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1.
Am J Hum Genet ; 107(2): 364-373, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32707086

RESUMO

We report bi-allelic pathogenic HPDL variants as a cause of a progressive, pediatric-onset spastic movement disorder with variable clinical presentation. The single-exon gene HPDL encodes a protein of unknown function with sequence similarity to 4-hydroxyphenylpyruvate dioxygenase. Exome sequencing studies in 13 families revealed bi-allelic HPDL variants in each of the 17 individuals affected with this clinically heterogeneous autosomal-recessive neurological disorder. HPDL levels were significantly reduced in fibroblast cell lines derived from more severely affected individuals, indicating the identified HPDL variants resulted in the loss of HPDL protein. Clinical presentation ranged from severe, neonatal-onset neurodevelopmental delay with neuroimaging findings resembling mitochondrial encephalopathy to milder manifestation of adolescent-onset, isolated hereditary spastic paraplegia. All affected individuals developed spasticity predominantly of the lower limbs over the course of the disease. We demonstrated through bioinformatic and cellular studies that HPDL has a mitochondrial localization signal and consequently localizes to mitochondria suggesting a putative role in mitochondrial metabolism. Taken together, these genetic, bioinformatic, and functional studies demonstrate HPDL is a mitochondrial protein, the loss of which causes a clinically variable form of pediatric-onset spastic movement disorder.


Assuntos
Encefalopatias/genética , Proteínas Mitocondriais/genética , Doenças Neurodegenerativas/genética , Paraplegia Espástica Hereditária/genética , Adolescente , Adulto , Alelos , Sequência de Aminoácidos , Criança , Feminino , Humanos , Masculino , Mitocôndrias/genética , Linhagem , Fenótipo , Adulto Jovem
2.
Basic Res Cardiol ; 117(1): 16, 2022 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-35353230

RESUMO

Emergency hematopoiesis is the driving force of the inflammatory response to myocardial infarction (MI). Increased proliferation of hematopoietic stem and progenitor cells (LSK) after MI enhances cell production in the bone marrow (BM) and replenishes leukocyte supply for local cell recruitment to the infarct. Decoding the regulation of the inflammatory cascade after MI may provide new avenues to improve post-MI remodeling. In this study, we describe the influence of adenosine diphosphate (ADP)-dependent P2Y12-mediated signaling on emergency hematopoiesis and cardiac remodeling after MI. Permanent coronary ligation was performed to induce MI in a murine model. BM activation, inflammatory cell composition and cardiac function were assessed using global and platelet-specific gene knockout and pharmacological inhibition models for P2Y12. Complementary in vitro studies allowed for investigation of ADP-dependent effects on LSK cells. We found that ADP acts as a danger signal for the hematopoietic BM and fosters emergency hematopoiesis by promoting Akt phosphorylation and cell cycle progression. We were able to detect P2Y12 in LSK, implicating a direct effect of ADP on LSK via P2Y12 signaling. P2Y12 knockout and P2Y12 inhibitor treatment with prasugrel reduced emergency hematopoiesis and the excessive inflammatory response to MI, translating to lower numbers of downstream progeny and inflammatory cells in the blood and infarct. Ultimately, P2Y12 inhibition preserved cardiac function and reduced chronic adverse cardiac remodeling after MI. P2Y12-dependent signaling is involved in emergency hematopoiesis after MI and fuels post-ischemic inflammation, proposing a novel, non-canonical value for P2Y12 antagonists beyond inhibition of platelet-mediated atherothrombosis.


Assuntos
Infarto do Miocárdio , Animais , Hematopoese , Leucócitos , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/metabolismo , Células-Tronco/metabolismo
3.
Transpl Infect Dis ; 24(3): e13821, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35247208

RESUMO

BACKGROUND: Vancomycin-resistant enterococci (VRE) colonization is common in liver transplant recipients and has been associated with worse posttransplant outcomes. METHODS: We conducted a retrospective cohort study at the University of Alberta Hospital including patients who underwent a liver transplant between September 2014 and December 2017. RESULTS: Of 343 patients, 68 (19.8%) had pretransplant VRE colonization and 27 (27/275, 9.8%) acquired VRE posttransplant, 67% were males and the median age was 56.5 years. VRE colonized patients at baseline had higher MELD scores and required longer posttransplant hospitalization. VRE colonization was associated with increased risk of early acute kidney injury (AKI) (64% vs. 52%, p = .044), clinically significant bacterial/fungal infection (29% vs. 17%, p = .012) and invasive VRE infection (5% vs. 1%, p = .017). Mortality at 2 years was 13% in VRE-colonized versus 7% in noncolonized (p = .085). On multivariate analysis, VRE colonization increased the risk of posttransplant AKI (HR 1.504, 95% CI: 1.077-2.100, p = .017) and clinically significant bacterial or fungal infection at 6 months (HR 2.038, 95% CI: 1.222-3.399, p = .006), and was associated with nonsignificant trend toward increased risk of mortality at 2 years posttransplant (HR 1.974 95% CI 0.890-4.378; p = .094). CONCLUSIONS: VRE colonization in liver transplant patients is associated with increased risk of early AKI, clinically significant infections, and a trend toward increased mortality at 2 years.


