| 1. |
- Albertsson-Wikland, Kerstin, 1947, et al.
(author)
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Longitudinal follow-up of growth in children born small for gestational age.
- 1993
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In: Acta paediatrica (Oslo, Norway : 1992). - 0803-5253. ; 82:5, s. 438-43
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Journal article (peer-reviewed)abstract
- Postnatal growth was followed in a population-based group of 123 small-for-gestational-age (SGA, birth weight < -2 SD) children (66 boys and 57 girls) to four years of age in order to determine the incidence and time of catch-up growth. Gestational age was determined by ultrasound in gestational weeks 16-17 in all pregnancies, thus eliminating the problem of distinguishing between SGA and preterm infants. Infants with well-defined causes for slow growth rate, i.e. those infants with chromosomal disorders, severe malformations, intrauterine viral infections or cerebral palsy, were excluded. The boys showed an extremely fast weight catch-up, 85% of them reaching weights greater than -2 SD at the age of three months and remaining above this level to the end of the study period. Such a fast catch-up growth was observed in only two-thirds of the girls, but at four years of age 85% of the girls were also above -2 SD. Length catch-up was more gradual than weight catch-up. Of the boys, 54% had lengths below -2 SD at birth, 26% at 1 year of age, 22% at 2 years of age, 17% at 2.5 years of age and 11% (n = 8) at 4 years of age. Corresponding figures for girls were: 69% at birth, 28% at 1 year, 15% at 2 years, 12% at 2.5 years and 5% (n = 3) at 4 years. At 4 years of age, only six boys and three girls remained below -2 SD for both weight and height.(ABSTRACT TRUNCATED AT 250 WORDS)
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| 2. |
- de-Wahl Granelli, Anne, 1970, et al.
(author)
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Impact of pulse oximetry screening on the detection of duct dependent congenital heart disease: a Swedish prospective screening study in 39,821 newborns.
- 2009
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In: BMJ (Clinical research ed.). - 1468-5833. ; 338
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To evaluate the use of pulse oximetry to screen for early detection of life threatening congenital heart disease. DESIGN: Prospective screening study with a new generation pulse oximeter before discharge from well baby nurseries in West Götaland. Cohort study comparing the detection rate of duct dependent circulation in West Götaland with that in other regions not using pulse oximetry screening. Deaths at home with undetected duct dependent circulation were included. SETTING: All 5 maternity units in West Götaland and the supraregional referral centre for neonatal cardiac surgery. PARTICIPANTS: 39,821 screened babies born between 1 July 2004 and 31 March 2007. Total duct dependent circulation cohorts: West Götaland n=60, other referring regions n=100. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative predictive values, and likelihood ratio for pulse oximetry screening and for neonatal physical examination alone. RESULTS: In West Götaland 29 babies in well baby nurseries had duct dependent circulation undetected before neonatal discharge examination. In 13 cases, pulse oximetry showed oxygen saturations
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| 3. |
- Mollberg, Margareta, 1953, et al.
(author)
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Obstetric brachial plexus palsy: a prospective study on risk factors related to manual assistance during the second stage of labor
- 2007
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In: Acta Obstet Gynecol Scand. - : Informa Healthcare. ; 86:2, s. 198-204
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Journal article (peer-reviewed)abstract
- BACKGROUND: To evaluate the association between obstetric brachial plexus palsy and obstetrical maneuvers during the second stage of delivery. METHODS: Prospective population-based case control study. Cases of obstetric brachial plexus palsy were compared with a randomly selected control group with regard to obstetric management. RESULTS: Five or more obstetrical maneuvers were used to deliver the infants in 82% in the obstetric brachial plexus palsy group versus 1.8% in the controls. Risk factors independently associated with obstetric brachial plexus palsy were force applied when downward traction was imposed on the fetal head (odds ratio 15.2; 95% confidence interval 8.4-27.7). The incidence of obstetric brachial plexus palsy in the infants in the population was 3.3 per thousand. At 18 months of age 16.1% (incidence of 0.05%) of children had residual functional deficits and downward traction with substantial force was applied in all these cases. CONCLUSIONS: Forceful downward traction applied to the head after the fetal third rotation represents an important risk factor of obstetric brachial plexus palsy in vaginal deliveries in cephalic presentation.
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| 4. |
- Noren, Håkan, 1948, et al.
