Jovanna Dahlgren

Dynamics and Stabilization of the Human Gut Microbiome during the First Year of Life.

The gut microbiota is central to human health, but its establishment in early life has not been quantitatively and functionally examined. Applying metagenomic analysis on fecal samples from a large cohort of Swedish infants and their mothers, we characterized the gut microbiome during the first year of life and assessed the impact of mode of delivery and feeding on its establishment. In contrast to vaginally delivered infants, the gut microbiota of infants delivered by C-section showed significantly less resemblance to their mothers. Nutrition had a major impact on early microbiota composition and function, with cessation of breast-feeding, rather than introduction of solid food, being required for maturation into an adult-like microbiota. Microbiota composition and ecological network had distinctive features at each sampled stage, in accordance with functional maturation of the microbiome. Our findings establish a framework for understanding the interplay between the gut microbiome and the human body in early life.

Noonan Syndrome: Clinical Features, Diagnosis, and Management Guidelines

Noonan syndrome (NS) is a common, clinically and genetically heterogeneous condition characterized by distinctive facial features, short stature, chest deformity, congenital heart disease, and other comorbidities. Gene mutations identified in individuals with the NS phenotype are involved in the Ras/MAPK (mitogen-activated protein kinase) signal transduction pathway and currently explain ∼61% of NS cases. Thus, NS frequently remains a clinical diagnosis. Because of the variability in presentation and the need for multidisciplinary care, it is essential that the condition be identified and managed comprehensively. The Noonan Syndrome Support Group (NSSG) is a nonprofit organization committed to providing support, current information, and understanding to those affected by NS. The NSSG convened a conference of health care providers, all involved in various aspects of NS, to develop these guidelines for use by pediatricians in the diagnosis and management of individuals with NS and to provide updated genetic findings.

Final height in short children born small for gestational age treated with growth hormone.

The aim of this observational study was to assess the long-term growth responses to GH treatment of children born small for gestational age (SGA). GH treatment was begun before puberty and continued to final height (FH). Seventy-seven short (height SD score below −2) prepubertal children born SGA (below −2 SD for birth weight and/or birth length), with a broad range of GH secretory capacity, were treated with GH in a daily dose of 33 μg/kg (0.1 U/kg), beginning before the onset of puberty. We observed a difference between adult and pretreatment projected height of 1.3 SD (9 cm) for the entire group. Among the children treated for >2 y before puberty, this mean gain (i.e. difference) in final height was 1.7 SD, whereas the mean gain was 0.9 SD among those in whom treatment was begun <2 y before puberty. Better catch-up growth was observed in the younger (r = −0.56, p < 0.0001), shorter (r = −0.49, p < 0.0001), and lighter (r = −0.46, p < 0.0001) subjects. We conclude that GH treatment improves the final height of short children born SGA. The height gain attained before the onset of puberty is maintained to final height. The younger, shorter, and lighter the child at the start of GH treatment, the better the response. Moreover, most of these SGA individuals treated with GH reach their target height.

Interleukin-6 in the Maternal Circulation Reaches the Rat Fetus in Mid-gestation

Maternal systemic infection during pregnancy may expose the fetus to infectious agents and high levels of mediators of the resulting inflammatory response, such as IL-6 (IL-6). Increased fetal and maternal levels of IL-6 have been associated with adverse neonatal outcome but might also stress the fetus and contribute to cardiovascular and neuroendocrine dysfunction in adulthood. It is unclear whether interleukines cross the placental barrier, although this matter has been little studied. The aim of this study was therefore to investigate if IL-6 administered to pregnant rats in vivo is transferred to the fetus. We injected 125I IL-6 i.v. to pregnant dams at gestation day 11–13 (mid-gestation) or 17–19 (late gestation). We found 125I-IL-6 in the exposed fetuses as well as in amniotic fluids. Fetal 125I-IL-6 levels were markedly higher in animals injected in mid-gestation compared with late pregnancy (p < 0.01). This difference was mirrored in a 15-fold higher unidirectional materno-fetal clearance for 125I-IL-6 in mid-gestation (p < 0.01). We conclude that the permeability of the rat placental barrier to IL-6 is much higher in mid-gestation than in late pregnancy. Maternally derived IL-6 may directly induce fetal injury but also stimulate the release of fetal stress hormones resulting in stimuli or insults in neuroendocrine structures and hormonal axes which might lead to disease at adult age.

