Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Clin Med ; 10(21)2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34768622

RESUMO

Primary ciliary dyskinesia (PCD) is a poorly understood disorder. It is primarily autosomal recessive and is prevalent in tribal communities of the United Arab Emirates due to consanguineous marriages. This retrospective study aimed to assess the pathogenicity of the genetic variants of PCD in indigenous patients with significant clinical respiratory problems. Pathogenicity scores of variants obtained from the chart review were consolidated using the Ensembl Variant Effect Predictor. The multidimensional dataset of scores was clustered into three groups based on their pathogenicity. Sequence alignment and the Jensen-Shannon Divergence (JSD) were generated to evaluate the amino acid conservation at the site of the variation. One-hundred and twelve variants of 28 genes linked to PCD were identified in 66 patients. Twenty-two variants were double heterozygous, two triple heterozygous, and seven homozygous. Of the thirteen novel variants, two, c.11839 + 1G > A in dynein, axonemal, heavy chain 11 (DNAH11) and p.Lys92Trpfs in dynein, axonemal, intermediate chain 1 (DNAI1) were associated with dextrocardia with situs inversus, and one, p.Gly21Val in coiled-coil domain-containing protein 40 (CCDC40), with absent inner dynein arms. Homozygous C1orf127:p.Arg113Ter (rs558323413) was also associated with laterality defects in two related patients. The majority of variants were missense involving conserved residues with a median JSD score of 0.747. Homology models of two deleterious variants in the stalk of DNAH11, p.Gly3102Asp and p.Leu3127Arg, revealed structural importance of the conserved glycine and leucine. These results define potentially damaging PCD variants in the region. Future studies, however, are needed to fully comprehend the genetic underpinnings of PCD.

2.
Front Pediatr ; 9: 722480, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34490170

RESUMO

Background: Risks of diagnostic radiation have become more notable lately, particularly in young children with chronic medical conditions. This study reports on the cumulative radiation from chest radiographs in children with asthma. Its main purpose was to review our current practice and suggest minimizing the use of chest radiographs. Methods: The study was retrospective and conducted at a pediatric tertiary center. Eligibility criteria included children 2-15 y, admitted between January 2017 and December 2018 for asthma management. Results: Of the 643 children admitted as "asthma exacerbation," 243 [40% females; age (mean ± SD) 5.4±3.3 y] met the study criteria for inclusion. Ninety-two (38%) children had a temperature of 38.8±0.7°C on the day of admission. Antibiotics were prescribed for 148 (61%) children, mainly for presumed pneumonia. Chest radiographs were requested for 214 (88%) children, mainly on the day of admission. Only 38 (18%) chest radiographs showed focal/multifocal pneumonia justifying antibiotic use. Significant predictors for requesting chest radiographs were antibiotic use for presumed pneumonia, lower oxygen saturation at presentation, and a requested blood culture. The rate of chest radiographs per year was negatively related to the child's age; the younger the child the higher the rate (model coefficient -0.259, P < 0.001). For children < 5 y, the rate of chest radiographs was 1.39 ± 1.21/y and radiation dose 0.028 ± 0.025 mSv/y. The corresponding rates for children ≥5 y were 0.78 ± 0.72/y and 0.008 ± 0.007 mSv/y, respectively (P < 0.001). Conclusion: Chest radiographs were commonly requested for children with asthma, especially younger children. Prospective studies are necessary to measure the impact of this practice on the children's health.

3.
Sci Rep ; 11(1): 2715, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33526882

RESUMO

Genetic variants of small airways and interstitial pulmonary disease have not been comprehensively studied. This cluster of respiratory disorders usually manifests from early infancy ('lung disease in utero'). In this study, 24 variants linked to these entities are described. The variants involved two genes associated with surfactant metabolism dysfunction (ABCA3 and CSF2RB), two with pulmonary fibrosis (MUC5B and SFTP), one with bronchiectasis (SCNN1B), and one with alpha-1-antitrypsin deficiency (SERPINA1). A nonsense variant, MUC5B:c.16861G > T, p.Glu5621*, was found in homozygous state in two siblings with severe respiratory disease from birth. One of the siblings also had heterozygous SFTPA1:c.675C > G, p.Asn225Lys, which resulted in a more severe respiratory disease. The sibling with only the homozygous MUC5B variant had lung biopsy, which showed alveolar simplification, interstitial fibrosis, intra-alveolar lipid-laden macrophages, and foci of foreign body giant cell reaction in distal airspaces. Two missense variants, MUC5B:c.14936 T > C, p.Ile4979Thr (rs201287218) and MUC5B:c.16738G > A, p.Gly5580Arg (rs776709402), were also found in compound heterozygous state in two siblings with severe respiratory disease from birth. Overall, the results emphasize the need for genetic studies for patients with complex respiratory problems. Identifying pathogenic variants, such as those presented here, assists in effective family counseling aimed at genetic prevention. In addition, results of genetic studies improve the clinical care and provide opportunities for participating in clinical trials, such as those involving molecularly-targeted therapies.


