| 1. |
- Aburawi, Elhadi, et al.
(author)
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Coronary Flow in Neonates with Impaired Intrauterine Growth.
- 2012
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In: Journal of the American Society of Echocardiography. - : Elsevier BV. - 1097-6795 .- 0894-7317. ; 25:3, s. 313-318
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Journal article (peer-reviewed)abstract
- BACKGROUND: Subclinical myocardial injury has been reported in newborns with fetal weights < 2 SDs for gestational age. Intrauterine growth restriction might affect cardiac function and coronary flow (CF). METHODS: Seventeen newborns with intrauterine growth restriction and 15 age-matched healthy controls were enrolled in the study. Blood flow in the umbilical artery and maternal uterine artery was assessed using Doppler velocimetry. Cardiac function and left anterior descending coronary artery CF were measured using transthoracic Doppler echocardiography at 1 week of age. RESULTS: The mean growth deviation of the newborns from normal was -2.5 ± 0.2 SDs. Percentage left ventricular shortening fraction was 39 ± 4.3% in patients and 42 ± 4.1% in controls (P = .40), and the mean left ventricular mass index was 86.6 g/m(2) in patients and 73.7 g/m(2) in controls (P < .01). The mean left anterior descending coronary artery diameter was 0.99 ± 0.1 mm in patients and 0.8 ± 0.1 mm in controls (P = .002). The left anterior descending coronary artery flow velocity-time integral was correlated with left ventricular mass index (r = 0.31, P = .007) and with mitral peak E/A ratio (r = 0.74, P = .01). Intrauterine growth restriction was associated with increased peak flow velocity in diastole (34.5 ± 4 vs 19 ± 6 cm/sec in controls, P = .0001), as well as increased CF (37 ± 7.3 vs 8.2 ± 3.0 mL/min in controls, P = .001). CONCLUSIONS: CF is significantly increased in neonates with impaired intrauterine growth. Left ventricular mass index is increased, but systolic and diastolic function remains normal. The clinical significance of increased CF is unclear, but it might lead to decreased CF reserve.
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| 2. |
- Austeng, Dordi, et al.
(author)
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Incidence of and risk factors for neonatal morbidity after active perinatal care : extremely preterm infants study in Sweden (EXPRESS)
- 2010
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In: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 99:7, s. 978-992
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Journal article (peer-reviewed)abstract
- Aims: The aim of this study was to determine the incidence of neonatal morbidity in extremely preterm infants and to identify associated risk factors. Methods: Population based study of infants born before 27 gestational weeks and admitted for neonatal intensive care in Sweden during 2004-2007. Results: Of 638 admitted infants, 141 died. Among these, life support was withdrawn in 55 infants because of anticipation of poor long-term outcome. Of 497 surviving infants, 10% developed severe intraventricular haemorrhage (IVH), 5.7% cystic periventricular leucomalacia (cPVL), 41% septicaemia and 5.8% necrotizing enterocolitis (NEC); 61% had patent ductus arteriosus (PDA) and 34% developed retinopathy of prematurity (ROP) stage >= 3. Eighty-five per cent needed mechanical ventilation and 25% developed severe bronchopulmonary dysplasia (BPD). Forty-seven per cent survived to one year of age without any severe IVH, cPVL, severe ROP, severe BPD or NEC. Tocolysis increased and prolonged mechanical ventilation decreased the chances of survival without these morbidities. Maternal smoking and higher gestational duration were associated with lower risk of severe ROP, whereas PDA and poor growth increased this risk. Conclusion: Half of the infants surviving extremely preterm birth suffered from severe neonatal morbidities. Studies on how to reduce these morbidities and on the long-term health of survivors are warranted.
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| 3. |
- Davoudi, Mina, et al.
(author)
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A mouse model of mitochondrial complex III dysfunction induced by myxothiazol.
- 2014
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In: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 446:4, s. 1079-1084
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Journal article (peer-reviewed)abstract
- Myxothiazol is a respiratory chain complex III (CIII) inhibitor that binds to the ubiquinol oxidation site Qo of CIII. It blocks electron transfer from ubiquinol to cytochrome b and thus inhibits CIII activity. It has been utilized as a tool in studies of respiratory chain function in in vitro and cell culture models. We developed a mouse model of biochemically induced and reversible CIII inhibition using myxothiazol. We administered myxothiazol intraperitoneally at a dose of 0.56mg/kg to C57Bl/J6 mice every 24h and assessed CIII activity, histology, lipid content, supercomplex formation, and gene expression in the livers of the mice. A reversible CIII activity decrease to 50% of control value occurred at 2h post-injection. At 74h only minor histological changes in the liver were found, supercomplex formation was preserved and no significant changes in the expression of genes indicating hepatotoxicity or inflammation were found. Thus, myxothiazol-induced CIII inhibition can be induced in mice for four days in a row without overt hepatotoxicity or lethality. This model could be utilized in further studies of respiratory chain function and pharmacological approaches to mitochondrial hepatopathies.