(author)
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STAN in clinical practice--the outcome of 2 years of regular use in the city of Gothenburg
- 2006
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In: Am J Obstet Gynecol. ; 195:1, s. 7-15
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The purpose of this study was to monitor the introduction of the STAN-methodology (Noventa Medical, Moelndal, Sweden). STUDY DESIGN: This was a prospective observational study covering the total population of deliveries at term during 2 years. Four thousand eight hundred and thirty out of 14,687 term pregnancies were monitored using the STAN S 21 fetal heart monitor and the associated clinical guidelines. Cord artery metabolic acidosis, neonatal outcome, and rates of operative deliveries for fetal distress were assessed. RESULTS: The annual rate of STAN usage increased from 28.1% to 37.7% and was associated with a significant reduction in metabolic acidosis rate in the total population from 0.76% to 0.44% (P < .05). The compliance with the clinical guidelines increased in cases requiring intervention. The rates for moderate/severe hypoxic neonatal encephalopathy were consistently low, 0.55 and 0.68 per 1000 deliveries, respectively, and corresponding to previous findings. The rate of operative delivery did not change during the 2 years in the total population. CONCLUSION: Increasing STAN usage provided consistent improvements in fetal outcome equalling those noted in the Swedish randomized controlled trial (RCT) without increasing operative interventions for fetal distress.
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| 5. |
- Wennergren, Göran, 1947, et al.
(author)
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Neonatal breathing control mediated via the central chemoreceptors.
- 1983
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In: Acta physiologica Scandinavica. - : Wiley. - 0001-6772 .- 1365-201X. ; 119:2, s. 139-46
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Journal article (peer-reviewed)abstract
- Respiratory changes elicited via the central chemoreceptor system have been studied in anesthetized newborn guinea pigs and newborn rabbits. Periodic breathing was induced by inhibition of the central chemoreceptors by superfusion with alkaline cerebrospinal fluid. The periodic breathing was promptly reversed to steady by increasing the oxygen or carbon dioxide concentration in the inspired air or by intravenous theophylline. Elicitation of periodic breathing simply by exposing the animals to hypoxia succeeded only when very low oxygen concentrations were given. Clearcut respiratory excitation was produced by small amounts of theophylline applied onto the ventral surface of the medulla. Not only theophylline intravenously but also theophylline topically applied on the ventral medullary surface normalized spontaneously developed periodic breathing. Application of meperidine onto the ventral medullary surface gave respiratory inhibition with dosages considerably lower than required when given intravenously. The results emphasize the importance of an adequate respiratory drive from the central chemoreceptors for the maintenance of a regular breathing pattern. The findings support a view that at least part of the respiratory effects seen in the newborn following administration of meperidine or theophylline is due to effect of the drugs on the central chemosensitive system.
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| 6. |
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| 7. |
- Wennergren, Göran, 1947, et al.
(author)
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The importance of differentiation among small for gestational age infants
- 1995
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In: Impact of antenatal and postnatal environmental factors on infant outcome. Editor Paul Johnson.. - Oxford, UK : Maternal Infant Health Care Research Centre, Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital.
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Conference paper (peer-reviewed)
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| 8. |
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| 9. |
- Wennergren, Margareta, 1948, et al.
(author)
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Obstetric characteristics and neonatal performance in a four-year small for gestational age population.
- 1988
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In: Obstetrics and gynecology. - 0029-7844. ; 72:4, s. 615-20
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Journal article (peer-reviewed)abstract
- Obstetric and neonatal performance were analyzed in an ultrasound-dated small for gestational age (SGA) population from 1982-1985. Eighty-three percent of 160 SGA infants were identified antenatally by means of intrauterine growth retardation (IUGR) risk scoring, and the pregnancies were supervised at a high-risk clinic. Fifty percent were delivered electively, predominantly in gestational weeks 38-39. Thirty percent were born preterm. The cesarean section rate was 40%. Perinatal mortality was 6%, or 4% when lethal malformations were excluded, ten times higher than the corresponding total population figures. Eleven percent of the fetuses had severe malformations. In the remaining SGA population, one infant died after experiencing severe perinatal asphyxia and another developed cerebral palsy; no other major sequelae were found before the age of 18 months. Hypoglycemia and hypothermia occurred frequently, but these problems were managed satisfactorily. The mean hospital stay for term infants was twice that of appropriate for gestational age infants. We conclude that the extra attention paid to the SGA population is well motivated. Future efforts should be directed toward improving the diagnostic techniques for IUGR, as most of the perinatal mortality occurred among SGA infants not identified before birth.
