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1.	Andersson, Björn, 1977, et al. (författare) Protein profiling identified dissociations between growth hormone-mediated longitudinal growth and bone mineralization in short prepubertal children 2011 Ingår i: Journal of Proteomics. - : Elsevier BV. - 1876-7737 .- 1874-3919. ; 74:1, s. 89-100 Tidskriftsartikel (refereegranskat)abstract Growth hormone (GH) promotes longitudinal growth and bone mineralization. In this study, a proteomic approach was used to analyze the association between serum protein expression pattern and height-adjusted bone mineralization in short prepubertal children receiving GH treatment. Patterns of protein expression were compared with those associated with longitudinal bone growth. Specific protein expression patterns associated with changes in height-adjusted bone mineralization in response to GH treatment were identified. Out of the 37 peaks found in significant regression models, 27 were uniquely present in models correlated with changes in bone mineralization and 7 peaks were uniquely present in models correlated with changes in height. The peaks identified corresponded to apolipoproteins, transthyretin, serum amyloid A4 and hemoglobin beta. We conclude that a proteomic approach could be used to identify specific protein expression patterns associated with bone mineralization in response to GH treatment and that height-adjusted bone mineralization and longitudinal bone growth are regulated partly by the same and partly by different mechanisms. Protein isoforms with different post-translational modifications might be of importance in the regulation of these processes. However, further validation is needed to assess the clinical significance of the results.
2.	Andersson, Björn, 1977, et al. (författare) Proteins related to lipoprotein profile were identified using a pharmaco-proteomic approach as markers for growth response to growth hormone (GH) treatment in short prepubertal children 2009 Ingår i: Proteome Science. - : Springer Science and Business Media LLC. - 1477-5956. ; 7 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: The broad range in growth observed in response to growth hormone (GH) treatment is mainly caused by individual variations in both GH secretion and GH sensitivity. Individual GH responsiveness can be estimated using evidence-based models that predict the response to GH treatment; however, these models can be improved. High-throughput proteomics techniques can be used to identify proteins that may potentially be used as variables in such models in order to improve their predictive ability. Previously we have reported that proteomic analyses can identify biomarkers that discriminate between short prepubertal children with idiopathic short stature (ISS) who show good or poor growth in response to GH treatment. In this study we used a pharmaco-proteomic approach to identify novel factors that correlate with the growth response to GH treatment in prepubertal children who are short due to GH deficiency or ISS. The study included 128 short prepubertal children receiving GH treatment, of whom 39 were GH-deficient and 89 had ISS. Serum protein expression profiles at study start and after 1 year of GH treatment were analyzed using SELDI-TOF. Cross-validated regression and random permutation analyses were performed to identify significant correlations between protein expression patterns and the 2-year growth response to GH treatment. RESULTS: At start of treatment we identified a combination of seven protein peaks that correlated with the 2-year growth response in the GH-deficient group (R2 = 0.73). After 1 year of treatment, a combination of four peaks in the GH-deficient group (R2 = 0.64), eight peaks in the ISS group R2 = 0.47) and eight peaks in the total study group correlated with the 2-year growth response R2 = 0.38).The peaks identified corresponded to apolipoproteins A-I, A-II, C-I, C-III, transthyretin and serum amyloid A 4, which are all part of the high-density lipoprotein. CONCLUSION: Using a proteomic approach we identified biomarkers related to the lipoprotein profile that could be used to predict growth response to GH treatment in prepubertal children who are short as a result of GH-deficiency or who have ISS.These results support our previous findings that apolipoproteins and transthyretin may have a role in GH sensitivity.
3.	Cakir, B., et al. (författare) Thrombocytopenia is associated with severe retinopathy of prematurity 2018 Ingår i: Jci Insight. - : American Society for Clinical Investigation. - 2379-3708. ; 3:19 Tidskriftsartikel (refereegranskat)abstract Retinopathy of prematurity (ROP) is characterized by abnormal retinal neovascularization in response to vessel loss. Platelets regulate angiogenesis and may influence ROP progression. In preterm infants, we assessed ROP and correlated with longitudinal postnatal platelet counts (n = 202). Any episode of thrombocytopenia (< 100 x 10(9)/l) at >= 30 weeks postmenstrual age (at onset of ROP) was independently associated with severe ROP, requiring treatment. Infants with severe ROP also had a lower weekly median platelet count compared with infants with less severe ROP. In a mouse oxygen-induced retinopathy model of ROP, platelet counts were lower at P17 (peak neovascularization) versus controls. Platelet transfusions at P15 and P16 suppressed neovascularization, and platelet depletion increased neovascularization. Platelet transfusion decreased retinal of vascular endothelial growth factor A (VEGFA) mRNA and protein expression; platelet depletion increased retinal VEGFA mRNA and protein expression. Resting platelets with intact granules reduced neovascularization, while thrombin-activated degranulated platelets did not. These data suggest that platelet releasate has a local antiangiogenic effect on endothelial cells to exert a downstream suppression of VEGFA in neural retina. Low platelet counts during the neovascularization phase in ROP is significantly associated with the development of severe ROP in preterm infants. In a murine model of retinopathy, platelet transfusion during the period of neovascularization suppressed retinopathy.
4.	Decker, Ralph, 1968, et al. (författare) Protein markers of body composition in response to growth hormone (GH) treatment in short prepubertal children 2010 Ingår i: Hormone Research Paediatr. Konferensbidrag (refereegranskat)abstract Background Recently our group identified lipoprotein biomarkers able to predict linear growth response to GH treatment in short prepubertal children. Previously, it was also shown that biomarkers identified by a proteomic approach were able to discriminate between good or poor growth responders to GH treatment. Hypothesis We hypothesize that high-throughput proteomics techniques can be used to identify proteins not only to predict longitudinal growth response, but also changes in body composition. Objectives The objectives are to implement newly identified biomarkers in future advanced prediction models to avoid over- and under-treatment with GH and to find surrogate markers for predictors difficult to access, e.g. growth hormone (GH) secretion capacity. Study design 128 short prepubertal children were included in the study receiving GH treatment, of whom 39 were GH-deficient and 89 had idiopathic short stature (ISS). Serum protein expression profiles at study start and after 1 year of GH treatment were analyzed using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). Body composition after 2 years was analyzed by DEXA. Statistics Cross-validated regression and random permutation analyses were performed to identify significant correlations between protein expression patterns and the 2-year changes in body composition during GH treatment. Results In the present study we identified biomarkers able to predict lean mass (from arms and legs) and the decrease in subcutaneous fat mass (from arms and legs) at 2 yrs using a pharmaco-proteomic approach. Apolipoproteins were identified as unique markers of the GH treatment on lean mass and of fat mass (r2 >0.32, p<0.05). Serum amyloid A4, belonging to the apolipoprotein family, was a marker of both muscle and fat mass. Conclusion We show a proteomic approach being suitable to identify biomarkers before start of GH treatment playing a role in lipid transport and lipid metabolism able to predict body composition at 1 and 2 years of GH treatment.
5.	Decker, Ralph, 1968, et al. (författare) Protein markers predict body composition during growth hormone (GH) treatment in short prepubertal children. 2013 Ingår i: Clinical Endocrinology. - : Wiley. - 0300-0664 .- 1365-2265. ; 79:5, s. 675-82 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: A high-throughput pharmaco-proteomic approach has previously been successfully used to identify lipoprotein biomarkers related to changes in longitudinal growth and bone mass in response to growth hormone (GH) treatment. The aim of this study was to identify protein markers involved in the diverse anabolic and lipolytic remodelling of body composition during GH treatment. DESIGN, PATIENTS AND MEASUREMENTS: The study population consisted of 128 prepubertal children receiving GH treatment. Thirty-nine were short as a result of GH deficiency and 89 had idiopathic short stature (ISS). Serum protein expression profiles at study start and after one year of GH treatment were analysed using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). Body composition was analysed by dual-energy X-ray absorptiometry (DXA), reliably estimating muscle mass from appendicular (arms and legs) lean soft tissue mass (LST). DXA was also used to estimate appendicular bone mineral content (BMC) and fat mass for the total body. RESULTS: Specific protein expression patterns associated with GH response in different body compartments were identified. Among identified proteins different isoforms of nutrition markers such as apolipoproteins (Apo) were recognized; Apo C-I, Apo A-II, serum amyloid A4 (SAA4) and transthyretin (TTR). In addition, unidentified peaks were associated with GH effects on specific body compartments. CONCLUSIONS: Our results suggest that unique protein markers are associated with remodelling of different body compartments during GH treatment, which in the future might be useful to optimize GH treatment not only with regard to longitudinal growth. © 2013 Blackwell Publishing Ltd.
