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1.
Am Heart J ; 271: 28-37, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38369218

RESUMO

BACKGROUND: Previous studies have suggested that there is wide variability in cardiac intensive care unit (CICU) length of stay (LOS); however, these studies are limited by the absence of detailed risk assessment at the time of admission. Thus, we evaluated inter-hospital differences in CICU LOS, and the association between LOS and in-hospital mortality. METHODS: Using data from the Critical Care Cardiology Trials Network (CCCTN) registry, we included 22,862 admissions between 2017 and 2022 from 35 primarily tertiary and quaternary CICUs that captured consecutive admissions in annual 2-month snapshots. The primary analysis compared inter-hospital differences in CICU LOS, as well as the association between CICU LOS and all-cause in-hospital mortality using a Fine and Gray competing risk model. RESULTS: The overall median CICU LOS was 2.2 (1.1-4.8) days, and the median hospital LOS was 5.9 (2.8-12.3) days. Admissions in the longest tertile of LOS tended to be younger with higher rates of pre-existing comorbidities, and had higher Sequential Organ Failure Assessment (SOFA) scores, as well as higher rates of mechanical ventilation, intravenous vasopressor use, mechanical circulatory support, and renal replacement therapy. Unadjusted all-cause in-hospital mortality was 9.3%, 6.7%, and 13.4% in the lowest, intermediate, and highest CICU LOS tertiles. In a competing risk analysis, individual patient CICU LOS was correlated (r2 = 0.31) with a higher risk of 30-day in-hospital mortality. The relationship remained significant in admissions with heart failure, ST-elevation myocardial infarction and non-ST segment elevation myocardial infarction. CONCLUSIONS: In a large registry of academic CICUs, we observed significant variation in CICU LOS and report that LOS is independently associated with all-cause in-hospital mortality. These findings could potentially be used to improve CICU resource utilization planning and refine risk prognostication in critically ill cardiovascular patients.


Assuntos
Unidades de Cuidados Coronarianos , Mortalidade Hospitalar , Tempo de Internação , Sistema de Registros , Humanos , Mortalidade Hospitalar/tendências , Masculino , Feminino , Tempo de Internação/estatística & dados numéricos , Idoso , Pessoa de Meia-Idade , Unidades de Cuidados Coronarianos/estatística & dados numéricos , Medição de Risco/métodos , Cuidados Críticos/estatística & dados numéricos , Estados Unidos/epidemiologia
2.
J Card Fail ; 30(5): 728-733, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38387758

RESUMO

BACKGROUND: There are limited data on how patients with cardiogenic shock (CS) die. METHODS: The Critical Care Cardiology Trials Network is a research network of cardiac intensive care units coordinated by the Thrombolysis In Myocardial Infarction (TIMI) Study Group (Boston, MA). Using standardized definitions, site investigators classified direct modes of in-hospital death for CS admissions (October 2021 to September 2022). Mutually exclusive categories included 4 modes of cardiovascular death and 4 modes of noncardiovascular death. Subgroups defined by CS type, preceding cardiac arrest (CA), use of temporary mechanical circulatory support (tMCS), and transition to comfort measures were evaluated. RESULTS: Among 1068 CS cases, 337 (31.6%) died during the index hospitalization. Overall, the mode of death was cardiovascular in 82.2%. Persistent CS was the dominant specific mode of death (66.5%), followed by arrhythmia (12.8%), anoxic brain injury (6.2%), and respiratory failure (4.5%). Patients with preceding CA were more likely to die from anoxic brain injury (17.1% vs 0.9%; P < .001) or arrhythmia (21.6% vs 8.4%; P < .001). Patients managed with tMCS were more likely to die from persistent shock (P < .01), both cardiogenic (73.5% vs 62.0%) and noncardiogenic (6.1% vs 2.9%). CONCLUSIONS: Most deaths in CS are related to direct cardiovascular causes, particularly persistent CS. However, there is important heterogeneity across subgroups defined by preceding CA and the use of tMCS.


