Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 275
Filtrar
1.
Eur Respir J ; 2024 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-39401856

RESUMEN

RATIONALE: Lung quantitative computed tomographic (qCT) severe asthma clusters have been reported, but their replication and underlying disease mechanisms are unknown. We identified and replicated qCT clusters of severe asthma in two independent asthma cohorts and determined their association with molecular pathways. METHODS: We used consensus clustering on qCT measurements of airway and lung CT scans, performed in 105 severe asthmatic adults from the U-BIOPRED cohort. The same qCT measurements were used to replicate qCT clusters in a subsample of the ATLANTIS asthma cohort (n=97). We performed integrated enrichment analysis using blood, sputum, bronchial biopsies, bronchial brushings and nasal brushings transcriptomics and blood and sputum proteomics to characterize radiomultiomic-associated clusters (RACs). RESULTS: qCT clusters and clinical features in U-BIOPRED were replicated in the matched ATLANTIS cohort. In the U-BIOPRED cohort, RAC1 (n=30) was predominantly female with elevated BMI, mild airflow limitation, normal qCT parameters and upregulation of the complement pathway. RAC2 (n=34) subjects had a lower degree of airflow limitation, airway wall thickness and dilatation, with upregulation of proliferative pathways, including neurotrophic receptor tyrosine kinase 2/tyrosine kinase receptor B (NTRK2/TRKB), and down-regulation of semaphorin pathways. RAC3 (n=41) showed increased lung attenuation area and air trapping, severe airflow limitation, hyperinflation, and upregulation of cytokine signaling and signaling by interleukin pathways, and matrix metallopeptidase 1, 2 and 9. CONCLUSIONS: U-BIOPRED severe asthma qCT clusters were replicated in a matched independent asthmatic cohort and associated with specific molecular pathways. Radiomultiomics might represent anovel strategy to identify new molecular pathways in asthma pathobiology.

2.
Sensors (Basel) ; 24(13)2024 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-39000943

RESUMEN

In view of the ever-increasing global energy demands and the imperative for sustainability in extraction methods, this article surveys subsidence monitoring systems applied to oil and gas fields located in offshore areas. Subsidence is an issue that can harm infrastructure, whether onshore or especially offshore, so it must be carefully monitored to ensure safety and prevent potential environmental damage. A comprehensive review of major monitoring technologies used offshore is still lacking; here, we address this gap by evaluating several techniques, including InSAR, GNSSs, hydrostatic leveling, and fiber optic cables, among others. Their accuracy, applicability, and limitations within offshore operations have also been assessed. Based on an extensive literature review of more than 60 published papers and technical reports, we have found that no single method works best for all settings; instead, a combination of different monitoring approaches is more likely to provide a reliable subsidence assessment. We also present selected case histories to document the results achieved using integrated monitoring studies. With the emerging offshore energy industry, combining GNSSs, InSAR, and other subsidence monitoring technologies offers a pathway to achieving precision in the assessment of offshore infrastructural stability, thus underpinning the sustainability and safety of offshore oil and gas operations. Reliable and comprehensive subsidence monitoring systems are essential for safety, to protect the environment, and ensure the sustainable exploitation of hydrocarbon resources.

3.
Clin Anat ; 2024 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-39101524

RESUMEN

Regional anatomy teaching forms a cornerstone of undergraduate medical education. Owing to an increase in teaching and learning content throughout the medical curriculum in recent years, contact hours and overall course durations in anatomy are under review worldwide. This study aimed to assess whether shortening the course content duration impacts learning gain and the ability to identify anatomical structures correctly. Undergraduate medical students of the Johannes Kepler University Linz (JKU; n = 310) and at the Medical University of Graz (MUG; n = 156) participating in regional anatomy courses were included. Whole body regional anatomy courses, including hands-on dissection and accompanying lectures, were delivered over one or three months. Course content and examination mode were kept consistent, while the duration of knowledge delivery was one or three months, respectively. Objective structured practical examinations (OSPE) were then carried out on prosections for the neck, thorax, and abdomen. 3-month course exposure resulted in significantly higher OSPE scores for the neck (49 vs. 37%), thorax (65 vs. 54%), and abdomen (65 vs. 45%), respectively. Further evaluation of the utility of different embalming types yielded higher 3-month scores in the neck and thorax regions with Thiel-embalmed tissues and thorax and abdomen regions in ethanol-glycerin-embalmed tissues. Course exposure over a more extended period, like three months, appears to be highly beneficial.

