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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. [ABSTRACT FROM AUTHOR]

Unlabelled: In congenital hyperinsulinism (HI). the in vivo pancreatic beta-cell function is poorly described. Among 14 neonates with severe hyperinsulinaemic hypoglycaemia, 2 patients had very prolonged or persistent hypoglycaemia and mutation in the sulphonylurea receptor SURI gene. Patient 1 had transient HI and was treated medically for 3.5 mo before clinical remission was seen. He had initially very high basal and stimulated C-peptide and insulin levels, followed by a state of normal preprandial values, but blunted beta-cell glucose sensitivity, before complete beta-cell normalization occurred. A single. paternal SURI mutation, G1382S, was found suggesting focal type HI. Patient 2 had persistent HI and underwent 3 pancreas resections up to the age of 2 y, 7 mo, followed by a state of mild diabetes. On biopsy, diffuse-type beta-cell hypertrophy was seen. The beta-cell response to glucose and glucagon stimulation was blunted before, as well as after, pancreas resections. Compound heterozygosity for the SUR1 mutations 3992-3c to g and N188S was found.Conclusion: Transient, possibly focal, HI with paternal SUR1 mutation was associated with a gradual, but complete normalization of the in vivo beta-cell function; in the diffuse type HI, a blunted beta-cell response to glucose and glucagon stimulation persisted. In vivo beta-cell stimulation tests may contribute to the characterization of the HI subtypes. [ABSTRACT FROM AUTHOR]

The article reports that F-Dihydroxyphenylalanine positron emission tomography is the preferred method for differentiation between focal and diffuse congenital hyperinsulinism and focus localization. Surgeons manages to perform curative limited resection of a focus without the risk of long-term diabetes through the sensitivity and accuracy in preoperative focus localization.

Charlotte Höybye,1 Lars Sävendahl,2 Henrik Thybo Christesen,3 Peter Lee,4 Birgitte Tønnes Pedersen,5 Michael Schlumpf,6 John Germak,7 Judith Ross8 1Department of Molecular Medicine and Surgery, Karolinska Institute and Department of Endocrinology, Metabolism and Diabetes, 2Department of Women’s and Children’s Health, Karolinska Institute and Division of Pediatrics, Karolinska University Hospital, Stockholm, Sweden; 3Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark; 4Department of Pediatrics, Penn State College of Medicine, Hershey, PA, USA; 5Global Development, Novo Nordisk A/S, Søborg, Denmark; 6Global Medical Affairs Biopharm, Novo Nordisk Health Care AG, Zurich, Switzerland; 7Clinical Development and Medical Affairs, Novo Nordisk Inc, Princeton, NJ, USA; 8Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA Objective: Randomized controlled trials have shown that growth hormone (GH) therapy has effects on growth, metabolism, and body composition. GH therapy is prescribed for children with growth failure and adults with GH deficiency. Carefully conducted observational study of GH treatment affords the opportunity to assess long-term treatment outcomes and the clinical factors and variables affecting those outcomes, in patients receiving GH therapy in routine clinical practice. Design: The NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web Enabled Research (ANSWER Program®) are two complementary, non-interventional, observational studies that adhere to current guidelines for pharmacoepidemiological data. Patients: The studies include pediatric and adult patients receiving Norditropin®, as prescribed by their physicians. Measurements: The studies gather long-term data on the safety and effectiveness of real-life treatment with the recombinant human GH, Norditropin®. We describe the origins, aims, objectives, and design methodology of the studies, as well as their governance and validity, strengths, and limitations. Conclusion: The NordiNet® IOS and ANSWER Program® studies will provide valid insights into the effectiveness and safety of GH treatment across a diverse and large patient population treated in accordance with real-world clinical practice and following the Good Pharmacoepidemiological Practice and STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines. Keywords: growth hormone replacement therapy, treatment outcome, pharmacoepidemiology, survey

Introduction: Insulinomas are extremely rare tumors in children and an uncommon first manifestation of MEN1 syndrome. Insulinomas are usually benign tumors with only a few reports of malignant cases in children. Aim(s): To investigate the morphological and genetic characteristics of Russian children with primary insulinomas. Materials and methods: Insulinoma was diagnosed biochemically and by imaging and was verified histopathologically. Sequencing of the MEN1 gene was performed and families of the mutation carriers were studied. Follow-up included screening for signs of MEN1 and metastases in case of malignant tumors. Results: Ten children aged 8-16 years were diagnosed to have primary pancreatic insulinoma. Of these, five (50%) were malignant and distant metastases were seen during follow-up in two children. Three out of nine children investigated (33.3%) were found to have mutations in the MEN1 gene and developed hyperparathyroidism and hyperprolactinemia during the following 10 years. One patient with w/t MEN1 developed hyperparathyroidism. In the two patients with MEN1 mutations where family biochemical testing was possible, relatives revealed the spectrum of MEN1 components, but with no clinical symptoms. Conclusion: MEN1 syndrome should be suspected in all cases of pediatric insulinomas. A high incidence of malignant insulinomas was seen. Contrary to the ENETS Guidelines, we recommend MEN1 analysis, histopathological investigations and specific follow-up in all children with primary insulinoma, and family testing in case of MEN1 mutations. [ABSTRACT FROM AUTHOR]

Objective: The phenotype mediated by HNF4A/HNF1A mutations is variable and includes diazoxide-responsive hyperinsulinaemic hypoglycaemia (HH) and maturity-onset diabetes of the young (MODY)., Design: We characterised an international multicentre paediatric cohort of patients with HNF4Aor HNF1Amutations presenting with HH over a 25-year period (1995-2020)., Methods: Clinical and genetic analysis data from five centres were obtained. Diazoxide responsiveness was defined as the ability to maintain normoglycaemia without intravenous glucose. Macrosomia was defined as a birth weight ≥90th centile. SPSS v.27.1 was used for data analysis., Results: A total of 34 patients (70.6% female, n = 24) with a mean age of 7.1 years (s.d. 6.4) were included. A total of 21 different heterozygous HNF4Amutations were identified in 29 patients (four novels). Four different previously described heterozygous HNF1A mutations were detected in five patients. Most (97.1%, n = 33) developed hypoglycaemia by day 2 of life. The mean birth weight was 3.8 kg (s.d. 0.8), with most infants macrosomic (n = 21, 61.8%). Diazoxide was commenced in 28 patients (82.3%); all responded. HH resolved in 20 patients (58.8%) following a median of 0.9 years (interquartile range (IQR): 0.2-6.8). Nine patients (n = 9, 26.5%) had developmental delay. Two patients developed Fanconi syndrome (p.Arg63Trp, HNF4A) and four had other renal or hepatic findings. Five (14.7%) developed MODY at a median of 11.0 years (IQR: 9.0-13.9). Of patients with inherited mutations (n = 25, 73.5%), a family history of diabetes was present in 22 (88.0%)., Conclusions: We build on the knowledge of the natural history and pancreatic and extra-pancreatic phenotypes of HNF4A/HNF1Amutations and illustrate the heterogeneity of this condition.

Background and Objective: Kabuki syndrome (KS), caused by pathogenic variants in KMT2D or KDM6A, is associated with hyperinsulinaemic hypoglycaemia (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 multicentre 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 < .001), and KDM6A-KS was more likely to be associated with HH than KMT2D-KS (21.8% vs. 3.5%, P < .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., (© 2020 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Purpose: To investigate the predictive performance of placental growth factor (PlGF) and soluble FMS-like kinase 1 (sFlt-1) on birth weight and small for gestational age (SGA), in a large, population-based cohort. Methods: Women enrolled in the population-based, prospective Odense Child Cohort Study with early (GA < 20 weeks) and/or late (≥20 weeks) pregnancy blood samples ( n  = 1937) were included. The association between log-transformed values of the biomarkers and birth weight Z-score was studied using multivariate regression models. The prediction of SGA overall, and in women developing preeclampsia, by biomarkers was evaluated using receiver operating characteristic analyses. Results: No substantial associations between early pregnancy biomarkers and SGA were seen. PlGF measured in late pregnancy demonstrated the strongest association with birth weight Z-score (adjusted β-coefficient = 0.43 [95%CI = 0.35; 0.50]). The area under curve (AUC) for predicting SGA was higher for sFlt-1/PlGF compared to sFlt-1 (0.74 versus 0.63, p  = .006) and reached excellent prediction for SGA after preeclampsia (AUC 0.94). Optimal sFlt-1/PlGF ratio cut-offs had higher negative predictive value (NPV) and positive predictive value (PPV) for SGA (cut-off > 5.0; NPV = 99.1%, PPV = 5.4%) compared to each marker individually. Conclusion: The sFlt-1/PlGF ratio is a potential predictor of SGA in population-based screening, particularly when preeclampsia is also present.

Background: Congenital hyperinsulinism (CHI) is a severe disease with a high risk of complications including neurological deficit. Persistent hypoglycemia in patients with focal form of CHI can not be managed with medical treatment in 96.4% of cases, what subsequently leads to surgical treatment. Currently, there is a lack of information regarding patients with focal form of CHI. This study is aimed at finding better approaches for diagnosis and treatment of patients with focal form of CHI., Aims: To study clinical, genetic and PET/CT findings of the focal form of CHI in Russian group of patients., Materials and Methods: The observational research included all patients with a histologically confirmed focal form of CHI, who were admitted to Endocrinology Research Centre during the period from January 2008 to January 2019. A statistical analysis of clinical data, genotype, and positron emission tomography (PET) with 18F-dihydroxyphenylalanine (18F-DOPA) was performed. The median follow-up was 18 months., Results: The study included 31 patients with focal CHI (14 boys, 45.2%). All patients had a neonatal presentation of the disease and demanded high levels of continuous glucose infusion to maintain euglycemia. The difference between the age of hypoglycemia presentation and the age of diagnosis ranged from 1 day to 3.9 months. In all cases, diazoxide was found to be ineffective. However, in 9 patients, it was possible to withdraw continuous glucose infusion and maintain euglycemia using octreotide in the preoperative period. A molecular genetic study allowed us to detect diverse pathogenic variants in ABCC8 and KCNJ11 genes in 30 patients. According to PET data with 18F-DOPA, the pancreatic index (PI) varied widely from 1.16 to 3.59. After partial resection of the pancreatic region with insulin hypersecretion, all patients showed complete recovery., Conclusions: The focal form of CHI is a severe condition with high prevalence of neurological complications. For preoperative diagnosis of the morphological form of the disease, it is necessary to conduct genetic analysis and radionuclide studies. Solely evaluation of mathematical parameters in 18F-DOPA PET without taking into account the visual data and the results of genetic analysis does not allow establishing the robust diagnosis. Timely diagnosis, identification of risk factors, and prevention of complications of persistent hypoglycemia are important tasks for clinicians.

Background: Medication errors (MEs) in neonates are frequent and associated with increased potential for harm compared with adults. The effect of learning from reported MEs is potentially lacking due to underreporting, lack of feedback and missing actions to improve medication safety. A new approach involving positive recognition of current and future strategies may facilitate greater exploration of how to improve medication safety in neonates. We aimed to explore current and potential future practices to prevent MEs in neonatal intensive care units (NICUs)., Methods: Focus group interviews of physicians and nurses were conducted at three Danish NICUs. Participants were included if they had at least 1 month of working experience and provided direct patient care. A semistructured interview guide involving three questions was used: (a) how do you feel about discussing prevention of MEs? (b) how do you currently prevent MEs from occurring? and (c) how can we become better at preventing MEs in the future? Content analysis was used to identify themes in the interviews., Results: Participants commented that MEs still occur and that action must be taken to improve medication safety. Current practices to prevent MEs involved technology, procedures, education, skills and hospital pharmacy services. Potential future practices to prevent MEs included customizing the computerized physician order entry systems to support optimal prescribing, standardizing the double-check process, training of calculation skills and teamwork and increased use of hospital pharmacy services., Conclusions: Several current and potential future practices to reduce MEs in NICUs were identified, highlighting the complexity of MEs. Our findings support an interdisciplinary multifaceted intervention involving both technical and nontechnical elements to improve medication safety in NICUs., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Background: Hospitalized children are prone to experience harm from medication errors (MEs). Strategies to prevent MEs can be developed from identified malfunctioning practices and conditions in the medication use process. In this study, we aimed to identify MEs and potentially unsafe medication practices (PUMPs) in hospitalized children, and to assess the potential harm of these, using raters of different professions., Methods: A 1-week observation using an undisguised technique was conducted on four paediatric hospital wards. One observer followed ward staff during medication prescribing, preparation and administration. MEs and PUMPs were documented using field notes. Three raters including a physician, a nurse and a clinical pharmacist assessed the potential harm of each ME and PUMP using a six-point Likert scale. Agreement was analysed using Fleiss' Kappa., Results: A total of 16 MEs and 809 PUMPs were identified involving a preparation and administration error rate of 8%. No actual harm to patients was observed during the study. Raters assessed the potential harm of 318 unique MEs and PUMPs. Only slight agreement was found (Kappa = 0.26-0.33). A 4-hour delay in the administration of intravenous cefuroxime received the highest harm score. Observations involving no information during prescribing and variations in medication preparation were considered potentially fatal for medications such as digoxin, morphine, enoxaparin and insulin., Conclusions: MEs and potentially unsafe practices and conditions may affect medication safety of hospitalized children. However, observed MEs did not result in any harm. The agreement among raters assessing the potential harm of observations was low. Alternative methods to determine the clinical relevance of errors are needed., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Background: Hospitalized children are at risk of medication errors (MEs) due to complex dosage calculations and preparations. Incident reporting systems may facilitate prevention of MEs but underreporting potentially undermines this system. We aimed to examine whether scenarios involving medications should be reported to a national mandatory incident reporting system and the likelihood of self- and peer-reporting these scenarios among paediatric nurses and physicians., Methods: Participants' reporting of MEs was explored through a questionnaire involving 20 medication scenarios. The scenarios represented different steps in the medication process, types of error, patient outcomes and medications. Reporting rates and odds ratios with 95% confidence interval [OR, (95% CI)] were calculated. Barriers to and enablers of reporting were identified through content analysis of participants' comments., Results: The response rate was 42% (291/689). Overall, 61% of participants reported that scenarios should be reported. The likelihood of reporting was 60% for self-reporting and 37% for peer-reporting. Nurses versus physicians, and healthcare professionals with versus without patient safety responsibilities assessed to a larger extent that the scenarios should be reported [OR = 1.34 (1.05-1.70) and OR = 1.41 (1.12-1.78), respectively]; were more likely to self-report, [OR = 2.81 (1.71-4.62) and OR = 2.93 (1.47-5.84), respectively]; and were more likely to peer-report [OR = 1.89 (1.36-2.63) and OR = 3.61 (2.57-5.06), respectively].Healthcare professionals with versus without management responsibilities were more likely to peer-report [OR = 5.16 (3.44-7.72)]. Participants reported that scenarios resulting in actual injury or incidents considered to have a learning potential should be reported., Conclusion: The likelihood of underreporting scenarios was high among paediatric nurses and physicians. Nurses and staff with patient safety responsibilities were more likely to assess that scenarios should be reported and to report. Incidents with actual injury or learning potential were more likely to be reported. The potential for improving reporting rates involving MEs seems high., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

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., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

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 β-cell death have been reported. The aim of this study was to clarify the molecular mechanisms by which 1,25(OH)2D3 contributes to β-cell protection against cytokine-induced β-cell dysfunction and death. Human and mouse islets were exposed to IL-1β and interferon-γ in the presence or absence of 1,25(OH)2D3. Effects on insulin secretion and β-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 β-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 β-cell function/phenotype. In conclusion, these findings demonstrate a direct protective effect of 1,25(OH)2D3 against inflammation-induced β-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.

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., (© 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.)

Objective: To determine if the addition of a multinutrient human milk fortifier to mother's milk while breastfeeding very preterm infants after hospital discharge is possible and whether it influences first-year growth., Methods: Of a cohort of 320 infants (gestational age: 24-32 weeks; birth weight: 535-2255 g), breastfed infants (65% [n = 207]) were randomly assigned shortly before hospital discharge to receive either unfortified (n = 102, group A) or fortified (n = 105, group B) mother's milk until 4 months' corrected age (CA). The remaining infants were bottle-fed with a preterm formula (group C). Follow-up was performed at term and at 2, 4, 6, and 12 months' CA., Results: Mean duration of breastfeeding after term was not significantly different between groups A and B (11.8 and 10.6 weeks, respectively). Weight, length, and head circumference were not significantly different between groups A and B at 12 months' CA. Compared with groups A and B, infants in group C had a higher increase in weight z score until term and in length z score until 6 months' CA. At 12 months' CA, boys in group C were significantly longer and heavier compared with those in groups A and B, whereas girls in group C were longer and heavier compared with those in group A only. A higher protein intake was related to a higher serum urea nitrogen level and growth., Conclusions: Fortification of mother's milk after hospital discharge while breastfeeding very preterm infants was possible without influencing breastfeeding duration but did not significantly influence growth parameters at 1 year of age compared with unfortified mother's milk.

In the last five years, our knowledge about the heterogenous syndrome of congenital hyperinsulinism (HI) has expanded explosively. HI may be familiar or sporadic, mild or severe, transitory or persistent, and histologically focal or diffuse. At least 63 disease-causing mutations have been found in the genes for the beta cell's ATP-dependent potassium channel, whose elements are the sulphonylurea receptor, SUR1, and Kir6.2. Other mutations cause enhancement of the glucose-stimulated ATP production in the beta cell. The resulting non-functional, or closed, potassium channel causes hypersecretion of insulin. Genetic screening has succeeded in detecting mutations in less than 50% of HI-patients. Genotype-phenotype relations, diagnosis and treatment are reviewed.

So far, gestational diabetes treated with tolbutamide has never been associated with severe hypoglycaemia in the newborn when the mother's diabetes was well controlled. We report a case of a premature neonate, gestational age 34 weeks, with severe and long-standing hypoglycaemia from birth. The mother had well-controlled gestational diabetes, treated with tolbutamide from the 24th week of gestation until delivery. The neonate had inappropriately high levels of serum proinsulin, insulin and C-peptide relative to blood glucose concentrations. From day 19 after birth, the levels were normalized. Serum tolbutamide was 140.6 micromol/l (38 microg/ml) at 3 h after birth. Zero-order kinetics were seen during the first 90 postnatal hours. The half-life of serum tolbutamide decreased from 46 to 6 h. It is suggested that tolbutamide, when given to the mother until delivery, may cause severe and prolonged hyperinsulinaemic hypoglycaemia in premature neonates. The initially prolonged tolbutamide half-lives and zero-order kinetics suggest immaturity of hepatic elimination during the first 2 days of postnatal life.

The acute diagnostic procedures in caustic ingestion are primarily directed towards the recognition of life-threatening complications such as airway obstruction, perforation of inner organs and, in severe acid ingestion, metabolic acidosis. The endoscopic injury grading forms the basis of a differentiated treatment. Not all patients need endoscopic evaluation; the indications are discussed. The treatment is controversial. Fluid given orally is recommended within few minutes of ingestion, and thus rarely administered at the arrival to the hospital. Here, the task is to secure the vital functions and to relieve pain. The prevention of oesophageal stricture in deep, (near)-circumferential ulcerations is essential for the further treatment. Once-formed strictures are usually treated with dilatation.

A 16 year retrospective review identified 179 patients hospitalized for ingestion of caustic products in Aarhus County, Denmark. Seventy-five were adults over 15 years of age and residents of Aarhus County. The average annual incidence rate of hospitalization for caustic injury in adults was 1/100,000 with an incidence of esophageal burns of 0.8/100,000/y. Of the adults 61% attempted suicide: of these 61% were women. The annual incidence rate for adult women attempting suicide had an increasing trend (p = 0.048). Changes of the incidence rate for unintentional ingestions and for male suicide attempts were not significant. More than half of the suicide attempts were by patients with a history of a psychiatric illness. Of the caustics ingested by adults 94% were liquids. Acids accounted for 55% of the ingested products. Suicidal ingestion of hydrochloric acid was fatal in 6 of 12 adults. The inavailability of liquid caustics in the homes of patients at suicidal risk might prevent impulsive ingestion.

The incidence of caustic ingestion varies with the availability of caustic products and preventive measures. A transient increase was seen in the US round 1970, in Denmark in the late seventies. Diagnosis and treatment of caustic ingestion injuries remains controversial, and must to a high degree be based on retrospective studies and animal studies, especially concerning the pathology and clinical course of the disease. These subjects are reviewed together with complications and prognosis. It is stressed, that ingestion of alkalies and acids result in a variety of lesions, depending on a number of factors listed. Ingestion of alkalies occurs in approximately 85% of all cases, with oesophageal stricture as the most frequent complication, and tracheal necrosis as the most frequent cause of death. Ingestion of acid in large amounts may lead to early gastric perforation, massive metabolic acidosis, and eventual death. Pyloric stenosis is the most common complication of acid ingestion. Approximately 33% of all patients admitted with (suspected) caustic injury reveal oesophageal damage. This leads to subsequent oesophageal stricture in 10-15%. Mortality is less than 10% in unselected groups.

A commissural-associational entorhino-entorhinal projection in the guinea pig was analyzed using anterograde and retrograde axonal tracing techniques. The projection originated in layer II and terminated in layer Ia of both the medial entorhinal area (MEA) and the lateral entorhinal area (LEA). A few cells in other layers, especially layer III, also contributed to the commissural system. The projection was largely homotopic with the exception of the most medial MEA, which projected ventrally like previously described projections from the para- and presubiculum to the superficial layers of the entorhinal area. The commissural fibers crossed the midline in the dorsal hippocampal commissure. The antero-posterior position of the fibers within the commissure reflected the ventrodorsal position of their origin in the entorhinal area.