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  • 1.
    Allbrand, Marianne
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Obstetrics and Gynaecology.
    Eklund, Daniel
    Örebro University, School of Medical Sciences.
    Cao, Yang
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Nilsson, Kerstin
    Örebro University, School of Medical Sciences.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Paediatrics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; University Health Care Research Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Gene expression of leptin, leptin receptor isoforms and inflammatory cytokines in placentas of obese women: Associations to birth weight and fetal sex2022In: Placenta, ISSN 0143-4004, E-ISSN 1532-3102, Vol. 117, p. 64-71Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Leptin signaling in placentas of obese women may influence fetal growth and may be dependent on fetal sex. The aim of this study was to investigate placental gene expression of leptin, its receptor and inflammatory cytokines in obese mothers in relation to offspring birth weight and sex.

    METHODS: In total, 109 placental tissue samples from severely obese women (body mass index in first trimester ≥35 kg/m2) giving birth vaginally at term to a healthy child were included. Quantitative real-time PCR was used for the analysis of leptin (LEP), its receptor LEPR with two splice variants, interleukin (IL)1B, chemokine (C-X-C motif) ligand 8 (CXCL8), tumour necrosis factor (TNF), IL6, IL10, hypoxia-inducible factor 1-alpha (HIF1A) and insulin receptor (INSR). The subjects were divided into three groups based on LEP expression percentiles (<25th percentile; 25-75th percentile and >75th percentile).

    RESULTS: A reverse U-shaped association between LEP expression and birth weight z-scores was found (R2 = 0.075, p = 0.005). Placental LEPRb expression was downregulated (p = 0.034) in those with highest LEP expression. Female infants had higher birth weight z-scores than males (0.58 (-1.49-2.88) vs 0.21 (-1.50-2.93), p = 0.020) and their placental LEPRb expression was upregulated (p = 0.047). The associations between expression of different genes differed by sex.

    DISCUSSION: A reverse U-shaped relationship between placental LEP expression and offspring birth weight z-scores was found together with sexual dimorphism in LEPRb expression indicating a complex regulation of fetal growth by placental leptin signaling in maternal obesity.

  • 2.
    Allbrand, Marianne
    et al.
    Örebro University, School of Medical Sciences.
    Eklund, Daniel
    Örebro University, School of Medical Sciences.
    Cao, Yang
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Åman, Jan
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Nilsson, Kerstin
    Örebro University, School of Medical Sciences.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Gene expression of leptin, leptin receptor isoforms, and inflammatory cytokines in placentas of obese women: associations to birth weight and foetal sexManuscript (preprint) (Other academic)
  • 3.
    Allbrand, Marianne
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Åman, Jan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences.
    Adipocytokines in placenta and cord blood in relation to maternal obesity, and foetal and postnatal growth of the child2015In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 82, no Suppl. 1, p. 47-48Article in journal (Other academic)
    Abstract [en]

    Background: The nutritional and hormonal state in utero may be a link between maternal obesity and obesity in the offspring. The gene expression in placentae in pregnancies complicated by diabetes is reduced for leptin, but increased for ghrelin. It is not known whether these genes’ expressions in placentae are altered in maternal obesity.

    Objectives and hypotheses: To compare obese and normal-weight women and their children concerning gene expressions of leptin and ghrelin in placentae; leptin, ghrelin, adiponectin, and C-peptide levels in cord blood, birth size and postnatal growth. Changes in the expression of these adipocytokines may lead to an altered hypothalamic sensitivity to leptin and ghrelin resulting in an increased risk of obesity in the offspring.

    Method: 32 women with pre-pregnancy obesity, but otherwise healthy, were compared to 32 matched, normal-weight controls. Full-term placenta biopsies were analysed with qPCR for leptin mRNA and ghrelin mRNA. Cord blood samples were examined with ELISA for leptin, ghrelin, adiponectin, and C-peptide concentrations. Birth size and postnatal growth of the children were collected from clinical registers at the Child Health Care Units.

    Results: The leptin and ghrelin gene expressions in placentae did not differ between obese and normal-weight women. The leptin concentration in cord blood was higher in children of obese mothers (P=0.021). It correlated with birth weight Z-score (r=0.467, P<0.001) and C-peptide level in cord blood (r=0.446, P<0.001). Children of obese women were slightly heavier at birth, but postnatal growth did not differ between groups. Children with birth weight  ≤−0.67 Z-score had higher ghrelin levels in cord blood than heavier children (P=0.042). The leptin level in cord blood correlated negatively with weight gain at 6 months (r=−0.332, P=0.009). The ghrelin level in cord blood correlated with weight gain at 3 months in girls (r=0.611, P=0.001), but not in boys. The adiponectin level in cord blood correlated negatively with length gain at 3 years in the obese group (r=−0.571, P=0.033), but not in the normal-weight group.

    Conclusion: Leptin and ghrelin placental gene expressions are not altered in obese women, but foetal adipocytokine production may influence early postnatal growth, possibly by influencing hunger signalling or insulin levels

  • 4.
    Allbrand, Marianne
    et al.
    Örebro University, School of Medical Sciences. Department of Obstetrics and Gynecology.
    Åman, Jan
    Department of Paediatrics, Örebro University Hospital, Örebro, Sweden.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Health Care Research Center, Region Örebro County, Örebro, Sweden; Department of Paediatrics, Örebro University Hospital, Örebro, Sweden.
    Placental ghrelin and leptin expression and cord blood ghrelin, adiponectin, leptin, and C-peptide levels in severe maternal obesity2017In: The Journal of Maternal-Fetal & Neonatal Medicine, ISSN 1476-7058, E-ISSN 1476-4954, Vol. 31, no 21, p. 2839-2846Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The purpose of this study is to investigate placental ghrelin and leptin expression as well as cord blood ghrelin and adiponectin levels in maternal obesity and associations between placental ghrelin expression, cord blood ghrelin levels and maternal and infant variables.

    MATERIALS AND METHODS: Placental ghrelin and leptin expression were analyzed by RT-PCR in 32 severely obese and 32 matched normal-weight women. Cord blood ghrelin, adiponectin, leptin, and C-peptide concentrations were analyzed by ELISA.

    RESULTS: Neither ghrelin nor leptin expression and neither cord blood ghrelin nor adiponectin levels differed between the groups. Placental ghrelin expression was associated with BMI at delivery in the obese women (r = 0.424, p = .016) and in the infants born to normal-weight women with their weight z-scores at six (r = -0.642, p = .010), nine (r = -0.441, p = .015), and 12 months of age (r = -0.402, p = .028).

    CONCLUSIONS: Placental ghrelin and leptin expression as well as cord blood ghrelin and adiponectin levels do not seem to be altered in severe maternal obesity. Placenta-derived ghrelin may influence the infants' postnatal weight gain, but possibly only when the mother has normal weight.

  • 5.
    Allbrand, Marianne
    et al.
    Örebro University, School of Medical Sciences. Department of Obstetrics and Gynecology.
    Åman, Jan
    Department of Pediatrics, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Nilsson, Kerstin
    Örebro University, School of Medical Sciences. Department of Obstetrics and Gynecology.
    Cao, Yang
    Örebro University, School of Medical Sciences. Örebro University Hospital. Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Department of Pediatrics, School of Medical Sciences, Örebro University, Örebro, Sweden; University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Expression of genes involved in inflammation and growth: does sampling site in human full-term placenta matter?2019In: Journal of Perinatal Medicine, ISSN 0300-5577, E-ISSN 1619-3997, Vol. 47, no 5, p. 539-546Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate the placental gene expression of substances in the inflammatory cascade and growth factors at nine different well-defined sampling sites in full-term placentas from 12 normal weight healthy non-smoking women with an uncomplicated singleton pregnancy.

    Methods: All placentas (six girls and six boys) were delivered vaginally. Quantitative real-time polymerase chain reaction was used to analyze toll receptor-2 and -4, interleukin-6 and -8, tumor necrosis factor-α, leptin, ghrelin, insulin-like growth factor-1 and -2, hepatocyte growth factor, hepatocyte growth factor receptor and insulin receptor (IR).

    Results: The leptin gene and the IR gene showed higher expression in lateral regions near the chorionic plate compared to central regions near the basal plate (P = 0.028 and P = 0.041, respectively).

    Conclusion: Our results suggest that the sampling site may influence the gene expression for leptin and IR in placental tissue obtained from full-term normal pregnancies. We speculate that this may be due to differences in placental structure and perfusion and may be important when future studies are designed.

  • 6.
    Chelslín, Felix
    et al.
    Örebro University, School of Medical Sciences.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
    Östling, Hanna
    Örebro University, School of Medical Sciences. Department of Women's Health.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Paediatrics.
    Differential microRNA expression in placentas of small-for-gestational age neonates with and without exposure to poor maternal gestational weight gain2021In: Journal of Perinatal Medicine, ISSN 0300-5577, E-ISSN 1619-3997, Vol. 49, no 5, p. 632-635Article in journal (Refereed)
  • 7.
    Chelslín, Felix
    et al.
    Örebro University, School of Medical Sciences. University Health Care Research Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. University Health Care Research Centre.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Inflammatory Response and Infection Susceptibility Centre (iRiSC) and X-HiDE Consortium, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Smoking during pregnancy is associated with the placental proteome2023In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 119, article id 108409Article in journal (Refereed)
    Abstract [en]

    Maternal smoking during pregnancy (MSDP) is a significant risk factor for the development of foetal, neonatal, and childhood morbidities. We hypothesized that infants exposed to MSDP have a distinct proteomic expression in their term placentas compared to infants without such an exposure. A total of 39 infants exposed (cord blood cotinine levels of >1ng/ml) and 44 infants not exposed to MSDP were included in the study. Women with chronic disease, body mass index of >30, or a history of uterine surgery were excluded. Total proteome abundance was analysed with quantitative mass spectrometry. For univariate analysis of differences in placental protein levels between groups, ANOVA with multiple testing corrections by the Benjamini-Hochberg method was used. For multivariate analysis, we used principal component analysis, partial least squares, lasso, random forest, and neural networks. The univariate analyses showed four differentially abundant proteins (PXDN, CYP1A1, GPR183, and KRT81) when heavy and moderate smoking groups were compared to non-smokers. With the help of machine learning, we found that an additional six proteins (SEPTIN3, CRAT, NAAA, CD248, CADM3, and ZNF648) were discriminants of MSDP. The placental abundance of these ten proteins together explained 74.1% of the variation in cord blood cotinine levels (p = 0.002). Infants exposed to MSDP showed differential abundance of proteins in term placentas. We report differential placental abundance of several proteins for the first time in the setting of MSDP. We believe that these findings supplement the current understanding of how MSDP affects the placental proteome.

