Intraoperative ultrasound imaging in the surgical treatment of congenital hyperinsulinism: prospective, blinded study.

BACKGROUND: In congenital hyperinsulinism (CHI), preoperative prediction of the histological subtype (focal, diffuse, or atypical) relies on genetics and 6-[18F]fluoro-l-3,4-dihydroxyphenylalanine (18F-DOPA) PET-CT. The scan also guides the localization of a potential focal lesion along with perioperative frozen sections. Intraoperative decision-making is still challenging. This study aimed to describe the characteristics and potential clinical impact of intraoperative ultrasound imaging (IOUS) during CHI surgery. METHODS: This was a prospective, observational study undertaken at an expert centre over a 2-year interval. IOUS was performed blinded to preoperative diagnostic test results (genetics and 18F-DOPA PET-CT), followed by unblinding and continued IOUS during pancreatic resection. Characteristics and clinical impact were assessed using predefined criteria. RESULTS: Eighteen consecutive, surgically treated patients with CHI, with a median age of 5.5 months, were included (focal 12, diffuse 3, atypical 3). Focal lesions presented as predominantly hypoechoic, oval lesions with demarcated or blurred margins. Patients with diffuse and atypical disease had varying echogenicity featuring stranding and non-shadowing hyperechoic foci in three of six, whereas these characteristics were absent from those with focal lesions. The blinded IOUS-based subclassification was correct in 17 of 18 patients; one diffuse lesion was misclassified as focal. IOUS had an impact on the surgical approach in most patients with focal lesions (9 of 12), and in those with diffuse (2 of 3) and atypical (2 of 3) disease when the resection site was close to the bile or pancreatic duct. CONCLUSION: Uniform IOUS characteristics made all focal lesions identifiable. IOUS had a clinical impact in 13 of 18 patients by being a useful real-time supplementary modality in terms of localizing focal lesions, reducing the need for frozen sections, and preserving healthy tissue and delicate structures.

Nasal continuous positive airway pressure with head cap fixation as a contributing factor to extensive scalp necrosis in a preterm neonate with early-onset sepsis and scalp hematoma.

BACKGROUND: Nasal continuous positive airway pressure (CPAP) is widely used in the treatment and prevention of respiratory distress in preterm neonates, with only few severe adverse skin effects reported. CASE PRESENTATION: A preterm neonate was born at 34 + 1 weeks of gestation, birth weight 1860 g, and presented with early-onset sepsis (EOS) and scalp hematoma. He developed respiratory distress day 2 after birth. Antibiotics, nasal CPAP and other supportive treatment were initiated. A scalp hematoma in the occipital region was complicated by nasal CPAP cap pressure leading to an extensive scalp necrosis equaling 6% of the total body surface. Debridement and skin grafting were performed day 11, and 51, respectively. The boy survived with good healing of the skin graft. CONCLUSION: The nasal CPAP head cap contributed to the development of severe, but potentially preventable, scalp necrosis in a preterm with birth-related scalp skin injury and EOS.

The association between angiogenic markers and fetal sex: Implications for preeclampsia research.

