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OBJECTIVE: Pathological retinal neovascularization is vision-threatening. In mouse oxygen-induced retinopathy (OIR) we sought to define mitochondrial respiration changes longitudinally during hyperoxia-induced vessel loss and hypoxia-induced neovascularization, and to test interventions addressing those changes to prevent neovascularization. METHODS: OIR was induced in C57BL/6J mice and retinal vasculature was examined at maximum neovessel formation. We assessed total proteome changes and the ratio of mitochondrial to nuclear DNA copy numbers (mtDNA/nDNA) of OIR vs. control retinas, and mitochondrial oxygen consumption rates (OCR) in ex vivo OIR vs. control retinas (BaroFuse). Pyruvate vs. vehicle control was supplemented to OIR mice either prior to or during neovessel formation. RESULTS: In OIR vs. control retinas, global proteomics showed decreased retinal mitochondrial respiration at peak neovascularization. OCR and mtDNA/nDNA were also decreased at peak neovascularization suggesting impaired mitochondrial respiration. In vivo pyruvate administration during but not prior to neovessel formation (in line with mitochondrial activity time course) suppressed NV. CONCLUSIONS: Mitochondrial energetics were suppressed during retinal NV in OIR. Appropriately timed supplementation of pyruvate may be a novel approach in neovascular retinal diseases.
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Very preterm infants are at high risk of growth failure. Poor weight gain is a prominent risk factor for retinopathy of prematurity (ROP) and optimizing nutrition could potentially promote growth and reduce ROP. Most infants at risk of ROP need parenteral nutrition initially and studies of enhanced parenteral provision of lipids and amino acids have suggested a beneficial effect on ROP. Higher amino acid intake was associated with lower incidence of hyperglycemia, a risk factor for ROP. For very preterm infants, providing unpasteurized fortified raw maternal breast milk appears to have a dose-dependent preventive effect on ROP. These infants become deficient in arachidonic acid (ArA) and docosahexaenoic acid (DHA) after birth when the maternal supply is lost. Earlier studies have investigated the impact of omega-3 fatty acids on ROP with mixed results. In a recent study, early enteral supplementation of ArA 100 mg/kg/d and DHA 50 mg/kg/d until term equivalent age reduced the incidence of severe ROP by 50%. IMPACT: Previous reviews of nutritional interventions to prevent morbidities in preterm infants have mainly addressed bronchopulmonary dysplasia, brain lesions and neurodevelopmental outcome. This review focusses on ROP. Neonatal enteral supplementation with arachidonic acid and docosahexaenoic acid, at levels similar to the fetal accretion rate, has been found to reduce severe ROP by 50% in randomized controlled trials.
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Approximately 90 % of infants born before 28 full weeks(extremely-preterm-infants) receive erythrocyte transfusions in early life. Umbilical cord blood(UCB) has been investigated as an alternative source for erythrocyte transfusions to preterm neonates. This retrospective study aimed to compile/evaluate spectrum of bacteria groups/species intermittently detected in processed UCB at National-Swedish-Cord blood bank, (NS-CBB) during the years 2008-2020. Consecutive data from the years 2008-2020 were investigated. UCB from healthy newborns born after 37 full weeks of gestation was collected following clamping of cord (1 min) through cannulation of umbilical vein(vaginal-and C-section-deliveries). In total, 5194 cord blood units (UCBUs) that met NS-CBB-guidelines for total nucleated-cell-content(TNC) were manufactured from 8875 collections. Of 5194 UCBUs,77,6 % were from vaginal-and 22,4 % from C-section deliveries.Samples(10 mL) were collected from surplus eryhtrocyte fraction post-processing(n = 5194), transferred into BACT/ALERT® aerobic/anaerobic culture flasks and monitored 10 days using BACT/ALERT®-3D-Microbial-Detection-Systems. Positive samples were subcultured and typed for bacterial groups and/or species. Out of 5194 processed sampled UCB units,186 (3,6 %) were discarded due to positive sterility tests, 92 % were detected in samples from vaginal-deliveries and 8 % from C-section-deliveries. In all,16 different groups of bacteria and 27 species were identified. Common bacterial/groups and species were anaerobe gram-negative rods(n = 28),coagulase-negative-staphylococci(n = 21),gram-positive rods(n = 21),anaerobe-gram-positive cocci(n = 20) and viridans-streptococci(n = 13). Extracted from these results,in positive samples(n = 13) from C-section deliveries, bacteria were found:viridans-streptococci(n = 7),Aerococcus-urinae(n = 1), Staphylococcus lugdunensis(n = 1),other coagulase-negative staphylococci(n = 1) or a mix of aerobic/anaerobic bacteria(n = 3). Our results are in alignment with previously published contamination rates in processed UCBUs. Still, results point towards importance of strict microbial monitoring when manufacturing UCBUs to achieve patient-safe- products for stem-cell transplantation/transfusion.