Assuntos
Doenças Pulmonares Intersticiais/genética , Pulmão/diagnóstico por imagem , Mutação , Polimorfismo de Nucleotídeo Único , Transportadores de Cassetes de Ligação de ATP/genética , Criança , Pré-Escolar , Subunidade beta Comum dos Receptores de Citocinas/genética , Canais Epiteliais de Sódio/genética , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Masculino , Mucina-5B/genética , Radiografia Torácica , Estudos Retrospectivos
4.
Pediatr Pulmonol ; 55(9): 2389-2401, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32662942

RESUMO

Founder mutations and autosomal recessive (AR) disorders are common in the Arabian Peninsula due to frequent consanguineous marriages. As a result, the pulmonary service at Tawam Hospital (Al Ain, UAE) routinely requests genetic testing for children with persistent (unexplained) respiratory problems. The main purpose of this report was to underscore the usefulness of these tests. Ten children with severe respiratory diseases due to complex genetic findings are described here. Forty-one variants (six novel) were detected, averaging four per patient (range: 1-9). Seven (17%) variants were homozygous and 34 (83%) heterozygous; some variants were known to show monoallelic expression. Using binomial probability distribution, the fetal-risk for having AR disorder(s) as a function of the number of shared variants by a couple ranged from 0.25 (having one shared variant) to 0.9249 (having nine shared variants). In cultures where increased size of homozygous genomic segments is common, children often have multiple variants that could cause complex clinical phenotypes. Identifying pathogenic variants assists in clinical care, family counseling, and disease prevention through genetic screening.


Assuntos
Doenças Respiratórias/genética , Criança , Pré-Escolar , Feminino , Testes Genéticos , Heterozigoto , Homozigoto , Humanos , Lactente , Masculino , Emirados Árabes Unidos
5.
BMC Pulm Med ; 19(1): 49, 2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30795758

RESUMO

BACKGROUND: The term hepatopulmonary syndrome typically applies to cyanosis that results from "intrapulmonary vascular dilatation" due to advanced liver disease. Similar findings may result from a congenital portosystemic shunt without liver disease. An adverse consequence of such shunts is intrapulmonary vascular dilatation, which affects the microvascular gas exchange units for oxygen. CASE PRESENTATION: Here, we describe a toddler with chronic cyanosis, exercise intolerance, and finger clubbing due to a malformation shunt between the portal vein and the inferior vena cava. A transcatheter embolization of the shunt resulted in resolution of his findings. CONCLUSIONS: Congenital portosystemic shunts need to be considered in the differential diagnosis of cyanosis.


Assuntos
Cianose/etiologia , Osteoartropatia Hipertrófica Secundária/etiologia , Veia Porta/anormalidades , Malformações Vasculares/complicações , Veia Cava Inferior/anormalidades , Angiografia , Pré-Escolar , Dilatação Patológica/diagnóstico por imagem , Ecocardiografia , Embolização Terapêutica , Humanos , Masculino , Veia Porta/diagnóstico por imagem , Artéria Pulmonar/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Ultrassonografia , Malformações Vasculares/diagnóstico por imagem , Malformações Vasculares/terapia , Veia Cava Inferior/diagnóstico por imagem
6.
J Bone Miner Metab ; 36(4): 392-398, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28766136

RESUMO

Phosphorescence O2 analyzer was used to measure calvarial bone cellular respiration (cellular mitochondrial O2 consumption) in Taylor Outbred mice in the presence and absence of zoledronic acid. This potent bisphosphonate inhibits osteoclast-mediated calcium resorption, and its effects on bone respiration have not been previously investigated. The change of O2 concentration with time was measured in closed vials containing phosphate-buffered saline (PBS), 5 mM glucose and 5-25 mg calvarial bone fragments, and it was complex for t = 0-30 h. Cyanide (specific inhibitor of cytochrome oxidase) halted O2 consumption, confirming the oxidation occurred in the respiratory chain. Initial rate of respiration was estimated from the zero-order plots d[O2]/dt for t = 0-4 h. For untreated specimens, the rate (mean ± SD) was 2.0 ± 1.2 µM O2 h-1 mg-1 (n = 6). This value was 7-10 times lower than that of other murine organs, but similar to that reported for rat and Guinea pig calvaria (averaging, 2.7 nmol O2 h-1 mg-1). The corresponding rate in the presence of 10-100 µM zoledronic acid was 2.7 ± 0.7 µM O2 h-1 mg-1 (n = 11), p = 0.216. The first-order plots ln ([O2] t  ÷ [O2] t=0) versus time for t = 0-30 h were also used to compare treated and untreated specimens. The rate (h-1 mg-1 103) for specimens incubated in PBS without glucose was 1.3 ± 0.6 (n = 3, p = 0.007), in PBS + glucose it was 10.7 ± 6.9 (n = 10), in PBS + glucose + 10 µM zoledronic acid it was 12.1 ± 6.7 (n = 10, p = 0.579), in PBS + glucose + 20 µM zoledronic acid it was 12.9 ± 3.3 (n = 9, p = 0.356), and in PBS + glucose + 100 µM zoledronic acid it was 13.7 ± 7.7 (n = 9, p = 0.447). Thus, exposure to high-doses of zoledronic acid over several hours imposed a statistically insignificant increase in calvarial bone cellular respiration.