Assuntos
Mortalidade Hospitalar , Choque Cardiogênico , Humanos , Choque Cardiogênico/mortalidade , Choque Cardiogênico/terapia , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Mortalidade Hospitalar/tendências , Unidades de Cuidados Coronarianos/estatística & dados numéricos , Cuidados Críticos/métodos , Causas de Morte/tendências , Unidades de Terapia Intensiva
3.
Heart Fail Clin ; 14(3): 255-269, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29966625

RESUMO

This article provides an overview of pulmonary arterial hypertension (PAH), beginning with the initial pathologic recognition of pulmonary hypertension more than 100 years ago and progressing to the current diagnostic categorization of PAH. It reviews the epidemiology, pathophysiology, genetics, and modern treatment of PAH. The article discusses several important recent studies that have highlighted the importance of new management strategies, including serial risk assessment and combination pharmacotherapy.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão Pulmonar/diagnóstico , Quimioterapia Combinada , Feminino , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/fisiopatologia , Masculino , Terapia de Alvo Molecular/métodos , Fatores de Risco , Taxa de Sobrevida
5.
Hum Mol Genet ; 21(6): 1350-63, 2012 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-22171073

RESUMO

LRRK2 (PARK8) is the most common genetic determinant of Parkinson's disease (PD), with dominant mutations in LRRK2 causing inherited PD and sequence variation at the LRRK2 locus associated with increased risk for sporadic PD. Although LRRK2 has been implicated in diverse cellular processes encompassing almost all cellular compartments, the precise functions of LRRK2 remain unclear. Here, we show that the Drosophila homolog of LRRK2 (Lrrk) localizes to the membranes of late endosomes and lysosomes, physically interacts with the crucial mediator of late endosomal transport Rab7 and negatively regulates rab7-dependent perinuclear localization of lysosomes. We also show that a mutant form of lrrk analogous to the pathogenic LRRK2(G2019S) allele behaves oppositely to wild-type lrrk in that it promotes rather than inhibits rab7-dependent perinuclear lysosome clustering, with these effects of mutant lrrk on lysosome position requiring both microtubules and dynein. These data suggest that LRRK2 normally functions in Rab7-dependent lysosomal positioning, and that this function is disrupted by the most common PD-causing LRRK2 mutation, linking endolysosomal dysfunction to the pathogenesis of LRRK2-mediated PD.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Fertilidade/fisiologia , Lisossomos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Animais , Animais Geneticamente Modificados , Western Blotting , Células Cultivadas , Drosophila/crescimento & desenvolvimento , Proteínas de Drosophila/genética , Endossomos/metabolismo , Feminino , Imunofluorescência , Imunoprecipitação , Masculino , Mutação/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas rab de Ligação ao GTP/genética , proteínas de unión al GTP Rab7
6.
Circ Cardiovasc Qual Outcomes ; 17(1): e010092, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38179787