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Sangue Fetal , Humanos , Estudos Retrospectivos , Recém-Nascido , Feminino , Bactérias , MasculinoRESUMO
AIM: To assess experience of care, well-being of parents and children's development in a cohort of extremely premature infants born <24 weeks of gestation in Sweden from 2007 to 2018. METHODS: A survey based on multiple questionnaires answered by 124/349 (35.5%) parents. RESULTS: The median age of parents and children was 43 and 9 years, respectively; 74.2% were mothers. Parents expressed high healthcare satisfaction. Following discharge from neonatal care, the satisfaction with the infant's treatment, support from personnel and being respected as a parent significantly declined but remained high. The criteria for suspected developmental deviation according to the screening test early symptomatic syndromes eliciting neurodevelopmental clinical examinations-questionnaire was fulfilled by 84.3%, 55.6% had suspected avoidant restrictive food intake disorder and 47.9% had visual perception problems. Parents experienced severe fatigue (48.6%) despite strong social support and family self-efficacy. Economic support was provided to 30.6%, and 37.9% of children were enrolled in habilitation services. CONCLUSION: This study highlighted the substantial challenges faced by parents of infants born before 24 weeks of gestation, including decreased satisfaction post-discharge, fatigue and concerns about children's well-being. The findings underscore the need for comprehensive family-centred support and long-term multi-professional follow-up centres.
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Appropriate nutrients are essential for cellular function. Dietary components can alter the risk of systemic metabolic diseases, including cardiovascular diseases, cancer, diabetes, and obesity, and can also affect retinal diseases, including age-related macular degeneration, diabetic retinopathy, and glaucoma. Dietary nutrients have been assessed for the prevention or treatment of retinal ischemic diseases and the diseases of aging. In this article, we review clinical and experimental evidence concerning the potential of some nutritional supplements to prevent or treat retinal ischemic diseases and provide further insights into the therapeutic effects of nutritional supplementation on retinopathies. We will review the roles of nutrients in preventing or protecting against retinal ischemic diseases.
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Anti-Inflamatórios , Antioxidantes , Suplementos Nutricionais , Doenças Retinianas , Humanos , Antioxidantes/uso terapêutico , Antioxidantes/administração & dosagem , Doenças Retinianas/dietoterapia , Doenças Retinianas/terapia , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/administração & dosagem , Animais , Isquemia/terapia , Isquemia/dietoterapiaRESUMO
Hyperglycemia in early postnatal life of preterm infants with incompletely vascularized retinas is associated with increased risk of potentially blinding neovascular retinopathy of prematurity (ROP). Neovascular ROP (Phase II ROP) is a compensatory but ultimately pathological response to the suppression of physiological postnatal retinal vascular development (Phase I ROP). Hyperglycemia in neonatal mice which suppresses physiological retinal vascular growth is associated with decreased expression of systemic and retinal fibroblast growth factor 21 (FGF21). FGF21 administration promoted and FGF21 deficiency suppressed the physiological retinal vessel growth. FGF21 increased serum adiponectin (APN) levels and loss of APN abolished FGF21 promotion of physiological retinal vascular development. Blocking mitochondrial fatty acid oxidation also abolished FGF21 protection against delayed physiological retinal vessel growth. Clinically, preterm infants developing severe neovascular ROP (versus non-severe ROP) had a lower total lipid intake with more parenteral and less enteral during the first 4 weeks of life. Our data suggest that increasing FGF21 levels in the presence of adequate enteral lipids may help prevent Phase I retinopathy (and therefore prevent neovascular disease).