Two-year outcome of laparoscopic Roux-en-Y gastric bypass in adolescents with severe obesity: results from a Swedish Nationwide Study (AMOS)

CONTEXT:The prevalence of obesity among adolescents has increased and we lack effective treatments.OBJECTIVE:To determine if gastric bypass is safe and effective for an unselected cohort of adolescents with morbid obesity in specialized health care.DESIGN, SETTING AND PATIENTS:Intervention study for 81 adolescents (13–18 years) with a body mass index (BMI) range 36–69 kg m−2 undergoing laparoscopic gastric bypass surgery in a university hospital setting in Sweden between April 2006 and May 2009. For weight change comparisons, we identified an adult group undergoing gastric bypass surgery (n=81) and an adolescent group (n=81) receiving conventional care.MAIN OUTCOME MEASUREMENTS:Two-year outcome regarding BMI in all groups, and metabolic risk factors and quality of life in the adolescent surgery group.RESULTS:Two-year follow-up rate was 100% in both surgery groups and 73% in the adolescent comparison group. In adolescents undergoing surgery, BMI was 45.5±6.1 (mean ±s.d.) at baseline and 30.2 (confidence interval 29.1–31.3) after 2 years (P<0.001) corresponding to a 32% weight loss and a 76% loss of excess BMI. The 2-year weight loss was 31% in adult surgery patients, whereas 3% weight gain was seen in conventionally treated adolescents. At baseline, hyperinsulinemia (>20 mU l−1) was present in 70% of the adolescent surgery patients, which was reduced to 0% at 1 year and 3% at 2 years. Other cardiovascular risk factors were also improved. Two-thirds of adolescents undergoing surgery had a history of psychopathology. Nevertheless, the treatment was generally well tolerated and, overall, quality of life increased significantly. Adverse events were seen in 33% of patients.CONCLUSIONS:Adolescents with severe obesity demonstrated similar weight loss as adults following gastric bypass surgery yet demonstrating high prevalence of psychopathology at baseline. There were associated benefits for health and quality of life. Surgical and psychological challenges during follow-up require careful attention.

Factors associated with discontinuation of breastfeeding before 1 month of age.

Background: Breastfeeding is associated with many benefits for both mother and child. Initiation rates are high in Sweden. Recently a slight decline is seen.

Adrenal steroid hormones in short children born small for gestational age

Programming of the endocrine axis has been postulated to occur during critical phases of fetal development and is affected by intrauterine growth retardation. The aim of this study was to investigate this hypothesis with regard to adrenal steroid hormones. Thus, serum cortisol and dehydroepiandrosterone sulphate (DHEAS) levels were compared in children born small for gestational age (SGA) who remained short and in children born at an appropriate size for gestational age (AGA), of both short and normal stature.

Growth Hormone (GH) Dosing during Catch-Up Growth Guided by Individual Responsiveness Decreases Growth Response Variability in Prepubertal Children with GH Deficiency or Idiopathic Short Stature