OBJECTIVE: Current research suggests sexual dimorphism between the male and female fetoplacental units, but with unknown relevance for preeclampsia. We investigated the association between fetal sex and concentrations of the angiogenic markers soluble Fms-like kinase 1 (sFlt-1), placental growth factor (PlGF), and sFlt-1/PlGF ratio in first and second-third trimester in women with/without preeclampsia, and the impact of fetal sex on the prognostic value of angiogenic markers for preeclampsia. STUDY DESIGN: Observational study in a prospective, population-based cohort of 2110 singleton pregnancies with 150 preeclampsia cases. RESULTS: Higher sFlt-1 concentrations were observed for women carrying female fetuses in first trimester (all, 1107.65 vs. 992.27pg/ml; preeclampsia cases, 1118.79 vs. 934.49pg/ml, p<0.05) and in second-third trimester (all, 1130.03 vs. 1043.15pg/ml; preeclampsia, 1480.30 vs. 1152.86pg/ml, p<0.05), with similar findings for the sFlt-1/PlGF ratio concentrations in first (29.67 vs. 27.39 p<0.05) and second-third trimester (3.56 vs. 3.22, p<0.05). In first trimester, log transformed concentrations of PlGF, sFlt-1 and sFlt-1/PlGF (all participants) and sFlt-1 (preeclampsia cases) associated with fetal sex in adjusted analyses (p<0.05). In second-third trimester, only log(sFlt-1) associated with fetal sex (all, p=0.028; preeclampsia, p=0.067) In receiver operating curve analysis, prediction of early-onset preeclampsia by sFlt-1/PlGF tended to be superior in pregnancies with female vs. male fetuses (p=0.06). CONCLUSION: Sexual dimorphism was observed for concentrations of angiogenic markers. Female fetal sex was associated to higher sFlt-1 and sFlt-1/PlGF ratio concentrations in both healthy pregnancies and women developing preeclampsia. Fetal sex should be considered in research and clinical use of angiogenic markers.

Maternal 25-hydroxyvitamin D level and fetal bone growth assessed by ultrasound: a systematic review.

OBJECTIVES: To assess systematically the role of maternal vitamin D levels in fetal bone growth. METHODS: PubMed, EMBASE and Cochrane databases were searched using the search words [Vitamin D] in combination with [fetal, fetus, intrauterine, or prenatal AND growth, development, bone, femur, or humerus]; [crown-rump length]; or [ultrasonography, prenatal]. Criteria for inclusion in this systematic review were data on maternal serum 25-hydroxyvitamin D (25(OH)D) during pregnancy and measurement of fetal growth by ultrasound. RESULTS: We identified 750 publications initially, from which five observational studies were selected for inclusion in the final review. The parameters studied were humerus length (HL) and femur length (FL) and their Z-scores, femoral volume, femoral distal metaphyseal cross-sectional area (CSA), femoral proximal metaphyseal diameter (PMD), femoral mid-shaft diameter and crown-rump length. In one study, 25(OH)D was associated directly with FL; in another study 25(OH)D only correlated with FL and HL Z-scores when calcium intake was insufficient. Two studies found no association between 25(OH)D and FL, but detected a direct association with femoral PMD, and an inverse relation with femoral distal metaphyseal CSA, respectively. CONCLUSIONS: Observational studies investigating the role of maternal vitamin D levels in fetal bone growth are sparse. Their evidence suggests that low maternal 25(OH)D levels may affect fetal bone growth under certain circumstances, especially in cases of simultaneous low calcium intake. Further studies are necessary.

Discovery of molecular pathways mediating 1,25-dihydroxyvitamin D3 protection against cytokine-induced inflammation and damage of human and male mouse islets of Langerhans.

Protection against insulitis and diabetes by active vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), in nonobese diabetic mice has until now mainly been attributed to its immunomodulatory effects, but also protective effects of this hormone on inflammation-induced ß-cell death have been reported. The aim of this study was to clarify the molecular mechanisms by which 1,25(OH)2D3 contributes to ß-cell protection against cytokine-induced ß-cell dysfunction and death. Human and mouse islets were exposed to IL-1ß and interferon-γ in the presence or absence of 1,25(OH)2D3. Effects on insulin secretion and ß-cell survival were analyzed by glucose-stimulated insulin release and electron microscopy or Hoechst/propidium iodide staining, respectively. Gene expression profiles were assessed by Affymetrix microarrays. Nuclear factor-κB activity was tested, whereas effects on secreted chemokines/cytokines were confirmed by ELISA and migration studies. Cytokine exposure caused a significant increase in ß-cell apoptosis, which was almost completely prevented by 1,25(OH)2D3. In addition, 1,25(OH)2D3 restored insulin secretion from cytokine-exposed islets. Microarray analysis of murine islets revealed that the expression of approximately 4000 genes was affected by cytokines after 6 and 24 hours (n = 4; >1.3-fold; P < .02), of which nearly 250 genes were modified by 1,25(OH)2D3. These genes belong to functional groups involved in immune response, chemotaxis, cell death, and pancreatic ß-cell function/phenotype. In conclusion, these findings demonstrate a direct protective effect of 1,25(OH)2D3 against inflammation-induced ß-cell dysfunction and death in human and murine islets, with, in particular, alterations in chemokine production by the islets. These effects may contribute to the beneficial effects of 1,25(OH)2D3 against the induction of autoimmune diabetes.