  • 8. Hoermann, Henrike
    et al.
    El-Rifai, Omar
    Schebek, Martin
    Lodefalk, Maria
    Örebro University, School of Medical Sciences.
    Brusgaard, Klaus
    Bachmann, Nadine
    Bergmann, Carsten
    Mayatepek, Ertan
    Christesen, Henrik
    Meissner, Thomas
    Kummer, Sebastian
    Characteristics of children with Kabuki syndrome and hyperinsulinemic hypoglycemia2019Conference paper (Other academic)
  • 9.
    Hoermann, Henrike
    et al.
    Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Düsseldorf, Medical Faculty, Düsseldorf, Germany.
    El-Rifai, Omar
    Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark. 3 Institute of Clinical Research, University of Southern Denmark Odense, Odense, Denmark.
    Schebek, Martin
    Department of Pediatric Diabetes, Children's Hospital Kassel, Kassel, Germany.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Pediatrics.
    Brusgaard, Klaus
    Institute of Clinical Research, University of Southern Denmark Odense, Odense, Denmark; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
    Bachmann, Nadine
    Center for Human Genetics, Bioscientia, Ingelheim, Germany; Medizinische Genetik Mainz, Limbach Genetics, Mainz, Germany.
    Bergmann, Carsten
    Center for Human Genetics, Bioscientia, Ingelheim, Germany; Medizinische Genetik Mainz, Limbach Genetics, Mainz, Germany.
    Roeper, Marcia
    Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Düsseldorf, Medical Faculty, Düsseldorf, Germany.
    Welters, Alena
    Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Düsseldorf, Medical Faculty, Düsseldorf, Germany.
    Salimi Dafsari, Roschan
    Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Düsseldorf, Medical Faculty, Düsseldorf, Germany.
    Blankenstein, Oliver
    Centre for Chronic Sick Children and Institute for Experimental Pediatric Endocrinology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
    Mayatepek, Ertan
    Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Düsseldorf, Medical Faculty, Düsseldorf, Germany.
    Christesen, Henrik
    Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark; Institute of Clinical Research, University of Southern Denmark Odense, Odense, Denmark; Odense Pancreas Centre OPAC, Odense University Hospital, Odense, Denmark.
    Meissner, Thomas
    Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Düsseldorf, Medical Faculty, Düsseldorf, Germany.
    Kummer, Sebastian
    Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Düsseldorf, Medical Faculty, Düsseldorf, Germany.
    Comparative meta-analysis of Kabuki syndrome with and without hyperinsulinemic hypoglycemia2020In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 93, no 3, p. 346-354Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVE: Kabuki syndrome (KS), caused by pathogenic variants in KMT2D or KDM6A, is associated with hyperinsulinemic hypoglycemia (HH) in 0.3-4% of patients. We characterized the clinical, biochemical and molecular data of children with KS and HH compared to children with KS without HH in a multicenter meta-analysis.

    METHODS: Data of seven new and 17 already published children with KS and HH were compared to 373 recently published KS patients without HH regarding molecular and clinical characteristics.

    RESULTS: Seven new patients were identified with seven different pathogenic variants in KDM6A (n=4) or KMT2D (n=3). All presented with HH on the first day of life and were responsive to diazoxide. KS was diagnosed between 9 months and 14 years of age. In the meta-analysis 24 KS patients with HH had a significantly higher frequency of variants in KDM6A compared to 373 KS patients without HH (50% vs. 11.5%, p<0.001), and KDM6A-KS was more likely to be associated with HH than KMT2D-KS (21.8% vs. 3.5%, p<0.001). Sex distribution and other phenotypic features did not differ between KS with and without HH.

    CONCLUSION: The higher incidence of HH in KDM6A-KS compared to KMT2D-KS indicates that KDM6A loss of function variants predispose more specifically to beta cell dysfunction compared to KMT2D variants. As difficulties to assign syndromic characteristics to KS in early infancy often lead to delayed diagnosis, genetic testing for KS should be considered in children with HH, especially in the presence of other extrapancreatic/syndromic features.

  • 10.
    Kiss, Eszter
    et al.
    Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.
    Wessmann, Sandra
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Department of Pathology and Cancer diagnostics, Karolinska University Hospital, Stockholm, Sweden.
    Carlson, Joseph W.
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA.
    Lundberg, Elena
    Institute of Clinical Science/Pediatrics, Umeå University, Umeå, Sweden.
    Stenmarker, Margaretha
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Futurum/Department of Paediatrics, Region Jönköping County, Jönköping, Sweden; Department of Paediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Bobeck, Johan
    Departement of Pediatrics, Region Kalmar, Kalmar, Sweden.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Pediatrics; University Health Care Research Center.
    Granulosa cell tumors in girls: Preliminary results of a meta-analysis of new and published cases2023In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 96, no Suppl. 4, p. 126-127, article id T6Article in journal (Other academic)
    Abstract [en]

    Background: Granulosa cell tumors (GCT) originate from sex cord/stromal tissue in the gonad. They are typically located in an ovary, but extra-gonadal localisation exists. These tumors are extremely rare in children and no systematic review has been published. The objective of this systematic review is to examine the following questions: What is the clinical picture of girls with a GCT? How are these patients treated and what is their prognosis?

    Methods: To be included in the review, the article had to present a new case with GCT fulfilling the following criteria: female human fetus or a girl aged < 19 years with clinical information included a tumor containing granulosa cells.

    The databases MEDLINE, Embase, Web of Science, and CINAHL were searched in November 2021. To find new cases, we asked pediatric endocrinologists in Sweden to report patients after informed consent had been secured. We also collected data from a Swedish paediatric reference pathology laboratory.

    Results: The search identified 1,894 published references of which 35 were duplicates. We have screened 1,859 abstracts. We are in the process of reading 824 selected articles in full text to check for eligibility. Individual participant data has been extractedfrom 20 of the published reports for preliminary results. Nineteen new Swedish cases with a GCT were identified.

    The preliminary analysis of 39 patients’ data shows an average age of 7.3 years at the time of diagnosis (range: antenatal diagnosis up to 18 years of age). Symptoms at presentation were: prepubertal breast enlargement, vaginal discharge/bleeding, abdominal distension or pain, pubic hair growth, fever, constipation, swelling of vulva or cliteromegaly, hyperpigmentation of the skin, primary/secondary amenorrhea, headache, hirsutism and advanced linear growth.

    The histopathological diagnosis was juvenile GCT in 76.9%, adult GCT in 12.8%, a mixed type of juvenile and adult GCT in 7.7% and another type of tumor containing granulosa cell component in 2.6% of the cases.

    All patients received surgical treatment except one with a post-mortem GCT diagnoses. Adjuvant chemotherapy was administered in two cases.

    Three patients (7.7%) died, two of them due to late discovery of the primary tumor and one secondary to local recurrence of the tumor with metastases 4 years after the primary diagnosis.

    Conclusion: GCT can present in all pediatric ages and often, but far from always, with endocrine symptoms such as peripheral precautious puberty. Data from this systematic review will hopefully promote early recognition of this malignant disease.

  • 11.
    Lennartsson, Olle
    et al.
    School of medical Sciences, Örebro University, Örebro, Sweden.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Department of Paediatrics, Örebro University Hospital, Örebro, Sweden; Division of Paediatric Endocrinology, Dep. of Women’s and Children’s health, Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Paediatrics, Örebro University Hospital, Örebro, Sweden; University Health Care Research Centre, Örebro, Sweden.
    Sex steroid priming decreases the frequency of divergent results between spontaneous and stimulated GH tests2023In: ESPE Abstracts, Bioscentifica , 2023, Vol. 97, article id P1-295Conference paper (Other academic)
  • 12.
    Lennartsson, Otto
    et al.
    Universitetssjukhuset Örebro, Örebro, Sverige.
    Lodefalk, Maria
    Universitetssjukhuset Örebro, Örebro, Sverige.
    Stor diskrepans mellan olika test vid utredning av kortvuxna barn2021In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 8Article in journal (Refereed)
  • 13.
    Lennartsson, Otto
    et al.
    Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; Department of Medical Sciences, Örebro University, Örebro, Sweden.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.
    Wehtje, Henrik
    Department of Orthopedic Surgery, Astrid Lindgrens Children's Hospital, Stockholm, Sweden; Karolinska University Hospital, Stockholm, Sweden; Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Stattin, Eva-Lena
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Sävendahl, Lars
    Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Case Report: Bilateral Epiphysiodesis Due to Extreme Tall Stature in a Girl With a De Novo DNMT3A Variant Associated With Tatton-Brown-Rahman Syndrome2021In: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 12, article id 752756Article in journal (Refereed)
    Abstract [en]

    Objective: To present a rare clinical case of a patient with Tatton-Brown-Rahman syndrome and the outcome of tall stature management with bilateral epiphysiodesis surgery at the distal femur and proximal ends of tibia and fibula.

    Study Design: Clinical case report.