6.	Hagman, Cecilia, et al. (författare) Club cell secretory protein (CC16) in gastric fluid at birth and subsequent lung disease in preterm infants 2018 Ingår i: Pediatric Pulmonology. - : Wiley. - 8755-6863. ; 53:10, s. 1399-1406 Tidskriftsartikel (refereegranskat)abstract BackgroundClub cell secretory protein (CC16) probably has a role in protecting the lung from inflammation. AimTo evaluate if low levels of CC16 in gastric fluid at birth, reflecting low levels of CC16 in the lung, would be associated with lung inflammation and respiratory morbidity. MethodsA study of 64 infants with mean gestational age 26.1 weeks. CC16 was analyzed in gastric fluid at birth. CC16, pro-inflammatory cytokines, and MMP-9 were analyzed in tracheal aspirate within 24h from birth. ResultsCC16 in gastric fluid increased with gestational age (P=0.033). Lower concentrations of CC16 in gastric fluid at birth were associated with higher concentrations of IL-1 (P=0.028), TNF- (P=0.034), and MMP-9 (P=0.015) in tracheal aspirate. Infants who needed mechanical ventilation at 24 and 72h of age had lower CC16 in gastric fluid than those not ventilated at these ages (P=0.011 and P=0.024, respectively). Lower CC16 in gastric fluid was associated with higher FiO(2) at 6h (P=0.009), higher PaCO2 at 24h (P=0.03), more ventilator days (P=0.012) and more days with supplemental oxygen (P=0.03). Infants who had either died or were still treated with supplemental oxygen at 36 weeks postmenstrual age had lower CC16 in gastric fluid than infants with none of these outcomes (P=0.049). ConclusionA low CC16 concentration in gastric fluid at birth was associated with increased inflammation in the trachea within the first 24h of life and with more need for respiratory support in the neonatal period.
7.	Hellgren, Gunnel, 1961, et al. (författare) A proteomic approach identified growth hormone dependent nutrition markers in children with idiopathic short stature 2008 Ingår i: Proteome Science. - : Springer Science and Business Media LLC. - 1477-5956. ; 6:1 Tidskriftsartikel (refereegranskat)abstract ABSTRACT: BACKGROUND: The broad range in growth observed in short prepubertal children receiving the same growth hormone (GH) dose is due to individual variation in GH responsiveness. This study used a pharmaco-proteomic approach in order to identify novel biomarkers that discriminate between short non-GH-deficient (GHD) children who show a good or poor growth response to GH treatment. A group of 32 prepubertal children with idiopathic short stature (ISS) were included in the study. Children were classified on the basis of their first year growth velocity as either good (high responders, n = 13; range, 0.9-1.3 standard deviation score (SDS) or poor (low responders, n = 19; range, 0.3-0.5 SDS) responders to GH treatment (33 microg/kg daily). Serum protein expression profiles before, and after 1 year of GH treatment, were analyzed on a weak cationic exchange array (CM10) using surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF-MS). RESULTS: Changes in the intensity of two protein peaks (13.788 kDa and 17.139 kD) during the study period allowed the correct classification of 82% of children as high and low responders, respectively. The 13.788 kD peak, transthyretin, decreased in the high-responder group and increased in the low-responder group during 1 year of GH treatment, whereas the 17.139 kDa peak, apolipoprotein A-II (Apo A-II) decreased in the high-responder group and remained unchanged in the low-responder group. These peaks were identified by the consistency of peak pattern in the spectra, serum depletion experiments using specific antibodies and mass spectrometry. CONCLUSION: Our results suggest that transthyretin and apolipoprotein A-II may have a role in GH sensitivity and could be used as markers to predict which short prepubertal children with ISS will show a good or poor response to GH treatment.
8.	Hellgren, Gunnel, 1961, et al. (författare) Construction of a soluble human GH-receptor/EGF-receptor hybrid and its activation by GH 2004 Ingår i: Cytokine. ; 25:6, s. 260-4 Tidskriftsartikel (refereegranskat)abstract To develop a cell-free system that can be used to measure cytokine bioactivity we have designed a soluble hybrid molecule consisting of the extracellular domain of the GH-receptor (GHR) and the intracellular domain of the epidermal growth factor receptor (EGFR). A DNA construct encoding this hybrid-receptor was inserted into a baculoviral expression vector and expressed in Sf9-cells. Activation of the hybrid-receptor by ligand-induced dimerization can be measured as the incorporation of radiolabeled phosphate into a biotinylated tyrosine kinase peptide substrate. The kinase activity in samples stimulated with GH (10 ng/ml) increased 5-fold compared to samples without addition of GH. This is the first example of a functional hybrid-receptor where the transmembrane domain has been deleted. Our results suggest that such hybrid-receptors may be used for detection of GH and other cytokine-receptor activating substances in biological fluids.
9.	Hellgren, Gunnel, 1961, et al. (författare) Decreased Platelet Counts and Serum Levels of VEGF-A, PDGF-BB, and BDNF in Extremely Preterm Infants Developing Severe ROP 2021 Ingår i: Neonatology. - : S. Karger AG. - 1661-7800 .- 1661-7819. ; 118, s. 18-27 Tidskriftsartikel (refereegranskat)abstract Introduction: Thrombocytopenia has been identified as an independent risk factor for retinopathy of prematurity (ROP), although underlying mechanisms are unknown. In this study, the association of platelet count and serum platelet-derived factors with ROP was investigated. Methods: Data for 78 infants born at gestational age (GA) <28 weeks were included. Infants were classified as having no/mild ROP or severe ROP. Serum levels of vascular endothelial growth factor A, platelet-derived growth factor BB, and brain-derived neurotrophic factor were measured in serum samples collected from birth until postmenstrual age (PMA) 40 weeks. Platelet counts were obtained from samples taken for clinical indication. Results: Postnatal platelet counts and serum concentrations of the 3 growth factors followed the same postnatal pattern, with lower levels in infants developing severe ROP at PMA 32 and 36 weeks (p < 0.05-0.001). With adjustment for GA, low platelet counts and low serum concentrations of all 3 factors at PMA 32 weeks were significantly associated with severe ROP. Serum concentrations of all 3 factors also strongly correlated with platelet count (p < 0.001). Conclusion: In this article, we show that ROP, platelet counts, and specific pro-angiogenic factors correlate. These data suggest that platelet-released factors might be involved in the regulation of retinal and systemic angiogenesis after extremely preterm birth. Further investigations are needed.
10.	Hellgren, Gunnel, 1961, et al. (författare) Effect of Preterm Birth on Postnatal Apolipoprotein and Adipocytokine Profiles 2015 Ingår i: Neonatology. - : S. Karger AG. - 1661-7800 .- 1661-7819. ; 108:1, s. 16-22 Tidskriftsartikel (refereegranskat)abstract Background: Critical metabolic changes preparing for ex utero life may occur at the fetal age of approximately 28-32 weeks, and preterm birth <28 weeks postmenstrual age (PMA) may affect these pathways. Children born <28 weeks often have poorer outcomes possibly due to a major shift in metabolism, including nutritional supply and a shift in lipid-transporting particles and lipid profile. This shift may occur in apolipoprotein and adipocytokine levels, which may influence metabolism. Objective: To determine whether there is a shift in apolipoprotein and adipocytokine levels in neonates born at a gestational age (GA) of 28 and 32 weeks, respectively. Methods: Blood samples from 47 infants (GA 32 weeks, n = 30 and GA 28 weeks, n = 17) were collected at birth and, in the GA28 group, also at PMA 32 weeks. Apolipoproteins A-1, A-2, B, C-2, C-3, and E were analyzed, as well as adiponectin and leptin levels. Results: Serum levels of apolipoproteins A-1, C-2, C-3, and E were lower at birth in the GA28 group compared to the GA32 group. Adiponectin and leptin levels were low at birth in the GA28 group. In the GA28 group 4 weeks after birth, leptin levels were still low, whereas adiponectin levels had increased to levels similar to those found at birth in the GA32 group. Apolipoprotein A-1, C-2, C-3, and E levels were negatively correlated with days receiving total parenteral nutrition. Conclusion: There are significant differences in apolipoprotein and adipocytokine levels, which can be associated with GA and birth weight. The impact of these changes on neonatal and future morbidity remains to be determined. (C) 2015 S. Karger AG, Basel
11.	Hellgren, Gunnel, 1961, et al. (författare) Increased postnatal concentrations of pro-inflammatory cytokines are associated with reduced IGF-I levels and retinopathy of prematurity 2018 Ingår i: Growth Hormone & Igf Research. - : Elsevier BV. - 1096-6374. ; 39, s. 19-24 Tidskriftsartikel (refereegranskat)abstract Objective: Retinopathy of prematurity (ROP) is a multifactorial disease linked to low insulin-like growth factor (IGF)-I levels and perhaps to postnatal inflammation. Here, we investigated the longitudinal postnatal serum concentrations of pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha in relation to IGF-I levels and ROP. Design: The study cohort included 52 infants born before 31 gestational weeks. The infants were screened for ROP and classified as non-ROP (n = 33), non-proliferative ROP (stages 1 and 2; n = 10), or proliferative ROP (stage 3, all treated for ROP; n = 9). Blood samples were collected at birth, 24 h after birth, and then weekly until at least 36 weeks postmenstrual age (PMA) (i.e., up to 13 weeks after birth). Circulating levels of IL-6 and TNF-alpha were evaluated in relation to circulating IGF-I levels and ROP. Results: IL-6 levels negatively correlated with IGF-I levels between 5 and 8 weeks after birth, (p < 0.01 to p < 0.05). At birth, the IL-6 and TNF-alpha levels were similar independent of later ROP. Twenty-four hours after birth, both IL-6 and TNF-alpha levels had increased in infants later treated for ROP (p < 0.05). Postnatal, infants treated for ROP had higher IL-6 levels than infants without ROP. Conclusions: The pro-inflammatory response is associated with low IGF-I levels and the development of ROP.