Parity and tanned white skin as novel predictors of vitamin D status in early pregnancy: a population-based cohort study.

CONTEXT: In pregnancy, vitamin D insufficiency and deficiency, defined as serum 25-hydroxyvitamin D (25(OH)D) <50 nM, and <25 nM, respectively, may have adverse effects for both mother and child. Prevalence estimates, and identification of subgroups at special risk, may be useful for the planning of preventive strategies. OBJECTIVE: To study the prevalence and risk factors of hypovitaminosis D in early pregnancy. DESIGN AND METHODS: In a cross-sectional study of 1348 women in early pregnancy from the Odense Child Cohort, Denmark, 25(OH)D was determined and correlated to demographic and lifestyle variables (age, nationality, skin tone, parity, prepregnancy body mass index (BMI), smoking and sun exposure), using multiple linear and logistic regression analyses for all year, or stratified for summer and winter. The risk of vitamin D insufficiency was expressed as odds ratios (OR) with 95% confidence intervals in brackets. RESULTS: The prevalence of vitamin D insufficiency and deficiency was estimated to 27·8% and 3·5% respectively. In adjusted analyses, vitamin D insufficiency was directly associated with winter season, OR = 1·89 (1·35-2·63); increasing prepregnancy BMI, OR = 1·06 (1·03-1·10); and smoking, OR = 2·7 (1·34-5·41); but was less frequent in nulliparous, OR = 0·47 (0·33-0·68) and tanned Caucasians, OR = 0·63 (0·41-0·97). Season-specific associations having parental origin from outside Europe in summer, OR = 4·13 (1·41-12·13); in winter smoking, OR = 3·15 (1·19-8·36); and prepregnancy BMI, OR = 1·12 (1·06-1·18). CONCLUSIONS: Vitamin D insufficiency was widespread in early pregnancy. Associations to smoking, prepregnancy BMI and origin outside Europe varied with season. Multiparity and not being tanned in Caucasians represent new risk factors of vitamin D insufficiency.

Pregestational body mass index is related to neonatal abdominal circumference at birth--a Danish population-based study.

OBJECTIVES: To examine the impact of maternal pregestational body mass index (BMI) and smoking on neonatal abdominal circumference (AC) and weight at birth. To define reference curves for birth AC and weight in offspring of healthy, nonsmoking, normal weight women. DESIGN: Population-based study. SETTING: Data from the Danish Medical Birth Registry. POPULATION: All live singletons without congenital malformations in Denmark 2004-10. METHODS: Data on 366,886 singletons at 35(+0) to 41(+6) weeks(+days) of gestation were extracted and analysed using multivariate linear regressions. MAIN OUTCOME MEASURES: Birth AC and weight in relation to pregestational maternal BMI, maternal smoking and medical conditions (any). RESULTS: Birth AC and weight increased with increasing pregestational BMI, and decreased with smoking (P < 0.0001). Reference curves were created for offspring of healthy, nonsmoking mothers with normal pregestational BMI. Mean AC ranged from 30.1 cm and 30.2 cm at 35 weeks of gestation to 33.9 cm and 34.1 cm at 41 weeks of gestation, for girls and boys, respectively. Mean birthweight ranged from 2581 and 2666 g at 35 weeks to 3705 and 3852 g at 41 weeks of gestation for girls and boys, respectively. Pregestational BMI correlated more to the Z score of birthweight than to the Z score of AC (P < 0.0001). CONCLUSION: Birth AC and weight are affected by maternal smoking status and pregestational BMI. Pregestational BMI correlated more to birthweight than to AC. Using data from healthy, nonsmoking mothers with normal pregestational BMI we have provided new reference curves for birth AC and birthweight.