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| 10. |
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| 11. |
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| 12. |
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| 13. |
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| 14. |
- Austeng, Dordi, et al.
(author)
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Incidence of and risk factors for neonatal morbidity after active perinatal care : extremely preterm infants study in Sweden (EXPRESS)
- 2010
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In: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 99:7, s. 978-992
-
Journal article (peer-reviewed)abstract
- Aims: The aim of this study was to determine the incidence of neonatal morbidity in extremely preterm infants and to identify associated risk factors. Methods: Population based study of infants born before 27 gestational weeks and admitted for neonatal intensive care in Sweden during 2004-2007. Results: Of 638 admitted infants, 141 died. Among these, life support was withdrawn in 55 infants because of anticipation of poor long-term outcome. Of 497 surviving infants, 10% developed severe intraventricular haemorrhage (IVH), 5.7% cystic periventricular leucomalacia (cPVL), 41% septicaemia and 5.8% necrotizing enterocolitis (NEC); 61% had patent ductus arteriosus (PDA) and 34% developed retinopathy of prematurity (ROP) stage >= 3. Eighty-five per cent needed mechanical ventilation and 25% developed severe bronchopulmonary dysplasia (BPD). Forty-seven per cent survived to one year of age without any severe IVH, cPVL, severe ROP, severe BPD or NEC. Tocolysis increased and prolonged mechanical ventilation decreased the chances of survival without these morbidities. Maternal smoking and higher gestational duration were associated with lower risk of severe ROP, whereas PDA and poor growth increased this risk. Conclusion: Half of the infants surviving extremely preterm birth suffered from severe neonatal morbidities. Studies on how to reduce these morbidities and on the long-term health of survivors are warranted.
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| 15. |
- Berg, Marie, 1955, et al.
(author)
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Early random capillary glucose level screening and multidisciplinary antenatal teamwork to improve outcome in gestational diabetes mellitus
- 2007
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In: Acta Obstet Gynecol Scand. ; 86:3, s. 283-90
-
Journal article (peer-reviewed)abstract
- BACKGROUND: This study describes maternal and neonatal characteristics and delivery outcome in women with gestational diabetes mellitus [GDM], compared to a control group. METHODS: A retrospective observational study of 719 women with GDM was undertaken in a Swedish urban district. All other parturients at the same hospital served as the control group. GDM was diagnosed using random capillary glucose levels at fixed intervals, beginning early in pregnancy. An oral glucose tolerance test was performed at glucose levels>or=7.0 mmol/l (127.8 mg/dl). Data was analysed according to glucose levels at diagnosis, ie, mild or severe GDM. RESULTS: GDM was diagnosed in 2.28% of the women who were older and had higher Body Mass Index [BMI]. A high proportion was of non-Nordic origin (44.5%); they had severe GDM more often (49.1%) than the Nordic group (33.1%). The GDM-mild group had less complications and abnormalities, compared to the GDM-severe group, although both groups differed from the control group in this respect. Delivery was spontaneous in 70.2% of GDM-mild, 65.7% of GDM-severe and 81.0% of the control group. LGA (+2 SD) was found in 4.8, 10.5 and 3.2%, respectively. CONCLUSION: Early non-fasting random universal screening and multidisciplinary antenatal teamwork intervention seems to be favourable, with low rates of excessive fetal growth, instrumental vaginal delivery and caesarean section.
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| 16. |
- Bertz, Fredrik, et al.