    Results: This is a 20-year-old female with a history of proportional tall stature, developmental psychomotor and language delay with autism spectrum behavior and distinctive facial features. At 12 years and 2 months of age she was in early puberty and 172.5 cm tall (+ 2.8 SDS) and growing approximately 2 SDS above midparental target height of 173 cm (+ 0.9 SDS). A bone age assessment predicted an adult height of 187.1 cm (+3.4 SDS). To prevent extreme tall stature, bilateral epiphysiodesis surgery was performed at the distal femur and proximal ends of tibia and fibula at the age of 12 years and 9 months. After the surgery her height increased by 12.6 cm to 187.4 cm of which approximately 10.9 cm occurred in the spine whereas leg length increased by only 1.7 cm resulting in a modest increase of sitting height index from 50% (-1 SDS) to 53% (+ 0.5 SDS). Genetic evaluation for tall stature and intellectual disability identified a de novo nonsense variant in the DNMT3A gene previously associated with Tatton-Brown-Rahman syndrome.

    Conclusion: Tatton-Brown-Rahman syndrome should be considered in children with extreme tall stature and intellectual disability. Percutaneous epiphysiodesis surgery to mitigate extreme tall stature may be considered.

  • 14.
    Lennartsson, Otto
    et al.
    Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Department of Pediatrics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Division of Pediatric Endocrinology and Center for Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Pediatrics.
    Discordance Between Stimulated and Spontaneous Growth Hormone Levels in Short Children Is Dependent on Cut-Off Level and Partly Explained by Refractoriness2020In: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 11, article id 584906Article in journal (Refereed)
    Abstract [en]

    Background: A growth hormone (GH) stimulation test is the recommended method for evaluating GH levels in children with possible GH deficiency (GHD). However, serial measurements of nocturnal spontaneous GH secretion are also performed. Divergent results from these tests have been reported, but with variable frequencies.

    Objectives: To investigate whether performing one or two GH tests is associated with the probability to diagnose a child with GHD; the frequency of divergent results in the arginine-insulin tolerance test (AITT) and the nocturnal spontaneous test using different cut-off levels, and whether refractoriness may explain some of the discordance.

    Methods: In a population-based setting, the medical records of all short children evaluated for possible GHD during January 1993-February 2017 were reviewed. Twenty-one patients had been evaluated with one GH test only and 102 children had been evaluated with a spontaneous nocturnal GH test followed immediately by a complete AITT. Divergent results were defined as having a pathological response on only one of the tests when using 3, 5, 7, and 10 µg/L as cut-offs for peak GH on both tests, 1.1 and 3.3 µg/L for mean nocturnal values and receiver operating characteristic curves-derived cut-offs for nocturnal values.

    Results: Children evaluated with one test only were more often diagnosed with GHD compared with children evaluated with both tests (48 vs. 19%, p = 0.019). Divergent results were found in 6-42% of the patients, with higher frequencies seen when higher cut-offs were applied. A higher proportion of patients with stimulated peak values ≤ 7 and ≤ 5 µg/L had a spontaneous peak within 2 h before the start of the AITT compared with patients with higher stimulated peak values (68 vs. 45%, p = 0.026, and 77 vs. 48%, p = 0.033, respectively).

    Conclusions: Divergent results between AITT and nocturnal spontaneous secretion are common in short children, dependent on the cut-offs applied and partly due to refractoriness. Performing both tests decreases the risk of over diagnosing GHD in short children.

  • 15.
    Lennartsson, Otto
    et al.
    Örebro University, School of Medical Sciences.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Department of Paediatrics, Örebro University Hospital, Örebro, Sweden; Division of Paediatric Endocrinology, Dep. of Women’s and Children’s health, Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Paediatrics; University Health Care Research Centre.
    Sex steroid priming decreases the frequency of divergent results between spontaneous and stimulated GH tests2023In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 96, no Suppl. 4, p. 287-287, article id P1-295Article in journal (Other academic)
    Abstract [en]

    Introduction: The diagnosis of growth hormone (GH) deficiency (GHD) is complicated by the low specificity of GH testing, especially in children before and during early pubertal stages. Sex steroid priming reduces false positive results in pre- and early pubertal children. However, only a small number of studies have assessed its efficacy in improving the diagnostic accuracy of GHD investigations.

    Aim: To evaluate the effect of sex steroid priming in GH testing on the prevalence of divergent results of spontaneous nocturnal secretion and arginine-insulin-tolerance test (AITT).

    Methods and Materials: This is a retrospective chart review of all 196 children investigated for GHD from January 1, 1993 until February 28, 2023 at the Department of Paediatrics, Örebro University Hospital, Örebro, Sweden. Of them 173 (89%) children had undergone both overnight GH sampling and AITT and 28 of 173 children (16%) had received estrogen priming prior to their tests. A GH peak concentration of ≥ 7.0 μg/L or more was considered normal for both tests.

    Results: Children receiving priming (36% girls) had a median age of 12.1 years (6.2–15.0) vs. 8.4 years (1.5 – 15.9) in children not primed (43% girls). Of the 173 children that had undergone both tests, 31 (18%) tested positive (<7.0 μg/L) on both tests, 22 (13%) tested positive on overnight sampling only, and 13 (8%) tested positive on AITT only. Of the 28 children who had received priming ,only one child had divergent results, with a positive result solely from AITT. Amongst non-primed children, 34 of 145 had divergent results with 21 (14.6%) testing positive on AITT, and 13 (9%) exhibiting a positive result on the spontaneous GH test. The frequency of divergent tests was significantly lower (p = 0.016) amongst primed children (3.6%) compared to non-primed children (23.6%).

    Conclusion: Our results show that sex steroid priming prio rto GHD testing with overnight sampling and AITT decreases the frequency of divergent results between the two tests and thus suggest that sex steroid priming decreases the risk of false positive results.

  • 16.
    Lodefalk, Maria
    Karolinska institutet, Stockholm, Sweden.
    Adolescent type 1 diabetes: Eating and gastrointestinal function2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Adolescents with type 1 diabetes (T1DM) are given nutritional education, but the knowledge about their adherence to the food recommendations and associations between dietary intake and metabolic control is poor. Gastrointestinal symptoms are more prevalent in adults with T1DM than in healthy controls, which may be due to disturbed gastrointestinal motility. The meal content affects the gastric emptying rate and the postprandial glycaemia in healthy adults and adults with type 2 diabetes. Meal ingestion also elicits several postprandial hormonal changes of importance for gastrointestinal motility and glycaemia. Eating disorders are more prevalent in young females with T1DM than in healthy females, and are associated with poor metabolic control. The prevalence of eating disorders in adolescent boys with T1DM is not known.

     This thesis focuses on eating and gastrointestinal function in adolescents with T1DM. Three population-based, cross-sectional studies demonstrated that adolescents with T1DM consume healthy foods more often and have a more regular meal pattern than age- and sex-matched controls. Yet both boys and girls are heavier than controls. The intake of saturated fat is higher and the intake of fibre is lower than recommended in adolescents with T1DM. Patients with poor metabolic control consume more fat and less carbohydrates than patients with better metabolic control. Gastrointestinal symptoms are common in adolescents with T1DM, but the prevalence is not increased compared with controls. Gastrointestinal symptoms in patients are associated with female gender, daily cigarette smoking, long duration of diabetes, poor metabolic control during the past year, and an irregular meal pattern. Adolescent boys with T1DM are heavier and have higher drive for thinness than healthy boys, but do not differ from them in scales measuring psychopathology associated with eating disorders. 

     In a randomized, cross-over study, we found that a meal with a high fat and energy content reduces the initial (0–2 hours) postprandial glycaemic response and delays gastric emptying in adolescents with T1DM given a fixed prandial insulin dose compared with a low-fat meal. The glycaemic response is significantly associated with the gastric emptying rate. Both a high- and a low-fat meal increase the postprandial concentrations of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) and suppress the postprandial ghrelin levels in adolescents with T1DM. The postprandial changes of these hormones are more pronounced after the high-fat meal. Insulin-like growth factor binding-protein (IGFBP) –1 concentrations decrease after insulin administration irrespective of meal ingestion. The GLP-1 response is negatively associated with the gastric emptying rate. The fasting ghrelin levels are negatively associated with the postprandial glycaemic response, and the fasting IGFBP-1 levels are positively associated with the fasting glucose levels.

     We conclude that nutritional education to adolescents with T1DM should focus more on energy intake and expenditure to prevent and treat weight gain. It should also focus on fat quality and fibre intake to reduce the risk of macrovascular complications and improve glycaemia. Gastrointestinal symptoms in adolescents with T1DM should be investigated and treated as in other people irrespective of having diabetes. However, adolescents with long duration of diabetes, poor metabolic control, and symptoms from the upper gut should have their gastric emptying rate examined during euglycaemia. There may be an increased risk for development of eating disorders in adolescent males with T1DM since they are heavier than healthy boys and have higher drive for thinness. This should be investigated in future, larger studies.

     For the first time, we showed that a fat-rich meal delays gastric emptying and reduces the initial glycaemic response in patients with T1DM. The action profile of the prandial insulin dose to a fat-rich meal may need to be postponed and prolonged compared with the profile to a low-fat meal to reach postprandial normoglycaemia. Circulating insulin levels affect postprandial GIP, GLP-1, and ghrelin, but not IGFBP-1, responses less than the meal content. The pronounced GIP-response to a fat- and energy-rich meal may promote adiposity, since GIP stimulates lipogenesis. Such an effect would be disadvantageous for adolescents with T1DM since they already have increased body fat mass and higher weights compared with healthy adolescents. Adolescents with T1DM may have subnormal postprandial ghrelin suppression, which may be due to their increased insulin resistance or elevated growth hormone levels. This needs to be investigated in future, controlled studies.