4.
Molecules ; 28(6)2023 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-36985621

RESUMEN

Three new tripod tetradentate phenolate-amines (H2L1, H2L4 and H2L9), together with seven more already related published ligands, were synthesized, and characterized. With these ligands, two new dinuclear doubly-bridged-phenoxido copper(II) complexes (3, 4), and six more complexes (1, 2, 5-8), a new trinuclear complex (9) with an alternative doubly-bridged-phenoxido and -methoxido, as well as the 1D polymer (10) were synthesized, and their molecular structures were characterized by spectroscopic methods and X-ray single crystal crystallography. The Cu(II) centers in these complexes exhibit distorted square-pyramidal arrangement in 1-4, mixed square pyramidal and square planar in 5, 6, and 9, and distorted octahedral (5+1) arrangements in 7 and 8. The temperature dependence magnetic susceptibility study over the temperature range 2-300 K revealed moderate-relatively strong antiferromagnetic coupling (AF) (|J| = 289-145 cm-1) in complexes 1-6, weak-moderate AF (|J| = 59 cm-1) in the trinuclear complex 9, but weak AF interactions (|J| = 3.6 & 4.6 cm-1) were obtained in 7 and 8. No correlation was found between the exchange coupling J and the geometrical structural parameters of the four-membered Cu2O2 rings.

5.
Pediatr Blood Cancer ; 69(7): e29469, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-34854550

RESUMEN

INTRODUCTION: Home-based treatment of febrile neutropenia (FN) in children with cancer with oral or intravenous antibiotics is safe and effective. There are limited data on the economic impact of this model of care. We evaluated the cost-effectiveness of implementing an FN programme, incorporating home-based intravenous antibiotics for carefully selected patients, in a tertiary paediatric hospital. METHODS: A decision analytic model was constructed to compare costs and outcomes of the home-based FN programme, with usual in-hospital treatment with intravenous antibiotics. The programme included a clinical decision rule to stratify patients by risk for severe infection and home-based eligibility criteria using disease, chemotherapy and patient-level factors. Health outcomes (quality of life) and probabilities of FN risk classification and home-based eligibility were based on prospectively collected data between 2017 and 2019. Patient-level costs were extracted from hospital administrative records. Cost-effectiveness was expressed as the incremental cost per quality-adjusted life year (QALY). FINDINGS: The mean health care cost of home-based FN treatment in low-risk patients was Australian dollars (A$) 7765 per patient compared to A$20,396 for in-hospital treatment (mean difference A$12,632 [95% CI: 12,496-12,767]). Overall, the home-based FN programme was the dominant strategy, being more effective (0.0011 QALY [95% CI: 0.0011-0.0012]) and less costly. Results of the model were most sensitive to proportion of children eligible for home-based care programme. CONCLUSION: Compared to in-hospital FN care, the home-based FN programme is cost-effective, with savings arising from cheaper cost of caring for children at home. These savings could increase as more patients eligible for home-based care are included in the programme.