Assuntos
Injúria Renal Aguda , Infecções por Bactérias Gram-Positivas , Transplante de Fígado , Enterococos Resistentes à Vancomicina , Injúria Renal Aguda/etiologia , Antibacterianos/uso terapêutico , Feminino , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Transplante de Fígado/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
4.
Clin Infect Dis ; 72(5): 845-852, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32025704

RESUMO

BACKGROUND: Cytomegalovirus (CMV) is the most common opportunistic pathogen, following solid organ transplantation (SOT), that leads to direct and indirect effects. The aim of this study was to assess the impact of CMV exposure at transplantation on the rate of posttransplant thrombotic events (TEs). METHODS: We conducted a retrospective cohort study of patients transplanted at the University of Alberta Hospital between July 2005 and January 2018. We included adult SOT CMV-seronegative recipients at transplantation who received an allograft from either a seropositive donor (D+/R-) or a seronegative donor (D-/R-). RESULTS: A total of 392 SOT recipients were included: 151 (39%) liver, 188 (48%) kidney, 45 (11%) pancreas, and 8 (2%) other transplants. The mean age was 47 years, 297 (76%) were males, and 181 (46%) had a CMV D+/R- donor. Patients in the CMV D+/R- cohort were slightly older (51 years versus 48 years in the D-/R- cohort; P = .036), while other variables, including cardiovascular risk factors and pretransplant TEs, were not different between groups. Overall, TEs occurred in 35 (19%) patients in the CMV D+/R- group, versus 21 (10%) in the CMV D-/R- group, at 5 years of follow-up (P = .008); the incidence rates per 100 transplant months were 5.12 and 1.02 in the CMV D+/R- and CMV D-/R- groups, respectively (P = .003). After adjusting for potential confounders with a Cox regression model, a CMV D+/R- transplantation was independently associated with an increased risk of a TE over 5 years (adjusted hazard ratio, 3.027; 95% confidence interval, 1.669-5.488). CONCLUSIONS: A CMV D+/R- transplantation is associated with an increased risk of a TE posttransplantation.


Assuntos
Infecções por Citomegalovirus , Transplante de Órgãos , Adulto , Antivirais/uso terapêutico , Citomegalovirus , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transplante de Órgãos/efeitos adversos , Estudos Retrospectivos
5.
Am J Med Genet A ; 185(1): 15-25, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33029936

RESUMO

Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5' end and 3' extension of precursor-U8. There was no obvious genotype-phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3' end processing of precursor-U8.


Assuntos
Calcinose/genética , Estudos de Associação Genética , Leucoencefalopatias/genética , RNA Nucleolar Pequeno/genética , Adolescente , Adulto , Idoso , Animais , Calcinose/complicações , Calcinose/patologia , Criança , Pré-Escolar , Consanguinidade , Modelos Animais de Doenças , Feminino , Heterozigoto , Humanos , Lactente , Recém-Nascido , Leucoencefalopatias/complicações , Leucoencefalopatias/patologia , Masculino , Pessoa de Meia-Idade , Patologia Molecular , Adulto Jovem , Peixe-Zebra/genética
6.
Liver Int ; 39(8): 1437-1447, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30919578

RESUMO

BACKGROUND AND AIMS: Cirrhosis is associated with dysbiosis, but its functional consequences are still largely unknown. Short-chain fatty acids (SCFAs) account for physiological interactions between the gut microbiota and host. Our aim was to assess the impact of cirrhotic dysbiosis on the production of SCFAs. METHODS: Seventeen patients with cirrhosis and 17 controls were selected. Microbiota composition in faecal samples was assessed by next-generation 16S rRNA gene sequencing. SCFAs were measured with GC-MS in faecal samples and after in vitro batch fermentations using arabinoxylan, resistant starch, pectin, and lactulose as substrates. RESULTS: Among the 17 cirrhotic patients (mean age 58, eight males), six, nine and two were, respectively, Child-Pugh class A, B and C. Eleven patients were on oral antibiotics, 11 on lactulose and 13 on proton pump inhibitors. Cirrhotic patients showed marked differences in the composition and diversity of gut microbiome when compared to controls, that were more pronounced with increased severity. Stool samples from cirrhotic patients showed lower SCFAs content and reduced capacity to produce SCFAs in batch fermentations, with butyrate production being the most abnormal. These functional aberrancies were more pronounced with greater liver disease severity. Abundance of Ruminococcus faecis (in family Ruminococcaceae), Faecalicatena fissicatena and Fusicatenibacter saccharivorans (in family Lachnospiraceae) was positively correlated with the SCFAs production. CONCLUSION: Cirrhotic dysbiosis is associated with a decreased capacity to ferment non-digestible carbohydrates into SCFAs, especially into butyrate. These functional abnormalities are more pronounced as disease progresses. These results might inform the design of gut-targeted therapies for cirrhosis.