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| 4. |
- Davoudi, Mina, et al.
(author)
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Complex I Function and Supercomplex Formation Are Preserved in Liver Mitochondria Despite Progressive Complex III Deficiency.
- 2014
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:1
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Journal article (peer-reviewed)abstract
- Functional oxidative phosphorylation requires appropriately assembled mitochondrial respiratory complexes and their supercomplexes formed mainly of complexes I, III and IV. BCS1L is the chaperone needed to incorporate the catalytic subunit, Rieske iron-sulfur protein, into complex III at the final stage of its assembly. In cell culture studies, this subunit has been considered necessary for supercomplex formation and for maintaining the stability of complex I. Our aim was to assess the importance of fully assembled complex III for supercomplex formation in intact liver tissue. We used our transgenic mouse model with a homozygous c.232A>G mutation in Bcs1l leading to decreased expression of BCS1L and progressive decrease of Rieske iron-sulfur protein in complex III, resulting in hepatopathy. We studied supercomplex formation at different ages using blue native gel electrophoresis and complex activity using high-resolution respirometry. In isolated liver mitochondria of young and healthy homozygous mutant mice, we found similar supercomplexes as in wild type. In homozygotes aged 27-29 days with liver disorder, complex III was predominantly a pre-complex lacking Rieske iron-sulfur protein. However, the main supercomplex was clearly detected and contained complex III mainly in the pre-complex form. Oxygen consumption of complex IV was similar and that of complex I was twofold compared with controls. These complexes in free form were more abundant in homozygotes than in controls, and the mRNA of complex I subunits were upregulated. In conclusion, when complex III assembly is deficient, the pre-complex without Rieske iron-sulfur protein can participate with available fully assembled complex III in supercomplex formation, complex I function is preserved, and respiratory chain stability is maintained.
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| 5. |
- Diaz, Francisca, et al.
(author)
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Mitochondrial disorders caused by mutations in respiratory chain assembly factors
- 2011
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In: Seminars in Fetal & Neonatal Medicine. - : Elsevier BV. - 1878-0946 .- 1744-165X. ; 16:4, s. 197-204
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Journal article (peer-reviewed)abstract
- Mitochondrial diseases involve the dysfunction of the oxidative phosphorylation (OXPHOS) system. This group of diseases presents with heterogeneous clinical symptoms affecting mainly organs with high energy demands. Defects in the multimeric complexes comprising the OXPHOS system have a dual genetic origin, mitochondrial or nuclear DNA. Although many nuclear DNA mutations involve genes coding for subunits of the respiratory complexes, the majority of mutations found to date affect factors that do not form part of the final complexes. These assembly factors or chaperones have multiple functions ranging from cofactor insertion to proper assembly/stability of the complexes. Although significant progress has been made in the last few years in the discovery of new assembly factors, the function of many remains elusive. Here, we describe assembly factors or chaperones that are required for respiratory chain complex assembly and their clinical relevance. (C) 2011 Elsevier Ltd. All rights reserved.
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| 6. |
- Fellman, Vineta
(author)
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GRACILE-oireyhtymä--vastasyntyneen vakava mitokondriotauti.
- 2012
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In: Duodecim; lääketieteellinen aikakauskirja. - 0012-7183. ; 128:15, s. 1560-1567
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Research review (peer-reviewed)abstract
- GRACILE syndrome belongs to the Finnish disease heritage, and is caused by a point mutation in the BCS1L-gene encoding a mitochondrial protein. This leads to dysfunction of the complex III in the respiratory chain. Significant fetal growth disturbance is the primary manifestation. Within the first day the newborn infant develops severe lactic acidosis. Hypoglycemia, elevated serum ferritin and conjugated bilirubin values and aminoaciduria imply mitochondrial liver disease and renal tubulopathy. In Finland, the diagnosis is based on the 232A>G mutation in the BCS1L-gene. No specific treatment is available. GRACILE syndrome leads to early death.
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| 7. |
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| 8. |
- Fellman, Vineta, et al.
(author)
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Mitochondrial hepatopathies in the newborn period.
