| 21. |
- Rajendran, Jayasimman, et al.
(författare)
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Alternative oxidase-mediated respiration prevents lethal mitochondrial cardiomyopathy
- 2018
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4676 .- 1757-4684. ; 2018
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Tidskriftsartikel (refereegranskat)abstract
- Alternative oxidase (AOX) is a non-mammalian enzyme that can bypass blockade of the complex III-IV segment of the respiratory chain (RC). We crossed a Ciona intestinalis AOX transgene into RC complex III (cIII)-deficient Bcs1lp.S78G knock-in mice, displaying multiple visceral manifestations and premature death. The homozygotes expressing AOX were viable, and their median survival was extended from 210 to 590 days due to permanent prevention of lethal cardiomyopathy. AOX also prevented renal tubular atrophy and cerebral astrogliosis, but not liver disease, growth restriction, or lipodystrophy, suggesting distinct tissue-specific pathogenetic mechanisms. Assessment of reactive oxygen species (ROS) production and damage suggested that ROS were not instrumental in the rescue. Cardiac mitochondrial ultrastructure, mitochondrial respiration, and pathological transcriptome and metabolome alterations were essentially normalized by AOX, showing that the restored electron flow upstream of cIII was sufficient to prevent cardiac energetic crisis and detrimental decompensation. These findings demonstrate the value of AOX, both as a mechanistic tool and a potential therapeutic strategy, for cIII deficiencies.
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| 22. |
- Rajendran, Jayasimman, et al.
(författare)
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Effect of high-carbohydrate diet on plasma metabolome in mice with mitochondrial respiratory chain complex III deficiency
- 2016
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 17:11
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial disorders cause energy failure and metabolic derangements. Metabolome profiling in patients and animal models may identify affected metabolic pathways and reveal new biomarkers of disease progression. Using liver metabolomics we have shown a starvation-like condition in a knock-in (Bcs1lc.232A>G) mouse model of GRACILE syndrome, a neonatal lethal respiratory chain complex III dysfunction with hepatopathy. Here, we hypothesized that a high-carbohydrate diet (HCD, 60% dextrose) will alleviate the hypoglycemia and promote survival of the sick mice. However, when fed HCD the homozygotes had shorter survival (mean ± SD, 29 ± 2.5 days, n = 21) than those on standard diet (33 ± 3.8 days, n = 30), and no improvement in hypoglycemia or liver glycogen depletion. We investigated the plasma metabolome of the HCD- and control diet-fed mice and found that several amino acids and urea cycle intermediates were increased, and arginine, carnitines, succinate, and purine catabolites decreased in the homozygotes. Despite reduced survival the increase in aromatic amino acids, an indicator of liver mitochondrial dysfunction, was normalized on HCD. Quantitative enrichment analysis revealed that glycine, serine and threonine metabolism, phenylalanine and tyrosine metabolism, and urea cycle were also partly normalized on HCD. This dietary intervention revealed an unexpected adverse effect of high-glucose diet in complex III deficiency, and suggests that plasma metabolomics is a valuable tool in evaluation of therapies in mitochondrial disorders.
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| 23. |
- Serdaroğlu, Esra, et al.
(författare)
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A Turkish BCS1L mutation causes GRACILE-like disorder
- 2017
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Ingår i: Turkish Journal of Pediatrics. - : The Turkish Journal of Pediatrics. - 0041-4301. ; 58:6, s. 658-661
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Tidskriftsartikel (refereegranskat)abstract
- A full-term growth-restricted female newborn (1790 g), presented with lactic acidosis (12.5 mmol/L) after birth. She had renal tubulopathy, cholestasis and elevated serum ferritin concentration (2819 ng/ml). Two similarly affected sisters had died before 3 months of age. Mitochondrial disorder was suspected since the disease resembled the Finnish GRACILE syndrome, caused by a homozygous mutation (c.232A>G) in BCS1L. Thus, we sequenced the BCS1L gene, encoding the assembly factor for respiratory chain complex III. The patient had a homozygous mutation (c.296C>T; p.P99L), for which both parents were heterozygous. In four previously published patients of Turkish origin, the same homozygous mutation resulted in complex III deficiency, tubulopathy, encephalopathy, and liver failure. The p.P99L mutation seems to be specific to Turkish population and leads to GRACILE-like or Leigh-like condition. Assembly defects in complex III should be investigated in the affected tissues, since fibroblasts may not exhibit the deficiency.