Asunto(s)
Neutropenia Febril , Neoplasias , Antibacterianos/uso terapéutico , Australia , Niño , Análisis Costo-Beneficio , Neutropenia Febril/tratamiento farmacológico , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Calidad de Vida
6.
Inorg Chem ; 61(29): 11124-11136, 2022 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-35815859

RESUMEN

Four novel CeIII mononuclear complexes of formulas [Ce(ntfa)3(MeOH)2] (1), [Ce(ntfa)3(5,5'-Me2bipy)] (2), [Ce(ntfa)3(terpy)] (3), and [Ce(ntfa)3(bipy)2] (4), where ntfa = 4,4,4-trifluoro-1-(naphthalen-2-yl)butane-1,3-dionato, 5,5'-Me2bipy = 5,5'-dimethyl-2,2'-dipyridyl, terpy = 2,2':6',2″-terpyridine, and bipy = 2,2'-bipyridine, have been synthesized and structurally characterized with CeIII displaying coordination numbers of 8, 8, 9, and 10, respectively. Magnetic measurements indicate that all the complexes show a field-induced single-ion magnet behavior under a small applied dc field. The magnetic analysis shows the relevance of the different spin relaxation mechanisms in the magnetic relaxation of the CeIII compounds, with special emphasis on the local-mode process. Multiconfigurational calculations were also performed to get more information on the axiality of the compounds.

7.
Molecules ; 27(3)2022 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-35164394

RESUMEN

A new series of mononuclear Ho3+ complexes derived from the ß-diketonate anions: 4,4,4-trifluoro-1-phenyl-1,3-butanedioneate (btfa-) and 4,4,4-trifuoro-1-(naphthalen-2-yl)-1,3-butanedionate (ntfa-) have been synthesized, [Ho(btfa)3(H2O)2] (1a), [Ho(ntfa)3(MeOH)2] (1b), (1), [Ho(btfa)3(phen)] (2), [Ho(btfa)3(bipy)] (3), [Ho(btfa)3(di-tbubipy)] (4), [Ho(ntfa)3(Me2bipy)] (5), and [Ho(ntfa)3(bipy)] (6), where phen is 1,10-phenantroline, bipy is 2,2'-bipyridyl, di-tbubipy is 4,4'-di-tert-butyl-2,2'-bipyridyl, and Me2bipy is 4,4'-dimethyl-2,2'-bipyridyl. These compounds have been characterized by elemental microanalysis and infrared spectroscopy as well as single-crystal X-ray difraction for 2-6. The central Ho3+ ions in these compounds display coordination number 8. The luminescence-emission properties of the pyridyl adducts 2-6 display a strong characteristic band in the visible region at 661 nm and a series of bands in the NIR region (excitation wavelengths (λex) of 367 nm for 2-4 and 380 nm for 5 and 6). The magnetic properties of the complexes revealed magnetically uncoupled Ho3+ compounds with no field-induced, single-molecule magnet (SMMs).

8.
Eur J Nutr ; 60(2): 861-872, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32476053

RESUMEN

BACKGROUND: Arachidonic (ARA) and docosahexaenoic acid (DHA) are constitutive to membrane phospholipids, and essential for brain and overall development. ARA/DHA pools in term infants (TI) are built during the third trimester, stored as adipose tissue triglycerides and predominantly distributed via plasma phosphatidylcholine (PC). In preterm infants (PTI), placental ARA/DHA supply is replaced by linoleic-acid (LA)-enriched nutrition. This study aimed to investigate the impact of PTI nutrition, compared to placental supply, on fatty acid composition in adipose tissue and blood. METHODS: Prospective observational study (4/2017-3/2019) in 12 PTI and 3 PTI with enterostomy (PTI/E) (gestational age (GA) < 32 weeks) with surgical intervention at term (± 6 weeks) and 14 TI (GA ≥ 34 weeks, surgical intervention < 2 weeks postnatally). PTI/E were analyzed descriptively only. PC and triglyceride fatty acids were analyzed with tandem mass spectrometry and gas chromatography, respectively. Results were compared between TI and PTI with Wilcoxon Test and shown as median [25th percentile-75th percentile] mol%. RESULTS: PTI had less ARA in adipose tissue TG (0.77[0.67-0.87]% vs. 1.04[0.95-1.14]%, p = 0.0003) and plasma PC (20.7[18.7-22.8]% vs. 28.3[22.7-33.5]%, p = 0.011) than TI. PTI also had less DHA in adipose tissue TG (0.6[0.4-0.8]% vs. 1.1[0.8-1.4]%, p = 0.006) and plasma PC (6.4[5.6-7.1]% vs. 8.4[7.8-13.1]%, p = 0.002). LA was increased in PTI's adipose tissue TG (10.0[8.8-12.3]% vs. 3.0[2.5-3.6]%, p < 0.0001) and plasma PC (48.4[44.6-49.6]% vs. 30.6[24.9-35.6]%, p = 0.0002). Similar differences were observed in erythrocyte PC. CONCLUSION: In PTI, LA is increased and ARA/DHA decreased in adipose tissue, plasma and erythrocyte lipids as proxies for other tissues, likely caused by PTI nutrition. This may contribute to impaired PTI development.