12.	Hellgren, Gunnel, 1961, et al. (författare) Proliferative Retinopathy Is Associated with Impaired Increase in BDNF and RANTES Expression Levels after Preterm Birth. 2010 Ingår i: Neonatology. - : S. Karger AG. - 1661-7819 .- 1661-7800. ; 98:4, s. 409-418 Tidskriftsartikel (refereegranskat)abstract Background: Extremely preterm delivery is, amongst other complications, associated with retinopathy of prematurity (ROP). Untreated, ROP can progress to visual impairment and blindness due to an overgrowth of new vessels in the retina and vitreous cavity. Objective: The aim of this study was to identify cytokine markers within the first weeks of life that could be used to predict the risk for development of ROP later in life. Methods: Serum levels of 27 different cytokines in infants born at gestational weeks 23-30 were analyzed using a multiplex immunoassay method and compared between infants who did not develop ROP and infants who later developed proliferative ROP. In addition, mRNA levels of brain-derived neurotrophic factor (BDNF) in retinas from mice exposed to hyperoxia were analyzed using quantitative real-time PCR. Results: At birth, serum levels of IL-5 were higher in infants with no ROP compared to infants with proliferative ROP. 10-14 days after birth, serum levels of BDNF and RANTES were lower in infants who later developed proliferative ROP compared to infants who did not develop ROP. Furthermore, mRNA expression levels of BDNF in retinas from mice exposed to hyperoxia were significantly lower at postnatal day 15 compared to retinas from mice in room air. Conclusions: These results indicate that BDNF and RANTES may be important factors in the selective vulnerability of ROP development in preterm infants.
13.	Hellgren, Gunnel, 1961, et al. (författare) Protein expression profiling supports ‘the biphasic model’ theory of bone mineralization in response to GH treatment in short prepubertal children 2010 Ingår i: Hormone Research Paediatr. Konferensbidrag (refereegranskat)abstract According ’the biphasic model’ of GH action in bone it has been suggested that, in the initial phase after the start of treatment, GH increases bone resorption, followed by a phase of increased bone formation. The aim of this study was to use a proteomic approach to identify serum protein markers associated with GH-dependent bone mineralization the first two years of GH treatment. The study group consisted of 128 short GH-treated prepubertal children; 39 GHD and 89 idiopathic short stature (ISS), included in a clinical trial. Serum protein expression profiles were analyzed using SELDI-TOF on 3 different ProteinChip surfaces. Peak data were analyzed using regression methods and random permutation tests with bone mineral content (BMC) as output variable, measured by dual energy x-ray absorptiometry (DEXA). To eliminate height influence of the results BMC was adjusted for height (BMCHA). BMCHA decreased during the 1st yr of treatment in both the GHD and the ISS groups, and then increased to a value higher than at start of treatment during the 2nd yr. Peak data analyses of the GHD group supported the ’the biphasic model’ theory. Different groups of peaks correlated with changes in BMCHA during the 1st yr compared to the 2nd yr. At start of treatment no regression models correlated with 1st yr delta BMCHA, whereas a group of 5 peaks correlated with the 2nd yr delta BMCHA (p=0.036). Changes in protein expression pattern 0 – 1 yr correlated with the 1st (p=0.016) and the 2nd (p=0.006) yr delta BMCHA. There was no overlap of peaks between the regression models correlated with the 1st and the 2nd yr delta BMCHA, respectively. Work is in progress to identify specific proteins of interest. We conclude that these results could be useful to explain the biology behind the different phases of bone metabolism in response to GH treatment. Peaks so far identified, indicate that different forms of monomeric and dimeric apolipoprotein A-2 probably are involved in these processes.
14.	Hellgren, Gunnel, 1961, et al. (författare) Protein profiling identified dissociations between growth hormone-mediated longitudinal growth and bone mineralization in prepubertal children 2010 Ingår i: Medicinska Riksstämman. ; Dec 1-3 Konferensbidrag (övrigt vetenskapligt/konstnärligt)
15.	Hellgren, Gunnel, 1961, et al. (författare) Proteomics in GH-treated short children – dissociation between proteins related to longitudinal growth, bone volume and bone mineralization 2009 Ingår i: Horm Res. - 1663-2818 .- 1663-2826. ; 72(Suppl 3) Konferensbidrag (refereegranskat)
16.	Hellgren, Gunnel, 1961 (författare) Receptors for growth hormone and prolactin. Regulation and activation 2000 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Cytokine receptor activation is dependent on ligand-induced receptor dimerization or oligomerization and subsequent activation of several intracellular proteins. Activation of Janus kinases (Jaks) is probably the first intracellular event that occurs after receptor dimerization. Signaling through both the growth hormone receptor (GHR) and the prolactin receptor (PrlR) is believed to be dependent on activation of Jak2; however, in vitro studies indicate that other Jak proteins can be phosphorylated in response to GH and Prl. The amount of biologically active hormone in the circulation, the number of functional receptors in the target tissue and factors involved in intracellular signaling determine the response to a particular cytokine. The general aim of this thesis was to study mechanisms that might influence the effects of GH and Prl in target tissues, and to produce a reagent for use in a cell-free assay to analyze biologically active GH.The presence of all known Jak proteins was demonstrated in human liver, rat liver and rat adipose tissue. Co-precipitation studies showed that Jak1, Jak2 and Tyk2 were associated with the GHR in human liver, whereas Jak1 and Jak2 interacted with the GHR in rat liver and rat adipose tissue. Furthermore, the relative amount of GHR-associated Jak1 and Jak2 differed markedly between rat liver and rat adipose tissue. These results indicate that Jak proteins other than Jak2 might influence GH signaling, in a tissue- and species-specific manner.Conditions involving an increased catabolic rate are believed to be associated with acquired GH insensitivity. The effects of surgically induced catabolism on GH sensitivity were investigated in patients undergoing elective abdominal surgery. In adipose tissue and skeletal muscle, changes in GHR expression correlated with changes in insulin-like growth factor I (IGF-I) expression before surgery compared with 3 days after surgery. IGF-I gene expression did not change in response to surgery in skeletal muscle. In contrast, IGF-I mRNA levels increased in adipose tissue, suggesting tissue differences in GH sensitivity. The 5'-untranslated regions (UTRs) in GHR transcripts differed between skeletal muscle and adipose tissue, suggesting that alternative promoter regions may be activated in these tissues during catabolism. Although PrlRs have not been identified in adipose tissue, there are indications that Prl may exert important metabolic actions on this tissue. We have detected expression of the long (L-PrlR) form and two short forms (S2-PrlR and S3-PrlR) of the PrlR in mouse adipose tissue. L-PrlR expression was higher in adipose tissue from lactating mice compared with male, virgin and pregnant mice. Furthermore, L-PrlR mRNA expression was increased in adipose tissue in Prl-transgenic mice. Concentrations of cytokines are usually determined by antibody-based assays that do not distinguish between biologically active and inactive isoforms. Bioassays are laborious and not suitable for analyses of multiple samples. As a first step in the development of an assay for measurement of bioactive GH, we have constructed a soluble hybrid receptor consisting of the extracellular domain of the GHR and the intracellular domain of the receptor for epidermal growth factor, containing an intrinsic tyrosine kinase domain. The hybrid receptor had GH-binding capacity as well as GH-induced tyrosine kinase activity. This provides a novel tool in the development of assays for bioactive GH, and the same concept may also be used for measurement of other cytokines.
17.	Hellgren, Gunnel, 1961, et al. (författare) Safety aspects of longitudinal administration of IGF-I/IGFBP-3 complex in neonatal mice. 2011 Ingår i: Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. - : Elsevier BV. - 1532-2238. ; 21:4, s. 205-11 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: Very preterm birth is associated with a high risk of morbidity. Infants born very preterm have low serum levels of insulin-like growth factor I (IGF-I), that further decrease after birth. IGF-I is essential for brain development and low serum levels have been associated with retinopathy of prematurity. The present study aimed to investigate the effects of prolonged administration of a low dose of rhIGF-I/rhIGFBP-3 on glucose levels and total body weight, as well as liver, spleen and brain weights, and gray and subcortical white matter in newborn mice. DESIGN: The study was performed as three different trials. In all experiments C57BL/6N mice were injected with a rhIGF-I/rhIGFBP-3 complex or saline. In the first experimental trial, blood glucose levels were assessed 30min, 1h, 1.5h, 3h, 6h, 24h and 48h after the rhIGF-I/rhIGFBP-3 or saline injection on postnatal day (PND) 6. In the second trial, mice were injected daily from PND 3 to 11 and sacrificed on PND 12 for analysis of IGF-I serum levels. In the third trial, body and organ weights and effects on gray and white matter were assessed on PND 18 after PND 3-11 treatments as above. Effects on gray and white matter were measured using immunoreactivity for microtubule-associated protein-2 (MAP-2), myelin basic protein (MBP), 2',3'-cyclic nucleotide 3' phosphodiesterase (CNPase), neurofilament and oligodendrocyte lineage transcription factor 2 (Olig2). RESULTS: Blood glucose levels were unchanged in the rhIGF-I/rhIGFBP-3-treated group compared to baseline. In the control group glucose levels increased 30min after the second saline injection; levels were not elevated at the subsequent time point. Three hours after the rhIGF-I/rhIGFBP-3 or saline, glucose levels were lower in rhIGF-I/rhIGFBP-3-treated animals than in saline treated (p=0.026). At PND 18, total body weight was higher in rhIGF-I/rhIGFBP-3-treated mice compared with controls (p<0.05), but there were no differences between groups in brain, liver or spleen weights. No differences in gray matter area were found between groups. Analyses of white matter markers showed an increased number of Olig2-positive cells in rhIGF-I/rhIGFBP-3-treated mice compared with controls (p<0.001). There were no differences between groups in terms of MBP, CNPase or neurofilament immunoreactivity. CONCLUSIONS: Prolonged administration of rhIGF-I/rhIGFBP-3 did not have a negative impact on blood glucose levels and was beneficial for total body growth.
