Artéria Mesentérica Inferior/diagnóstico por imagem , Polivinil/efeitos adversos , Estudos Retrospectivos , Tantálio/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
13.
J Evol Biol ; 29(2): 277-91, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26528622

RESUMO

Analyses of arthropod genomes have shown that the genes in the different innate humoral immune responses are conserved. These genes encode proteins that are involved in immune signalling pathways that recognize pathogens and activate immune responses. These immune responses include phagocytosis, encapsulation of the pathogen and production of effector molecules for pathogen elimination. So far, most studies have focused on insects leaving other major arthropod groups largely unexplored. Here, we annotate the immune-related genes of six arachnid genomes and present evidence for a conserved pattern of some immune genes, but also evolutionary changes in the arachnid immune system. Specifically, our results suggest that the family of recognition molecules of beta-1,3-glucanase-related proteins (ßGRPs) and the genes from the immune deficiency (IMD) signalling pathway have been lost in a common ancestor of arachnids. These findings are consistent with previous work suggesting that the humoral immune effector proteins are constitutively produced in arachnids in contrast to insects, where these have to be induced. Further functional studies are needed to verify this. We further show that the full haemolymph clotting cascade found in the horseshoe crab is retrieved in most arachnid genomes. Tetranychus lacks at least one major component, although it is possible that this cascade could still function through recruitment of a different protein. The gel-forming protein in horseshoe crabs, coagulogen, was not recovered in any of the arachnid genomes; however, it is possible that the arachnid clot consists of a related protein, spätzle, that is present in all of the genomes.


Assuntos
Aracnídeos/genética , Aracnídeos/imunologia , Genoma/genética , Imunidade Inata/genética , Sequência de Aminoácidos , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Aracnídeos/classificação , Proteínas Sanguíneas/genética , Defensinas/química , Defensinas/genética , Dosagem de Genes , Genômica , Hemolinfa/imunologia , Sistema Imunitário/imunologia , Domínios Proteicos/genética , Alinhamento de Sequência , Transdução de Sinais/genética
14.
Genome Announc ; 3(4)2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26272574

RESUMO

The bacterial pathogen Francisella tularensis was recently renewed as a tier-one select agent. F. tularensis subsp. tularensis (type A) and holarctica (type B) are of clinical relevance. Here, we report the complete genome of a virulent F. tularensis type B strain and describe its usefulness in comparative genomics.

15.
Mol Psychiatry ; 20(2): 176-82, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25666757

RESUMO

Cerebral palsy (CP) is a common, clinically heterogeneous group of disorders affecting movement and posture. Its prevalence has changed little in 50 years and the causes remain largely unknown. The genetic contribution to CP causation has been predicted to be ~2%. We performed whole-exome sequencing of 183 cases with CP including both parents (98 cases) or one parent (67 cases) and 18 singleton cases (no parental DNA). We identified and validated 61 de novo protein-altering variants in 43 out of 98 (44%) case-parent trios. Initial prioritization of variants for causality was by mutation type, whether they were known or predicted to be deleterious and whether they occurred in known disease genes whose clinical spectrum overlaps CP. Further, prioritization used two multidimensional frameworks-the Residual Variation Intolerance Score and the Combined Annotation-dependent Depletion score. Ten de novo mutations in three previously identified disease genes (TUBA1A (n=2), SCN8A (n=1) and KDM5C (n=1)) and in six novel candidate CP genes (AGAP1, JHDM1D, MAST1, NAA35, RFX2 and WIPI2) were predicted to be potentially pathogenic for CP. In addition, we identified four predicted pathogenic, hemizygous variants on chromosome X in two known disease genes, L1CAM and PAK3, and in two novel candidate CP genes, CD99L2 and TENM1. In total, 14% of CP cases, by strict criteria, had a potentially disease-causing gene variant. Half were in novel genes. The genetic heterogeneity highlights the complexity of the genetic contribution to CP. Function and pathway studies are required to establish the causative role of these putative pathogenic CP genes.


Assuntos
Paralisia Cerebral/genética , Heterogeneidade Genética , Predisposição Genética para Doença/genética , Adulto , Animais , Estudos de Coortes , Exoma , Feminino , Biblioteca Gênica , Idade Gestacional , Humanos , Masculino , Mutação , Pais , Análise de Sequência de DNA
16.
Med Eng Phys ; 36(9): 1176-84, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25070022