Asunto(s)
Ácidos Docosahexaenoicos , Ácido Linoleico , Tejido Adiposo , Ácidos Grasos , Femenino , Cromatografía de Gases y Espectrometría de Masas , Humanos , Recién Nacido , Recien Nacido Prematuro , Placenta , Embarazo
9.
Molecules ; 25(15)2020 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-32722383

RESUMEN

A novel series of mononuclear five-coordinated pseudohalido-Cu(II) complexes displaying distorted square bipyramidal: [Cu(L1)(NCS)2] (1), [Cu(L2)(NCS)2] (2) and [Cu(L3)(NCS)]ClO4 (5) as well as distorted trigonal bipyramidal: [Cu(isp3tren)(N3)]ClO4 (3), [Cu(isp3tren)(dca)]ClO4 (4) and [Cu(tedmpza)(dca)]ClO4·0.67H2O (6) geometries had been synthesized and structurally characterized using X-ray single crystal crystallography, elemental microanalysis, IR and UV-vis spectroscopy, and molar conductivity measurements. Different N-donor amine skeletons including tridentate: L1 = [(2-pyridyl)-2-ethyl)-(3,4-dimethoxy)-2-methylpyridyl]methylamine and L2 = [(2-pyridyl)-2-ethyl)-(3,5-dimethyl-4-methoxy)-2-methyl-pyridyl]methylamine, and tetradentate: L3 = bis(2-ethyl-di(3,5-dimethyl-1H-pyrazol-1-yl)-[2-(3,4-dimethoxy-pyridylmethyl)]amine, tedmpza = tris[(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]amine and isp3tren = tris[(2-isopropylamino)ethyl)]amine ligands were employed. Molecular structural parameters such as nature of coligand, its chelate ring size and steric environment incorporated into its skeleton, which lead to adopting one of the two limiting geometries in these complexes and other reported compounds are analyzed and correlated to their assigned geometries in solutions. Similar analysis were extended to other five-coordinated halido-Cu(II) complexes.


Asunto(s)
Aminas/química , Complejos de Coordinación/química , Cobre/química , Piridinas/química , Ligandos , Estructura Molecular , Pirazoles/química , Soluciones
10.
Phys Rev Lett ; 123(1): 016101, 2019 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-31386422

RESUMEN

We report the detection and quantification of nuclear spin incoherent scattering from hydrogen occupying interstitial sites in a thin film of vanadium. The neutron wave field is enhanced in a quantum resonator with magnetically switchable boundaries. Our results provide a pathway for the study of dynamics at surfaces and in ultrathin films using inelastic and/or quasielastic neutron scattering methods.