Assuntos
Difosfonatos/farmacologia , Imidazóis/farmacologia , Crânio/citologia , Animais , Respiração Celular/efeitos dos fármacos , Glucose/farmacologia , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Crânio/efeitos dos fármacos , Ácido Zoledrônico
7.
Toxicol Mech Methods ; 23(8): 610-6, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23738705

RESUMO

CONTEXT: Amiodarone (an iodinated benzofuran) is a Class III antiarrhythmic drug that produces significant pulmonary disease. Proposed mechanisms of this cytotoxicity include necrosis, apoptosis, mitochondrial dysfunction and glutathione depletion. OBJECTIVE: This study was designed primarily to explore whether amiodarone impairs lung tissue cellular bioenergetics in BALB/c and Taylor Outbred mice. MATERIALS AND METHODS: Cellular respiration (mitochondrial O2 consumption), ATP, caspase activity and glutathione were measured in lung fragments incubated in vitro with 22 µM amiodarone for several hours. RESULTS: Without amiodarone, lung tissue cellular mitochondrial O2 consumption decayed exponentially with time, showing two distinct phases sharply separated at t ≥ 150 min. The rate of cellular respiration was 6-10-fold higher in the late phase compared to the early phase (p<0.0001). Lung tissue ATP also decayed exponentially with time, suggesting "uncoupling oxidative phosphorylation" was the responsible mechanism (low cellular ATP with high mitochondrial O2 consumption, resulting in rapid depletion of cellular metabolic fuels). Although intracellular caspase activity increased exponentially with time, the uncoupling was not prevented by the pancaspase inhibitor zVAD-fmk (N-benzyloxycarbonyl-val-ala-asp (O-methyl)-fluoromethylketone). The same profiles were noted in the presence of amiodarone; but cellular ATP decayed 50% faster. Cellular glutathione for untreated tissue was 560 ± 287 pmol mg(-1) (n=12) and for treated tissue was 490 ± 226 pmol mg(-1) (n=12, p=0.5106). CONCLUSION: Uncoupling oxidative phosphorylation was demonstrated in untreated mouse lung tissues. Amiodarone lowered cellular ATP. Further studies are needed to explore the susceptibility of the lung to these deleterious insults and their relevance to human diseases.


Assuntos
Amiodarona/toxicidade , Pulmão/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Caspases/metabolismo , Cromatografia Líquida de Alta Pressão , Glutationa/metabolismo , Técnicas In Vitro , Pulmão/enzimologia , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos BALB C
8.
BMC Res Notes ; 6: 12, 2013 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-23311890

RESUMO

BACKGROUND: This study aimed to establish a suitable in vitro system for investigating effects of respiratory pathogens and toxins on lung tissue bioenergetics (cellular respiration and ATP content) and caspase activity. Wistar rats and C57Bl/6 mice were anesthetized by sevoflurane inhalation. Lung fragments were then collected and incubated at 37°C in a continuously gassed (with 95% O2:5% CO2) Minimal Essential Medium (MEM) or Krebs-Henseleit buffer. Phosphorescence O2 analyzer that measured dissolved O2 concentration as a function of time was used to monitor the rate of cellular mitochondrial O2 consumption. Cellular ATP content was measured using the luciferin/luciferase system. The caspase-3 substrate N-acetyl-asp-glu-val-asp-7-amino-4-methylcoumarin (Ac-DEVD-AMC) was used to monitor intracellular caspase activity; cleaved AMC moieties (reflecting caspase activity) were separated on HPLC and detected by fluorescence. Lung histology and immunostaining with anti-cleaved caspase-3 antibody were also performed. RESULTS: For Wistar rats, the values of kc and ATP for 0 < t ≤ 7 h (mean ± SD) were 0.15 ± 0.02 µM O2 min-1 mg-1 (n = 18, coefficient of variation, Cv = 13%) and 131 ± 69 pmol mg-1 (n = 16, Cv = 53%), respectively. The AMC peak areas remained relatively small despite a ~5-fold rise over 6 h. Good tissue preservation was evident despite time-dependent increases in apoptotic cells. Lung tissue bioenergetics, caspase activity and structure were deleterious in unoxygenated or intermittently oxygenated solutions. Incubating lung tissue in O2 depleted MEM for 30 min or anesthesia by urethane had no effect on lung bioenergetics, but produced higher caspase activity. CONCLUSIONS: Lung tissue bioenergetics and structure could be maintained in vitro in oxygenated buffer for several hours and, thus, used as biomarkers for investigating respiratory pathogens or toxins.


Assuntos
Caspases/metabolismo , Metabolismo Energético , Pulmão/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Pulmão/enzimologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Ratos , Ratos Wistar
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...