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Hiperglicemia , Retinopatia da Prematuridade , Recém-Nascido , Humanos , Animais , Camundongos , Recém-Nascido Prematuro , Hiperglicemia/complicações , LipídeosRESUMO
BACKGROUND: The activation of dendritic cells (DCs) is pivotal for generating antigen-specific T-cell responses to eradicate tumor cells. Hence, immunotherapies targeting this interplay are especially intriguing. Moreover, it is of interest to modulate the tumor microenvironment (TME), as this harsh milieu often impairs adaptive immune responses. Oncolytic viral therapy presents an opportunity to overcome the immunosuppression in tumors by destroying tumor cells and thereby releasing antigens and immunostimulatory factors. These effects can be further amplified by the introduction of transgenes expressed by the virus. METHODS: Lokon oncolytic adenoviruses (LOAd) belong to a platform of chimeric serotype Ad5/35 viruses that have their replication restricted to tumor cells, but the expression of transgenes is permitted in all infected cells. LOAd732 is a novel oncolytic adenovirus that expresses three essential immunostimulatory transgenes: trimerized membrane-bound CD40L, 4-1BBL and IL-2. Transgene expression was determined with flow cytometry and ELISA and the oncolytic function was evaluated with viability assays and xenograft models. The activation profiles of DCs were investigated in co-cultures with tumor cells or in an autologous antigen-specific T cell model by flow cytometry and multiplex proteomic analysis. Statistical differences were analyzed with Kruskal-Wallis test followed by Dunn's multiple comparison test. RESULTS: All three transgenes were expressed in infected melanoma cells and DCs and transgene expression did not impair the oncolytic activity in tumor cells. DCs were matured post LOAd732 infection and expressed a multitude of co-stimulatory molecules and pro-inflammatory cytokines crucial for T-cell responses. Furthermore, these DCs were capable of expanding and stimulating antigen-specific T cells in addition to natural killer (NK) cells. Strikingly, the addition of immunosuppressive cytokines TGF-ß1 and IL-10 did not affect the ability of LOAd732-matured DCs to expand antigen-specific T cells and these cells retained an enhanced activation profile. CONCLUSIONS: LOAd732 is a novel immunostimulatory gene therapy based on an oncolytic adenovirus that expresses three transgenes, which are essential for mediating an anti-tumor immune response by activating DCs and stimulating T and NK cells even under imunosuppressive conditions commonly present in the TME. These qualities make LOAd732 an appealing new immunotherapy approach.
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Melanoma , Linfócitos T , Humanos , Proteômica , Melanoma/genética , Melanoma/terapia , Células Matadoras Naturais , Citocinas/metabolismo , Terapia Genética , Células Dendríticas , Microambiente TumoralRESUMO
BACKGROUND: Growth factors important for normal brain development are low in preterm infants. This study investigated the link between growth factors and preterm brain volumes at term. MATERIAL/METHODS: Infants born <28 weeks gestational age (GA) were included. Endogenous levels of insulin-like growth factor (IGF)-1, brain-derived growth factor, vascular endothelial growth factor, and platelet-derived growth factor (expressed as area under the curve [AUC] for serum samples from postnatal days 1, 7, 14, and 28) were utilized in a multivariable linear regression model. Brain volumes were determined by magnetic resonance imaging (MRI) at term equivalent age. RESULTS: In total, 49 infants (median [range] GA 25.4 [22.9-27.9] weeks) were included following MRI segmentation quality assessment and AUC calculation. IGF-1 levels were independently positively associated with the total brain (p < 0.001, ß = 0.90), white matter (p = 0.007, ß = 0.33), cortical gray matter (p = 0.002, ß = 0.43), deep gray matter (p = 0.008, ß = 0.05), and cerebellar (p = 0.006, ß = 0.08) volume adjusted for GA at birth and postmenstrual age at MRI. No associations were seen for other growth factors. CONCLUSIONS: Endogenous exposure to IGF-1 during the first 4 weeks of life was associated with total and regional brain volumes at term. Optimizing levels of IGF-1 might improve brain growth in extremely preterm infants. IMPACT: High serum levels of insulin-like growth factor (IGF)-1 during the first month of life were independently associated with increased total brain volume, white matter, gray matter, and cerebellar volume at term equivalent age in extremely preterm infants. IGF-1 is a critical regulator of neurodevelopment and postnatal levels are low in preterm infants. The effects of IGF-1 levels on brain development in extremely preterm infants are not fully understood. Optimizing levels of IGF-1 may benefit early brain growth in extremely preterm infants. The effects of systemically administered IGF-1/IGFBP3 in extremely preterm infants are now being investigated in a randomized controlled trial (Clinicaltrials.gov: NCT03253263).