     

     

    List of papers
    1. Food habits, energy and nutrient intake in adolescents with Type 1 diabetes mellitus
    Open this publication in new window or tab >>Food habits, energy and nutrient intake in adolescents with Type 1 diabetes mellitus
    2006 (English)In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 23, no 11, p. 1225-1232Article in journal (Refereed) Published
    Abstract [en]

    AIMS: The aims were to describe the food habits of adolescents with Type 1 diabetes (Type 1 DM) and to compare them with healthy control subjects; to describe the distribution of energy-providing nutrients in patients and compare it with current recommendations and previous reports; and finally, to investigate associations between dietary intake and glycaemic control. METHODS: One hundred and seventy-four adolescents with Type 1 DM and 160 age- and sex-matched healthy control subjects completed a validated food frequency questionnaire, and 38 randomly chosen patients completed a prospective 4-day food record. RESULTS: Patients ate more regularly, and more often ate fruit and fruit juice, potatoes and root vegetables, meat, fish, egg, offal and sugar-free sweets than control subjects. Control subjects more often ate ordinary sweets and snacks. Patients chose coarse rye bread and dairy products with less fat to a greater extent than control subjects. Patients were heavier than control subjects. The intake of saturated fat was higher in patients compared with recommendations and, for boys with diabetes, the intake of protein was higher than recommended. Patients with poorer glycaemic control ate vegetables, fruit and fish less often than patients with better control. CONCLUSIONS: The food habits of adolescents with Type 1 DM were healthier than those of control subjects. The intake of energy-providing nutrients was in line with current recommendations and showed improvements compared with previous reports, with the exception of fibre intake. The association between dietary intake and glycaemic control needs further investigation in prospective studies.

    Place, publisher, year, edition, pages
    Oxon, United Kingdom: Wiley-Blackwell, 2006
    Keywords
    Adolescence, diet, glycaemic control, Type 1 diabetes
    National Category
    Medical and Health Sciences Pediatrics Endocrinology and Diabetes
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-12064 (URN)10.1111/j.1464-5491.2006.01971.x (DOI)000241367000012 ()17054600 (PubMedID)2-s2.0-33750175427 (Scopus ID)
    Available from: 2010-10-05 Created: 2010-10-05 Last updated: 2017-12-12Bibliographically approved
    2. Effects of fat supplementation on postprandial GIP, GLP-1, ghrelin and IGFBP-1 levels: a pilot study on adolescents with type 1 diabetes
    Open this publication in new window or tab >>Effects of fat supplementation on postprandial GIP, GLP-1, ghrelin and IGFBP-1 levels: a pilot study on adolescents with type 1 diabetes
    Show others...
    2010 (English)In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 73, no 5, p. 355-62Article in journal (Refereed) Published
    Abstract [en]

    Aims: To compare the responses of GIP, GLP-1, ghrelin and IGFBP-1 between meals with different fat and energy content in adolescents with type 1 diabetes (T1DM) and to relate them to gastric emptying and glycaemia.

    Methods: On different days and in a random order, 7 adolescents with T1DM ingested a high- and low-fat meal (fat content: 38 and 2 g, energy content: 640 and 320 kcal, respectively). At normoglycaemia, the same prandial insulin dose was given at both meals and to all subjects. Postprandial blood samples were taken repeatedly over 4 hours. Gastric emptying was estimated by the paracetamol absorption method.

    Results: The area under the curve (AUC) for GIP(0-240 min) and for GLP-1(0-120 min) was larger, but smaller for relative ghrelin(0-240 min), after the high-fat meal (p = 0.002, 0.030 and 0.043, respectively). IGFBP-1 decreased significantly, but not differently, after the meals. Larger GLP-1 secretion correlated with slower gastric emptying (p = 0.029) and higher fasting ghrelin levels correlated with lower postprandial glycaemia (p = 0.007).

    Conclusion: In adolescents with T1DM, the postprandial responses of GIP, GLP-1 and ghrelin, but not that of IGFBP-1, depend more on meal size than on insulin.

    Place, publisher, year, edition, pages
    Basel, Switzerland: S. Karger, 2010
    Keywords
    Adolescence, gastric emptying, ghrelin, IGFBP-1, incretin hormones, type 1 diabetes
    National Category
    Medical and Health Sciences Nutrition and Dietetics
    Identifiers
    urn:nbn:se:oru:diva-44976 (URN)10.1159/000308168 (DOI)000277570100008 ()20389106 (PubMedID)2-s2.0-77954040563 (Scopus ID)
    Available from: 2015-06-23 Created: 2015-06-23 Last updated: 2022-02-11Bibliographically approved
    3. Gastrointestinal symptoms in adolescents with type 1 diabetes
    Open this publication in new window or tab >>Gastrointestinal symptoms in adolescents with type 1 diabetes
    2010 (English)In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 11, no 4, p. 265-70Article in journal (Refereed) Published
    Abstract [en]

    Objective: To compare the prevalence of gastrointestinal (GI) symptoms in adolescents with and without type 1 diabetes (T1DM) and to relate the symptoms in patients to demographic, socioeconomic, diabetes-specific variables, and food habits.

    Method: In a population-based, cross-sectional setting, 173 adolescents with T1DM and 160 matched controls completed a questionnaire. Moreover, 13 patients and 1 control were excluded due to having a GI disorder.

    Results: Moreover, 75% of patients and 77% of controls reported at least one GI symptom (ns). More girls than boys reported symptoms. Reflux episodes were more prevalent in patients with poorer socioeconomic status. Poor appetite, loss of weight, an uncomfortable feeling of fullness, swallowing difficulties, and nausea were more prevalent in patients smoking daily compared with patients not smoking daily. Vomiting was more prevalent in patients with duration of diabetes >7 yr, and patients with reflux episodes had higher glycated hemoglobin (HbA1c). Belching and early satiety were more prevalent in patients with an irregular meal pattern.

    Conclusions: GI symptoms in adolescents are common, but the prevalence is not increased in those with T1DM. GI symptoms in adolescents with T1DM are associated with female sex, poorer socioeconomic status, daily cigarette smoking, longer duration of diabetes, poorer metabolic control, and an irregular meal pattern.

    Place, publisher, year, edition, pages
    Hoboken, USA: John Wiley & Sons, 2010
    Keywords
    Adolescent, diabetes mellitus, food habits, GI, type 1
    National Category
    Medical and Health Sciences Gastroenterology and Hepatology
    Identifiers
    urn:nbn:se:oru:diva-44974 (URN)10.1111/j.1399-5448.2010.00664.x (DOI)000278196700010 ()20618744 (PubMedID)2-s2.0-77954485881 (Scopus ID)
    Available from: 2015-06-23 Created: 2015-06-23 Last updated: 2022-02-11Bibliographically approved
    4. Effects of fat supplementation on glycaemic response and gastric emptying in adolescents with Type 1 diabetes
    Open this publication in new window or tab >>Effects of fat supplementation on glycaemic response and gastric emptying in adolescents with Type 1 diabetes
    2008 (English)In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 25, no 9, p. 1030-1035Article in journal (Refereed) Published
    Abstract [en]

    AIMS: To compare the glycaemic response to meals with different fat content in adolescents with Type 1 diabetes mellitus (T1DM) and to investigate associations with gastric emptying.

    METHODS: In this randomized, cross-over study, paired results were obtained from seven adolescents with T1DM who ingested on different days two meals with the same carbohydrate and protein content, but different fat and energy content (2 and 38 g fat, 320 and 640 kcal, respectively). Paracetamol was mixed into the meals and gastric emptying was estimated by the paracetamol absorption method. All subjects were normoglycaemic and given 7 IU insulin aspart at commencement of ingestion. Postprandial blood samples were taken during 4 h.

    RESULTS: The areas under the curves for plasma glucose and serum paracetamol concentrations were larger after the low-fat than after the high-fat meal during the first 2 h (P = 0.047 and P = 0.041, respectively). The difference between meals in time-to-peak in glucose and paracetamol concentrations did not reach statistical significance (high-fat vs. low-fat meal: 210 min (120-240) vs. 120 min (50-240), P = 0.080 and 120 min (75-180) vs. 60 min (60-120), P = 0.051, respectively). Changes in glucose concentrations correlated with simultaneous changes in paracetamol concentrations (P < 0.001).

    CONCLUSIONS: For the first time, we have shown that the initial glycaemic response is reduced after a meal with higher compared with a meal with lower fat content in adolescents with T1DM given a rapid-acting insulin analogue preprandially. The type and dose of preprandial insulin may need adjustment to the fat content of the meal to reach postprandial normoglycaemia.

    Place, publisher, year, edition, pages
    Oxford: Blackwell, 2008
    Keywords
    adolescents, dietary fat, gastric emptying, postprandial glycaemic response, Type 1 diabetes
    National Category
    Medical and Health Sciences Endocrinology and Diabetes Clinical Medicine
    Research subject
    Internal Medicine
    Identifiers
    urn:nbn:se:oru:diva-6949 (URN)10.1111/j.1464-5491.2008.02530.x (DOI)000259542100005 ()19183308 (PubMedID)2-s2.0-50649124859 (Scopus ID)
    Available from: 2009-05-27 Created: 2009-05-27 Last updated: 2023-12-08Bibliographically approved
    5. Higher drive for thinness in adolescent males with insulin-dependent diabetes mellitus compared with healthy controls
    Open this publication in new window or tab >>Higher drive for thinness in adolescent males with insulin-dependent diabetes mellitus compared with healthy controls
    2003 (English)In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 92, p. 114-117Article in journal (Refereed) Published
    Place, publisher, year, edition, pages
    Oslo, Norway: Taylor & Francis, 2003
    Keywords
    diabetes mellitus, ätstörning, ungdomar, pojkar
    National Category
    Medical and Health Sciences Pediatrics
    Research subject
    Pediatrics
    Identifiers
    urn:nbn:se:oru:diva-46125 (URN)10.1111/j.1651-2227.2003.tb00480.x (DOI)000181612300021 ()12650311 (PubMedID)2-s2.0-0347927478 (Scopus ID)
    Available from: 2015-10-15 Created: 2015-10-15 Last updated: 2022-11-15Bibliographically approved
    Download full text (pdf)
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  • 17.
    Lodefalk, Maria
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Pediatrics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Allbrand, Marianne
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Solna, Sweden; Department of Epidemiology and Public Health, University College London, London, UK.
    Duration of the pushing phase of labor is inversely associated with expression of TNF, IL6, IGF1 and IGF2 in human placenta2022In: The Journal of Maternal-Fetal & Neonatal Medicine, ISSN 1476-7058, E-ISSN 1476-4954, Vol. 35, no 25, p. 6476-6482Article in journal (Refereed)
    Abstract [en]

    Objective: Gene expression in placenta differs between vaginal and cesarean deliveries, but the influence of the duration of labor on placental gene expression is incompletely known. Our aim was to investigate associations between duration of labor and expression of some genes involved in growth or inflammation in human placental tissue.