(author)
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Diet and exercise weight-loss trial in lactating overweight and obese women
- 2012
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In: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165. ; 96:4, s. 698-705
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Journal article (peer-reviewed)abstract
- Background: Current evidence suggests a combined treatment of postpartum weight loss of diet and exercise. However, to our knowledge, neither their separate and interactive effects nor long-term outcomes have been evaluated. Objective: We evaluated whether a 12-wk dietary behavior modification (D) treatment to decrease energy intake, physical exercise behavior modification (E) treatment to implement moderate aerobic exercise, or combined dietary and physical exercise behavior modification (DE) treatment compared with control (usual care) (C) reduces body weight in lactating women measured at the end of treatment and at a 1-y follow-up 9 mo after treatment termination. Design: At 10-14 wk postpartum, 68 lactating Swedish women with a prepregnancy BMI (in kg/m(2)) of 25-35 were randomly assigned to D, E, DE, or C groups. Measurements were made at baseline, after the intervention, and again at a 1-y follow-up 9 mo later. A 2 x 2 factorial approach was used to analyze main and interaction effects of treatments. Results: Weight changes after the intervention and 1-y follow-up were -8.3 +/- 4.2 and -10.2 +/- 5.7 kg, respectively, in the D group; -2.4 +/- 3.2 and -2.7 +/- 5.9 kg, respectively, in the E group; -6.9 +/- 3.0 and -7.3 +/- 6.3 kg, respectively, in the DE group; and -0.8 +/- 3.0 and -0.9 +/- 6.6 kg, respectively, in the C group. The main effects of D treatment, but not of E treatment, on weight were significant at both times (P < 0.001). Conclusions: Dietary treatment provided clinically relevant weight loss in lactating postpartum women, which was sustained at 9 mo after treatment. The combined treatment did not yield significant weight or body-composition changes beyond those of dietary treatment alone. This trial was registered at clinicaltrials.gov as NCT01343238. Am J Clin Nutr 2012;96:698-705.
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| 17. |
- Fellman, Vineta, et al.
(author)
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One-year survival of extremely preterm infants after active perinatal care in Sweden.
- 2009
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In: JAMA : the journal of the American Medical Association. - : American Medical Association (AMA). - 1538-3598 .- 0098-7484. ; 301:21, s. 2225-33
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Journal article (peer-reviewed)abstract
- Up-to-date information on infant survival after extremely preterm birth is needed for assessing perinatal care services, clinical guidelines, and parental counseling.
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| 18. |
- Jansson, Nina, 1976, et al.
(author)
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Maternal hormones linking maternal body mass index and dietary intake to birth weight.
- 2008
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In: American Journal of Clinical Nutrition. - Bethesda, USA : American Society for Nutrition. - 0002-9165 .- 1938-3207. ; 87:6, s. 1743-9
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Journal article (peer-reviewed)abstract
- BACKGROUND: Obese women often give birth to large-for-gestational age infants (typically defined as a birth weight greater than the 90th percentile), who are at risk of birth injuries and of developing metabolic syndrome later in life. The mechanisms underlying increased fetal growth remain to be established. OBJECTIVE: We aimed to identify maternal hormones that can explain the link between dietary intake, body mass index (BMI), and birth weight. DESIGN: Pregnant women with BMIs (in kg/m(2)) ranging from 17 to 44 (n = 49) were recruited in gestational weeks 8-12. Serum hormone concentrations were measured and dietary history interviews were performed in the first and third trimesters. Multiple regression models were produced to identify hormones that correlate with birth weight and are influenced by BMI or dietary factors. RESULTS: We found a strong positive correlation between BMI and first- and third-trimester insulin and leptin concentrations and a negative correlation between BMI and first-trimester adiponectin and first- and third-trimester insulin-like growth factor binding protein-1 (IGFBP-1). Maternal total fat intake in the first trimester was positively correlated with maternal leptin and inversely correlated with adiponectin. In addition, third-trimester total fat intake was positively correlated with circulating resistin concentrations. First-trimester maternal serum resistin was positively correlated with birth weight, whereas third-trimester maternal IGFBP-1 was negatively correlated with birth weight. CONCLUSIONS: High first-trimester maternal serum resistin and low third-trimester IGFBP-1 were correlated with increased birth weight. We propose that low serum concentrations of IGFBP-1 represent a link between high BMI and increased fetal growth by increasing the bioavailability of insulin-like growth factor-I, which up-regulates placental nutrient transport.
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| 19. |
- Lager, Susanne, 1978, et al.
(author)
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Effect of IL-6 and TNF-α on fatty acid uptake in cultured human primary trophoblast cells.