RESUMO

BACKGROUND: Wide interhospital variations exist in cardiovascular intensive care unit (CICU) admission practices and the use of critical care restricted therapies (CCRx), but little is known about the differences in patient acuity, CCRx utilization, and the associated outcomes within tertiary centers. METHODS: The Critical Care Cardiology Trials Network is a multicenter registry of tertiary and academic CICUs in the United States and Canada that captured consecutive admissions in 2-month periods between 2017 and 2022. This analysis included 17 843 admissions across 34 sites and compared interhospital tertiles of CCRx (eg, mechanical ventilation, mechanical circulatory support, continuous renal replacement therapy) utilization and its adjusted association with in-hospital survival using logistic regression. The Pratt index was used to quantify patient-related and institutional factors associated with CCRx variability. RESULTS: The median age of the study population was 66 (56-77) years and 37% were female. CCRx was provided to 62.2% (interhospital range of 21.3%-87.1%) of CICU patients. Admissions to CICUs with the highest tertile of CCRx utilization had a greater burden of comorbidities, had more diagnoses of ST-elevation myocardial infarction, cardiac arrest, or cardiogenic shock, and had higher Sequential Organ Failure Assessment scores. The unadjusted in-hospital mortality (median, 12.7%) was 9.6%, 11.1%, and 18.7% in low, intermediate, and high CCRx tertiles, respectively. No clinically meaningful differences in adjusted mortality were observed across tertiles when admissions were stratified by the provision of CCRx. Baseline patient-level variables and institutional differences accounted for 80% and 5.3% of the observed CCRx variability, respectively. CONCLUSIONS: In a large registry of tertiary and academic CICUs, there was a >4-fold interhospital variation in the provision of CCRx that was primarily driven by differences in patient acuity compared with institutional differences. No differences were observed in adjusted mortality between low, intermediate, and high CCRx utilization sites.


Assuntos
Cardiologia , Monitorização Hemodinâmica , Idoso , Feminino , Humanos , Masculino , Unidades de Cuidados Coronarianos , Cuidados Críticos , Mortalidade Hospitalar , Unidades de Terapia Intensiva , Sistema de Registros , Estados Unidos/epidemiologia , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Ensaios Clínicos como Assunto
7.
Pulm Circ ; 13(2): e12225, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37063745

RESUMO

Findings of an enlarged pulmonary artery diameter (PAd) and increased pulmonary artery to ascending aorta ratio (PA:AA) on contrast-enhanced computed tomography pulmonary angiography (CTPA) are associated with increased mortality in particular groups of patients with cardiopulmonary disease. However, the frequency and prognostic significance of these incidental findings has not been studied in unselected patients evaluated in the Emergency Department (ED). This study aims to determine the prevalence and associated prognosis of enlarged pulmonary artery measurements in an ED cohort. We measured PA and AA diameters on 990 CTPA studies performed in the ED. An enlarged PA diameter was defined as >27 mm in females and >29 mm in males, while an increased PA:AA was defined as >0.9. Poisson regression was performed to calculate prevalence ratios for relevant comorbidities, and multivariable Cox regression was performed to calculate hazard ratios (HR) for mortality of patients with enlarged pulmonary artery measurements. An enlarged PAd was observed in 27.9% of 990 patients and was more commonly observed in older patients and in patients with obesity or heart failure. Conversely, PA:AA was increased in 34.2% of subjects, and was more common in younger patients and those with peripheral vascular disease or obesity. After controlling for age, sex, and comorbidities, both enlarged PAd (HR 1.29, 95% CI 1.00-1.68, p = 0.05) and PA:AA (HR 1.70, 95% CI 1.31-2.22 p < 0.01) were independently associated with mortality. In sum, enlarged PAd and increased PA:AA are common in patients undergoing CTPAs in the ED setting and both are independently associated with mortality.

8.
Eur Heart J Acute Cardiovasc Care ; 12(10): 651-660, 2023 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-37640029

RESUMO

AIMS: Invasive haemodynamic assessment with a pulmonary artery catheter is often used to guide the management of patients with cardiogenic shock (CS) and may provide important prognostic information. We aimed to assess prognostic associations and relationships to end-organ dysfunction of presenting haemodynamic parameters in CS. METHODS AND RESULTS: The Critical Care Cardiology Trials Network is an investigator-initiated multicenter registry of cardiac intensive care units (CICUs) in North America coordinated by the TIMI Study Group. Patients with CS (2018-2022) who underwent invasive haemodynamic assessment within 24 h of CICU admission were included. Associations of haemodynamic parameters with in-hospital mortality were assessed using logistic regression, and associations with presenting serum lactate were assessed using least squares means regression. Sensitivity analyses were performed excluding patients on temporary mechanical circulatory support and adjusted for vasoactive-inotropic score. Among the 3603 admissions with CS, 1473 had haemodynamic data collected within 24 h of CICU admission. The median cardiac index was 1.9 (25th-75th percentile, 1.6-2.4) L/min/m2 and mean arterial pressure (MAP) was 74 (66-86) mmHg. Parameters associated with mortality included low MAP, low systolic blood pressure, low systemic vascular resistance, elevated right atrial pressure (RAP), elevated RAP/pulmonary capillary wedge pressure ratio, and low pulmonary artery pulsatility index. These associations were generally consistent when controlling for the intensity of background pharmacologic and mechanical haemodynamic support. These parameters were also associated with higher presenting serum lactate. CONCLUSION: In a contemporary CS population, presenting haemodynamic parameters reflecting decreased systemic arterial tone and right ventricular dysfunction are associated with adverse outcomes and systemic hypoperfusion.