18.	Hellgren, Gunnel, 1961, et al. (författare) Serum concentrations of vascular endothelial growth factor in relation to retinopathy of prematurity. 2016 Ingår i: Pediatric research. - : Springer Science and Business Media LLC. - 1530-0447 .- 0031-3998. ; 79, s. 70-75 Tidskriftsartikel (refereegranskat)abstract The role of vascular endothelial growth factor (VEGF) in the pathogenesis of retinopathy of prematurity (ROP) has been clearly established. However, little is known about temporal changes in circulating VEGF concentrations in the preterm infant. The objective was to determine the longitudinal serum concentrations of VEGF in relation to ROP.
19.	Hellgren, Gunnel, 1961, et al. (författare) The growth hormone receptor exon 3-deleted/full-length polymorphism and response to growth hormone therapy in prepubertal idiopathic short children 2015 Ingår i: Growth Hormone & IGF Research. - : Elsevier BV. - 1096-6374 .- 1532-2238. ; 25:3, s. 127-135 Tidskriftsartikel (refereegranskat)abstract Objective: The primary aim of the study was to evaluate d3-GHR as a possible cause of increased GH sensitivity in children with delayed infancy-childhood transition (DICT). The secondary aim was to investigate the impact of the GHR exon 3 deleted/full-length (d3/f1) polymorphism on GH treatment response in prepubertal children classified as having idiopathic short stature (ISS). Design: Study subjects included 167 prepubescent longitudinally followed children classified as having ISS. Children were randomized to standard-dose GH treatment (33 mu g kg(-1) day(-1)), to double-dose treatment (67 mu g kg(-1) day(-1)), or to an untreated control group. Growth and metabolic outcome were evaluated at birth (n = 166), after one year of treatment (n = 59) and at adult height (n = 145). Genotyping of the GHR d3/f1 polymorphism was performed using TaqMan SNP genotyping of tagSNP rs6873545. Results: Birth and early growth data did not reach the predetermined level of statistical significance for difference between genotypes. Growth and IGF-1 response after one year of GH treatment did not differ between genotypes. IGFBP-3(SDS) was higher in untreated d3-GHR carriers than in untreated fl/fl individuals, whereas there was insufficient evidence for higher IGFBP-3(SDS) in treated d3-GHR carriers. Genotype did not explain the growth response to treatment, and no differences in height(SDS), height gain, or difference in height to midparental height(SDS) between genotype groups were found at adult height. Conclusion: The common GHR d3/fl polymorphism is probably not a cause of DICT in children with ISS, and our results do not suggest that the d3-GHR genotype is associated with increased sensitivity to GH in children with ISS.
20.	Hellström, Ann, 1959, et al. (författare) Docosahexaenoic Acid and Arachidonic Acid Levels Are Associated with Early Systemic Inflammation in Extremely Preterm Infants 2020 Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 12:7 Tidskriftsartikel (refereegranskat)abstract Fetal and early postnatal inflammation have been associated with increased morbidity in extremely preterm infants. This study aimed to demonstrate if postpartum levels of docosahexaenoic acid (DHA) and arachidonic acid (AA) were associated with early inflammation. In a cohort of 90 extremely preterm infants, DHA and AA in cord blood, on the first postnatal day and on postnatal day 7 were examined in relation to early systemic inflammation, defined as elevated C-reactive protein (CRP) and/or interleukin-6 (IL-6) within 72 h from birth, with or without positive blood culture. Median serum level of DHA was 0.5 mol% (95% CI (confidence interval) 0.2-0.9,P= 0.006) lower than the first postnatal day in infants with early systemic inflammation, compared to infants without signs of inflammation, whereas levels of AA were not statistically different between infants with and without signs of inflammation. In cord blood, lower serum levels of both DHA (correlation coefficient -0.40;P= 0.010) and AA (correlation coefficient -0.54;p< 0.001) correlated with higher levels of IL-6. Levels of DHA or AA did not differ between infants with and without histological signs of chorioamnionitis or fetal inflammation. In conclusion, serum levels of DHA at birth were associated with the inflammatory response during the early postnatal period in extremely preterm infants.
21.	Hellström, Ann, 1959, et al. (författare) Effect of Enteral Lipid Supplement on Severe Retinopathy of Prematurity A Randomized Clinical Trial 2021 Ingår i: JAMA Pediatrics. - : American Medical Association (AMA). - 2168-6203 .- 2168-6211. ; 175:4, s. 359-367 Tidskriftsartikel (refereegranskat)abstract IMPORTANCE Lack of arachidonic acid (AA) and docosahexaenoic acid (DHA) after extremely preterm birth may contribute to preterm morbidity, including retinopathy of prematurity (ROP). OBJECTIVE To determine whether enteral supplementation with fatty acids from birth to 40 weeks' postmenstrual age reduces ROP in extremely preterm infants. DESIGN, SETTING, AND PARTICIPANTS The Mega Donna Mega trial, a randomized clinical trial, was a multicenter study performed at 3 university hospitals in Sweden from December 15, 2016, to December 15, 2019. The screening pediatric ophthalmologists were masked to patient groupings. A total of 209 infants born at less than 27 weeks' gestation were tested for eligibility, and 206 infants were included. Efficacy analyses were performed on as-randomized groups on the intention-to-treat population and on the per-protocol population using as-treated groups. Statistical analyses were performed from February to April 2020. INTERVENTIONS Infants received either supplementation with an enteral oil providing AA (100mg/kg/d) and DHA (50mg/kg/d) (AA:DHA group) or no supplementation within 3 days after birth until 40 weeks' postmenstrual age. MAIN OUTCOMES AND MEASURES The primary outcomewas severe ROP (stage 3 and/or type 1). The secondary outcomes were AA and DHA serum levels and rates of other complications of preterm birth. RESULTS A total of 101 infants (58 boys [57.4%]; mean [SD] gestational age, 25.5 [1.5] weeks) were included in the AA:DHA group, and 105 infants (59 boys [56.2%]; mean [SD] gestational age, 25.5 [1.4] weeks) were included in the control group. Treatment with AA and DHA reduced severe ROP compared with the standard of care (16 of 101 [15.8%] in the AA:DHA group vs 35 of 105 [33.3%] in the control group; adjusted relative risk, 0.50 [95% CI, 0.28-0.91]; P =.02). The AA:DHA group had significantly higher fractions of AA and DHA in serum phospholipids compared with controls (overall mean difference in AA:DHA group, 0.82 mol% [95% CI, 0.46-1.18 mol%]; P <.001; overall mean difference in control group, 0.13 mol% [95% CI, 0.01-0.24 mol%]; P =.03). There were no significant differences between the AA:DHA group and the control group in the rates of bronchopulmonary dysplasia (48 of 101 [47.5%] vs 48 of 105 [45.7%]) and of any grade of intraventricular hemorrhage (43 of 101 [42.6%] vs 42 of 105 [40.0%]). In the AA:DHA group and control group, respectively, sepsis occurred in 42 of 101 infants (41.6%) and 53 of 105 infants (50.5%), serious adverse events occurred in 26 of 101 infants (25.7%) and 26 of 105 infants (24.8%), and 16 of 101 infants (15.8%) and 13 of 106 infants (12.3%) died. CONCLUSIONS AND RELEVANCE This study found that, compared with standard of care, enteral AA:DHA supplementation lowered the risk of severe ROP by 50% and showed overall higher serum levels of both AA and DHA. Enteral lipid supplementation with AA:DHA is a novel preventive strategy to decrease severe ROP in extremely preterm infants.