11.
Soft Matter ; 15(3): 371-380, 2019 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-30519692

RESUMEN

Entangled polymers are deformed by a strong shear flow. The shape of the polymer, called the form factor, is measured by small angle neutron scattering. However, the real-space molecular structure is not directly available from the reciprocal-space data, due to the phase problem. Instead, the data has to be fitted with a theoretical model of the molecule. We approximate the unknown structure using piecewise straight segments, from which we derive an analytical form factor. We fit it to our data on a semi-dilute entangled polystyrene solution under in situ shear flow. The character of the deformation is shown to lie between that of a single ideal chain (viscous) and a cross-linked network (elastic rubber). Furthermore, we use the fitted structure to estimate the mechanical stress, and find a fairly good agreement with rheology literature.

12.
Orthopade ; 48(12): 992-997, 2019 Dec.
Artículo en Alemán | MEDLINE | ID: mdl-31659422

RESUMEN

BACKGROUND: The need for effective training methods for positive adaptations in muscle strength and bone mineralization, suitable for all groups of patients, arises in both rehabilitation and pre-habilitation. In addition to mechanical stress, an increased metabolic stress, by means of reduced blood supply of the muscle, seems to induce positive adaptations as well. OBJECTIVES: Description of the effects of resistance training and opportunities of blood-flow restriction training in a clinical setting. METHODS: Key and specialized literature RESULTS: Regularly applied high mechanical loads are suitable to induce increases in muscle strength and mass as well as bone mineralization. In principle, the trainability of these tissues is given over the entire life span, although the adaptation of the muscle mass is reduced in the prepubertal and later stages of life. Classic strength training is particularly suitable as a training method to apply this stimulus quality (mechanical stress). For some years now, however, there has been increasing evidence that even low-intensity resistance training associated with metabolic stress is capable of producing hypertrophic effects and increasing muscle strength. This observation is particularly interesting for target groups whose mechanical capacity of the musculoskeletal system is reduced. Blood-flow-restriction training is particularly suitable as a training method for the application of this stimulus quality (metabolic stress). The data available on the effectiveness of low-intensity stress protocols on bone structure is still insufficient. Further research is needed to make evidence-based recommendations.


Asunto(s)
Adaptación Fisiológica/fisiología , Fuerza Muscular/fisiología , Músculo Esquelético/irrigación sanguínea , Entrenamiento de Fuerza/métodos , Estrés Mecánico , Metabolismo Energético/fisiología , Humanos , Músculo Esquelético/fisiología
13.
Unfallchirurg ; 122(12): 934-940, 2019 Dec.
Artículo en Alemán | MEDLINE | ID: mdl-31650192

RESUMEN

Idiopathic shoulder stiffness (i.e. frozen shoulder, FS) is a common pathology of the glenohumeral joint characterized by a sudden onset of pain syndrome and progressive restriction of the range of motion. While the histological changes of FS are accompanied by synovial inflammation and increasing capsular fibrosis, the underlying cause of FS is still unknown. The treatment options for FS are multifarious and include medication, local steroid injection, physiotherapy, hydrodistension, manipulation under anesthesia, arthroscopic and open capsular release. As the disease is usually self-limiting and the symptoms resolve after 2-3 years, especially conservative treatment measures are often clinically applied; however, in this context there is still no scientifically based consensus on which treatment measures are most likely to contribute to symptom relief in which phase of the disease. For this reason, this article focuses on the description of the scientifically investigated conservative treatment methods in FS and their temporal classification into the classical three-phase course of the disease.


Asunto(s)
Bursitis , Tratamiento Conservador , Artropatías , Artroscopía , Bursitis/terapia , Humanos , Artropatías/terapia , Rango del Movimiento Articular , Articulación del Hombro , Resultado del Tratamiento
14.
Insect Mol Biol ; 26(1): 113-126, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-28054419