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| 24. |
- Serenius, Fredrik, et al.
(författare)
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Neurodevelopmental Outcomes Among Extremely Preterm Infants 6.5 Years After Active Perinatal Care in Sweden
- 2016
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Ingår i: Jama Pediatrics. - Chicago : American Medical Association (AMA). - 2168-6203 .- 2168-6211. ; 170:10, s. 954-963
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Active perinatal care increases the rate of survival of extremely preterm infants, but there are concerns that improved survival might increase the rate of disabled survivors. OBJECTIVE To determine the neurodevelopmental outcomes of a national cohort of children 6.5 years of age who had been born extremely preterm (<27 weeks' gestational age) in Sweden. DESIGN, SETTING, AND PARTICIPANTS Population-based prospective cohort study of consecutively born extremely preterm infants. All of these infants were born in Sweden during the period from April 1, 2004, to March 31, 2007. Of 707 live-born extremely preterm infants, 486 (68.7%) survived to 6.5 years of age. These children were assessed and compared with matched controls who had been born at term. Comparison estimates were adjusted for demographic differences. Assessments ended in February 2014, and analysis started thereafter. MAIN OUTCOMES AND MEASURES Cognitive ability was measured with the fourth edition of the Wechsler Intelligence Scale for Children (WISC-IV), and the mean (SD) scores of the children who had been born extremely preterm were compared with those of the controls. Clinical examinations and parental questionnaires were used for diagnosis of cerebral palsy, hearing and vision impairments, and cognition for the children who were not assessed with the WISC-IV. RESULTS Of 486 eligible infants who were born extremely preterm, 441 (90.7%) were assessed at 6.5 years of age (59 by medical record review only) alongside 371 controls. The adjusted mean (SD) full-scale WISC-IV score was 14.2 (95% CI, 12.1-16.3) points lower for children who had been born extremely preterm than for controls. Cognitive disability was moderate for 18.8% of extremely preterm children and 2.2% of controls (P < .001), and it was severe for 11.1% of extremely preterm children and 0.3% of controls (P < .001). Cerebral palsy was observed in 9.5% of extremely preterm children and 0.0% of controls (P < .001), blindness was observed in 2.0% of extremely preterm children and 0.0% of controls (P < .001), and hearing impairment was observed in 2.1% of extremely preterm children and 0.5% of controls (P = .07). Overall, 36.1%(95% CI, 31.7%-40.6%) of extremely preterm children had no disability, 30.4%(95% CI 26.3%-34.8%) had mild disability, 20.2%(95% CI, 16.6%-24.2%) had moderate disability, and 13.4%(95% CI, 10.5%-16.9%) had severe disability. For extremely preterm children, moderate or severe overall disability decreased with gestational age at birth (adjusted odds ratio per week, 0.65 [95% CI, 0.54-0.79]; P < .001) and increased from 26.6% to 33.5%(P = .01) for children assessed both at 2.5 and 6.5 years. CONCLUSIONS AND RELEVANCE Of the 441 extremely preterm infants who had received active perinatal care, 293 (66.4%) had no or mild disability at 6.5 years; of the 371 controls, 11 (3.0%) had moderate or severe disability. Disability rates at 6.5 years increased relative to the rates at 2.5 years. Results are relevant for health care professionals and planners, and for clinicians counseling families facing extremely preterm births.
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| 25. |
- Svanberg, Emilie Krite, et al.
(författare)
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Non-invasive monitoring of oxygen in the lungs of newborn infants using diode laser spectroscopy
- 2016
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Ingår i: Cancer Imaging and Therapy, CANCER 2016. - 9781943580101 ; Part F13-CANCER 2016
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Konferensbidrag (refereegranskat)abstract
- The main purpose of this study was to investigate a novel non-invasive optical technique for rapid bedside detection of oxygen gas in the lungs of full-term newborn infants. The results suggest that the technique will be clinically useful as a diagnostic and monitoring tool for infants with lung disorders.
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| 26. |
- Sveinsdóttir, Kristbjörg, et al.