Assuntos
Hemodinâmica , Choque Cardiogênico , Humanos , Prognóstico , Resistência Vascular , Lactatos
9.
Nature ; 441(7097): 1162-6, 2006 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-16672981

RESUMO

Parkinson's disease is the second most common neurodegenerative disorder and is characterized by the degeneration of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction has been implicated as an important trigger for Parkinson's disease-like pathogenesis because exposure to environmental mitochondrial toxins leads to Parkinson's disease-like pathology. Recently, multiple genes mediating familial forms of Parkinson's disease have been identified, including PTEN-induced kinase 1 (PINK1; PARK6) and parkin (PARK2), which are also associated with sporadic forms of Parkinson's disease. PINK1 encodes a putative serine/threonine kinase with a mitochondrial targeting sequence. So far, no in vivo studies have been reported for pink1 in any model system. Here we show that removal of Drosophila PINK1 homologue (CG4523; hereafter called pink1) function results in male sterility, apoptotic muscle degeneration, defects in mitochondrial morphology and increased sensitivity to multiple stresses including oxidative stress. Pink1 localizes to mitochondria, and mitochondrial cristae are fragmented in pink1 mutants. Expression of human PINK1 in the Drosophila testes restores male fertility and normal mitochondrial morphology in a portion of pink1 mutants, demonstrating functional conservation between human and Drosophila Pink1. Loss of Drosophila parkin shows phenotypes similar to loss of pink1 function. Notably, overexpression of parkin rescues the male sterility and mitochondrial morphology defects of pink1 mutants, whereas double mutants removing both pink1 and parkin function show muscle phenotypes identical to those observed in either mutant alone. These observations suggest that pink1 and parkin function, at least in part, in the same pathway, with pink1 functioning upstream of parkin. The role of the pink1-parkin pathway in regulating mitochondrial function underscores the importance of mitochondrial dysfunction as a central mechanism of Parkinson's disease pathogenesis.


Assuntos
Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Mitocôndrias/fisiologia , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Apoptose , Drosophila melanogaster/enzimologia , Drosophila melanogaster/fisiologia , Epistasia Genética , Teste de Complementação Genética , Humanos , Infertilidade Masculina/genética , Infertilidade Masculina/patologia , Longevidade/genética , Longevidade/fisiologia , Masculino , Mitocôndrias/patologia , Músculos/metabolismo , Músculos/patologia , Mutação/genética , Doença de Parkinson/genética , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Fenótipo , Transporte Proteico , Espermátides/metabolismo , Espermátides/patologia , Ubiquitina-Proteína Ligases
10.
Pulm Circ ; 12(4): e12170, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36518235

RESUMO

Chronic thromboembolic pulmonary hypertension (CTEPH) and acute pulmonary embolism (PE) are related phenotypes, however, previous reports have suggested that genetic risk factors for CTEPH and PE differ. Here we report that a family history of VTE is equally frequent in individuals with CTEPH and PE, suggesting that shared genetic variants may influence risk of both phenotypes. We also provide the first estimate of the frequency of familial CTEPH, which we identified in 2.2% of CTEPH patients in our cohort.