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Lactente Extremamente Prematuro , Fator de Crescimento Insulin-Like I , Lactente , Humanos , Recém-Nascido , Fator de Crescimento Insulin-Like I/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Encéfalo , Substância Cinzenta/metabolismo , Idade Gestacional , Imageamento por Ressonância Magnética/métodosRESUMO
BACKGROUND: Nearly one in ten children is born preterm. The degree of immaturity is a determinant of the infant's health. Extremely preterm infants have higher morbidity and mortality than term infants. One disease affecting extremely preterm infants is retinopathy of prematurity (ROP), a multifactorial neurovascular disease that can lead to retinal detachment and blindness. The advances in omics technology have opened up possibilities to study protein expressions thoroughly with clinical accuracy, here used to increase the understanding of protein expression in relation to immaturity and ROP. METHODS: Longitudinal serum protein profiles the first months after birth in 14 extremely preterm infants were integrated with perinatal and ROP data. In total, 448 unique protein targets were analyzed using Proximity Extension Assays. RESULTS: We found 20 serum proteins associated with gestational age and/or ROP functioning within mainly angiogenesis, hematopoiesis, bone regulation, immune function, and lipid metabolism. Infants with severe ROP had persistent lower levels of several identified proteins during the first postnatal months. CONCLUSIONS: The study contributes to the understanding of the relationship between longitudinal serum protein levels and immaturity and abnormal retinal neurovascular development. This is essential for understanding pathophysiological mechanisms and to optimize diagnosis, treatment and prevention for ROP. IMPACT: Longitudinal protein profiles of 14 extremely preterm infants were analyzed using a novel multiplex protein analysis platform combined with perinatal data. Proteins associated with gestational age at birth and the neurovascular disease ROP were identified. Among infants with ROP, longitudinal levels of the identified proteins remained largely unchanged during the first postnatal months. The main functions of the proteins identified were angiogenesis, hematopoiesis, immune function, bone regulation, lipid metabolism, and central nervous system development. The study contributes to the understanding of longitudinal serum protein patterns related to gestational age and their association with abnormal retinal neuro-vascular development.
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Nascimento Prematuro , Retinopatia da Prematuridade , Proteínas Sanguíneas , Criança , Feminino , Idade Gestacional , Humanos , Lactente , Lactente Extremamente Prematuro , Recém-Nascido , Gravidez , Retinopatia da Prematuridade/diagnósticoRESUMO
OBJECTIVES: The aim of the study was to evaluate the relationships between intake of mother's own milk (MOM), compared with intake of pasteurized donor milk (DM), and postnatal growth, incidence of retinopathy of prematurity (ROP) and bronchopulmonary dysplasia (BPD), in extremely preterm infants. METHODS: Swedish population-based cohort of surviving extremely preterm infants born 2004 to 2007. Exposure to MOM and DM was investigated from birth until 32âweeks postmenstrual age (PMA) in 453 infants. Primary outcome variables were change in z-score (Δ) from birth to 32âweeks PMA for weight, length, and head circumference (HC). Secondary outcomes were incidence of ROP and BPD. Mixed models adjusting for confounders were used to investigate the association between exposures and outcomes. RESULTS: Infants' mean gestational age (GA) was 25.4âweeks. Unadjusted, MOM (per 10âmLâ·âkg-1â·âday-1) was associated with Δweight and ΔHC with beta estimates of 0.03 z-score units (95% CI, 0.02-0.04, Pâ<â0.001) and 0.03 z-score units (95% CI, 0.01-0.05, Pâ=â0.003), respectively. After adjustment for predefined confounders, the association remained significant for Δweight and ΔHC. A similar pattern was found between Δweight and each 10% increase of MOM. Unadjusted, a higher intake of MOM (mLâ·âkg-1â·âday-1) was significantly associated to a lower probability of any ROP and severe ROP; however, these associations did not remain in the adjusted analyses. No associations were found between MOM (mLâ·âkg-1â·âday-1) and BPD. Moreover, no associations were found between DM and growth or morbidity outcomes. CONCLUSIONS: An increased intake of MOM, as opposed to DM (and not formula feeding), was associated with improved postnatal weight gain and HC growth from birth until 32âweeks PMA in extremely preterm infants. Interventions aiming at increasing early intake of unpasteurized MOM for extremely preterm infants should be encouraged.