    Methods: Placenta samples (n = 126) were collected after an uncomplicated, singleton pregnancy and term vaginal delivery at orebro University Hospital, Sweden. Duration of labor was recorded by the midwife in the delivery room. The expression of the following genes was analyzed by RT-qPCR: tumor necrosis factor (TNF), interleukin-6 (IL6), C-X-C motif chemokine ligand 8, toll-like receptor (TLR) 2, TLR4, insulin receptor, insulin-like growth factor (IGF) 1, IGF2, leptin, hepatocyte growth factor (HGF) and HGF receptor (MET). Multivariable linear regression models were used for the evaluation of associations with labor duration adjusting for potential confounding factors. The Benjamini-Hoschberg method was used to correct for multiple testing.

    Results: The expression of TNF, IL6, IGF1 and IGF2 was inversely associated with the duration of the pushing phase of labor (B coefficients (95% confidence interval) = -0.150 (-0.277 to -0.023), -0.159 (-0.289 to -0.029), -0.099 (-0.176 to -0.021), and -0.081 (-0.145 to -0.017), respectively).

    Conclusions: Longer duration of pushing is associated with downregulation of the expression of genes in placenta from vaginal deliveries. Future research on gene expression in labored placenta should take into account associations with labor duration and especially the pushing phase. Potential impact of these associations on the mother, the fetus and the new-born infant should also be explored.

  • 18.
    Lodefalk, Maria
    et al.
    Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden; Department of Paediatrics, Örebro University Hospital, Örebro, Sweden.
    Carlsson-Skwirut, C.
    Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Holst, J. J.
    Department of Medical Physiology, Panum Institute, Copenhagen, Denmark .
    Aman, J.
    Department of Paediatrics, Örebro University Hospital, Örebro, Sweden.
    Bang, P
    Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Effects of fat supplementation on postprandial GIP, GLP-1, ghrelin and IGFBP-1 levels: a pilot study on adolescents with type 1 diabetes2010In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 73, no 5, p. 355-62Article in journal (Refereed)
    Abstract [en]

    Aims: To compare the responses of GIP, GLP-1, ghrelin and IGFBP-1 between meals with different fat and energy content in adolescents with type 1 diabetes (T1DM) and to relate them to gastric emptying and glycaemia.

    Methods: On different days and in a random order, 7 adolescents with T1DM ingested a high- and low-fat meal (fat content: 38 and 2 g, energy content: 640 and 320 kcal, respectively). At normoglycaemia, the same prandial insulin dose was given at both meals and to all subjects. Postprandial blood samples were taken repeatedly over 4 hours. Gastric emptying was estimated by the paracetamol absorption method.

    Results: The area under the curve (AUC) for GIP(0-240 min) and for GLP-1(0-120 min) was larger, but smaller for relative ghrelin(0-240 min), after the high-fat meal (p = 0.002, 0.030 and 0.043, respectively). IGFBP-1 decreased significantly, but not differently, after the meals. Larger GLP-1 secretion correlated with slower gastric emptying (p = 0.029) and higher fasting ghrelin levels correlated with lower postprandial glycaemia (p = 0.007).

    Conclusion: In adolescents with T1DM, the postprandial responses of GIP, GLP-1 and ghrelin, but not that of IGFBP-1, depend more on meal size than on insulin.

  • 19.
    Lodefalk, Maria
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Pediatrics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; University Health Care Research Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Chelslín, Felix
    Örebro University, School of Medical Sciences. Department of Pediatrics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Patriksson Karlsson, Johanna
    University Health Care Research Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Hansson, Stefan R
    Department of Obstetrics and Gynecology, Institute of Clinical Sciences Lund, Lund University, 221 00 Lund, Sweden; Department of Obstetrics and Gynecology, Skåne University Hospital, 214 28 Malmö, Sweden.
    Placental Changes and Neuropsychological Development in Children: A Systematic Review2023In: Cells, E-ISSN 2073-4409, Vol. 12, no 3, article id 435Article, review/survey (Refereed)
    Abstract [en]

    Placental dysfunction may increase the offspring's later-life disease risk. The objective of this systematic review was to describe associations between pathological placental changes and neuropsychological outcomes in children after the neonatal period. The inclusion criteria were human studies; original research; direct placental variables; neuropsychological outcomes; and analysis between their associations. The exclusion criterion was the offspring's age-0-28 days or >19 years. The MEDLINE and EMBASE databases were last searched in May 2022. We utilized the ROBINS-I for the risk of bias assessment and performed a narrative synthesis. In total, 3252 studies were identified, out of which 16 were included (i.e., a total of 15,862 participants). Half of the studies were performed on children with neonatal complications, and 75% of the studies reported an association between a placental change and an outcome; however, following the completion of the funnel plots, a risk of publication bias was indicated. The largest study described a small association between placental size and a risk of psychiatric symptoms in boys only. Inconsistency between the studies limited the evidence in this review. In general, no strong evidence was found for an association between pathological placental changes and childhood neuropsychological outcomes after the neonatal period. However, the association between placental size and mental health in boys indicates a placental sexual dimorphism, thereby suggesting an increased vulnerability for male fetuses.

  • 20.
    Lodefalk, Maria
    et al.
    Örebro University, School of Medical Sciences. Department of Paediatrics, Örebro University Hospital, Örebro, Sweden.
    Frykholm, Carina
    Immunology, Genetics, and Pathology, University of Uppsala, Uppsala, Sweden.
    Esbjörner, Elisabeth
    Department of Paediatrics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Ljunggren, Östen
    Medical Sciences, University of Uppsala, Uppsala, Sweden.
    Hypercalcaemia in a Patient with 2p13.2-p16.1 Duplication2016In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 85, no 3, p. 213-218Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Partial duplication of 2p is a rare condition that causes facial anomalies, psychomotor delay, and growth failure. Hypercalcaemia is rare in children. So far, duplication of 2p has never been associated with hypercalcaemia.

    METHODS: Here, we report a girl with a partial duplication of 2p presenting with moderate to severe hypercalcaemia at the age of 2 years. She also had hypercalciuria, nephrocalcinosis, decreased renal function, and secondary hyperparathyroidism at presentation. She was thoroughly investigated, including genetic testing of the CYP24A1, CASR, ALPL, and NOD2 genes, to determine the cause of hypercalcaemia.

    RESULTS: 1,25-dihydroxyvitamin D levels were increased. Hypercalcaemia and hypercalciuria responded well to glucocorticoids but not to cinacalcet. Hyperparathyroidism resolved with improving renal function. Apart from the known duplication of 2p, no pathogenic variants were detected in the studied genes. The duplication of 2p contains the PPP3R1 gene, which encodes for the calcineurin B subunit.

    CONCLUSION: We conclude that partial duplication of 2p can be associated with hypercalcaemia and hypercalciuria and hypothesise that the underlying mechanism is an increased extra-renal, parathyroid hormone-independent 25-hydroxyvitamin D 1α-hydroxylase activity, leading to raised amounts of 1,25-dihydroxyvitamin D. The increased enzymatic activity could possibly be caused by calcineurin B subunit-related macrophage stimulation.

  • 21.
    Lodefalk, Maria
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Paediatrics, Örebro University Hospital, Örebro, Sweden; University Health Care Research Center, Region Örebro County, Örebro, Sweden.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Department of Paediatrics, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden; Division of Paediatric Endocrinology, Department of Women’s and Children’s Health, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    To Prime or Not to Prime - Is That Still a Question?: A Comment on the US Guidelines on Growth Hormone and Insulin-Like Growth Factor-I Treatment in Children and Adolescents2017In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 88, no 2, p. 179-180Article in journal (Refereed)
  • 22.
    Lodefalk, Maria
    et al.
    Department of Paediatric Diabetology and Endocrinology, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm; Department of Paediatrics, Örebro University Hospital, Örebro.
    Åman, Jan
    Department of Paediatric Diabetology and Endocrinology, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm; Department of Paediatrics, Örebro University Hospital, Örebro.
    Food habits, energy and nutrient intake in adolescents with Type 1 diabetes mellitus2006In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 23, no 11, p. 1225-1232Article in journal (Refereed)
    Abstract [en]

    AIMS: The aims were to describe the food habits of adolescents with Type 1 diabetes (Type 1 DM) and to compare them with healthy control subjects; to describe the distribution of energy-providing nutrients in patients and compare it with current recommendations and previous reports; and finally, to investigate associations between dietary intake and glycaemic control. METHODS: One hundred and seventy-four adolescents with Type 1 DM and 160 age- and sex-matched healthy control subjects completed a validated food frequency questionnaire, and 38 randomly chosen patients completed a prospective 4-day food record. RESULTS: Patients ate more regularly, and more often ate fruit and fruit juice, potatoes and root vegetables, meat, fish, egg, offal and sugar-free sweets than control subjects. Control subjects more often ate ordinary sweets and snacks. Patients chose coarse rye bread and dairy products with less fat to a greater extent than control subjects. Patients were heavier than control subjects. The intake of saturated fat was higher in patients compared with recommendations and, for boys with diabetes, the intake of protein was higher than recommended. Patients with poorer glycaemic control ate vegetables, fruit and fish less often than patients with better control. CONCLUSIONS: The food habits of adolescents with Type 1 DM were healthier than those of control subjects. The intake of energy-providing nutrients was in line with current recommendations and showed improvements compared with previous reports, with the exception of fibre intake. The association between dietary intake and glycaemic control needs further investigation in prospective studies.