- 2011
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In: Placenta. - : Elsevier BV. - 1532-3102 .- 0143-4004. ; 32:2, s. 121-7
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Journal article (peer-reviewed)abstract
- Maternal obesity and gestational diabetes (GDM) are conditions associated with fetal overgrowth and excessive fat accumulation in the fetus, implicating an increased placental nutrient transfer in these pregnancies. Obese and GDM mothers have altered metabolism and hormone levels, including elevation of maternal circulatory lipids and pro-inflammatory cytokines. We tested the hypothesis that interleukin (IL)-6 and tumor necrosis factor (TNF)-α stimulate placental fatty acid transport, as these pro-inflammatory cytokines have been shown to affect lipid metabolism in other tissues. In cultured primary human trophoblast cells IL-6, but not TNF-α, stimulated fatty acid accumulation, as measured by BODIPY fluorescence. The increased fatty acid accumulation could not be explained by an increased expression of key components in placental fatty acid transport, such as adipophilin, fatty acid transport protein (FATP)1, FATP4, or lipoprotein lipase. In a cohort of lean and overweight/obese pregnant women, increasing maternal third trimester IL-6 plasma concentrations correlated with decreasing placental lipoprotein lipase activity. However, as no effect on lipoprotein lipase activity was observed in cultured trophoblast cells after exposure to either IL-6 or TNF-α, the correlation between maternal circulatory IL-6 levels and placental lipoprotein lipase activity at term is unlikely to represent a cause-and-effect relationship. In conclusion, high levels of IL-6 stimulate trophoblast fatty acid accumulation, which could contribute to an excessive nutrient transfer in conditions associated with elevated maternal IL-6 such as obesity and gestational diabetes.
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| 20. |
- Magnusson, AnneLiese, et al.
(author)
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Glucose metabolism in the human preterm and term placenta tusof IUGR fees
- 2004
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In: Placenta. ; 25:4, s. 337-46
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Journal article (peer-reviewed)abstract
- Many fetuses suffering from intrauterine growth restriction (IUGR) are hypoglycaemic. However, the underlying mechanisms are not well established. An increased placental glucose consumption in IUGR could impair glucose transfer across the placenta. In this study we used two different approaches to investigate glucose metabolism in preterm and term placentae of IUGR fetuses. We determined activity and protein expression of the three rate-limiting glycolytic enzymes phosphofructo kinase (PFK), pyruvate kinase (PK) and hexokinase (HXK) in a cytoplasmic fraction of homogenates of placentae obtained from IUGR and appropriate for gestational age (AGA) pregnancies. Protein expression was assessed using Western blot and enzyme activities were determined in a spectrophotometer by measuring the rate of NADH oxidation (PFK and PK) or NADP reduction (HXK) in enzyme reactions coupled to the respective enzyme. To determine the distribution of the glycolytic enzymes immunocytochemistry was performed. We also measured glucose consumption and lactate production in fresh placental villous tissue using a perifusion system. The expression of PFK, PK and HXK as well as the activity of PK and HXK was unaltered in IUGR placentae. The activity of PFK on the other hand was 32 per cent lower in IUGR placentae (n=24, P<0.05). Immunocytochemistry confirmed the distribution of the enzymes to the cytoplasm of the syncytiotrophoblast. Placental glucose consumption in IUGR [0.06+/-0.01 micromol/(min*g), n=5] was not different from AGA [0.06+/-0.005 micromol/(min*g), n=12], whereas lactate production was decreased by 28 per cent in IUGR. These results do not support the hypothesis of increased placental glucose consumption but suggest an altered glycolytic pathway in the IUGR placenta.
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| 21. |
- Magnusson, AnneLiese, et al.
(author)
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Triglyceride hydrolase activities and expression of fatty acid binding proteins in the human placenta in pregnancies complicated by intrauterine growth restriction and diabetes
- 2004
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In: J Clin Endocrinol Metab. ; 89:9, s. 4607-14
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Journal article (peer-reviewed)abstract
- Triglyceride (TG) hydrolases in the placental microvillous plasma membrane (MVM) release fatty acids from circulating lipoproteins and represent the critical initial step in transplacental fatty acid transfer. We investigated the activity of two TG hydrolases in MVM isolated from placentas of appropriately grown for gestational age pregnancies and pregnancies complicated by intrauterine growth restriction (IUGR), insulin-dependent diabetes mellitus (IDDM) or gestational diabetes mellitus (GDM). In addition, we measured protein expression of lipoprotein lipase (LPL) in MVM and two fatty acid binding proteins (L- and C-FABP) in placental homogenates. The TG hydrolase activities were assessed by measuring hydrolysis of (3)H-trioleic acid incorporated into intralipid micelles after incubation with MVM. The placenta-specific TG hydrolase activity (optimum at pH 6) did not differ in the patient groups studied. MVM LPL activity (optimum at pH 8) was reduced by 47% in preterm IUGR (n = 8, P < 0.05), compared with gestational age-matched controls. The LPL activity in placentas of IDDM pregnancies was increased by 39% (n = 8, P < 0.05), compared with controls. No significant differences were observed in cases of GDM. We found no alteration in protein expression of LPL or C-FABP. The expression of L-FABP was increased by 112% (n = 8, P < 0.05) in IDDM and 64% (n = 8, P < 0.05) in GDM. These results indicate that alterations in MVM LPL activity and expression of L-FABP may contribute to the altered lipid deposition and metabolism in IUGR and diabetic pregnancies.