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Lactente Extremamente Prematuro , Mães , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Leite Humano , MorbidadeRESUMO
AIM: The aim of this review was to compile existing evidence on the role of platelets in the development of severe retinopathy of prematurity (ROP), highlight the strengths and weaknesses of the available studies and critically discuss the reported data. METHODS: A comprehensive literature search was conducted on PubMed from January 2000 to January 2022, and the reference lists of the included studies were screened manually. RESULTS: There were 19 primary studies that fulfilled the eligibility criteria. Experimental research indicated lower platelet count in mice oxygen-induced retinopathy model compared with normoxia controls, while platelet transfusions suppressed neovascularisation. The latter finding was not consistently confirmed in clinical research, where a low platelet count, an increased number of thrombopenic episodes and of platelet transfusions have all been implicated in the development of ROP requiring treatment, either type I or aggressive posterior or both. However, existing studies exhibit significant clinical heterogeneity and present methodological limitations that imperil their reliability and validity. CONCLUSION: Platelet deficiency has been associated with severe ROP. However, critical thresholds of platelet parameters are still unrecognised. Future research is required to determine whether platelet parameters can be predictive biomarkers for ROP requiring treatment and at what thresholds.
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Retinopatia da Prematuridade , Trombocitopenia , Animais , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Camundongos , Oxigênio , Reprodutibilidade dos Testes , Retinopatia da Prematuridade/complicações , Estudos Retrospectivos , Trombocitopenia/complicaçõesRESUMO
AIM: This study investigated childhood diagnoses in children born extremely preterm before 24 weeks of gestation. METHODS: Diagnoses of neurodevelopmental disorders and selected somatic diagnoses were retrospectively retrieved from national Swedish registries for children born before 24 weeks from 2007 to 2018. Their individual medical files were also examined. RESULTS: We studied 383 children born at a median of 23.3 (range 21.9-23.9) weeks, with a median birthweight of 565 (range 340-874) grams. Three-quarters (75%) had neurodevelopmental disorders, including speech disorders (52%), intellectual disabilities (40%), attention deficit hyperactivity disorder (30%), autism spectrum disorders (24%), visual impairment (22%), cerebral palsy (17%), epilepsy (10%) and hearing impairment (5%). More boys than girls born at 23 weeks had intellectual disabilities (45% vs. 27%, p < 0.01) and visual impairment (25% vs. 14%, p < 0.01). Just over half of the cohort (55%) received habilitation care. The majority (88%) had somatic diagnoses, including asthma (63%) and failure to thrive/short stature (39%). CONCLUSION: Most children born before 24 weeks had neurodevelopmental disorders and/or additional somatic diagnoses in childhood and were referred to habilitation services. Clinicians should be aware of the multiple health and developmental problems affecting these children. Resources are needed to identify their long-term support needs at an early stage.
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Transtorno do Espectro Autista , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Criança , Feminino , Humanos , Recém-Nascido , Masculino , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/epidemiologia , Estudos Retrospectivos , Transtornos da VisãoRESUMO
AIM: To describe survival and neonatal morbidities in infants born before 24 weeks of gestation during a 12-year period. METHODS: Data were retrieved from national registries and validated in medical files of infants born before 24 weeks of gestation 2007-2018 in Sweden. Temporal changes were evaluated. RESULTS: In 2007-2018, 282 live births were recorded at 22 weeks and 460 at 23 weeks of gestation. Survival to discharge from hospital of infants born alive at 22 and 23 weeks increased from 20% to 38% (p = 0.006) and from 45% to 67% (p < 0.001) respectively. Caesarean section increased from 12% to 22% (p = 0.038) for infants born at 22 weeks. Neonatal morbidity rates in infants alive at 40 weeks of postmenstrual age (n = 399) were unchanged except for an increase in necrotising enterocolitis from 0 to 33% (p = 0.017) in infants born at 22 weeks of gestation. Bronchopulmonary dysplasia was more common in boys than girls, 90% versus 82% (p = 0.044). The number of infants surviving to 40 weeks doubled over time. CONCLUSION: Increased survival of infants born before 24 weeks of gestation resulted in increasing numbers of very immature infants with severe neonatal morbidities likely to have a negative impact on long-term outcome.