  • 23.
    Lodefalk, Maria
    et al.
    Pediatric Endocrinology and Diabetes Unit, Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.
    Åman, Jan
    Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.
    Gastrointestinal symptoms in adolescents with type 1 diabetes2010In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 11, no 4, p. 265-70Article in journal (Refereed)
    Abstract [en]

    Objective: To compare the prevalence of gastrointestinal (GI) symptoms in adolescents with and without type 1 diabetes (T1DM) and to relate the symptoms in patients to demographic, socioeconomic, diabetes-specific variables, and food habits.

    Method: In a population-based, cross-sectional setting, 173 adolescents with T1DM and 160 matched controls completed a questionnaire. Moreover, 13 patients and 1 control were excluded due to having a GI disorder.

    Results: Moreover, 75% of patients and 77% of controls reported at least one GI symptom (ns). More girls than boys reported symptoms. Reflux episodes were more prevalent in patients with poorer socioeconomic status. Poor appetite, loss of weight, an uncomfortable feeling of fullness, swallowing difficulties, and nausea were more prevalent in patients smoking daily compared with patients not smoking daily. Vomiting was more prevalent in patients with duration of diabetes >7 yr, and patients with reflux episodes had higher glycated hemoglobin (HbA1c). Belching and early satiety were more prevalent in patients with an irregular meal pattern.

    Conclusions: GI symptoms in adolescents are common, but the prevalence is not increased in those with T1DM. GI symptoms in adolescents with T1DM are associated with female sex, poorer socioeconomic status, daily cigarette smoking, longer duration of diabetes, poorer metabolic control, and an irregular meal pattern.

  • 24.
    Lodefalk, Maria
    et al.
    Örebro University, School of Health and Medical Sciences. Paediatric Endocrinology and Diabetes Unit, Department of Woman and Child Health, Karolinska Institute, Stockholm; Department of Paediatrics, Örebro University Hospital, Örebro, Sweden.
    Åman, Jan
    Örebro University, School of Health and Medical Sciences. Departm ent of Paediatrics, Örebro University Hospital, Örebro, Sweden.
    Bang, P.
    Paediatric Endocrinology and Diabetes Unit, Department of Woman and Child Health, Karolinska Institute, Stockholm.
    Effects of fat supplementation on glycaemic response and gastric emptying in adolescents with Type 1 diabetes2008In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 25, no 9, p. 1030-1035Article in journal (Refereed)
    Abstract [en]

    AIMS: To compare the glycaemic response to meals with different fat content in adolescents with Type 1 diabetes mellitus (T1DM) and to investigate associations with gastric emptying.

    METHODS: In this randomized, cross-over study, paired results were obtained from seven adolescents with T1DM who ingested on different days two meals with the same carbohydrate and protein content, but different fat and energy content (2 and 38 g fat, 320 and 640 kcal, respectively). Paracetamol was mixed into the meals and gastric emptying was estimated by the paracetamol absorption method. All subjects were normoglycaemic and given 7 IU insulin aspart at commencement of ingestion. Postprandial blood samples were taken during 4 h.

    RESULTS: The areas under the curves for plasma glucose and serum paracetamol concentrations were larger after the low-fat than after the high-fat meal during the first 2 h (P = 0.047 and P = 0.041, respectively). The difference between meals in time-to-peak in glucose and paracetamol concentrations did not reach statistical significance (high-fat vs. low-fat meal: 210 min (120-240) vs. 120 min (50-240), P = 0.080 and 120 min (75-180) vs. 60 min (60-120), P = 0.051, respectively). Changes in glucose concentrations correlated with simultaneous changes in paracetamol concentrations (P < 0.001).

    CONCLUSIONS: For the first time, we have shown that the initial glycaemic response is reduced after a meal with higher compared with a meal with lower fat content in adolescents with T1DM given a rapid-acting insulin analogue preprandially. The type and dose of preprandial insulin may need adjustment to the fat content of the meal to reach postprandial normoglycaemia.

  • 25.
    Rodanaki, Maria
    et al.
    Örebro University, School of Medical Sciences. Department of Paediatrics.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Paediatrics, School of Medical Sciences, Örebro University, Örebro, Sweden; University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Forssell, Katharina
    Department of Paediatrics, Central Hospital, Karlstad, Sweden.
    Arvidsson, Carl-Göran
    Department of Paediatrics, Västerås Hospital, Västerås, Sweden.
    Forssberg, Maria
    Department of Paediatrics, Central Hospital, Karlstad, Sweden.
    Åman, Jan
    Department of Paediatrics, School of Medical Sciences, Örebro University, Örebro, Sweden.
    The Incidence of Childhood Thyrotoxicosis Is Increasing in Both Girls and Boys in Sweden2019In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 91, no 3, p. 195-202Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We found an increase in the incidence rate (IR) of childhood thyrotoxicosis (CT) during the 1990s in central Sweden. The optimal treatment method for CT is a subject that is still debated upon.

    OBJECTIVES: To investigate whether the increase in IR of CT in Sweden persists and to study the treatment outcome.

    METHOD: Children <16 years of age diagnosed with CT during 2000-2009 and living in 1 of 5 counties in central Sweden were identified retrospectively using hospital registers. Data on clinical and biochemical characteristics and outcomes of treatment were collected from medical records. The corresponding data from 1990 to 1999 were pooled with the new data.

    RESULTS: In total, 113 children were diagnosed with CT during 1990-2009 in the study area. The overall IR was 2.2/100,000 person-years (95% CI 1.2-2.5/100,000 person-years). The IR was significantly higher during 2000-2009 than during 1990-1999 (2.8/100,000 [2.2-3.6] vs. 1.6/100,000 person-years [1.2-2.2], p = 0.006). The increase was significant for both sexes. Seventy percent of the patients who completed the planned initial treatment with antithyroid drugs (ATDs) and were not lost to follow-up relapsed within 3 years. Boys tended to relapse earlier than girls (6.0 months after drug withdrawal [95% CI 1.9-10.0] vs. 12.0 months [95% CI 6.8-17.3], p = 0.074).

    CONCLUSIONS: The IR of CT is increasing in both girls and boys. Relapse rate after withdrawal of ATD treatment is 70%. Boys tend to relapse earlier than girls, and this needs to be further investigated.

  • 26.
    Rodanaki, Maria
    et al.
    Örebro University, School of Medical Sciences. Department of Pediatrics.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Pediatrics, Örebro University, Örebro, Sweden; Faculty of Medicine and Health, University Health Care Research Center, Örebro University, Örebro, Sweden.
    Åman, Jan
    Department of Pediatrics, Örebro University, Örebro, Sweden.
    Incidence and Treatment Outcome of Childhood Thyrotoxicosis2018In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 90, no Suppl.1, p. 90-91, article id RFC5.3Article in journal (Refereed)
    Abstract [en]

    Aim: To study the incidence of childhood thyrotoxicosis in five counties in central Sweden during 1990–2009 and to study the treatment outcome.

    Methods: Children below the age of 16 years diagnosed with thyrotoxicosis during the 20-years period and living in the study area were identified retrospectively. Data on the total number of children below 16 years of age living in the area during the study period was collected from the National Board of Statistics, Sweden. Data regarding clinical and biochemical characteristics and the outcome of the treatment were collected from medical records.

    Results: 113 patients were identified. The annual incidence was 2.2/100,000 children during the whole study period. The incidence was higher during the last ten studied years as compared to the first ten studied years (2.8 vs. 1.6/100,000, p = 0.006). The increase in incidence was seen in both girls and boys (p = 0.041 and p = 0.038, respectively). Treatment with antithyroid drugs (ATD) was the first hand choice, but 69% of the patients relapsed within three years after the planned discontinuation of the ATD treatment. Boys relapsed more often than girls (p = 0.013), but we could not identify any other significant predictor for relapse.

    Conclusion: Thyrotoxicosis is uncommon in pediatric patients but the incidence seems to be increasing. The outcome of the initial treatment with ATD is poor with high relapse rates. Boys seems to have an increased risk for relapse compared to girls. More studies are needed to identify an optimal treatment protocol for each individual.

  • 27.
    Rodanaki, Maria
    et al.
    Örebro University, School of Medical Sciences. Department of Paediatrics.
    Rask, Eva
    Örebro University, School of Medical Sciences. University Health Care Research Centre.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Paediatrics; University Health Care Research Centre.
    A Randomized Trial of the Effect of a GnRH Analogue Injection on Ghrelin Levels in Girls2022In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 95, no 5, p. 442-451Article in journal (Refereed)
    Abstract [en]

    Introduction: Ghrelin concentrations decline during puberty by an unclear mechanism. Acylated ghrelin (AG) is unstable in sampling tubes, but no standardized sampling protocol exists. We hypothesized that ghrelin levels decrease as a consequence of increased gonadotropin-releasing hormone (GnRH) signalling and that the addition of a protease inhibitor to sampling tubes preserves the AG levels.