22.	Hellström, Ann, 1959, et al. (författare) The IGF system and longitudinal growth in preterm infants in relation to gestational age, birth weight and gender 2020 Ingår i: Growth Hormone & Igf Research. - : Elsevier BV. - 1096-6374. ; 51, s. 46-57 Tidskriftsartikel (refereegranskat)abstract Objective: Growth factors in the blood of very preterm infants may reflect growth and contribute to the understanding of early development. We investigated postnatal levels of insulin-like growth factors (IGFs) in infants born very preterm and related them to early growth development. Design: Blood samples were analyzed weekly for IGF-I, IGF-II, IGF binding protein (BP)-1, IGFBP-3, and acid-label subunit (ALS). Methods: 73 children born very preterm (gestational age (GA) < 32 weeks) were divided according to their gender-specific birth weight standard deviation score (SDS) into either appropriate for GA (AGA) or small for GA (SGA). Fifty-two (71%) and forty-three (59%) infants completed follow-up with anthropometry at approximately 3 years and at 5 years of age respectively. Thirty-six subjects (49%) had blood sampling for IGF-I and IGFBP-3 measurements up to 3 years of age. Results: IGF-I, IGFBP-3, and ALS levels increased in all groups from week 31 to week 36, with generally lower levels in the SGAs, with a concomitant lower growth velocity. Postnatal ALS was strongly associated with IGF-I and IGFBP-3 in boys, girls and AGA infants. IGF-II was higher in earlier born preterms (GA < 27 weeks) at postmenstrual ages 27.5-29.9 weeks compared with SGAs and late GA (GA >= 27 weeks) preterms (p <.0001). IGF-II, in contrast to IGF-I, did not differ between SGAs and AGAs at weeks 31-36. Mean IGFBP-1 was highest in the SGAs compared to AGAs at mean week 28,5 and 31 (p=.001) and IGFBP-1 levels were elevated in relation to IGF-I in the SGAs at that period. At follow-up, the increase in IGF-I between week 31 and 33.5 was a significant positive determinant of height SDS at 3 and 5 years of age in forward multiple regression analysis, independent of target height. Conclusion: This is the first study to investigate postnatal ALS levels in preterm infants. In very preterm infants, IGF-II is less affected by size at birth during early postnatal weeks compared with IGF-I. Early elevated IGFBP-1 might protect the SGA infants from an intense metabolic rate. Our results indicate that anabolic and metabolic processes during weeks 31-36 predicts later height.
23.	Hellström, William, et al. (författare) C-Peptide Suppression during Insulin Infusion in the Extremely Preterm Infant Is Associated with Insulin Sensitivity 2019 Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 104:9, s. 3902-3910 Tidskriftsartikel (refereegranskat)abstract Context: Little is known about the individual response of glucose-regulating factors to administration of exogenous insulin infusion in extremely preterm infants. Objective: To evaluate longitudinal serum concentrations of insulin, C-peptide, and plasma glucose levels in a high-frequency sampling regimen in extremely preterm infants treated with insulin because of hyperglycemia. Design: Prospective longitudinal cohort study. Setting: Two university hospitals in Sweden between December 2015 and September 2016. Patients and Intervention: Serum samples were obtained from nine extremely preterm infants, gestational age between 22 (+3) and 26 (+5) weeks (+ days), with hyperglycemia (plasma-glucose >10 mmol/L) at the start of insulin infusion, at 12, 24, and every 24 hours thereafter during ongoing infusion, and 12, 24, and 72 hours after the end of insulin infusion. Main outcome measures: Longitudinal serum concentrations of insulin and C-peptide and plasma glucose levels. Results: During insulin infusion, the serum C-peptide concentrations decreased compared with at start of infusion (P = 0.036), and then increased after ending the infusion. Individual insulin sensitivity based on the nonfasting plasma glucose/insulin ratio at the start of insulin infusion correlated with the initial decrease in serum ΔC-peptide[after 12h] (P = 0.007) and the degree of lasting decrease in serum ΔC-peptide[after end of infusion] (P = 0.015). Conclusion: Exogenous insulin infusion suppressed the C-peptide concentration to individually different degrees. In addition, the effect of insulin infusion on β cells may be linked to individual insulin sensitivity, where a low insulin sensitivity resulted in a more pronounced decrease in C-peptide during insulin infusion.
24.	Hellström, William, et al. (författare) Postnatal serum IGF-1 levels associate with brain volumes at term in extremely preterm infants 2023 Ingår i: Pediatric Research. - : Springer Science and Business Media LLC. - 0031-3998 .- 1530-0447. ; 93:3, s. 666-674 Tidskriftsartikel (refereegranskat)abstract 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, beta = 0.90), white matter (p = 0.007, beta = 0.33), cortical gray matter (p = 0.002, beta = 0.43), deep gray matter (p = 0.008, beta = 0.05), and cerebellar (p = 0.006, beta = 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).
25.	Klevebro, S., et al. (författare) Elevated levels of IL-6 and IGFBP-1 predict low serum IGF-1 levels during continuous infusion of rhIGF-1/rhIGFBP-3 in extremely preterm infants 2020 Ingår i: Growth Hormone and IGF Research. - : Elsevier BV. - 1096-6374. ; 50, s. 1-8 Tidskriftsartikel (refereegranskat)abstract Objective: Steady state insulin-like growth factor-1 (IGF-1) levels vary significantly during continuous intravenous infusion of recombinant human insulin-like growth factor-1/recombinant human insulin-like growth factor binding protein-3 (rhIGF-1/rhIGFBP-3) in the first weeks of life in extremely preterm infants. We evaluated interleukin-6 (IL-6) and insulin-like growth factor binding protein-1 (IGFBP-1) levels as predictors of low IGF-1 levels. Methods: Nineteen extremely preterm infants were enrolled in a trial, 9 received rhIGF-1/rhIGFBP-3 and 10 received standard neonatal care. Blood samples were analyzed daily for IGF-1, IL-6 and IGFBP-1 during intervention with rhIGF-1/rhIGFBP-3. Results: Thirty seven percent of IGF-1 values during active treatment were <20 μg/L. Among treated infants, higher levels of IL-6, one and two days before sampled IGF-1, were associated with IGF-1 < 20 μg/L, gestational age adjusted OR 1.30 (95% CI 1.03–1.63), p = .026, and 1.57 (95% CI 1.26–1.97), p < .001 respectively. Higher levels of IGFBP-1 one day before sampled IGF-1 was also associated with IGF-1 < 20 μg/L, gestational age adjusted OR 1.74 (95% CI 1.19–2.53), p = .004. Conclusion: In preterm infants receiving continuous infusion of rhIGF-1/rhIGFBP-3, higher levels of IL-6 and IGFBP-1 preceded lower levels of circulating IGF-1. These findings demonstrate a need to further evaluate if inflammation and/or infection suppress serum IGF-1 levels. The trial is registered at ClinicalTrials.gov (NCT01096784). © 2019
26.	Ley, David, et al. (författare) Longitudinal infusion of insulin-like growth factor-I and IGF-binding protein-3 complex to five preterm infants: pharmacokinetics and short term safety. 2013 Ingår i: Pediatric Research. - : Springer Science and Business Media LLC. - 0031-3998 .- 1530-0447. ; 63:1, s. 68-74 Tidskriftsartikel (refereegranskat)abstract Background:In preterm infants, low levels of insulin like growth factor-I (IGF-I) and IGF binding protein 3 (IGFBP-3) are associated with impaired brain growth and retinopathy of prematurity (ROP).Treatment with IGF-I/IGFBP-3 may be beneficial for brain development and decrease prevalence of ROP.Methods:In a phase II pharmacokinetic and safety study, five infants (3 girls) with a median (range) gestational age (GA) of 26+6 (26+0 - 27+2) weeks and birth weight (BW) of 990 (900-1212) g received continuous intravenous infusion of rhIGF-I/rhIGFBP-3. Treatment was initiated during the first postnatal day and continued for median (range) 168h (47-168) in doses between 21 - 111 µg/kg/24h.Results:Treatment with rhIGF-I/rhIGFBP-3 was associated with higher serum IGF-I and IGFBP-3 concentrations (p<0.001) than model-predicted endogenous levels. Out of 74 IGF-I samples measured during study drug infusion, 37 (50%) were within target range, 4 (5%) above and 33 (45%) were below. Predicted dose of rhIGF-I/rhIGFBP-3 to establish circulating levels of IGF-I within the intrauterine range in a 1000g infant was 75-100 µg/kg/24h. No hypoglycemia or other adverse effects were recorded.Conclusion:Continuous intravenous infusion of rhIGF-I/rhIGFBP-3 was effective in increasing serum concentrations of IGF-I and IGFBP-3. Administration during study was safe.Pediatric Research (2012); doi:10.1038/pr.2012.146.