(författare)
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Relation of Retinopathy of Prematurity to Brain Volumes at Term Equivalent Age and Developmental Outcome at 2 Years of Corrected Age in Very Preterm Infants
- 2018
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Ingår i: Neonatology. - : S. Karger AG. - 1661-7800 .- 1661-7819. ; 114:1, s. 46-52
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Tidskriftsartikel (refereegranskat)abstract
- Background: Retinopathy of prematurity (ROP) is a major complication of preterm birth and has been associated with later visual and nonvisual impairments. Objectives: To evaluate relationships between any stage of ROP, brain volumes, and developmental outcomes. Methods: This study included 52 very preterm infants (gestational age [mean +/- SD]: 26.4 +/- 1.9 weeks). Total brain, gray matter, unmyelinated white matter (UWMV), and cerebellar volumes were estimated in 51 out of 52 infants by magnetic resonance imaging at term-equivalent age. Bayley Scales of Infant Development were used to assess developmental outcomes in 49 out of 52 in-fants at a mean corrected age of 24.6 months. Results: Nineteen out of 52 infants developed any stage of ROP. Infants with ROP had a lower median (IQR) UWMV (173 [156-181] vs. 204 [186-216] mL, p < 0.001) and cerebellar volume (18.3 [16.5-20] vs. 22.3 [20.3-24.7] mL, p < 0.001) than infants without ROP. They also had a lower median (IQR) mental developmental index (72 [56-83] vs. 100 [88-104], p < 0.001) and a lower psychomotor developmental index (80 [60-85] vs. 92 [81-103], p = 0.002). Brain volumes and developmental outcomes did not differ among infants with different stages of ROP. Conclusion: Any stage of ROP in preterm infants was associated with a reduced brain volume and an impaired developmental outcome. These results suggest that common pathways may lead to impaired neural and neurovascular development in the brain and retina and that all stages of ROP may be considered in future studies on ROP and development. (c) 2018 S. Karger AG, Basel
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| 27. |
- Tegelberg, Saara, et al.
(författare)
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Respiratory chain complex III deficiency due to mutated BCS1L : A novel phenotype with encephalomyopathy, partially phenocopied in a Bcs1l mutant mouse model
- 2017
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Ingår i: Orphanet Journal of Rare Diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Mitochondrial diseases due to defective respiratory chain complex III (CIII) are relatively uncommon. The assembly of the eleven-subunit CIII is completed by the insertion of the Rieske iron-sulfur protein, a process for which BCS1L protein is indispensable. Mutations in the BCS1L gene constitute the most common diagnosed cause of CIII deficiency, and the phenotypic spectrum arising from mutations in this gene is wide. Results: A case of CIII deficiency was investigated in depth to assess respiratory chain function and assembly, and brain, skeletal muscle and liver histology. Exome sequencing was performed to search for the causative mutation(s). The patient's platelets and muscle mitochondria showed respiration defects and defective assembly of CIII was detected in fibroblast mitochondria. The patient was compound heterozygous for two novel mutations in BCS1L, c.306A > T and c.399delA. In the cerebral cortex a specific pattern of astrogliosis and widespread loss of microglia was observed. Further analysis showed loss of Kupffer cells in the liver. These changes were not found in infants suffering from GRACILE syndrome, the most severe BCS1L-related disorder causing early postnatal mortality, but were partially corroborated in a knock-in mouse model of BCS1L deficiency. Conclusions: We describe two novel compound heterozygous mutations in BCS1L causing CIII deficiency. The pathogenicity of one of the mutations was unexpected and points to the importance of combining next generation sequencing with a biochemical approach when investigating these patients. We further show novel manifestations in brain, skeletal muscle and liver, including abnormality in specialized resident macrophages (microglia and Kupffer cells). These novel phenotypes forward our understanding of CIII deficiencies caused by BCS1L mutations.
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| 28. |
- Thunqvist, Per, et al.