    Methods: In this randomized, placebo-controlled, cross-over study, 13 girls with suspected central precocious puberty were included. They performed an adjusted GnRH stimulation test twice and were given Relefact LHRH (R)(100 mu g/m(2)) or saline in a randomized order. Blood was sampled repeatedly for 150 min for the analysis of hormone concentrations. Oestradiol levels were only measured at baseline. The protease inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) was added to the sampling tubes. Specific ELISA kits were used for the analysis of AG and desacylated ghrelin (DAG) levels.

    Results: Neither AG nor DAG levels changed after GnRH analogue injection in comparison to saline. The addition of AEBSF preserved AG levels (650.1 +/- 257.1 vs. 247.6 +/- 123.4 pg/mL, p < 0.001) and decreased DAG levels (51.9 [12.5-115.7] vs. 143.5 [71.4-285.7] pg/mL, p < 0.001). Both AG and DAG levels were inversely associated with insulin levels (r = -0.73, p = 0.005, and r = -0.78, p = 0.002, respectively). AG levels were inversely associated with oestradiol levels (rho = -0.57, p = 0.041).

    Conclusion: Ghrelin levels do not decrease following a pharmacological dose of a GnRH analogue in the short term in girls. Addition of a protease inhibitor to the sampling tubes decreases AG degradation, resulting in preserved AG and decreased DAG levels. (C) 2022 The Author(s). Published by S. Karger AG, Basel

  • 28.
    Rodanaki, Maria
    et al.
    Örebro University, School of Medical Sciences. Department of Paediatrics.
    Rask, Eva
    Örebro University, School of Medical Sciences. University Health Care Centre.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Paediatrics; University Health Care Centre.
    Adding a protease inhibitor to sampling tubes increases the acylated ghrelin and decreases the desacylated ghrelin levels in girls2021In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 94, no Suppl. 1, p. 111-112Article in journal (Other academic)
    Abstract [en]

    Introduction: Ghrelin is a growth hormone-releasing acylated peptide stimulating the appetite, mainly produced in the stomach, and with an important role in pubertal development (1). Two ghrelin forms have been described, acylated (AG) and desacylated (DAG), but it is debated whether DAG is an active hormone or a degradation product of AG (2). Our aim was to evaluate the effects of adding the protease inhibitor 4-(2-aminoethyl) benzenesufonyl fluoride hydrochloride (AEBSF) to sampling tubes and acidification of plasma on levels of AG and DAG in girls with suspected central precocious puberty (CPP).

    Methods: 13 girls aged 6.6 to 10.1 years with suspected CPP undergoing a gonadotropin-releasing hormone stimulation test during 2015-2017 at the Departments of Paediatrics, at Örebro or Uppsala University Hospital were included. Blood samples were collected at 0 min in precooled EDTA tubes with or without AEBSF at a final concentration of 2mg/ml. After cold centrifugation, HCl at a final concentration of 50 μmol/l, was added to 50% of the plasma tubes containing AEBSF. The AG and DAG concentrations were measured by ELISA kits. Comparison was performed using one-way ANOVA for repeated measurements.

    Results: The mean plasma AG levels were significantly higher after the addition of AEBSF only (650.9 +/- 257.1 pg/ml) or AEBSF+HCl (681.2 +/- 299 pg/ml) compared to the concentrations without additives (247.6 +/- 123.4 pg/ml, p<0.01 for both comparisons). There was no significant difference between the AG levels after AEBSF and AEBSF+HCl addition. The plasma levels of DAG were significantly lower after the addition of AEBSF+HCl (69.3 +/- 30.6 pg/ml) and even further lowered after the addition of AEBSF only (56.3+/- 30.9 pg/ml) compared to the concentrations of DAG in tubes without any additives (149.9 +/- 73.7 pg/ml, p < 0.01 for both comparisons).

    Discussion: Due to the unstable nature of AG, special procedures are required for accurate measurement of its plasma levels in children, including the use of a protease inhibitor like AEBSF. However, DAG was still measurable indicating that it may not only be a degradation product of AG. 1. Kojima M, Kangawa K. Ghrelin: structure and function. Physiol Rev. 2005;85(2):495-522.2. Blatnik M, Soderstrom CI, Dysinger M, Fraser SA. Prandial ghrelin attenuation provides evidence that des-acyl ghrelin may be an artifact of sample handling in human plasma. Bio-analysis. 2012;4(20):2447-55.

  • 29.
    Rodanaki, Maria
    et al.
    Örebro University, School of Medical Sciences. Department of Pediatrics and Adolescent Medicine.
    Rask, Eva
    Örebro University, School of Medical Sciences. Department of Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; University Health Care Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Pediatrics and Adolescent Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; University Health Care Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Delayed puberty in boys in central Sweden: an observational study on diagnosing and management in clinical practice2022In: BMJ Open, E-ISSN 2044-6055, Vol. 12, no 2, article id e057088Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To compare the usefulness of the classical definition of delayed puberty (DP) in boys with puberty nomograms and to describe the management of DP in boys in a hospital-based setting.

    STUDY DESIGN: Observational retrospective multicentre study with a short-term follow-up.

    SETTING AND PARTICIPANTS: Boys diagnosed with DP during 2013-2015 at paediatric departments in four counties in central Sweden. The medical records of 165 boys were reviewed.

    PRIMARY AND SECONDARY OUTCOME MEASURES: Number of boys with DP after re-evaluation of the diagnosis according to the classical definition in comparison with puberty nomograms. Description of investigations performed and treatment provided to boys with DP.

    RESULTS: In total, 45 and 58 boys were found to have DP according to the classical definition and the nomograms, respectively. Biochemical and/or radiological testing was performed in 91% of the 58 boys, but an underlying disease was only found in 9% of them. Approximately 79% of the boys received testosterone treatment, either as injections of testosterone enanthate or as testosterone undecanoate.

    CONCLUSIONS: Puberty nomograms may be helpful instruments when diagnosing pubertal disorders in boys as they are not limited to an age close to 14 years and also identify boys with pubertal arrest. The majority of boys with DP undergo biochemical or radiological examinations, but underlying diseases are unusual emphasising the need for structural clinical practice guidelines for this patient group.

  • 30.
    Rodanaki, Maria
    et al.
    Örebro University, School of Medical Sciences. Department of Pediatrics, Örebro University Hospital, Örebro,.
    Rask, Eva
    Örebro University, School of Medical Sciences. Department of Endocrinology, Örebro University, Örebro, Sweden.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Pediatrics.
    Incidence of Delayed Puberty in Adolescents: A Population-Based Study in a County in Central Sweden2018In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 90, no Suppl.1, p. 510-510, article id P2-P311Article in journal (Refereed)
    Abstract [en]

    Introduction: Delayed puberty is defined as the absence of physical signs of puberty by the age of 14 years in boys and 13 years in girls. According to this definition, the prevalence of delayed puberty would be 2%, if the ages of pubertal onset were normally distributed in the population. However, the prevalence or incidence of delayed puberty has not been described before, as far as we know. Our aim was to study the incidence of delayed puberty in central Sweden.

    Methods: In this population-based retrospective study all adolescents given the ICD-10 diagnosis “delayed puberty” in Örebro county during the period 2013-2015 were identified. Adolescents with other diagnoses potentially related to delayed puberty (e.g. short stature) were also identified to ensure that there were no additional cases. The medical records of these patients, except those not willing to participate, were systematically reviewed to ensure that the diagnosis was correct. The cases were then categorized into four groups depending on how accurate we found the diagnosis (certain, possible, wrong diagnosis, or unclear cases). Data on the total numbers of adolescents in Örebro county were obtained from the authority of statistics in Sweden.

    Results: One hundred and twenty-eight of 180 eligible medical records were reviewed (response rate: 71 %). Nine boys and one girl were diagnosed with delayed puberty during the study time period and fulfilled our strict criteria for a certain diagnosis and 4 boys were classified as possible new cases. The total population in Örebro county for boys aged 14-18 years was on average 6,546 each year during the time period. The minimal annual incidence for boys was 46 per 100,000 (95% confidence interval (CI) 15-142 per 100,000). When possible cases were included, the annual incidence for boys increased to 66 (CI 26-170) per 100,000. Due to the low number of girls with delayed puberty no incidence for girls was calculated.

    Discussion: This is, to our knowledge, the first study describing the incidence of delayed puberty in boys. We evaluated the accuracy of the diagnosis using strict criteria. The presented incidence should be regarded as the minimum incidence since some adolescents with delayed puberty may not seek medical advice or may be unrecognized by the health services in schools. Because of our small study population, larger studies are needed to confirm our findings and for calculation of the incidence in girls, where our data implies a much lower incidence.

  • 31.
    Rodanaki, Maria
    et al.
    Örebro University, School of Medical Sciences. Department of Paediatrics.
    Rask, Eva
    Örebro University, School of Medical Sciences. Department of Medicine; University Health Care Centre.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Paediatrics; University Health Care Centre.
    The effect of a GnRH analogue injection on the circulating levels of kisspeptin-1 in girls with suspected central precocious puberty2022In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 95, no Suppl. 2, p. 341-341, article id P1-151Article in journal (Other academic)
    Abstract [en]

    Introduction: Kisspeptin stimulates the gonadotropin releasing hormone (GnRH) neurons in hypothalamus initiating puberty. However, it is not known whether GnRH inhibits kisspeptin secretion by negative feedback and whether there are any associations between circulating levels of kisspeptin and other hormones, like ghrelin, important for the onset of puberty.