RESUMEN

Aedes aegypti is a major vector for arboviruses such as dengue, chikungunya and Zika viruses. During acquisition of a viremic bloodmeal, an arbovirus infects mosquito midgut cells before disseminating to secondary tissues, including the salivary glands. Once virus is released into the salivary ducts it can be transmitted to another vertebrate host. The midgut is surrounded by a basal lamina (BL) in the extracellular matrix, consisting of a proteinaceous mesh composed of collagen IV and laminin. BL pore size exclusion limit prevents virions from passing through. Thus, the BL probably requires remodelling via enzymatic activity to enable efficient virus dissemination. Matrix metalloproteinases (MMPs) are extracellular endopeptidases that are involved in remodelling of the extracellular matrix. Here, we describe and characterize the nine Ae. aegypti encoded MMPs, AeMMPs 1-9, which share common features with other invertebrate and vertebrate MMPs. Expression profiling in Ae. aegypti revealed that Aemmp4 and Aemmp6 were upregulated during metamorphosis, whereas expression of Aemmp1 and Aemmp2 increased during bloodmeal digestion. Aemmp1 expression was also upregulated in the presence of a bloodmeal containing chikungunya virus. Using polyclonal antibodies, AeMMP1 and AeMMP2 were specifically detected in tissues associated with the mosquito midgut.


Asunto(s)
Aedes/enzimología , Metaloproteinasas de la Matriz/metabolismo , Aedes/genética , Aedes/crecimiento & desarrollo , Aedes/virología , Secuencia de Aminoácidos , Animales , Virus Chikungunya/fisiología , Femenino , Tracto Gastrointestinal/enzimología , Expresión Génica , Genoma de los Insectos , Humanos , Masculino , Metaloproteinasas de la Matriz/genética , Metamorfosis Biológica , Datos de Secuencia Molecular , Homología de Secuencia de Ácido Nucleico
15.
J Org Chem ; 82(8): 4160-4169, 2017 04 21.
Artículo en Inglés | MEDLINE | ID: mdl-28378583

RESUMEN

Unique iodine-containing meroditerpenes iodocallophycoic acid A (1) and iodocallophycols A-D (2-5) were discovered from the Fijian red alga Callophycus sp. Because flexibility of the molecular skeleton impaired full characterization of relative stereochemistries by NMR spectroscopy, a DFT-based theoretical model was developed to derive relevant interproton distances which were compared to those calculated from NOE measurements, yielding the relative stereochemistries. The correct 2S,6S,7S,10S,14S enantiomers were then identified by comparison of theoretical and experimental ECD spectra. Biological activities of these iodinated and brominated meroditerpenes and additional new, related bromophycoic acid F (6) and bromophycoic acid A methyl ester (7), were evaluated for relevant human disease targets. Iodocallophycoic acid A (1) showed moderate antibiotic activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF) with MIC values of 1.4 and 2.2 µg mL-1, respectively. It also potentiated the anti-MRSA activity of oxacillin in a synergistic fashion, resulting in an 8-fold increase in oxacillin potency, for a MIC of 16 µg mL-1.


Asunto(s)
Diterpenos/análisis , Yodo/química , Rhodophyta/química , Diterpenos/química , Diterpenos/farmacología , Enterococcus faecium/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Modelos Teóricos , Análisis Espectral/métodos , Estereoisomerismo
16.
Phys Chem Chem Phys ; 19(2): 1335-1341, 2017 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-27973632

RESUMEN

This study provides a comprehensive insight into the effects of controlled off-stoichiometry on the structural and multiferroic properties of the hexagonal manganite LuMn1-xO3+δ (x = 0.02; δ ∼ 0), supported by neutron powder diffraction measurements confirming single phase P63cm symmetry and evidencing a relevant ferromagnetic component, below TN ∼ 90 K, which breaks the archetypal geometrically frustrated antiferromagnetic state typically ascribed to LuMnO3. The perturbations in the triangular disposition of spins prompt an additional electric polarization contribution and a clear enhancement of the magnetoelectric coupling which are in good agreement with the results of first principles calculations. In addition, Raman spectroscopy, dielectric permittivity, pyroelectric current and magnetic measurements as a function of temperature point out the precursor effects of the magnetic phase transitions involving a strong coupling between spins, lattice and electric order, even above the Néel temperature.