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| 22. |
- Magnusson-Olsson, AnneLiese, et al.
(author)
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Gestational and hormonal regulation of human placental lipoprotein lipase
- 2006
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In: J Lipid Res. ; 47:11, s. 2551-61
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Journal article (peer-reviewed)abstract
- The fetal demand for FFA increases as gestation proceeds, and LPL represents one potential mechanism for increasing placental lipid transport. We examined LPL activity and protein expression in first trimester and term human placenta. The LPL activity was 3-fold higher in term (n = 7; P < 0.05) compared with first trimester (n = 6) placentas. The LPL expression appeared lower in microvillous membrane from first trimester (n = 2) compared with term (n = 2) placentas. We incubated isolated placental villous fragments with a variety of effectors [GW 1929, estradiol, insulin, cortisol, epinephrine, insulin-like growth factor-1 (IGF-1), and tumor necrosis factor-alpha] for 1, 3, and 24 h to investigate potential regulatory mechanisms. Decreased LPL activity was observed after 24 h of incubation with estradiol (1 micro g/ml), insulin, cortisol, and IGF-1 (n = 12; P < 0.05). We observed an increase in LPL activity after 3 h of incubation with estradiol (20 ng/ml) or hyperglycemic medium plus insulin (n = 7; P < 0.05). To conclude, we suggest that the gestational increase in placental LPL activity represents an important mechanism to enhance placental FFA transport in late pregnancy. Hormonal regulation of placental LPL activity by insulin, cortisol, IGF-1, and estradiol may be involved in gestational changes and in alterations in LPL activity in pregnancies complicated by altered fetal growth.
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| 23. |
- Roos, Sara, 1979, et al.
(author)
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Regulation of amino acid transporters by glucose and growth factors in cultured primary trophoblast cells is mediated by mTOR signaling
- 2009
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In: American Journal of Physiology - Cell Physiology. - : American Physiological Society. - 0363-6143 .- 1522-1563. ; 298, s. C723-C731
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Journal article (peer-reviewed)abstract
- Inhibition of mammalian target of rapamycin (mTOR) signaling in cultured human primary trophoblast cells reduces the activity of key placental amino acid transporters. However, the upstream regulators of placental mTOR are unknown. We hypothesized that glucose, insulin, and IGF-I regulate placental amino acid transporters by inducing changes in mTOR signaling. Primary human trophoblast cells were cultured for 24 h with media containing various glucose concentrations, insulin, or IGF-I, with or without the mTOR inhibitor rapamycin, and, subsequently, the activity of system A, system L, and taurine (TAUT) transporters was measured. Glucose deprivation (0.5 mM glucose) did not significantly affect Thr172-AMP-activated protein kinase phosphorylation or REDD1 expression but decreased S6 kinase 1 phosphorylation at Thr389. The activity of system L decreased in a dose-dependent manner in response to decreasing glucose concentrations. This effect was abolished in the presence of rapamycin. Glucose deprivation had two opposing effects on system A activity: 1) an “adaptive” upregulation mediated by an mTOR-independent mechanism and 2) downregulation by an mTOR-dependent mechanism. TAUT activity was increased after incubating cells with glucose-deprived media, and this effect was largely independent of mTOR signaling. Insulin and IGF-I increased system A activity and insulin stimulated system L activity, effects that were abolished by rapamycin. We conclude that the mTOR pathway represents an important intracellular regulatory link between nutrient and growth factor concentrations and amino acid transport in the human placenta.intrauterine growth restriction (IUGR) and accelerated fetal growth represent two important clinical conditions that occur in 15% of all pregnancies (1, 2). Aberrant fetal growth is associated with an increased risk of perinatal morbidity (7) as well as metabolic abnormalities in adult life, such as obesity, type 2 diabetes, and cardiovascular disease (6, 12, 46). The most important determinant of fetal growth is nutrient availability, which is highly dependent on placental transport capacity. The mechanisms underlying altered fetal growth remain to be established, but accumulating evidence implicates changes in the activity of specific placental