11.
Clin Appl Thromb Hemost ; 28: 10760296211073277, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35000431

RESUMO

Chronic thromboembolic pulmonary hypertension (CTEPH) is a serious complication of acute pulmonary embolism (PE) which remains underdiagnosed. A better understanding of risk factors for CTEPH would improve our ability to predict which PE survivors are at risk. Several medical conditions-including malignancy, splenectomy, thyroid hormone supplementation, the presence of an intravascular device, inflammatory bowel disease, osteomyelitis, and non-O blood group-have been associated with increased risk of CTEPH, primarily in studies comparing patients with CTEPH to individuals with non-thrombotic conditions. Because many of these conditions increase thrombosis risk, it remains unclear whether their association with CTEPH reflects a general effect on thrombosis risk, or a specific effect on the risk of developing CTEPH as an outcome of thrombosis. We performed a case-control study comparing the frequencies of these conditions in patients with CTEPH versus patients with acute PE who did not develop CTEPH. The conditions studied were equally frequent in the CTEPH and PE cohorts, although there was a trend towards an increased frequency of splenectomy and non-O blood group among the CTEPH cohort. Thus, other than the possible exceptions of splenectomy and non-O blood group, the investigated medical conditions do not appear likely to increase the risk of CTEPH as an outcome of acute PE, and thus are unlikely to be useful in predicting CTEPH risk among PE survivors.


Assuntos
Hipertensão Pulmonar/etiologia , Embolia Pulmonar/epidemiologia , Medição de Risco/métodos , Doença Aguda , Adulto , Idoso , Estudos de Casos e Controles , Doença Crônica , Ecocardiografia , Feminino , Seguimentos , Humanos , Hipertensão Pulmonar/epidemiologia , Hipertensão Pulmonar/fisiopatologia , Incidência , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/complicações , Embolia Pulmonar/diagnóstico , Fatores de Risco , Taxa de Sobrevida/tendências , Estados Unidos/epidemiologia
12.
Proc Natl Acad Sci U S A ; 105(38): 14503-8, 2008 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-18799731

RESUMO

Mutations in PTEN-induced kinase 1 (pink1) or parkin cause autosomal-recessive and some sporadic forms of Parkinson's disease. pink1 acts upstream of parkin in a common genetic pathway to regulate mitochondrial integrity in Drosophila. Mitochondrial morphology is maintained by a dynamic balance between the opposing actions of mitochondrial fusion, controlled by Mitofusin (mfn) and Optic atrophy 1 (opa1), and mitochondrial fission, controlled by drp1. Here, we explore interactions between pink1/parkin and the mitochondrial fusion/fission machinery. Muscle-specific knockdown of the fly homologue of Mfn (Marf) or opa1, or overexpression of drp1, results in significant mitochondrial fragmentation. Mfn-knockdown flies also display altered cristae morphology. Interestingly, knockdown of Mfn or opa1 or overexpression of drp1, rescues the phenotypes of muscle degeneration, cell death, and mitochondrial abnormalities in pink1 or parkin mutants. In the male germline, we also observe genetic interactions between pink1 and the testes-specific mfn homologue fuzzy onion, and between pink1 and drp1. Our data suggest that the pink1/parkin pathway promotes mitochondrial fission and/or inhibits fusion by negatively regulating mfn and opa1 function, and/or positively regulating drp1. However, pink1 and parkin mutant flies show distinct mitochondrial phenotypes from drp1 mutant flies, and flies carrying a heterozygous mutation in drp1 enhance the pink1-null phenotype, resulting in lethality. These results suggest that pink1 and parkin are likely not core components of the drp1-mediated mitochondrial fission machinery. Modification of fusion and fission may represent a novel therapeutic strategy for Parkinson's disease.