27.	Lundgren, Pia, 1967, et al. (författare) Aggressive Posterior Retinopathy of Prematurity Is Associated with Multiple Infectious Episodes and Thrombocytopenia 2017 Ingår i: Neonatology. - : S. Karger AG. - 1661-7800 .- 1661-7819. ; 111:1, s. 79-85 Tidskriftsartikel (refereegranskat)abstract © 2016 S. Karger AG, BaselBackground: The most severe form of rapidly progressing retinopathy of prematurity (ROP) is termed aggressive posterior ROP (APROP). APROP frequently causes severe visual impairment in affected preterm infants despite timely and appropriate laser treatment. Objectives: We investigated the postnatal characteristics associated with APROP development in a national Swedish cohort. Methods: This retrospective, 1:1 matched case-control study included all infants that developed APROP in zone 1 (n = 9) between 2008 and 2012. Control infants, matched for gestational age and birth weight, developed ROP no worse than stage 2 (n = 9). We retrieved data from medical records on infant birth characteristics, postnatal morbidities, and blood analyses from birth to the first ROP treatment. Infectious episodes included sepsis, C-reactive protein ≥10 mg/l, and other clinical signs of infection that required antibiotic treatment. A platelet count <100 × 109/l was considered to be thrombocytopenia. Results: All APROP cases postnatally developed at least two infectious episodes, one in the first month and one around the time of ROP diagnosis. All APROP cases exhibited thrombocytopenia in the first month, and 6/9 exhibited thrombocytopenia around the time of ROP diagnosis. Compared to the controls, APROP cases more frequently developed necrotizing enterocolitis (8/9 vs. 1/9; p < 0.01) and sepsis (9/9 vs. 3/9; p < 0.01), and they had significantly lower median platelet counts (90 × 109/l, range 4-459, vs. 158 × 109/l, range 20-500; p < 0.001). Conclusion: Multiple infectious episodes and thrombocytopenia, particularly around the time of ROP diagnosis, were associated with APROP development.
28.	Lundgren, Pia, 1967, et al. (författare) Association between low fatty acid levels and platelet count in infants with Retinopathy of Prematurity. 2020 Ingår i: Acta paediatrica. - Oxford : Wiley. - 1651-2227 .- 0803-5253. ; 109:12, s. 2547-2548 Tidskriftsartikel (refereegranskat)
29.	Lundgren, Pia, 1967-, et al. (författare) Erythropoietin serum levels, versus anaemia as risk factors for severe retinopathy of prematurity 2019 Ingår i: Pediatric Research. - : Nature Publishing Group. - 0031-3998 .- 1530-0447. ; 86:2, s. 276-282 Tidskriftsartikel (refereegranskat)abstract Background: Preterm infants with anaemia are treated with recombinant human erythropoietin (rhEPO). It is debated whether rhEPO treatment is a risk factor for retinopathy of prematurity (ROP). We evaluated longitudinal EPO and haemoglobin levels, blood transfusions and neonatal morbidities as risk factors for severe ROP.Method: This prospective study included 78 Swedish infants, born <28 weeks gestational age (GA), screened for ROP. We tested serum EPO levels on postnatal days 1, 7, 14 and 28 and at postmenstrual ages 32, 36 and 40 weeks. Haemoglobin levels and blood transfusions were recorded during postnatal weeks 1-4. Anaemia was defined as haemoglobin ≤110 g/L.Results: During postnatal week 1, infants with severe ROP requiring treatment (28%) more frequently developed anaemia (42.9% versus 8.0%, P = 0.003) and had higher mean EPO levels (postnatal day 7: 14.2 versus 10.8 mIU/mL, P = 0.003) compared to infants with no or less severe ROP not requiring treatment. In multivariable analyses, GA and anaemia during week 1 remained significant risk factors, but elevated EPO level postnatal day 7 was no longer significant.Conclusions: Among infants born <28 weeks GA, anaemia during week 1 was a significant risk factor for severe ROP requiring treatment but not elevated EPO levels.
30.	Löfqvist, Chatarina, 1964, et al. (författare) Association of Retinopathy of Prematurity With Low Levels of Arachidonic Acid A Secondary Analysis of a Randomized Clinical Trial 2018 Ingår i: Jama Ophthalmology. - : American Medical Association (AMA). - 2168-6165. ; 136:3, s. 271-277 Tidskriftsartikel (refereegranskat)abstract IMPORTANCE Mice with oxygen-induced retinopathy fed matched diets except for omega-3 long-chain polyunsaturated fatty acids (LC-PUFAs) vs omega-6 LC-PUFAs demonstrate relative antiangiogenic and neuroprotective associations of omega-3 LC-PUFAs. However, supplementing preterm infants with LC-PUFAs has been inconsistent in reducing major preterm morbidities. However, few studies measured serum lipid levels after supplementation. OBJECTIVE To examine the associated risk of retinopathy of prematurity (ROP) from the levels of circulating omega-3 and omega-6 LC-PUFAs. DESIGN, SETTING, AND PARTICIPANTS This longitudinal clinical study was a further analysis of serum lipid levels from a randomized controlled trial cohort of 90 infants born at gestational age (GA) less than 28 weeks. From April 4, 2013, to September 22, 2015, cord blood samples, followed by venous blood samples, were obtained at birth and at 1, 7, 14, and 28 days after birth and then at postmenstrual age (PMA) 32, 36, and 40 weeks at the neonatal intensive care unit at Sahlgrenska University Hospital in Goteborg, Sweden. MAIN OUTCOMES AND MEASURES Serum phospholipid fatty acids were transmethylated and measured by gas chromatography-mass spectrometry. Mann-Whitney test, logistic regression Spearman rank correlation, and receiver operating characteristic curve analysis were used to compare differences between infants with no ROP and infants who developed ROP. RESULTS Serum levels from 78 infants (43 male [55%]; mean [SD] GA, 25.5 [1.4] weeks) with a known ROP outcome were evaluated. Lower area under the curve (AUC) of arachidonic acid (AA) (20: 4 omega-6) was seen in infants with a later diagnosis of ROP compared with infants with no ROP in the first month of life (mean, 34.05 [95% CI, 32.10-36.00] vs 37.15 [95% CI, 34.85-39.46]; P < .05). In addition, lower levels of AA at 32 weeks' PMA were seen in infants with later severe ROP compared with in those without ROP (mean, 7.06 [95% CI, 6.60-7.52] vs 8.74 [95% CI, 7.80-9.67]; P < .001). In logistic modeling, low postnatal serum levels of AA and GA at birth identified with a sensitivity greater than 90% of infants who developed ROP. CONCLUSIONS AND RELEVANCE Low postnatal levels of the omega-6 LC-PUFAs (AA) are strongly associated with ROP development. Evaluating postnatal AA fraction after birth in addition to GA may be useful for ROP prediction.
31.	Löfqvist, Chatarina, 1964, et al. (författare) Low Postnatal Serum IGF-I levels is Associated with Bronchopulmonary Dysplasia (BPD). 2012 Ingår i: Acta paediatrica. - : Wiley. - 1651-2227 .- 0803-5253. ; 101:12, s. 1211-1216 Tidskriftsartikel (refereegranskat)abstract Aim: To characterize postnatal changes in serum IGF-I in relation to development of bronchopulmonary dysplasia (BPD) in very preterm infants. Methods: Longitudinal study of 108 infants with mean (SD) gestational age 27.2 (2.2) weeks. Weekly serum samples of IGF-I were analyzed from birth until postmenstrual age 36 weeks. Multivariate models were developed to identify independent predictors of BPD. Results: Postnatal mean IGF-I levels at postnatal day 3 to 21 were lower in infants with BPD compared to infants with no BPD (16 vs. 26 ug/L, p<0.001). Longitudinal postnatal change in IGF-I levels (IGF-I regression coefficient (β), postnatal days 3 to 21, was lower in infants with BPD compared to infants with no BPD (0.28 vs. 0.97, p=0.002) and mean IGF-I during postmenstrual age 30-33 weeks was lower in infants with BPD as compared to infants without BPD (22 vs. 29 ug/L, p<0.001). In a binomial multiple regression model lower gestational age, male gender and lower mean serum IGF-I levels during postnatal day 3-21 were the most predictive risk factors associated with BPD (r(2) =0.634, p<0.001). Conclusion: Lower IGF-I concentrations during the first weeks after very preterm birth are associated with later development of BPD. © 2012 The Author(s)/Acta Paediatrica © 2012 Foundation Acta Paediatrica.
32.	Löfqvist, Chatarina, 1964, et al. (författare) Validating impact of temporal changes of adiponectin in relation to ROP development 2016 Ingår i: Investigative Ophthalmology & Visual Science. - 0146-0404. Konferensbidrag (övrigt vetenskapligt/konstnärligt)
33.	Najm, Svetlana, et al. (författare) Effects of a lipid emulsion containing fish oil on polyunsaturated fatty acid profiles, growth and morbidities in extremely premature infants: A randomized controlled trial 2017 Ingår i: Clinical Nutrition ESPEN. - : Elsevier BV. - 2405-4577. ; 20, s. 17-23 Tidskriftsartikel (refereegranskat)abstract © 2017 The Authors Background & aims The purpose of the study was to compare the effects of the parenteral emulsion SMOFlipid ® , with 15% fish oil, with Clinoleic ® on retinopathy of prematurity (ROP) and other morbidities and growth, and to compare their impact on longitudinal serum levels of fatty acids. Retinopathy of prematurity, other morbidity and growth were correlated with each parenteral lipid supplement. Methods Ninety infants born at gestational age < 28 weeks were randomized to treatment with SMOFlipid ® or Clinoleic ® . Two thirds (66%) of the infants received parenteral nutrition for up to 14 days birth (median 8, range 2–14 days), and additional 25% of the infants received for up to 28 days after birth (median 21, range 15–28 days). Cord blood samples and then venous blood samples were obtained at ages 1, 7, 14, and 28 days and at postmenstrual age (PMA) 32, 36, and 40 weeks. Breastmilk was collected at postnatal day 7, and at PMA 32 and 40 weeks. Serum phospholipid and breastmilk total fatty acids were analyzed by gas chromatography–mass spectrometry. Treatment groups were compared with regard to ROP, bronchopulmonary dysplasia, necrotizing enterocolitis, patent ductus arteriosus sepsis and growth between birth and 36 weeks. Results Infants on SMOFlipid ® had higher fractions of omega-3 LCPUFA eicosapentaenoic acid (EPA) and slightly higher omega-3 LCPUFA docosahexaenoic acid (DHA) fraction and a decreased arachidonic acid (AA) to DHA ratio from one week after birth up to 32 postmenstrual weeks compared to infants on Clinoleic ® . Treatment groups did not differ in morbidities or growth. Conclusion Supplementation with SMOFlipid ® containing 15% fish oil during parenteral nutrition increased EPA substantially, DHA marginally, reduced AA and decreased AA to DHA ratio. It did not reduce morbidity or affect growth. Since extremely preterm infants accumulate a large deficit of DHA and AA, studies on more prolonged or different levels of DHA and AA supplementation are warranted.