CONTEXT Weight-based GH dosing results in a wide variation in growth response in children with GH deficiency (GHD) or idiopathic short stature (ISS). OBJECTIVE The hypothesis tested was whether individualized GH doses, based on variation in GH responsiveness estimated by a prediction model, reduced variability in growth response around a set height target compared with a standardized weight-based dose. SETTING A total of 153 short prepubertal children diagnosed with isolated GHD or ISS (n = 43) and at least 1 SD score (SDS) below midparental height SDS (MPH(SDS)) were included in this 2-yr multicenter study. INTERVENTION The children were randomized to either a standard (43 microg/kg.d) or individualized (17-100 microg/kg.d) GH dose. MAIN OUTCOME MEASURE We measured the deviation of height(SDS) from individual MPH(SDS) (diffMPH(SDS)). The primary endpoint was the difference in the range of diffMPH(SDS) between the two groups. RESULTS The diffMPH(SDS) range was reduced by 32% in the individualized-dose group relative to the standard-dose group (P < 0.003), whereas the mean diffMPH(SDS) was equal: -0.42 +/- 0.46 and -0.48 +/- 0.67, respectively. Gain in height(SDS) 0-2 yr was equal for the GH-deficient and ISS groups: 1.31 +/- 0.47 and 1.36 +/- 0.47, respectively, when ISS was classified on the basis of maximum GH peak on the arginine-insulin tolerance test or 24-h profile. CONCLUSION Individualized GH doses during catch-up growth significantly reduce the proportion of unexpectedly good and poor responders around a predefined individual growth target and result in equal growth responses in children with GHD and ISS.

Pregnancy and insulin resistance.

Several conditions are associated with insulin resistance (IR), and the mechanism behind this state is multifactorial. Pathological states (such as visceral obesity, low energy expenditure, high carbohydrate consumption, and sleep deprivation) and more physiological states (such as puberty and pregnancy) will lead to increased IR. During puberty, the high levels of sex steroids as well as the high levels of growth hormone (GH) are responsible for decreased insulin sensitivity. During pregnancy, the high levels of several diabetogenic hormones lead to a state of IR. A pronounced physiological decrease in peripheral insulin sensitivity occurs as pregnancy proceeds. In contrast, gestational diabetes mellitus (GDM) is a pathological state of carbohydrate intolerance beginning or first recognized during pregnancy, which leads to increased risk of adverse pregnancy outcome. Obese women, an increasing part of the fertile female population, develop a more pronounced IR during pregnancy, with a higher risk of developing GDM.

Age- and Sex-Specific Reference Intervals Across Life Span for Insulin-Like Growth Factor Binding Protein 3 (IGFBP-3) and the IGF-I to IGFBP-3 Ratio Measured by New Automated Chemiluminescence Assays

CONTEXT Measurement of IGF-binding protein-3 (IGFBP-3) can aid the diagnosis of GH-related diseases. Furthermore, epidemiological studies suggest that IGFBP-3 and the molar IGF-I to IGFBP-3 ratio are associated with clinical end points like cancer or cardiovascular disease. However, their clinical use is limited by the lack of validated reference intervals. OBJECTIVE The objective of the study was the establishment of age- and sex-specific reference intervals for IGFBP-3 and the molar IGF-I to IGFBP-3 ratio by newly developed automated immunoassays. SETTING This was a multicenter study with samples from 11 cohorts from the United States, Canada, and Europe. PARTICIPANTS A total of 14 970 healthy subjects covering all ages from birth to senescence participated in the study. MAIN OUTCOME MEASURES Concentrations of IGFBP-3 and the IGF-I to IGFBP-3 ratio as determined by the IDS iSYS IGF-I and IGFBP-3 assays were measured. RESULTS Both the concentration of IGFBP-3 and the IGF-I to IGFBP-3 ratio are mainly determined by age. IGFBP-3 concentrations increase until the age of 22 years, with a plateau being visible between 15 and 25 years. Determined by the high peripubertal peak in IGF-I, the peak in the IGF-I to IGFBP-3 ratio occurs already around the age of 15 years, with a slightly earlier and higher peak in females. Beyond the age of 60 years, IGFBP-3 concentrations remain higher in females, whereas IGF-I as well as the IGF-I to IGFBP-3 ratio remains significantly higher in males. CONCLUSIONS We present an extensive set of assay-specific age- and sex-adjusted normative data for concentrations of IGFBP-3 and the molar IGF-I to IGFBP-3 ratio and demonstrate distinct sex specific differences across the life span.