Agreement between Cochrane Neonatal reviews and clinical practice guidelines for newborns in Denmark: a cross-sectional study.

OBJECTIVE: To assess agreement between Cochrane Neonatal Group reviews and clinical practice guidelines in Denmark. DESIGN: Retrospective analysis of clinical guidelines for newborn infants. MATERIALS: All Cochrane neonatal reviews and Danish clinical guidelines for newborn infants. MAIN OUTCOME MEASURES: The recommendations from the Cochrane reviews and local clinical guidelines were compared and classified as being in agreement, in partial agreement or in disagreement. Authors of guidelines were asked whether Cochrane reviews had been considered during guideline development and reasons for any disagreements. Heterogeneity among departments was assessed. RESULTS: 173 interventions evaluated in Cochrane neonatal reviews were included. All 17 Danish neonatal departments agreed to participate, but only 14 (82%) delivered data. Agreement between reviews and guidelines was observed for a median of 132 interventions (76%) (range 129-134), partial agreement was observed for 31 interventions (18%) (range 29-33), and disagreement was observed for 10 interventions (6%) (range 8-13) (kappa = 0.56, range 0.53-0.59). Most of the latter 10 interventions were not recommended in the reviews but were recommended in the guidelines. There were numerous reasons for disagreement, the most common being usage of evidence with higher bias risks than randomised trials in guidelines development. Overall, Cochrane reviews were rarely (10%) used during guideline development. For nine guideline topics (5%) there was diversity among the Danish departments' recommendations. CONCLUSIONS: There is good agreement between Cochrane reviews and neonatal guidelines in Denmark. However, Cochrane reviews were rarely used for guideline development. Heterogeneity among guidelines produced by the various neonatal departments seems moderate.

Hyperinsulinemic hypoglycemia in Beckwith-Wiedemann syndrome due to defects in the function of pancreatic beta-cell adenosine triphosphate-sensitive potassium channels.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome that is clinically and genetically heterogeneous. Hyperinsulinemic hypoglycemia occurs in about 50% of children with BWS and, in the majority of infants, it resolves spontaneously. However, in a small group of patients the hypoglycemia can be persistent and may require pancreatectomy. The mechanism of persistent hyperinsulinemic hypoglycemia in this group of patients is unclear. PATIENTS AND METHODS: Using patch-clamp techniques on pancreatic tissue obtained at the time of surgery, we investigated the electrophysiological properties of ATP-sensitive K(+) (K(ATP)) channels in pancreatic beta-cells in a patient with BWS and severe medically-unresponsive hyperinsulinemic hypoglycemia. RESULTS: Persistent hyperinsulinism was found to be caused by abnormalities in K(ATP) channels of the pancreatic beta-cell. Immunofluorescence studies using a SUR1 antibody revealed perinuclear pattern of staining in the BWS cells, suggesting a trafficking defect of the SUR1 protein. No mutations were found in the genes ABCC8 and KCNJ11 encoding for the two subunits, SUR1 and KIR6.2, respectively, of the K(ATP) channel. Genetic analysis of this patients BWS showed evidence of mosaic paternal isodisomy. CONCLUSIONS: In this novel case of BWS with mosaic paternal uniparental disomy for 11p15, persistent hyperinsulinism was due to abnormalities in K(ATP) channels of the pancreatic beta-cell. The mechanism/s by which mosaic paternal uniparental disomy for 11p15 causes a trafficking defect in the SUR1 protein of the K(ATP) channel remains to be elucidated.