Assuntos
Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Mitocôndrias/metabolismo , Doença de Parkinson/genética , Proteínas Quinases/genética , Animais , Drosophila melanogaster/enzimologia , Expressão Gênica , Masculino , Mitocôndrias/enzimologia , Mitocôndrias/ultraestrutura , Músculos/enzimologia , Músculos/metabolismo , Mutação , Fenótipo , Espermatogênese/genética , Testículo/metabolismo , Ubiquitina-Proteína Ligases
13.
Genes (Basel) ; 11(11)2020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-33233517

RESUMO

Group 1 pulmonary hypertension (pulmonary arterial hypertension; PAH) is a rare disease characterized by remodeling of the small pulmonary arteries leading to progressive elevation of pulmonary vascular resistance, ultimately leading to right ventricular failure and death. Deleterious mutations in the serine-threonine receptor bone morphogenetic protein receptor 2 (BMPR2; a central mediator of bone morphogenetic protein (BMP) signaling) and female sex are known risk factors for the development of PAH in humans. In this narrative review, we explore the complex interplay between the BMP and estrogen signaling pathways, and the potentially synergistic mechanisms by which these signaling cascades increase the risk of developing PAH. A comprehensive understanding of these tangled pathways may reveal therapeutic targets to prevent or slow the progression of PAH.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Estrogênios/metabolismo , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/metabolismo , Animais , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Feminino , Humanos , Masculino , Transdução de Sinais
14.
J Neurosci ; 28(53): 14500-10, 2008 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-19118185

RESUMO

Recently, a mutation in the mitochondrial protease Omi/HtrA2, G399S, was found in sporadic Parkinson's disease (PD) patients, leading to the designation of Omi/HtrA2 as PD locus 13 (PARK13). G399S reportedly results in reduced Omi protease activity. In vitro studies have suggested that Omi/HtrA2 acts downstream of PINK1, mutations in which mediate recessive forms of PD. We, as well as other, have previously shown that the Drosophila homologs of the familial PD genes, PINK1 (PARK6) and PARKIN (PARK2), function in a common genetic pathway to regulate mitochondrial integrity and dynamics. Whether Omi/HtrA2 regulates mitochondrial integrity and whether it acts downstream of PINK1 in vivo remain to be explored. Here, we show that Omi/HtrA2 null mutants in Drosophila, in contrast to pink1 or parkin null mutants, do not show mitochondrial morphological defects. Extensive genetic interaction studies do not provide support for models in which Omi/HtrA2 functions in the same genetic pathway as pink1, or carries out partially redundant functions with pink1, at least with respect to regulation of mitochondrial integrity and dynamics. Furthermore, Omi/HtrA2 G399S retains significant, if not full, function of Omi/HtrA2, compared with expression of protease-compromised versions of the protein. In light of recent findings showing that G399S can be found at comparable frequencies in PD patients and healthy controls, we do not favor a hypothesis in which Omi/HtrA2 plays an essential role in PD pathogenesis, at least with respect to regulation of mitochondrial integrity in the pink1/parkin pathway.


Assuntos
Proteínas de Drosophila/metabolismo , Serina Endopeptidases/metabolismo , Transdução de Sinais/genética , Fatores Etários , Animais , Animais Geneticamente Modificados , Animais Recém-Nascidos , Drosophila , Proteínas de Drosophila/genética , Feminino , Fertilidade/genética , Proteínas de Fluorescência Verde/genética , Serina Peptidase 2 de Requerimento de Alta Temperatura A , Masculino , Microscopia Eletrônica de Transmissão/métodos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Mutação/genética , Fenótipo , RNA Mensageiro/metabolismo , Serina Endopeptidases/genética , Estresse Psicológico/genética , Estresse Psicológico/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Ubiquitina-Proteína Ligases
15.
Curr Opin Neurobiol ; 17(3): 331-7, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17499497