RESUMO

Aortic dissection is a life-threatening process in which the weakened wall develops a tear, causing separation of wall layers. The dissected layers separate the original true aortic lumen and a newly created false lumen. If untreated, the condition can be fatal. Flow rate in the false lumen is a key feature for false lumen patency, which has been regarded as one of the most important predictors of adverse early and later outcomes. Detailed flow analysis in the dissected aorta may assist vascular surgeons in making treatment decisions, but computational models to simulate flow in aortic dissections often involve several assumptions. The purpose of this study is to assess the computational models adopted in previous studies by comparison with in vivo velocity data obtained by means of phase-contrast magnetic resonance imaging (PC-MRI). Aortic dissection geometry was reconstructed from computed tomography (CT) images, while PC-MRI velocity data were used to define inflow conditions and to provide distal velocity components for comparison with the simulation results. The computational fluid dynamics (CFD) simulation incorporated a laminar-turbulent transition model, which is necessary for adequate flow simulation in aortic conditions. Velocity contours from PC-MRI and CFD in the two lumens at the distal plane were compared at four representative time points in the pulse cycle. The computational model successfully captured the complex regions of flow reversal and recirculation qualitatively, although quantitative differences exist. With a rigid wall assumption and exclusion of arch branches, the CFD model over-predicted the false lumen flow rate by 25% at peak systole. Nevertheless, an overall good agreement was achieved, confirming the physiological relevance and validity of the computational model for type B aortic dissection with a relatively stiff dissection flap.


Assuntos
Aneurisma Aórtico/fisiopatologia , Dissecção Aórtica/fisiopatologia , Simulação por Computador , Imageamento por Ressonância Magnética/métodos , Modelos Cardiovasculares , Dissecção Aórtica/patologia , Aneurisma Aórtico/patologia , Velocidade do Fluxo Sanguíneo , Diástole/fisiologia , Humanos , Hidrodinâmica , Masculino , Pessoa de Meia-Idade , Sístole/fisiologia , Tomografia Computadorizada por Raios X
17.
Clin Exp Immunol ; 178(3): 459-69, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25046553

RESUMO

In areas without newborn screening for severe combined immunodeficiency (SCID), disease-defining infections may lead to diagnosis, and in some cases, may not be identified prior to the first year of life. We describe a female infant who presented with disseminated vaccine-acquired varicella (VZV) and vaccine-acquired rubella infections at 13 months of age. Immunological evaluations demonstrated neutropenia, isolated CD4 lymphocytopenia, the presence of CD8(+) T cells, poor lymphocyte proliferation, hypergammaglobulinaemia and poor specific antibody production to VZV infection and routine immunizations. A combination of whole exome sequencing and custom-designed chromosomal microarray with exon coverage of primary immunodeficiency genes detected compound heterozygous mutations (one single nucleotide variant and one intragenic copy number variant involving one exon) within the IL7R gene. Mosaicism for wild-type allele (20-30%) was detected in pretransplant blood and buccal DNA and maternal engraftment (5-10%) demonstrated in pretransplant blood DNA. This may be responsible for the patient's unusual immunological phenotype compared to classical interleukin (IL)-7Rα deficiency. Disseminated VZV was controlled with anti-viral and immune-based therapy, and umbilical cord blood stem cell transplantation was successful. Retrospectively performed T cell receptor excision circle (TREC) analyses completed on neonatal Guthrie cards identified absent TREC. This case emphasizes the danger of live viral vaccination in severe combined immunodeficiency (SCID) patients and the importance of newborn screening to identify patients prior to high-risk exposures. It also illustrates the value of aggressive pathogen identification and treatment, the influence newborn screening can have on morbidity and mortality and the significant impact of newer genomic diagnostic tools in identifying the underlying genetic aetiology for SCID patients.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Varicela/etiologia , Linfopenia/etiologia , Mutação , Receptores de Interleucina-7/genética , Rubéola (Sarampo Alemão)/etiologia , Imunodeficiência Combinada Severa/genética , Vacinação/efeitos adversos , Variações do Número de Cópias de DNA , Exoma , Feminino , Humanos , Lactente , Análise de Sequência com Séries de Oligonucleotídeos , Imunodeficiência Combinada Severa/imunologia
18.
Horm Behav ; 66(2): 339-45, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24928571