Assuntos
Metabolismo dos Carboidratos , Disbiose/metabolismo , Ácidos Graxos Voláteis/metabolismo , Microbioma Gastrointestinal , Cirrose Hepática/microbiologia , Estudos de Casos e Controles , Disbiose/virologia , Fezes/microbiologia , Feminino , Humanos , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade
7.
Adv Sci (Weinh) ; 10(18): e2207455, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37092588

RESUMO

Recent global events such as COVID-19 pandemic amid rising rates of chronic lung diseases highlight the need for safer, simpler, and more available treatments for respiratory failure, with increasing interest in extracorporeal membrane oxygenation (ECMO). A key factor limiting use of this technology is the complexity of the blood circuit, resulting in clotting and bleeding and necessitating treatment in specialized care centers. Microfluidic oxygenators represent a promising potential solution, but have not reached the scale or performance required for comparison with conventional hollow fiber membrane oxygenators (HFMOs). Here the development and demonstration of the first microfluidic respiratory assist device at a clinical scale is reported, demonstrating efficient oxygen transfer at blood flow rates of 750 mL min⁻1 , the highest ever reported for a microfluidic device. The central innovation of this technology is a fully 3D branching network of blood channels mimicking key features of the physiological microcirculation by avoiding anomalous blood flows that lead to thrombus formation and blood damage in conventional oxygenators. Low, stable blood pressure drop, low hemolysis, and consistent oxygen transfer, in 24-hour pilot large animal experiments are demonstrated - a key step toward translation of this technology to the clinic for treatment of a range of lung diseases.


Assuntos
COVID-19 , Oxigenação por Membrana Extracorpórea , Animais , Humanos , Microfluídica , Pandemias , Oxigênio
8.
Expert Rev Anti Infect Ther ; 17(5): 363-373, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30977692

RESUMO

Introduction: Vancomycin-resistant enterococci (VRE) colonization and subsequent infection results in increased morbidity, mortality and use of health-care resources. The burden of VRE colonization in liver transplant candidates and recipients is significant. VRE colonization is a marker of gut dysbiosis and its impact on the microbiota-liver axis, may negatively affect graft function and result in negative outcomes pre- and post-transplantation. Areas covered: In this article we describe the epidemiology of VRE colonization, risk factors for VRE infection, health-care costs associated with VRE, with a focus on the impact of VRE colonization on liver transplant recipients' fecal microbiota, the therapeutic strategies for VRE decolonization and proposed pathophysiologic mechanisms of VRE colonization in liver transplant recipients. Expert opinion: VRE colonization results in a significant loss of bacterial microbiome diversity. This may have metabolic consequences, with low production of short-chain fatty acids which may, in turn, result in immune dysregulation. As antibiotics have failed to decolonize the gut, alternative strategies such as fecal microbiota transplantation (FMT), stimulation of intestinal antimicrobial peptides and phage therapy warrants future studies.


Assuntos
Antibacterianos/administração & dosagem , Infecções por Bactérias Gram-Positivas/epidemiologia , Transplante de Fígado , Animais , Antibacterianos/farmacologia , Bacteriófagos , Transplante de Microbiota Fecal/métodos , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Enterococos Resistentes à Vancomicina/isolamento & purificação
9.
Expert Rev Anti Infect Ther ; 16(9): 723-732, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30092153

RESUMO

INTRODUCTION: Recurrent urinary tract infections (UTI) are a common clinical problem in kidney transplant recipients. Due to the complex urological anatomy derived from the implantation of the kidney graft, the spectrum of the disease and the broad underlying pathophysiological mechanisms. Recurrent UTI worsen the quality of life, decrease the graft survival and increase the costs of kidney transplantation. Areas covered: In this review, we describe the definitions, clinical characteristics, pathophysiological mechanisms and microbiology of recurrent urinary tract infections in kidney transplantations. The actual published literature on the management of recurrent urinary tract infections is based on case series, observational cohorts and very few clinical trials. In this review, the available evidence is compiled to propose evidence-based strategies to manage these complex cases. Expert commentary: The management of recurrent urinary tract infections in kidney transplant patients requires a proper diagnosis of the underlying mechanism. Early identification of structural or functional urological abnormalities, potentially amenable for surgical correction, is crucial for a successful management. The use of antibiotics to prevent recurrent infections should be carefully evaluated to avoid side effects and emergence of antibiotic-resistant microorganisms.


Assuntos
Antibacterianos/administração & dosagem , Transplante de Rim , Infecções Urinárias/tratamento farmacológico , Antibacterianos/efeitos adversos , Farmacorresistência Bacteriana , Sobrevivência de Enxerto , Humanos , Qualidade de Vida , Recidiva , Transplantados , Infecções Urinárias/diagnóstico , Infecções Urinárias/fisiopatologia
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