(författare)
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Lung function after extremely preterm birth-A population-based cohort study (EXPRESS)
- 2018
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Ingår i: Pediatric Pulmonology. - : Wiley. - 8755-6863 .- 1099-0496. ; 53:1, s. 64-72
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: Follow-up studies of children and young adults born very-to-moderately preterm show persistent and significant lung function deficits. The aim of the study was to determine lung function and airway mechanics in school-aged children born in 2004 to 2007 and extremely preterm (after 22-26 weeks of gestation).METHODS: In a population-based cohort of children born extremely preterm and controls born at term (n = 350), follow-up at 6½-years-of-age was performed using spirometry and impulse oscillometry. Associations to gestational age, smallness for gestational age (SGA), and bronchopulmonary dysplasia (BPD) were assessed.RESULTS: Children born extremely preterm had lower forced vital capacity (FVC, z-score: -0.7, 95%CI: -1.0;-0.4), forced expiratory volume (FEV1 , z-score: -1.1, 95%CI: -1.4; -0.8), higher frequency-dependence of resistance (R5-20 , 0.09, 95%CI: 0.05; 0.12 kPa · L-1 · s-1 ) and larger area under the reactance curve (AX, 0.78, 95%CI: 0.49; 1.07 kPa · L-1 ) than controls. In children born at 22-24 weeks of gestation, 24% had FVC and 44% had FEV1 below the lower limit of normal. SGA and severe BPD only marginally contributed to pulmonary outcomes. Asthma-like disease was reported in 40% of extremely preterm children and 15% of controls.CONCLUSION: Many children born extremely preterm have altered airway mechanics and significant obstructive reduction in lung function. This warrants consideration for treatment and continued follow-up.
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| 29. |
- Westerlund, Emil, et al.
(författare)
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Oxygen consumption in platelets as an adjunct diagnostic method for pediatric mitochondrial disease
- 2017
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Ingår i: Pediatric Research. - : Springer Science and Business Media LLC. - 1530-0447 .- 0031-3998. ; 83, s. 455-465
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Tidskriftsartikel (refereegranskat)abstract
- Diagnosing mitochondrial disease (MD) is a challenge. In addition to genetic analyses, clinical practice is to perform invasive procedures such as muscle biopsy for biochemical and histochemical analyses. Blood cell respirometry is rapid and noninvasive. Our aim was to explore its possible role in diagnosing MD.MethodsBlood samples were collected from 113 pediatric patients, for whom MD was a differential diagnosis. A respiratory analysis model based on ratios (independent of mitochondrial specific content) was derived from a group of healthy controls and tested on the patients. The diagnostic accuracy of platelet respirometry was evaluated against routine diagnostic investigation.ResultsMD prevalence in the cohort was 16%. A ratio based on the respiratory response to adenosine diphosphate in the presence of complex I substrates had 96% specificity for disease and a positive likelihood ratio of 5.3. None of the individual ratios had sensitivity above 50%, but a combined model had 72% sensitivity.ConclusionNormal findings of platelet respirometry are not able to rule out MD, but pathological results make the diagnosis more likely and could strengthen the clinical decision to perform further invasive analyses. Our results encourage further study into the role of blood respirometry as an adjunct diagnostic tool for MD.
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| 30. |
- Wikström, Sverre, 1978-, et al.
(författare)
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Early Electroencephalography Suppression and Postnatal Morbidities Correlate with Cerebral Volume at Term-Equivalent Age in Very Preterm Infants
- 2018
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Ingår i: Neonatology. - : S. Karger. - 1661-7800 .- 1661-7819. ; 113:1, s. 15-20
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Early brain activity is associated with long-term outcome. Establishing a relation also with postnatal brain growth may increase our understanding of early life influences on preterm brain development.OBJECTIVES: The aim of this study was to investigate whether early electroencephalography (EEG) activity in infants born very preterm is associated with brain volumes at term, and whether postnatal morbidity affects this association.METHODS: Very preterm infants (n = 38) with a median gestational age (GA) of 25.6 weeks had early recordings of single-channel EEG. The percentage of suppressed EEG, i.e., interburst intervals (IBI%) between 24 and 72 h of age, was analyzed in relation to brain volumes on magnetic resonance imaging performed at term-equivalent age, taking into account neonatal morbidities.RESULTS: Early electrocortical depression and a higher IBI% were associated with increased cerebrospinal fluid volume (CSFV) and lower total brain volume relative to intracranial volume, also after adjustment for GA, postnatal morbidities, morphine administration, and postnatal head growth. Overall, an increase in IBI% to 1 SD from the mean corresponded with an increase in CSFV to +0.7 SD and a decrease in brain volume to -0.7 SD. The presence of 2 or more postnatal morbidities were associated with around 10% lower brain volumes.CONCLUSIONS: More suppressed early EEG activity of very preterm infants is associated with lower brain volume and increased CSFV at term age, also when adjusting for postnatal morbidities. The findings indicate the importance of pre- and early postpartal determinants of postnatal brain growth, possibly also including activity-dependent mechanisms for brain growth.
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