RESUMO

Mutations in PARKIN, PTEN-induced kinase 1 (PINK1) and DJ-1 are found in autosomal recessive forms and some sporadic cases of Parkinson's disease. Recent work on these genes underscores the central importance of mitochondrial dysfunction and oxidative stress in Parkinson's disease. In particular, pink1 and parkin loss-of-function mutants in Drosophila show similar phenotypes, and pink1 acts upstream of parkin in a common genetic pathway to regulate mitochondrial function. DJ-1 has a role in oxidative stress protection, but a direct role of DJ-1 in mitochondrial function has not been fully established. Importantly, defects in mitochondrial function have also been identified in patients who carry both PINK1 and PARKIN mutations, and in those who have sporadic Parkinson's disease. Future studies of the biochemical interactions between Pink1 and Parkin, and identification of other components in this pathway, are likely to provide insight into Parkinson's disease pathogenesis, and might identify new therapeutic targets.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Mitocôndrias/patologia , Proteínas Oncogênicas/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Proteínas Quinases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mitocôndrias/metabolismo , Proteínas Oncogênicas/genética , Doença de Parkinson/genética , Proteína Desglicase DJ-1 , Proteínas Quinases/genética , Ubiquitina-Proteína Ligases/genética
16.
Chest ; 155(2): 384-390, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30732691

RESUMO

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a serious sequela of pulmonary embolism (PE) and occurs in about 3% of acute PE survivors. Common inherited thrombophilias, including the Factor V Leiden mutation, are not associated with increased risk of CTEPH, even though they increase the risk for VTE. Whether other inherited genetic factors contribute to the risk of developing CTEPH remains unknown. Familial clustering of a disease can indicate inherited genetic risk for that disease. In this study, the Utah Population Database (UPDB), a unique genealogy resource, was used to assess whether CTEPH cases cluster in families. METHODS: Prevalent CTEPH patients in Utah were identified and were then matched to control subjects. Using the UPDB, the Genealogical Index of Familiality (a statistical measure of relatedness of individuals with a given phenotype) was calculated. The UPDB was also used to calculate the relative risk of CTEPH and VTE in the family members of patients with CTEPH. RESULTS: This study found that Utah patients with CTEPH are significantly more related than would be expected by chance, with both close and distant relationships identified. We also found that the relative risk of VTE was significantly increased among first-degree relatives of CTEPH probands. CONCLUSIONS: The study data suggest that heritable genetic factors influence an individual's risk of developing CTEPH, providing the strongest evidence to date for a genetic contribution to CTEPH risk. Although our data suggest that these inherited genetic factors likely also increase the risk for VTE, they are likely to be distinct from the common inherited thrombophilias.


Assuntos
Hipertensão Pulmonar/epidemiologia , Hipertensão Pulmonar/genética , Embolia Pulmonar/epidemiologia , Embolia Pulmonar/genética , Idoso , Doença Crônica , Análise por Conglomerados , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Prevalência , Utah/epidemiologia
17.
ACR Open Rheumatol ; 1(1): 26-36, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31777777

RESUMO

OBJECTIVE: We sought to determine if any histopathologic component of the pulmonary microcirculation can distinguish systemic sclerosis (SSc)-related pulmonary fibrosis (PF) with and without pulmonary hypertension (PH). METHODS: Two pulmonary pathologists blindly evaluated 360 histologic slides from lungs of 31 SSc-PF explants or autopsies with (n = 22) and without (n = 9) PH. The presence of abnormal small arteries, veins, and capillaries (pulmonary microcirculation) was semiquantitatively assessed in areas of preserved lung architecture. Capillary proliferation (CP) within the alveolar walls was measured by its distribution, extent (CP % involvement), and maximum number of layers (maximum CP). These measures were then evaluated to determine the strength of their association with right heart catheterization-proven PH. RESULTS: Using consensus measures, all measures of CP were significantly associated with PH. Maximum CP had the strongest association with PH (P = 0.013; C statistic 0.869). Maximum CP 2 or more layers and CP % involvement 10% or greater were the optimal thresholds that predicted PH, both with a sensitivity of 56% and specificity of 91%. The CP was typically multifocal rather than focal or diffuse and was associated with a background pattern of usual interstitial pneumonia. There was a significant but weaker relationship between the presence of abnormal small arteries and veins and PH. CONCLUSION: In the setting of advanced SSc-PF, the histopathologic feature of the pulmonary microcirculation best associated with PH was capillary proliferation in architecturally preserved lung areas.