RESUMO

We have hypothesized that estradiol enhances basal forebrain cholinergic function and cognitive performance, at least in part, via activation of the novel estrogen receptor GPR30. Here we evaluated the effects of estradiol, G-1 (a selective GPR30 agonist), and tamoxifen (TAM; an ERα/ERß antagonist that also acts as a GPR30 agonist), on acetylcholine (ACh) release in the hippocampus, as well as the ability to block the effects of 17ß-estradiol (E) or TAM with the GPR30 antagonist G-15. Note that G-1 was included to evaluate the effects of selectively activating GPR30, whereas TAM was included to differentiate effects of E associated with activation of GPR30 vs. ERα or ERß. The study was designed to test effects on potassium-stimulated release, as well as on ACh release stimulated by feeding. Effects of feeding were included because the tasks we used previously to demonstrate beneficial effects of E on cognitive performance were motivated by food reward, and we hypothesized that E may enhance performance by increasing ACh release in association with that reward. Ovariectomized rats were treated for 1week, and ACh release was evaluated using in vivo microdialysis. In addition, rats were fed at the same time daily for several days and were fasted overnight prior to microdialysis. For each rat, ACh release was evaluated under basal conditions, in response to feeding, and in response to elevated potassium. Both feeding and elevated potassium increased ACh release in the hippocampus. In response to feeding, E, G-1, and TAM all significantly increased the percent change in release. The effects of E and TAM were blocked by G-15, and the effects of combining E+TAM did not differ significantly from the effects of E or TAM alone. In response to elevated potassium, E, and TAM significantly increased the percent change in ACh release. G-1 produced a slightly lesser effect. The effect of TAM was reduced by G-15, but the effect of E was not. These findings suggest that activation of GPR30 is both necessary and sufficient to account for the effects of E on ACh release associated with feeding. In contrast, activation of GPR30 appears to be sufficient, but may not be necessary for increased release associated with elevated potassium. The changes associated with feeding are consistent with the effects of E, G-1 and G-15 on acquisition of a spatial learning task previously described. These data confirm and extend previous reports, and support a hypothesis wherein E treatment can improve learning on specific tasks by activating GPR30 and enhancing ACh release in association with food reward.


Assuntos
Acetilcolina/metabolismo , Estradiol/farmacologia , Hipocampo/metabolismo , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Acetilcolina/farmacologia , Animais , Condicionamento Operante/efeitos dos fármacos , Estradiol/metabolismo , Antagonistas de Estrogênios/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Feminino , Hipocampo/efeitos dos fármacos , Potássio/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Tamoxifeno/farmacologia
19.
Eur J Vasc Endovasc Surg ; 47(5): 462-9, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24594295

RESUMO

OBJECTIVES: Identification of those patients with high-risk asymptomatic carotid plaques remains an elusive but essential step in stroke prevention. Inflammation is a key process in plaque destabilization and the propensity of atherosclerotic lesions to cause clinical sequelae. There is currently no clinical imaging technique available to assess the degree of inflammation associated with plaques. This study aims at visualizing and characterizing atherosclerosis using antibody-conjugated superparamagnetic iron oxide (SPIO) particles as an MRI probe to assess inflammation in human atherosclerotic plaques. METHODS: Atherosclerotic plaques were collected from 20 consecutive patients (n=10 from symptomatic patients, n=10 from asymptomatic patients) undergoing carotid endarterectomy (CEA) for extracranial high-grade internal carotid artery (ICA) stenosis (>70% luminal narrowing). Inflammatory markers on human atherosclerotic plaques were detected and characterized by ex vivo magnetic resonance imaging (MRI) using anti-VCAM-1 antibody and anti-E-selectin antibody-conjugated SPIO with confirmatory immunohistochemistry. RESULTS: Inflammation associated with human ex vivo atherosclerotic plaques could be imaged using dual antibody-conjugated SPIO by MRI. Symptomatic plaques could be distinguished from asymptomatic ones by the degree of inflammation, and the MR contrast effect was significantly correlated with the degree of plaque inflammation (r=.64, p<.001). The asymptomatic plaque population exhibited heterogeneity in terms of inflammation. The dual-targeted SPIO-induced MR signal not only tracked closely with endothelial activation (i.e. endothelial expression of VCAM-1 and E-selectin), but also reflected the macrophage burden within plaque lesions, offering a potential imaging tool for quantitative MRI of inflammatory activity in atherosclerosis. CONCLUSIONS: These functional molecular MRI probes constitute a novel imaging tool for ex vivo characterization of atherosclerosis at a molecular level. Further development and translation into the clinical arena will facilitate more accurate risk stratification in carotid artery disease in the future.


Assuntos
Estenose das Carótidas/diagnóstico , Selectina E/metabolismo , Compostos Férricos , Inflamação/metabolismo , Imageamento por Ressonância Magnética/métodos , Placa Aterosclerótica/diagnóstico , Molécula 1 de Adesão de Célula Vascular/metabolismo , Idoso , Biomarcadores/metabolismo , Estenose das Carótidas/etiologia , Estenose das Carótidas/cirurgia , Meios de Contraste , Endarterectomia das Carótidas , Feminino , Humanos , Imuno-Histoquímica , Inflamação/diagnóstico , Masculino , Placa Aterosclerótica/complicações , Placa Aterosclerótica/metabolismo , Reprodutibilidade dos Testes
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...