- 2011
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In: Seminars in Fetal & Neonatal Medicine. - : Elsevier BV. - 1878-0946 .- 1744-165X. ; 16, s. 222-228
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Journal article (peer-reviewed)abstract
- Mitochondrial disorders recognized in the neonatal period usually present as a metabolic crisis combined with one or several organ manifestations. Liver disorder in association with a respiratory chain deficiency may be overlooked since liver dysfunction is common in severely sick newborn infants. Lactacidosis, hypoglycemia, elevated serum transaminases and conjugated bilirubin are common signs of mitochondrial hepatopathy. Hepatosplenomegaly may occur in severe cases. A clinical picture with fetal growth restriction, postnatal lactacidosis, hypoglycemia, coagulopathy, and cholestasis, especially in combination with neurological symptoms or renal tubulopathy, should alert the neonatologist to direct investigations on mitochondrial disorder. A normal lactate level does not exclude respiratory chain defects. The most common liver manifestation caused by mutated mitochondrial DNA (deletion) is Pearson syndrome. Recently, mutations in several nuclear DNA genes have been identified that lead to mitochondrial hepatopathy, e.g. mitochondrial depletion syndrome caused by DGUOK, MPV17, SUCLG1, POLG1, or C10ORF2 mutations. A combination of lactacidosis, liver involvement, and Fanconi type renal tubulopathy is common when the complex III assembly factor BCS1L harbors mutations, the most severe disease with consistent genotype-phenotype correlation being the GRACILE syndrome. Mutations in nuclear translation factor genes (TRMU, EFG1, and EFTu) of the respiratory chain enzyme complexes have recently been identified. Diagnostic work-up of neonatal liver disorder should include assessment of function and structure of the complexes as well as mutation screening for known genes. So far, treatment is mainly symptomatic.
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| 9. |
- Gram, Magnus, et al.
(author)
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The radical-binding lipocalin A1M binds to a Complex I subunit and protects mitochondrial structure and function.
- 2013
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In: Antioxidants & Redox Signaling. - : Mary Ann Liebert Inc. - 1557-7716 .- 1523-0864. ; 18:16, s. 2017-2028
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Journal article (peer-reviewed)abstract
- Aims: During cell death, energy-consuming cell degradation and recycling programs are performed. Maintenance of energy-delivery during cell death is therefore crucial but the mechanisms to keep the mitochondrial functions intact during these processes are poorly understood. We have investigated the hypothesis that the heme- and radical-binding ubiquitous protein A1M (α1-microglobulin) is involved in protection of the mitochondria against oxidative insult during cell death. Results: Using blood cells, keratinocytes and liver cells, we show that A1M binds with high affinity to apoptosis-induced cells and is localized to mitochondria. The mitochondrial Complex I subunit NDUFAB1 was identified as a major molecular target of the A1M-binding. Furthermore, A1M was shown to inhibit the swelling of mitochondria, and to reverse the severely abrogated ATP-production of mitochondria when exposed to heme and ROS. Innovation: Import of the radical- and heme-binding protein A1M from the extracellular compartment confers protection of mitochondrial structure and function during cellular insult. Conclusion: A1M binds to a subunit of Complex I and has a role in assisting the mitochondria to maintain its energy delivery during cell death. A1M may also, at the same time, counteract and eliminate the ROS generated by the mitochondrial respiration to prevent oxidative damage to surrounding healthy tissue.
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| 10. |
- Hansen-Pupp, Ingrid, et al.
(author)
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Postnatal Decrease in Circulating Insulin-Like Growth Factor-I and Low Brain Volumes in Very Preterm Infants.
- 2011
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In: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 96:4, s. 1129-1135
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Journal article (peer-reviewed)abstract
- Context: IGF-I and IGF binding protein-3 (IGFBP-3) are essential for growth and maturation of the developing brain. Objective: The aim of this study was to evaluate the association between postnatal serum concentrations of IGF-I and IGFBP-3 and brain volumes at term in very preterm infants. Design: Fifty-one infants with a mean (sd) gestational age (GA) of 26.4 (1.9) wk and birth weight (BW) of 888 (288) g were studied, with weekly blood sampling of IGF-I and IGFBP-3 from birth until 35 gestational weeks (GW) and daily calculation of protein and caloric intake. Magnetic resonance images obtained at 40 GW were segmented into total brain, cerebellar, cerebrospinal fluid, gray matter, and unmyelinated white matter volumes. Main Outcome Measures: We evaluated brain growth by measuring brain volumes using magnetic resonance imaging. Results: Mean IGF-I concentrations from birth to 35 GW correlated with total brain volume, unmyelinated white matter volume, gray matter volume, and cerebellar volume [r = 0.55 (P < 0.001); r = 0.55 (P < 0.001); r = 0.44 (P = 0.002); and r = 0.58 (P < 0.001), respectively]. Similar correlations were observed for IGFBP-3 concentrations. Correlations remained after adjustment for GA, mean protein and caloric intakes, gender, severe brain damage, and steroid treatment. Protein and caloric intakes were not related to brain volumes. Infants with BW small for GA had lower mean concentrations of IGF-I (P = 0.006) and smaller brain volumes (P = 0.001-0.013) than infants with BW appropriate for GA. Conclusion: Postnatal IGF-I and IGFBP-3 concentrations are positively associated with brain volumes at 40 GW in very preterm infants. Normalization of the IGF-I axis, directly or indirectly, may support normal brain development in very preterm infants.
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