    Methods: Thirteen girls with suspected central precocious puberty performed an adjusted GnRH stimulation test twice, placebo-controlled in a randomized order, at Örebro or Uppsala University Hospital, Sweden. Blood was sampled 0, 30, 60, 90, 120 and 150 min after the iv injection of either Relefact LHRH® or saline. The protease inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) was added to the sampling tubes to a final concentration of 2 mg/ml. An ELISA kit from LifeSpan BioSciences, Inc. (No LS-F8231) was used for the analyses of Kisspeptin-1 levels. The levels of acylated ghrelin were analyzed with Millipore® Human Ghrelin (Active) ELISA kit (#EZGRA-88K). Serum ultrasensitive estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), insulin and glucose levels were analyzed using the usual clinical methods.

    Results: The median Kisspeptin-1 level at baseline was 39 pg/ml (min–max: 0.1–221.3 pg/ml). The area-under-the curve for Kisspeptin-1 levels was not significantly lower after the GnRH injection as compared to the placebo injection. We did not find any significant correlations between the levels of kisspeptin-1 and acylated ghrelin, estradiol, LH, FSH, or insulin. However, we could see a positive correlation between kisspeptin-1 and glucose levels at baseline (Spearman’s rank test, rho = 0.63, p=0.021).

    Discussion: We did not find evidence of a negative feedback mechanism between GnRH and kisspeptin in girls with suspected central precocious puberty since the circulating levels of kisspeptin-1 were unaffected by an intravenous injection of a GnRH analogue. However, paracrine actions in the hypothalamus cannot be ruled out by this study. The positive correlation found between kisspeptin-1 and glucose levels is in accordance with previous findings in both adults and children, suggesting a possible role for kisspeptin signaling in glucose metabolism.

  • 32.
    Rodanaki, Maria
    et al.
    Örebro University, School of Medical Sciences. Department of Paediatrics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Rask, Eva
    Department of Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; University Health Care Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Paediatrics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; University Health Care Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden .
    The effect of a GnRH analogue injection on thecirculating levels of kisspeptin-1 in girls withsuspected central precocious puberty2022In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 95, no Sup. 2, p. 341-341, article id P1-151Article in journal (Other academic)
  • 33. Samuelson, Gösta
    et al.
    Åman, Jan
    Örebro University, School of Health and Medical Sciences.
    Lodefalk, Maria
    Detlofsson, Ingalill
    Cederholm, Ulla
    Vall, Helene
    Mat vid diabetes2008In: Barn- och ungdomsdiabetes / [ed] Sture Sjöblad, Lund: Studentlitteratur , 2008, 2, p. 93-101Chapter in book (Other academic)
  • 34.
    [Svensson] Lodefalk, Maria
    et al.
    Department of Paediatrics, Örebro University Hospital.
    Engström, Ingemar
    Department of Paediatrics, Örebro University Hospital; Psychiatric Research Centre, Örebro.
    Åman, Jan
    Department of Paediatrics, Örebro University Hospital.
    Higher drive for thinness in adolescent males with insulin-dependent diabetes mellitus compared with healthy controls2003In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 92, p. 114-117Article in journal (Refereed)
  • 35.
    Östling, Hanna
    et al.
    Örebro University, School of Medical Sciences.
    Kruse, Robert
    Örebro University, School of Medical Sciences.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Infants born small-for-gestational age have different placental expression of microRNAs2017In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 88, no Suppl. 1, p. 100-101, article id P1-508Article in journal (Other academic)
  • 36.
    Östling, Hanna
    et al.
    Örebro University, School of Medical Sciences. Department of Obstetrics and Gynecology.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Pediatrics.
    Placental expression of microRNAs in infants born small for gestational age2019In: Placenta, ISSN 0143-4004, E-ISSN 1532-3102, Vol. 81, p. 46-53Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: The molecular mechanisms behind poor foetal growth are not fully known. The aim of this study was to explore global microRNA expression in placentas of infants born small for gestational age (SGA) compared to infants with a normal birth weight (NBW).

    METHODS: Placental biopsies from term infants were identified in a biobank and divided into four groups: infants born SGA with (n = 13) or without (n = 9) exposure to low maternal gestational weight gain (GWG) and infants born with NBWs with (n = 20) or without (n = 26) exposure to low GWG. All women and infants were healthy, and no woman smoked during pregnancy. Only vaginal deliveries were included. Next-generation sequencing was performed with single read sequencing of >9 million reads per sample. Differential microRNA expression was analysed using ANOVA for unequal variances (Welch) with multiple testing corrections through the Benjamini-Hochberg method. A fold change >2 and a corrected p value < 0.05 were considered significant. Adjustments for possible confounding factors were made using a linear regression model.

    RESULTS: A total of 1870 known, mature human microRNAs were detected in the sample. MiR-3679-5p and miR-193b-3p were significantly upregulated, and miR-379-3p, miR-335-3p, miR-4532, miR-519e-3p, miR-3065-5p, and miR-105-5p were significantly downregulated after adjustment for potential confounding factors in SGA infants with normal GWG compared to infants with NBWs and normal GWG.

    DISCUSSION: Infants born unexplained SGA show differential microRNA expression in their placenta. Important pathways for the differentially expressed microRNAs include inflammation and the insulin-IGF system.

  • 37.
    Östling, Hanna
    et al.
    Örebro University, School of Medical Sciences. Department of Obstetrics and Gynaecology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Paediatrics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Backman, Helena
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Obstetrics and Gynaecology.
    Kruse, Robert
    Örebro University, School of Medical Sciences. iRiSC - Inflammatory Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Global microRNA and protein expression in human term placenta2022In: Frontiers in Medicine, E-ISSN 2296-858X, Vol. 9, article id 952827Article in journal (Refereed)
    Abstract [en]

    Introduction: Description of the global expression of microRNAs (miRNAs) and proteins in healthy human term placentas may increase our knowledge of molecular biological pathways that are important for normal fetal growth and development in term pregnancy. The aim of this study was to explore the global expression of miRNAs and proteins, and to point out functions of importance in healthy term placentas.

    Materials and methods: Placental samples (n = 19) were identified in a local biobank. All samples were from uncomplicated term pregnancies with vaginal births and healthy, normal weight newborns. Next-generation sequencing and nano-scale liquid chromatographic tandem mass spectrometry were used to analyse miRNA and protein expression, respectively.

    Results: A total of 895 mature miRNAs and 6,523 proteins were detected in the placentas, of which 123 miRNAs and 346 proteins were highly abundant. The miRNAs were in high degree mapped to chromosomes 19, 14, and X. Analysis of the highly abundant miRNAs and proteins showed several significantly predicted functions in common, including immune and inflammatory response, lipid metabolism and development of the nervous system.

    Discussion: The predicted function inflammatory response may reflect normal vaginal delivery, while lipid metabolism and neurodevelopment may be important processes for the term fetus. The data presented in this study, with complete miRNA and protein findings, will enhance the knowledge base for future research in the field of placental function and pathology.

  • 38.
    Östling, Hanna
    et al.
    Örebro University, School of Medical Sciences. Department of Obstetrics and Gynaecology.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Paediatrics; University Health Care Research Centre.
    Backman, Helena
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Obstetrics and Gynaecology.
    Kruse, Robert
    Örebro University, School of Medical Sciences. iRiSC - Inflammatory Response and Infection Susceptibility Centre; Department of Clinical Research Laboratory.
    Global microRNA and protein expression in human term placenta may improve our understanding of fetal growth2022In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 95, no Suppl. 2, p. 247-247, article id P1-91Article in journal (Other academic)
    Abstract [en]

    Introduction: The placenta is an endocrine organ vital to fetal growth. It has multiple functions: pregnancy maintenance, nutrient and oxygen transport to the fetus, and removal of waste products among other functions. MicroRNAs (miRNAs) and proteins are significant mediators of these functions. A description of their global expression in healthy placenta may increase our understanding of the molecular biological pathways that are important for normal fetal growth and development. The aims of this study were to explore the global expression of both miRNAs and proteins in the same samples of human term healthy placenta and to describe involved pathways.

    Methods: Nineteen term placenta samples from healthy women with uncomplicated pregnancies were identified in a local sample collection. The samples were derived from uncomplicated vaginal deliveries with healthy normal weight new-borns (5 females). Next generation sequencing and nano-scale liquid chromatographic tandem mass spectrometry were used for the analyses of miRNA and protein expression, respectively. Ingenuity Pathway Analysis was used for functional bioinformatics analyses.

    Results: A total of 895 mature miRNAs and 6,523 proteins were detected in the placenta samples, whereof 123 miRNAs and 346 proteins were highly abundant. The miRNAs were in high degree mapped to chromosomes 19, 14 and X. The most abundant proteins served as enzymes (23%), transporters (10%) or transcription regulators (8%). Of the 20 most significant downstream functions for the highly expressed miRNAs and proteins, respectively, eight shared functions were found, namely Cellular function and maintenance, Cell death and survival, Cell-to-cell signaling and interaction, Cellular assembly and organization, Organismal development, Digestive system development and function, Hepatic system development and function, and Inflammatory response.

    Discussion: As far as we know, this is the first study presenting both global miRNA and protein expression in the same placenta sample set from healthy term pregnancies. Two of the chromosomes found to have high presence of miRNA genes in the present study are known to contain placenta-specific miRNA clusters (chromosomes 14 and 19), while chromosome X might have been identified here since it has a higher density of miRNA genes than autosomes. The biological functions for the miRNAs and proteins point at basic cellular actions and clearly illustrate that development is an important task during fetal life. Profound knowledge of miRNA and protein expression in healthy placenta can improve the management of aberrant fetal growth and development.

  • 39.
    Östling, Hanna
    et al.
    Örebro University, School of Medical Sciences. Department of Obstetrics and Gynaecology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Paediatrics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; University Health Care Research Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Backman, Helena
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Obstetrics and Gynaecology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Kruse, Robert
    Örebro University, School of Medical Sciences. iRiSC - Inflammatory Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Global microRNA and protein expression in humanterm placenta may improve our understandingof fetal growth2022In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 95, no 2, p. 247-247, article id P1-91Article in journal (Other academic)
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