17.
Am J Hum Genet ; 93(2): 211-23, 2013 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-23849775

RESUMEN

The human mitochondrial genome encodes RNA components of its own translational machinery to produce the 13 mitochondrial-encoded subunits of the respiratory chain. Nuclear-encoded gene products are essential for all processes within the organelle, including RNA processing. Transcription of the mitochondrial genome generates large polycistronic transcripts punctuated by the 22 mitochondrial (mt) tRNAs that are conventionally cleaved by the RNase P-complex and the RNase Z activity of ELAC2 at 5' and 3' ends, respectively. We report the identification of mutations in ELAC2 in five individuals with infantile hypertrophic cardiomyopathy and complex I deficiency. We observed accumulated mtRNA precursors in affected individuals muscle and fibroblasts. Although mature mt-tRNA, mt-mRNA, and mt-rRNA levels were not decreased in fibroblasts, the processing defect was associated with impaired mitochondrial translation. Complementation experiments in mutant cell lines restored RNA processing and a yeast model provided additional evidence for the disease-causal role of defective ELAC2, thereby linking mtRNA processing to human disease.


Asunto(s)
Cardiomiopatía Hipertrófica/genética , Mitocondrias/genética , Mutación , Proteínas de Neoplasias/genética , Procesamiento Postranscripcional del ARN , ARN Mensajero/genética , Secuencia de Aminoácidos , Cardiomiopatía Hipertrófica/metabolismo , Cardiomiopatía Hipertrófica/patología , Núcleo Celular/genética , Núcleo Celular/metabolismo , Transporte de Electrón/genética , Endorribonucleasas/genética , Endorribonucleasas/metabolismo , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Prueba de Complementación Genética , Humanos , Lactante , Masculino , Mitocondrias/metabolismo , Datos de Secuencia Molecular , Músculos/metabolismo , Músculos/patología , Proteínas de Neoplasias/metabolismo , Linaje , ARN Mensajero/metabolismo , ARN Mitocondrial , ARN Ribosómico/genética , ARN Ribosómico/metabolismo , ARN de Transferencia/genética , ARN de Transferencia/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo
18.
Am J Hum Genet ; 90(2): 314-20, 2012 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-22284826

RESUMEN

Exome sequencing of an individual with congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, and lactic acidosis, all typical symptoms of Sengers syndrome, discovered two nonsense mutations in the gene encoding mitochondrial acylglycerol kinase (AGK). Mutation screening of AGK in further individuals with congenital cataracts and cardiomyopathy identified numerous loss-of-function mutations in an additional eight families, confirming the causal nature of AGK deficiency in Sengers syndrome. The loss of AGK led to a decrease of the adenine nucleotide translocator in the inner mitochondrial membrane in muscle, consistent with a role of AGK in driving the assembly of the translocator as a result of its effects on phospholipid metabolism in mitochondria.


Asunto(s)
Cardiomiopatías/enzimología , Catarata/enzimología , Codón sin Sentido , Mitocondrias/enzimología , Proteínas Mitocondriales/deficiencia , Fosfotransferasas (Aceptor de Grupo Alcohol)/deficiencia , Adulto , Alelos , Cardiomiopatías/genética , Catarata/genética , Niño , Exoma , Femenino , Heterocigoto , Humanos , Lactante , Recién Nacido , Masculino , Mitocondrias/genética , Translocasas Mitocondriales de ADP y ATP/genética , Proteínas Mitocondriales/genética , Músculos/metabolismo , Fenotipo , Fosfolípidos/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Adulto Joven
19.
J Inherit Metab Dis ; 38(3): 391-403, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25526709