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Mortalidade Infantil , Doenças do Prematuro , Cesárea , Feminino , Idade Gestacional , Humanos , Lactente , Lactente Extremamente Prematuro , Recém-Nascido , Doenças do Prematuro/epidemiologia , Masculino , Morbidade , Gravidez , Taxa de SobrevidaRESUMO
Photoreceptors have high energy demands and a high density of mitochondria that produce ATP through oxidative phosphorylation (OXPHOS) of fuel substrates. Although glucose is the major fuel for CNS brain neurons, in photoreceptors (also CNS), most glucose is not metabolized through OXPHOS but is instead metabolized into lactate by aerobic glycolysis. The major fuel sources for photoreceptor mitochondria remained unclear for almost six decades. Similar to other tissues (like heart and skeletal muscle) with high metabolic rates, photoreceptors were recently found to metabolize fatty acids (palmitate) through OXPHOS. Disruption of lipid entry into photoreceptors leads to extracellular lipid accumulation, suppressed glucose transporter expression, and a duel lipid/glucose fuel shortage. Modulation of lipid metabolism helps restore photoreceptor function. However, further elucidation of the types of lipids used as retinal energy sources, the metabolic interaction with other fuel pathways, as well as the cross-talk among retinal cells to provide energy to photoreceptors is not fully understood. In this review, we will focus on the current understanding of photoreceptor energy demand and sources, and potential future investigations of photoreceptor metabolism.
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Células FotorreceptorasRESUMO
AIMS/HYPOTHESIS: Proliferative diabetic retinopathy (PDR) with retinal neovascularisation (NV) is a leading cause of vision loss. This study identified a set of metabolites that were altered in the vitreous humour of PDR patients compared with non-diabetic control participants. We corroborated changes in vitreous metabolites identified in prior studies and identified novel dysregulated metabolites that may lead to treatment strategies for PDR. METHODS: We analysed metabolites in vitreous samples from 43 PDR patients and 21 non-diabetic epiretinal membrane control patients from Japan (age 27-80 years) via ultra-high-performance liquid chromatography-mass spectrometry. We then investigated the association of a novel metabolite (creatine) with retinal NV in mouse oxygen-induced retinopathy (OIR). Creatine or vehicle was administered from postnatal day (P)12 to P16 (during induced NV) via oral gavage. P17 retinas were quantified for NV and vaso-obliteration. RESULTS: We identified 158 metabolites in vitreous samples that were altered in PDR patients vs control participants. We corroborated increases in pyruvate, lactate, proline and allantoin in PDR, which were identified in prior studies. We also found changes in metabolites not previously identified, including creatine. In human vitreous humour, creatine levels were decreased in PDR patients compared with epiretinal membrane control participants (false-discovery rate <0.001). We validated that lower creatine levels were associated with vascular proliferation in mouse retina in the OIR model (p = 0.027) using retinal metabolomics. Oral creatine supplementation reduced NV compared with vehicle (P12 to P16) in OIR (p = 0.0024). CONCLUSIONS/INTERPRETATION: These results suggest that metabolites from vitreous humour may reflect changes in metabolism that can be used to find pathways influencing retinopathy. Creatine supplementation could be useful to suppress NV in PDR. Graphical abstract.