amino acid transporters as a critical factor contributing to abnormal fetal growth (27, 54). Experimental evidence supports the hypothesis that changes in placental nutrient transporter activity are a cause of rather than a response to altered fetal growth. For example, in pregnant rats subjected to protein malnutrition, it is likely that downregulation of the placental system A amino acid transporter directly contributes to the development of IUGR (26).In IUGR, fetuses may be hypoglycemic (15) and have reduced circulating levels of insulin (43) and IGF-I (4, 34). The maternal levels of glucose (15) and IGF-I (40, 41) may also be reduced in this condition. The placenta of the IUGR fetus could therefore be exposed to decreased levels of glucose, hormones, and growth factors. Both insulin and IGF-I stimulate placental system A activity (24, 30, 31). These results suggest that extracellular cues regulate placental nutrient transporters and, as a consequence, fetal nutrient supply, but the cellular mechanisms remain to be fully established.The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that is regulated by a multitude of intracellular and extracellular signals. For example, mTOR is activated by growth factors and nutrient levels, such as amino acids (59), and inhibited by numerous stress conditions, such as cellular energy depletion (13, 17). Glucose may also regulate mTOR signaling through energy production in the form of ATP (13, 17). The AMP-activated protein kinase (AMPK) is regulated by the AMP-to-ATP ratio, which rises under nutrient deprivation and activates AMPK (10). Activated AMPK can in turn phosphorylate tuberous sclerosis complex 2 (TSC2), leading to mTOR inactivation (23). AMPK is phosphorylated and activated by LKB1 (52), and it has been shown that phosphorylation of LKB1 at Ser428 is essential for AMPK activation by metformin, and the authors speculate that LKB1-Ser428 phosphorylation may be a common pathway required for AMPK activation (60). There might also be additional, AMPK-independent, pathways involved in energy depletion. A recent report has shown that REDD1 (regulated in development and DNA damage responses 1) in mouse embryonic fibroblasts is induced by chronic energy depletion, and this in turn leads to inactivation of mTOR complex 1 (mTORC1) measured as phosphorylation of S6 kinase 1 (S6K1) at Thr389, independent of AMPK (55).Insulin and IGF-I activate the tyrosine kinase activity of its receptors to phosphorylate the insulin receptor substrate 1, which in turn activates phosphatidylinositol 3-kinase (PI3K) to generate PI(3,4,5)P3. Phosphatidylinositol 3,4,5-trisphosphate (PIP3) binding to Akt leads to the translocation of Akt to the plasma membrane, where it is phosphorylated and activated. The activation of Akt positively modulates mTORC1 function, by phosphorylating, and inhibiting, TSC2 (reviewed in Ref. 59).We have previously shown that inhibition of mTOR reduces the activity of placental system L, system A, and the taurine transporter (TAUT) (50). Since the activity of these amino acid transporter systems is downregulated in the placenta in association to IUGR (14, 19, 28, 37, 45) and placental mTOR activity has been reported to be decreased in IUGR (49, 62), it is possible that mTOR signaling plays an important role in regulating placental amino acid transporters in vivo. However, the upstream regulators of placental mTOR are unknown. We hypothesized that glucose, insulin, and IGF-I regulate placental amino acid transporter activity by inducing changes in mTOR signaling. To test this hypothesis, human primary trophoblast cells were incubated with media containing various concentrations of glucose, insulin, or IGF-I in the presence or absence of the specific mTOR inhibitor rapamycin. Subsequently, the activity of system L, system A, and the taurine transporter was measured. To investigate whether the AMPK pathway and/or REDD1 is activated in glucose-deprived primary trophoblasts, the protein expression of phosphorylated (P)-Thr172-AMPKα, total AMPK, P-Ser428-LKB1, and REDD1 in control and glucose-deprived cells was also studied.
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| 24. |
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| 25. |
- Söderberg, Margareta, 1948, et al.
(author)
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Astmabehandling
- 1999
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In: Allergi och annan överkänslighet i praktisk sjukvård, Andra upplagan. - Lund : Studentlitteratur. - 9144009100 ; , s. 181-218
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Book chapter (other academic/artistic)
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