19.
Chest ; 151(4): 821-828, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27884767

RESUMO

BACKGROUND: Differentiating pulmonary venoocclusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) from idiopathic pulmonary arterial hypertension (IPAH) or heritable pulmonary arterial hypertension (HPAH) is important clinically. Mutations in eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) cause heritable PVOD and PCH, whereas mutations in other genes cause HPAH. The aim of this study was to describe the frequency of pathogenic EIF2AK4 mutations in patients diagnosed clinically with IPAH or HPAH. METHODS: Sanger sequencing and deletion/duplication analysis were performed to detect mutations in the bone morphogenetic protein receptor type II (BMPR2) gene in 81 patients diagnosed at 30 North American medical centers with IPAH (n = 72) or HPAH (n = 9). BMPR2 mutation-negative patients (n = 67) were sequenced for mutations in four other genes (ACVRL1, ENG, CAV1, and KCNK3) known to cause HPAH. Patients negative for mutations in all known PAH genes (n = 66) were then sequenced for mutations in EIF2AK4. We assessed the pathogenicity of EIF2AK4 mutations and reviewed clinical characteristics of patients with pathogenic EIF2AK4 mutations. RESULTS: Pathogenic BMPR2 mutations were identified in 8 of 72 (11.1%) patients with IPAH and 6 of 9 (66.7%) patients with HPAH. A novel homozygous EIF2AK4 mutation (c.257+4A>C) was identified in 1 of 9 (11.1%) patients diagnosed with HPAH. The novel EIF2AK4 mutation (c.257+4A>C) was homozygous in two sisters with severe pulmonary hypertension. None of the 72 patients with IPAH had biallelic EIF2AK4 mutations. CONCLUSIONS: Pathogenic biallelic EIF2AK4 mutations are rarely identified in patients diagnosed with HPAH. Identification of pathogenic biallelic EIF2AK4 mutations can aid clinicians in differentiating HPAH from heritable PVOD or PCH.


Assuntos
Hipertensão Pulmonar/genética , Mutação/genética , Proteínas Serina-Treonina Quinases/genética , Adulto , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , América do Norte
20.
Clin Chest Med ; 37(3): 523-34, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27514598

RESUMO

This article provides an overview of pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH), two disorders that challenge clinicians, radiologists, and pathologists because they often mimic pulmonary arterial hypertension (PAH). The article reviews the features that differentiate PVOD and PCH from PAH. The article also describes the overlap of PVOD and PCH, highlighted by recent reports of families diagnosed with PVOD or PCH caused by EIF2AK4 mutations. In addition, the article outlines current approaches to the diagnosis and treatment of PVOD and PCH.


Assuntos
Hemangioma Capilar/diagnóstico , Hipertensão Pulmonar/diagnóstico , Neoplasias Pulmonares/diagnóstico , Neoplasias Primárias Múltiplas/diagnóstico , Pneumopatia Veno-Oclusiva/diagnóstico , Diagnóstico Diferencial , Hemangioma Capilar/genética , Hemangioma Capilar/patologia , Hemangioma Capilar/fisiopatologia , Humanos , Hipertensão Pulmonar/fisiopatologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/fisiopatologia , Mutação , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/fisiopatologia , Proteínas Serina-Treonina Quinases/genética , Pneumopatia Veno-Oclusiva/genética , Pneumopatia Veno-Oclusiva/patologia , Pneumopatia Veno-Oclusiva/fisiopatologia
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