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Retinopatia Diabética/metabolismo , Metabolômica , Corpo Vítreo/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminoácidos/análise , Animais , Cromatografia Líquida de Alta Pressão , Creatina/administração & dosagem , Creatina/análise , Retinopatia Diabética/fisiopatologia , Feminino , Humanos , Masculino , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Neovascularização Retiniana/metabolismo , Corpo Vítreo/químicaRESUMO
Following preterm birth, serum levels of insulin-like growth factor 1 (IGF-1) decrease compared to corresponding in utero levels. A recent clinical trial indicated that supplementation with recombinant human (rh) IGF-1/rhIGF-binding protein 3 (rhIGF-1/rhIGFBP-3) prevents severe intraventricular hemorrhage (IVH) in extremely preterm infants. In a preterm rabbit pup model, we characterized endogenous serum and hepatic IGF-1, along with brain distribution of IGF-1 and IGF-1 receptor (IGF1R). We then evaluated the effects of rhIGF-1/rhIGFBP-3 on gene expression of regulators of cerebrovascular maturation and structure. Similar to preterm infants, serum IGF-1 concentrations decreased rapidly after preterm birth in the rabbit pup. Administration of rhIGF-1/rhIGFBP-3 restored in utero serum levels but was rapidly eliminated. Immunolabeled IGF1R was widely distributed in multiple brain regions, displaying an abundant density in the choroid plexus and sub-ependymal germinal zones. Increased IGF-1 immunoreactivity, distributed as IGF1R, was detected 4 h after rhIGF-1/rhIGFBP-3 administration. The rhIGF-1/rhIGFBP-3 treatment led to upregulation of choroid plexus genes involved in vascular maturation and structure, with corresponding protein translation for most of these genes. The preterm rabbit pup model is well suited for evaluation of IGF-1-based prevention of IVH. Administration of rhIGF-1/rhIGFBP-3 affects cerebrovascular maturation, suggesting a role for it in preventing preterm IVH.
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Fator de Crescimento Insulin-Like I , Nascimento Prematuro , Animais , Proteínas de Transporte , Humanos , Lactente Extremamente Prematuro , Recém-Nascido , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina , Coelhos , Proteínas RecombinantesRESUMO
BACKGROUND: Preterm birth and its complications are the primary cause of death among children under the age of 5. Among the survivors, morbidity both perinatally and later in life is common. The dawn of novel technical platforms for comprehensive and sensitive analysis of protein profiles in blood has opened up new possibilities to study both health and disease with significant clinical accuracy, here used to study the preterm infant and the physiological changes of the transition from intrauterine to extrauterine life. METHODS: We have performed in-depth analysis of the protein profiles of 14 extremely preterm infants using longitudinal sampling. Medical variables were integrated with extensive profiling of 448 unique protein targets. RESULTS: The preterm infants have a distinct unified protein profile in blood directly at birth regardless of clinical background; however, the pattern changed profoundly postnatally, expressing more diverse profiles only 1 week later and further on up to term-equivalent age. Clusters of proteins depending on temporal trend were identified. CONCLUSION: The protein profiles and the temporal trends here described will contribute to the understanding of the physiological changes in the intrauterine-extrauterine transition, which is essential to adjust early-in-life interventions to prone a normal development in the vulnerable preterm infants. IMPACT: We have performed longitudinal and in-depth analysis of the protein profiles of 14 extremely preterm infants using a novel multiplex protein analysis platform. The preterm infants had a distinct unified protein profile in blood directly at birth regardless of clinical background. The pattern changed dramatically postnatally, expressing more diverse profiles only 1 week later and further on up to term-equivalent age. Certain clusters of proteins were identified depending on their temporal trend, including several liver and immune proteins. The study contributes to the understanding of the physiological changes in the intrauterine-extrauterine transition.
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Proteínas Sanguíneas/química , Lactente Extremamente Prematuro/sangue , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Idade Gestacional , Humanos , Lactente Extremamente Prematuro/crescimento & desenvolvimento , Recém-Nascido , Estudos Longitudinais , Masculino , Placenta/metabolismo , Gravidez , Nascimento Prematuro , Proteoma , SuéciaRESUMO
BACKGROUND: Docosahexaenoic acid (DHA) and arachidonic acid (AA) are important for fetal brain growth and development. Our aim was to evaluate the association between serum DHA and AA levels and brain volumes in extremely preterm infants. METHODS: Infants born at <28 weeks gestational age in 2013-2015, a cohort derived from a randomized controlled trial comparing two types of parenteral lipid emulsions, were included (n = 90). Serum DHA and AA levels were measured at postnatal days 1, 7, 14, and 28, and the area under the curve was calculated. Magnetic resonance (MR) imaging was performed at term-equivalent age (n = 66), and volumes of six brain regions were automatically generated. RESULTS: After MR image quality assessment and area under the curve calculation, 48 infants were included (gestational age mean [SD] 25.5 [1.4] weeks). DHA levels were positively associated with total brain (B = 7.966, p = 0.012), cortical gray matter (B = 3.653, p = 0.036), deep gray matter (B = 0.439, p = 0.014), cerebellar (B = 0.932, p = 0.003), and white matter volume (B = 3.373, p = 0.022). AA levels showed no association with brain volumes. CONCLUSIONS: Serum DHA levels during the first 28 postnatal days were positively associated with volumes of several brain structures in extremely preterm infants at term-equivalent age. IMPACT: Higher serum levels of DHA in the first 28 postnatal days are positively associated with brain volumes at term-equivalent age in extremely preterm born infants. Especially the most immature infants suffer from low DHA levels in the first 28 postnatal days, with little increase over time. Future research is needed to explore whether postnatal fatty acid supplementation can improve brain development and may serve as a nutritional preventive and therapeutic treatment option in extremely preterm infants.
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Encéfalo/anatomia & histologia , Ácidos Docosa-Hexaenoicos/sangue , Lactente Extremamente Prematuro , Ácido Araquidônico , Estudos de Coortes , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Tamanho do ÓrgãoRESUMO
PURPOSE: Choline is an essential nutrient for fetal and infant growth and development. Parenteral nutrition used in neonatal care lack free choline but contain small amounts of lipid-bound choline in the form of phosphatidylcholine (PC). Here, we examined the longitudinal development of serum free choline and metabolically related compounds betaine and methionine in extremely preterm infants and how the concentrations were affected by the proportion of parenteral fluids the infants received during the first 28 postnatal days (PNDs). METHODS: This prospective study included 87 infants born at gestational age (GA) < 28 weeks. Infant serum samples were collected PND 1, 7, 14, and 28, and at postmenstrual age (PMA) 32, 36, and 40 weeks. The serum concentrations of free choline, betaine, and methionine were determined by 1H NMR spectroscopy. RESULTS: The median (25th-75th percentile) serum concentrations of free choline, betaine, and methionine were 33.7 (26.2-41.2), 71.2 (53.2-100.8), and 25.6 (16.4-35.3) µM, respectively, at PND 1. The choline concentration decreased rapidly between PND one and PND seven [18.4 (14.1-26.4) µM], and then increased over the next 90 days, though never reaching PND one levels. There was a negative correlation between a high intake of parenteral fluids and serum-free choline. CONCLUSION: Circulating free choline in extremely preterm infants is negatively affected by the proportion of parenteral fluids administered. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02760472, April 29, 2016, retrospectively registered.
Assuntos
Colina , Lactente Extremamente Prematuro , Betaína , Humanos , Lactente , Recém-Nascido , Nutrição Parenteral , Estudos ProspectivosRESUMO
To examine whether free fatty acid receptor 4 (FFAR4) activation can protect against choroidal neovascularization (CNV), which is a common cause of blindness, and to elucidate the mechanism underlying the inhibition, we used the mouse model of laser-induced CNV to mimic angiogenic aspects of age-related macular degeneration (AMD). Laser-induced CNV was compared between groups treated with an FFAR4 agonist or vehicle, and between FFAR4 wild-type (Ffar4+/+) and knock out (Ffar4-/-) mice on a C57BL/6J/6N background. The ex vivo choroid-sprouting assay, including primary retinal pigment epithelium (RPE) and choroid, without retina was used to investigate whether FFAR4 affects choroidal angiogenesis. Western blotting for pNF-ĸB/NF-ĸB and qRT-PCR for Il-6, Il-1ß, Tnf-α, Vegf, and Nf-ĸb were used to examine the influence of FFAR4 on inflammation, known to influence CNV. RPE isolated from Ffar4+/+ and Ffar4-/- mice were used to assess RPE contribution to inflammation. The FFAR4 agonist suppressed laser-induced CNV in C57BL/6J mice, and CNV increased in Ffar4-/- compared to Ffar4+/+ mice. We showed that the FFAR4 agonist acted through the FFAR4 receptor. The FFAR4 agonist suppressed mRNA expression of inflammation markers (Il-6, Il-1ß) via the NF-ĸB pathway in the retina, choroid, RPE complex. The FFAR4 agonist suppressed neovascularization in the choroid-sprouting ex vivo assay and FFAR4 deficiency exacerbated sprouting. Inflammation markers were increased in primary RPE cells of Ffar4-/- mice compared with Ffar4+/+ RPE. In this mouse model, the FFAR4 agonist suppressed CNV, suggesting FFAR4 to be a new molecular target to reduce pathological angiogenesis in CNV.