34.	Nilsson, Anders K., 1982, et al. (författare) Influence of Human Milk and Parenteral Lipid Emulsions on Serum Fatty Acid Profiles in Extremely Preterm Infants. 2019 Ingår i: JPEN - Journal of Parenteral and Enteral Nutrition. - : Wiley. - 0148-6071 .- 1941-2444. ; 43:1, s. 152-161 Tidskriftsartikel (refereegranskat)abstract Infants born prematurely are at risk of a deficiency in ω-6 and ω-3 long-chain polyunsaturated fatty acids (LC-PUFAs) arachidonic acid (AA) and docosahexaenoic acid (DHA). We investigated how fatty acids from breast milk and parenteral lipid emulsions shape serum LC-PUFA profiles in extremely preterm infants during early perinatal life.Ninety infants born < 28 weeks gestational age were randomized to receive parenteral lipids with or without the ω-3 LC-PUFAs eicosapentaenoic acid (EPA) and DHA (SMOFlipid: Fresenius Kabi, Uppsala, Sweden, or Clinoleic: Baxter Medical AB, Kista, Sweden, respectively). The fatty acid composition of infant serum phospholipids was determined from birth to postmenstrual age 40 weeks, and in mother's milk total lipids on postnatal day 7. Enteral and parenteral intake of LC-PUFAs was correlated with levels in infant serum.Infants administered parenteral ω-3 LC-PUFAs received 4.4 and 19.3 times more DHA and EPA, respectively, over the first 2 weeks of life. Parenteral EPA but not DHA correlated with levels in infant serum. We found linear relationships between dietary EPA and DHA and infant serum levels in the Clinoleic (Baxter Medical AB) group. The volume of administered SMOFlipid (Fresenius Kabi) was inversely correlated with serum AA, whereas Clinoleic (Baxter Medical AB) inversely correlated with serum EPA and DHA.There appears to be no or low correlation between the amount of DHA administered parenterally and levels measured in serum. Whether this observation reflects serum phospholipid fraction only or truly represents the amount of accreted DHA needs to be investigated. None of the parenteral lipid emulsions satisfactorily maintained high levels of both ω-6 and ω-3 LC-PUFAs in infant serum.
35.	Nilsson, Anders K., 1982, et al. (författare) Long-chain polyunsaturated fatty acids decline rapidly in milk from mothers delivering extremely preterm indicating the need for supplementation. 2018 Ingår i: Acta paediatrica. - : Wiley. - 1651-2227 .- 0803-5253. ; 107:6, s. 1020-1027 Tidskriftsartikel (refereegranskat)abstract Our aim was perform an in-depth analysis of the composition of fatty acids in milk from mothers delivering extremely preterm babies. We investigated longitudinal changes in milk fatty acid profiles and the relationship between several types of fatty acids, including omega-3 and omega-6.Milk samples were collected at three stages of lactation from 78 mothers who delivered at less than 28 weeks of pregnancy at the Sahlgrenska University Hospital, Gothenburg, Sweden, from April 2013 to September 2015. Fatty acid composition was analysed by gas chromatography-mass spectrometry.A reduction in long-chain polyunsaturated fatty acids (LCPUFAs) was observed during the lactation period. The concentrations of arachidonic acid and docosahexaenoic acid declined from medians of 0.34 to 0.22 mol% and 0.29 to 0.15 mol%, respectively, between postnatal day seven and a post-menstrual age of 40 weeks. Strong correlations were found between the intermediates of several classes of fatty acids, including omega-3, omega-6 and omega-9.A rapid reduction in LCPUFA content in the mother's milk during the lactation period emphasises the importance of fatty acid supplementation to infants born extremely preterm, at least during the period corresponding to the third trimester, when rapid development of the brain and adipose tissue require high levels of LCPUFAs. This article is protected by copyright. All rights reserved.
36.	Nilsson, Anders K., 1982, et al. (författare) Longitudinal Serum Metabolomics in Extremely Premature Infants: Relationships With Gestational Age, Nutrition, and Morbidities 2022 Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-453X .- 1662-4548. ; 16 Tidskriftsartikel (refereegranskat)abstract An increasing number of extremely premature infants survive the neonatal period and beyond. Little is known about the maturation of the preterm infant's metabolome and its relation to the development of morbidities. Using 1H-NMR, we investigated the serum metabolic profile of 87 infants born at a gestational age (GA) <28 weeks [mean GA (SD) 25.4 (1.4) weeks] in samples longitudinally collected from birth to term equivalent age. The infant metabolome was analyzed in relation to GA, postnatal age, nutrition, and preterm morbidities. At postnatal day 1, low GA correlated with high levels of 3-hydroxyisobutyrate, acetate, acetoacetate, acetone, formate, glucose, and valine. Nearly all quantified metabolites displayed postnatal concentration changes. For example, the two phospholipid-related metabolites myo-inositol and ethanolamine displayed a similar decline from birth over the first weeks of life, irrespectively of GA. The proportion of enteral/parenteral energy intake in the first 28 days significantly correlated with mean levels of 52% of the analyzed metabolites. Low enteral energy intake was associated with high serum levels of 3-hydroxyisobutyrate, creatinine, glucose, glycerol, histidine, lactate, leucine, lysine, methionine, ornithine, phenylalanine, proline, threonine, and uridine. There were also significant correlations between high enteral intake and high serum levels of isoleucine and tyrosine. Retinopathy of prematurity (ROP) and bronchopulmonary dysplasia (BPD) outcomes were not significantly associated with metabolite levels in the neonatal period after correcting for multiple testing. In conclusion, the serum metabolome of extremely premature infants changes substantially in the neonatal period, largely driven by the gradual transfer from total parenteral nutrition to full enteral feeding. Further studies are needed to disentangle the intricate relationships between the metabolome, nutritional management, GA, and the development of preterm morbidities.
37.	Nilsson, Anders K., 1982, et al. (författare) Preterm infant circulating sex steroid levels are not altered by transfusion with adult male plasma: a retrospective multicentre cohort study 2022 Ingår i: Archives of Disease in Childhood-Fetal and Neonatal Edition. - : BMJ. - 1359-2998 .- 1468-2052. ; 107:6, s. 577-582 Tidskriftsartikel (refereegranskat)abstract Sex hormones delivered via plasma transfusions from adult male donors to very preterm infants do not alter the circulating plasma concentrations in the infant, irrespective of gender. Objective To determine if plasma transfusions with male donor plasma to very preterm infants affect circulatory levels of sex steroids. Design and patients Retrospective multicentre cohort study in 19 infants born at gestational age Setting Three neonatal intensive care units in Sweden. Main outcome measures Concentrations of sex steroids and sex hormone-binding globulin (SHBG) in donor plasma and infant plasma measured before and after a plasma transfusion and at 6, 12, 24 and 72 hours. Results The concentrations of progesterone, dehydroepiandrosterone and androstenedione were significantly lower in donor plasma than in infant plasma before the transfusion (median (Q1-Q3) 37.0 (37.0-37.0), 1918 (1325-2408) and 424 (303-534) vs 901 (599-1774), 4119 (2801-14 645) and 842 (443-1684) pg/mL), while oestrone and oestradiol were higher in donor plasma (17.4 (10.4-20.1) and 16.0 (11.7-17.2) vs 3.1 (1.1-10.2) and 0.25 (0.25-0.25) pg/mL). Median testosterone and dihydrotestosterone (DHT) levels were 116-fold and 21-fold higher in donor plasma than pre-transfusion levels in female infants, whereas the corresponding difference was not present in male infants. Plasma sex steroid levels were unchanged after completed transfusion compared with pre-transfusion levels, irrespective of the gender of the receiving infant. The SHBG concentration was significantly higher in donor than in recipient plasma (22.8 (17.1-33.5) vs 10.2 (9.1-12.3) nmol/L) before transfusion but did not change in the infants after the transfusion. Conclusions A single transfusion of adult male plasma to preterm infants had no impact on circulating sex steroid levels.
38.	Nilsson, Anders K., 1982, et al. (författare) Serum choline in extremely preterm infants declines with increasing parenteral nutrition 2021 Ingår i: European Journal of Nutrition. - : Springer Science and Business Media LLC. - 1436-6207 .- 1436-6215. ; 60:2, s. 1081-108932588218 Tidskriftsartikel (refereegranskat)abstract 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(1)H 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) mu M, respectively, at PND 1. The choline concentration decreased rapidly between PND one and PND seven [18.4 (14.1-26.4) mu M], 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.
39.	Nilsson, Anders K., 1982, et al. (författare) Sphingolipidomics of serum in extremely preterm infants : Association between low sphingosine-1-phosphate levels and severe retinopathy of prematurity 2021 Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier. - 1388-1981 .- 1879-2618. ; 1866:7 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Extremely preterm infants are at risk of developing retinopathy of prematurity (ROP) that can cause impaired vision or blindness. Changes in blood lipids have been associated with ROP. This study aimed to monitor longitudinal changes in the serum sphingolipidome of extremely preterm infants and investigate the relationship to severe ROP development.METHODS: This is a prospective study that included 47 infants born <28 gestational weeks. Serum samples were collected from cord blood and at postnatal days 1, 7, 14, and 28, and at postmenstrual weeks (PMW) 32, 36, and 40. Serum sphingolipids and phosphatidylcholines were extracted and analyzed by LC-MS/MS. Associations between sphingolipid species and ROP were assessed using mixed models for repeated measures.RESULTS: The serum concentration of all investigated lipid classes, including ceramide, mono- di- and trihexosylceramide, sphingomyelin, and phosphatidylcholine displayed distinct temporal patterns between birth and PMW40. There were also substantial changes in the lipid species composition within each class. Among the analyzed sphingolipid species, sphingosine-1-phosphate showed the strongest association with severe ROP, and this association was independent of gestational age at birth and weight standard deviation score change.CONCLUSIONS: The serum phospho- and sphingolipidome undergoes significant remodeling during the first weeks of the preterm infant's life. Low postnatal levels of the signaling lipid sphingosine-1-phosphate are associated with the development of severe ROP.
40.	Nilsson, Anders K., 1982, et al. (författare) The proteome signature of cord blood plasma with high hematopoietic stem and progenitor cell count 2022 Ingår i: Stem Cell Research. - : Elsevier BV. - 1873-5061. ; 61 Tidskriftsartikel (refereegranskat)abstract Hematopoietic stem and progenitor cells (HSPC) from umbilical cord blood (UCB) are used for transplantation to treat blood disorders. Methods to estimate the HSPC count in umbilical cord blood, and thereby identify high-value blood units, are time-consuming and costly. Recent studies indicate that the UCB plasma protein composition relates to the HSPC count. We compared the plasma proteome of UCB with high vs low HSPC cell count (> 115 x 10(6) vs < 51 x 10(6) CD34(+) cells l(-1)) by using a combination of global untargeted MS quantitative proteomics and targeted proximity extension assay (PEA) proteomics. For the MS platform, 96 proteins differed significantly between the CD34(+) groups, and out of these, 44 proteins showed more than a two-fold difference. Seven pathways were enriched in high CD34(+) samples, including pathways relating to platelets, coagulation, and lipid transport. For the PEA platform, 61 proteins were differentially abundant, and among these 7 proteins showed more than a two-fold difference between groups. In the PEA data, a high CD34(+) cell count was associated with a protein hub with functions in platelet degranulation. We conclude that the HSPC count is related to the UCB plasma proteome, but that further studies are needed to discern if these findings reflect causal relationships.
41.	Pupp, Ingrid, et al. (författare) Early Surge in Circulatory Adiponectin Is Associated With Improved Growth at Near Term in Very Preterm Infants. 2015 Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 100:6, s. 2380-7 Tidskriftsartikel (refereegranskat)abstract Adiponectin enhances insulin sensitivity and may play a role in fetal and postnatal growth.
42.	Swolin-Eide, Diana, 1968, et al. (författare) Variation of bone acquisition during growth hormone treatment in children can be explained by proteomic biomarkers, bone formation markers, body composition and nutritional factors 2018 Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 116, s. 144-153 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: Growth hormone (GH) regulates both longitudinal growth and bone acquisition in children, and has profound metabolic effects. The aim was to investigate the association between proteomic biomarkers, body fat, nutrition and bone formation markers, and longitudinal growth in response to GH during the first year of treatment. The degree to which changes in these factors could explain variations in GH-dependent longitudinal growth and bone mineralization was also assessed. METHODS: The individualized GH dose trial included 128 short prepubertal children with either normal (non-GH-deficient) or reduced levels of GH secretion (GH-deficient) (mean age+/-SD, 8.6+/-2.6years; 90 boys), i.e., with a broad range of GH-secretion and GH-responsiveness, receiving GH treatment (mean 43mug/kg/day). Blood samples were taken and dual-energy X-ray absorptiometry (DXA) measured at baseline and 1year of treatment. Step-wise multiple regression models were constructed including three steps with different independent variables added at each step to explain the variance in outcome variables (heightSDS, bone mineral content (BMC) and bone mineral density (BMD). Independent variables included in Step I were previously identified proteomic markers related to GH treatment response, bone formation markers (intact PINP, bone-specific alkaline phosphatase and osteocalcin), variables at treatment start (GH dose mU/kg/day, GH maximum secretion, and difference between child's current and mid-parental heightSDS). Step II explored the added influence of body composition data (body mass index or DXA). Step III explored the added influence of serum nutritional markers and hormones. RESULTS: Step I variables explained 71% of the variation in first year heightSDS gain, median (minimum-maximum) 0.8 (0.24-1.67); and the proportion explained rose to 73% following inclusion of step II variables and 75% following step III. Corresponding values for total body BMC were 58%, 78%, and 80%, respectively. Proportions fell by approximately 20% when BMC was adjusted for height; 33%, 57%, and 57% for steps I, II, and III, respectively. Corresponding values for total body BMD were 29%, 39%, and 45%, respectively. CONCLUSION: For total BMC, as much as 80% of the variation during the first year of GH treatment could be explained by proteomic biomarkers, body fat, nutrition and bone formation markers, whereas for height-adjusted BMC 57% could be explained. The inclusion of information about either body composition (fat/lean mass) or nutritional markers contributed with approximately 20%. The variation in heightSDS gain could be explained to 75%. Hence, information of fat or nutrition markers was needed for explaining the variation in bone acquisition to the same magnitude as explaining the variation in height response.
43.	Wang, Xiaoyang, 1965, et al. (författare) White matter damage after chronic subclinical inflammation in newborn mice. 2009 Ingår i: Journal of child neurology. - : SAGE Publications. - 1708-8283 .- 0883-0738. ; 24:9, s. 1171-8 Tidskriftsartikel (refereegranskat)abstract Preterm infants exposed to inflammation are at increased risk of white matter injury and/or cerebral palsy. To investigate the effect of chronic inflammation on the developing white matter, we administered low-dose lipopolysaccharide once a day from postnatal days 3 to 11, examined white matter changes at postnatal day 12, and monitored serum levels of insulin-like growth factor 1 and insulin-like factor binding protein-3. A single injection of lipopolysaccharide decreased the serum insulin-like growth factor 1 level but not the insulin-like factor binding protein-3 level. At postnatal day 12, quantification of immunohistochemical staining for axonal, myelin, and oligodendrocyte markers revealed impaired myelination in subcortical white matter. In addition, brain gray matter volume decreased and spleen and liver weight increased at postnatal day 12. These data suggest chronic subclinical inflammation hampers development of white and gray matter in early life, which may be associated with insulin-like growth factor 1 deficiency.
44.	Zhong, Wen, et al. (författare) Dramatic changes in blood protein levels during the first week of life in extremely preterm infants 2021 Ingår i: Pediatric Research. - : Springer Science and Business Media LLC. - 0031-3998 .- 1530-0447. ; 89, s. 604-612 Tidskriftsartikel (refereegranskat)abstract 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.
45.	Åberg, Maria A I, 1972, et al. (författare) Selective introduction of antisense oligonucleotides into single adult CNS progenitor cells using electroporation demonstrates the requirement of STAT3 activation for CNTF-induced gliogenesis 2001 Ingår i: Mol Cell Neurosci. - : Elsevier BV. ; 17:3, s. 426-43 Tidskriftsartikel (refereegranskat)abstract We have developed a novel method in which antisense DNA is selectively electroporated into individual adult neural progenitor cells. By electroporation of antisense oligonucleotides against signal transducer and activator of transcription 3 (STAT3) we demonstrate that ciliary neurotrophic factor (CNTF) is an instructive signal for astroglial type 2 cell fate specifically mediated via activation of STAT3. Activation of the mitogen-activated protein kinase (MAPK) signaling pathway induced only a transient increase in glial fibrillary acidic protein (GFAP) expression, and inhibition of this signaling pathway did not block the induction by CNTF of glial differentiation in progenitor cells. In addition we show that microelectroporation is a new powerful method for introducing antisense agents into single cells in complex cellular networks.

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