RESUMEN

Pyruvate oxidation defects (PODs) are among the most frequent causes of deficiencies in the mitochondrial energy metabolism and represent a substantial subset of classical mitochondrial diseases. PODs are not only caused by deficiency of subunits of the pyruvate dehydrogenase complex (PDHC) but also by various disorders recently described in the whole pyruvate oxidation route including cofactors, regulation of PDHC and the mitochondrial pyruvate carrier. Our own patients from 2000 to July 2014 and patients identified by a systematic survey of the literature from 1970 to July 2014 with a pyruvate oxidation disorder and a genetically proven defect were included in the study (n=628). Of these defects 74.2% (n=466) belong to PDHC subunits, 24.5% (n=154) to cofactors, 0.5% (n=3) to PDHC regulation and 0.8% (n=5) to mitochondrial pyruvate import. PODs are underestimated in the field of mitochondrial diseases because not all diagnostic centres include biochemical investigations of PDHC in their routine analysis. Cofactor and transport defects can be missed, if pyruvate oxidation is not measured in intact mitochondria routinely. Furthermore deficiency of the X-chromosomal PDHA1 can be biochemically missed depending on the X-inactivation pattern. This is reflected by an increasing number of patients diagnosed recently by genetic high throughput screening approaches. PDHC deficiency including regulation and import affect mainly the glucose dependent central and peripheral nervous system and skeletal muscle. PODs with combined enzyme defects affect also other organs like heart, lung and liver. The spectrum of clinical presentation of PODs is still expanding. PODs are a therapeutically interesting group of mitochondrial diseases since some can be bypassed by ketogenic diet or treated by cofactor supplementation. PDHC kinase inhibition, chaperone therapy and PGC1α stimulation is still a matter of further investigations.


Asunto(s)
Proteínas Hierro-Azufre/metabolismo , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/diagnóstico , Complejo Piruvato Deshidrogenasa/metabolismo , Tiamina Pirofosfato/metabolismo , Ácido Tióctico/metabolismo , Metabolismo Energético , Femenino , Humanos , Proteínas Hierro-Azufre/clasificación , Masculino , Oxidación-Reducción , Complejo Piruvato Deshidrogenasa/clasificación , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/tratamiento farmacológico , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/genética , Tiamina Pirofosfato/clasificación , Ácido Tióctico/clasificación
20.
J Inherit Metab Dis ; 38(4): 629-40, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25778941

RESUMEN

Inherited disorders of mitochondrial energy metabolism form a large and heterogeneous group of metabolic diseases. More than 250 gene defects have been reported to date and this number continues to grow. Mitochondrial diseases can be grouped into (1) disorders of oxidative phosphorylation (OXPHOS) subunits and their assembly factors, (2) defects of mitochondrial DNA, RNA and protein synthesis, (3) defects in the substrate-generating upstream reactions of OXPHOS, (4) defects in relevant cofactors and (5) defects in mitochondrial homeostasis. Deficiency of more than one respiratory chain enzyme is a common finding. Combined defects are found in 49 % of the known disease-causing genes of mitochondrial energy metabolism and in 57 % of patients with OXPHOS defects identified in our diagnostic centre. Combined defects of complexes I, III, IV and V are typically due to deficiency of mitochondrial DNA replication, RNA metabolism or translation. Defects in cofactors can result in combined defects of various combinations, and defects of mitochondrial homeostasis can result in a generalised decrease of all OXPHOS enzymes. Noteworthy, identification of combined defects can be complicated by different degrees of severity of each affected enzyme. Furthermore, even defects of single respiratory chain enzymes can result in combined defects due to aberrant formation of respiratory chain supercomplexes. Combined OXPHOS defects have a great variety of clinical manifestations in terms of onset, course severity and tissue involvement. They can present as classical encephalomyopathy but also with hepatopathy, nephropathy, haematologic findings and Perrault syndrome in a subset of disorders.


Asunto(s)
Enfermedades Mitocondriales/genética , Metabolismo Energético/genética , Humanos , Fosforilación Oxidativa
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA