Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations

Objective: The phenotype associated with heterozygous HNF4A gene mutations has recently been extended to include diazoxide responsive neonatal hypoglycemia in addition to maturity-onset diabetes of the young (MODY). To date, mutation screening has been limited to patients with a family history consistent with MODY. In this study, we investigated the prevalence of HNF4A mutations in a large cohort of patients with diazoxide responsive hyperinsulinemic hypoglycemia (HH). Subjects and methods: We sequenced the ABCC8, KCNJ11, GCK, GLUD1, and/or HNF4A genes in 220 patients with HH responsive to diazoxide. The order of genetic testing was dependent upon the clinical phenotype. Results: A genetic diagnosis was possible for 59/220 (27%) patients. KATP channel mutations were most common (15%) followed by GLUD1 mutations causing hyperinsulinism with hyperammonemia (5.9%), and HNF4A mutations (5%). Seven of the 11 probands with a heterozygous HNF4A mutation did not have a parent affected with diabetes, and four de novo mutations were confirmed. These patients were diagnosed with HI within the first week of life (median age 1 day), and they had increased birth weight (median +2.4 SDS). The duration of diazoxide treatment ranged from 3 months to ongoing at 8 years. Conclusions: In this large series, HNF4A mutations are the third most common cause of diazoxide responsive HH. We recommend that HNF4A sequencing is considered in all patients with diazoxide responsive HH diagnosed in the first week of life irrespective of a family history of diabetes, once KATP channel mutations have been excluded

Hypoadiponectinemia in Extremely Low Gestational Age Newborns with Severe Hyperglycemia – A Matched-Paired Analysis

BACKGROUND: Hyperglycemia is commonly observed in extremely low gestational age newborns (ELGANs) and is associated with both increased morbidity and mortality. The objective of this study was to examine the relationship between neonatal hyperglycemia and adiponectin levels in ELGANs. METHODOLOGY/PRINCIPAL FINDINGS: Ten preterm infants between 22+6/7 and 27+3/7 weeks' gestation with neonatal hyperglycemia (defined as pre-feeding blood glucose levels above 200mg/dl on two consecutive measurements with a maximum parenteral glucose infusion of 4 mg/kg*min(-1)) formed the case cohort of this study. To every single patient of this case cohort a patient with normal fasting ( = pre-feeding) blood glucose levels was matched in terms of gestational age and gender. Adiponectin ELISAs were performed both at onset of hyperglycemia and at term-equivalent age. In the case cohort 9/10 patients had to be treated with insulin for 1-26 days (range 0.01-0.4 IU/kg*h(-1)). Compared to matched-paired controls, significant hypoadiponectinemia was observed at onset of hyperglycemia in these affected patients (6.9 µg/ml versus 15.1 µg/ml, p = 0.009). At term equivalent age, normoglycemia without any insulin treatment was found in both groups. Moreover, adiponectin levels at that time were no longer significantly different (12.3 µg/ml versus 20.0 µg/ml; p = 0.051) possibly indicating a mechanistic relevance of this adipokine in regulating insulin sensitivity in ELGANs. CONCLUSIONS/SIGNIFICANCE: Decreased circulating adiponectin levels are correlated with hyperglycemia in ELGANs and may contribute to the pathogenesis of impaired glucose homeostasis in these infants. These findings suggest that adiponectin might be a potential future drug target for the potentially save treatment of hyperglycemia in pre-term infants

Congenital Diarrhea and Cholestatic Liver Disease: Phenotypic Spectrum Associated with MYO5B Mutations.

Myosin Vb (MYO5B) is a motor protein that facilitates protein trafficking and recycling in polarized cells by RAB11- and RAB8-dependent mechanisms. Biallelic MYO5B mutations are identified in the majority of patients with microvillus inclusion disease (MVID). MVID is an intractable diarrhea of infantile onset with characteristic histopathologic findings that requires life-long parenteral nutrition or intestinal transplantation. A large number of such patients eventually develop cholestatic liver disease. Bi-allelic MYO5B mutations are also identified in a subset of patients with predominant early-onset cholestatic liver disease. We present here the compilation of 114 patients with disease-causing MYO5B genotypes, including 44 novel patients as well as 35 novel MYO5B mutations, and an analysis of MYO5B mutations with regard to functional consequences. Our data support the concept that (1) a complete lack of MYO5B protein or early MYO5B truncation causes predominant intestinal disease (MYO5B-MVID), (2) the expression of full-length mutant MYO5B proteins with residual function causes predominant cholestatic liver disease (MYO5B-PFIC), and (3) the expression of mutant MYO5B proteins without residual function causes both intestinal and hepatic disease (MYO5B-MIXED). Genotype-phenotype data are deposited in the existing open MYO5B database in order to improve disease diagnosis, prognosis, and genetic counseling

Pharmacological Neuroprotection of the Preterm Brain: Current Evidence and Perspectives

Despite improvements in viability, the long-term neurodevelopmental outcomes of preterm babies remain serious concern as a significant percentage of these infants develop neurological and/or intellectual impairment, and they are also at increased risk of psychiatric illnesses later in life. The current challenge is to develop neuroprotective approaches to improve adverse outcomes in preterm survivors. The purpose of this review was to provide an overview of the current evidence on pharmacological agents targeting the neuroprotection of the preterm brain. Among them, magnesium sulfate, given antenatally to pregnant women with imminent preterm birth before 30 to 34 weeks of gestation, as well as caffeine administered to preterm infants after birth, exhibited neuroprotective effects for human preterm brain. Erythropoietin treatment of preterm infants did not result in neuroprotection at 2 years of age in two out of three published large randomized controlled trials; however, long-term follow-up of these infants is needed to come to definite conclusions. Further studies are also required to assess whether melatonin, neurosteroids, inhaled nitric oxide, allopurinol, or dietary supplements (omega-3 fatty acids, choline, curcumin, etc.) could be implemented as neuroprotectants in clinical practice. Furthermore, other pharmacological agents showing promising signs of neuroprotective efficacy in preclinical studies (growth factors, hyaluronidase inhibitors or treatment, antidiabetic drugs, cannabidiol, histamine-H3 receptor antagonists, etc.), as well as stem cell-or exosomal-based therapies and nanomedicine, may prove useful in the future as potential neuroprotective approaches for human preterm brain. Key Points Magnesium and caffeine have neuroprotective effects for the preterm brain. Follow-up of infants treated with erythropoietin is needed. Neuroprotective efficacy of several drugs in animals needs to be shown in humans. © 2020 Georg Thieme Verlag. All rights reserved

Disparities of infant and neonatal mortality trends in Greece during the years of economic crisis by ethnicity, place of residence and human development index: a nationwide population study

OBJECTIVE: To study trends of infant mortality rate (IMR) and neonatal mortality rate in Greece during the period 2004-2016 and explore the role of sociodemographic factors in the years of crisis. DESIGN: Nationwide individual data for live births and infant (0-11 months) deaths provided by the Hellenic Statistical Authority were examined using Poisson, joinpoint regression and interrupted time series (ITS) analyses. SETTING: Greece. PARTICIPANTS: All infant deaths (n=4862) over the 13-year period, of which 87.2% were born to Greek mothers, and respective live births. MAIN OUTCOME MEASURES: Evolution of IMR (0-364 days), early (<7 days) neonatal mortality rate (ENMR), late (7-27 days) neonatal mortality rate (LNMR) and post neonatal (28-364 days) mortality rate (PNMR) trends, by maternal nationality, place of residence and Human Development Index (HDI). RESULTS: By Poisson regression, overall, during the study period, among infants of Greek mothers, IMR and PNMR declined significantly (-0.9%; 95% CI -1.7% to -0.1% and -1.6%; -3.0% to -0.2% annually, respectively), although differentially by place of residence (IMRurban: -2.1%; -2.9% to -1.3%, IMRrural: +10.6%; 7.6% to 13.6%). By contrast, among infants of non-Greek mothers, the low starting IMR/ENMR/LNMR/PNMR increased significantly (max ENMR:+12.5%; 8.6% to 16.5%) leading to a non-significant time-trend pattern overall in Greece. The inverse associations of HDI with IMR, ENMR and PNMR were restricted to Greek mothers' infants. Joinpoint regression analyses among Greek mothers' infants indicated non-significant increasing trends of IMR and ENMR following the crisis (+9.3%, 2012-2016, p=0.07 and +10.2%, 2011-2016, p=0.06, respectively). By contrast, the high (+17.1%; 8.1% to 26.9%, p=0.002) IMR increases among non-Greek infants were restricted to 2004-2011 and equalised to those of Greek mothers' infants thereafter. ITS analyses in preset years (2008, 2010, 2012) identified significantly increasing trends in IMR, LNMR and PNMR after 2012, and in ENMR after 2010, among Greek mothers' infants. CONCLUSIONS: HDI and rural residence were significantly associated with IMR. The strongly decreasing IMR trends among Greek-mothers' infants were stagnated after a lag time of ~4 years of crisis approximating the previously sharply increasing trends among non-Greeks

Impact of cerebrospinal fluid syndromic testing in the management of children with suspected central nervous system infection

The aim of the study was to evaluate the impact of the use of BioFire® FilmArray® meningitis/encephalitis(FA-ME) panel which enables rapid automated CSF testing for 14 common viral, bacterial, and yeast pathogens that cause CNS infections, in the management of children with suspected CNS infection. A prospective cohort study was performed on children admitted to a tertiary pediatric hospital, over a period of 1 year, with possible CNS infection and CSF pleocytosis (&amp;gt; 15 cells/mm3). Children were randomized 1:1, either to use FA-ME or separate molecular CSF microbiological tests according to usual pediatric practice in the hospital. Length of hospital stay, duration of antimicrobials, and total cost of hospitalization were compared between groups. A total of 142 children were included in the study (71 cases). A pathogen was detected in 37/71(52.1%) children with the use of FA-ME and in 16/71(22.5%) in the control group (P value &amp;lt; 0.001). In aseptic meningitis cases a virus was detected in 27/61(44.2%) and in 11/66(16.7%) controls (P value &amp;lt; 0.001). Median (IQR) length of stay in cases and controls with aseptic meningitis was 5(4–8) and 8(6–10) days, respectively (P value &amp;lt; 0. 001). The median (IQR) duration of antimicrobials in cases and controls was 4(2–5.7) and 7(5–10) days, respectively (P value &amp;lt; 0.001). The hospitalization cost was calculated in cases and controls 1042€ (932–1372) and 1522€ (1302–1742), respectively (P value &amp;lt; 0.001). The use of FA-ME was able to reduce significantly the use of antimicrobials, the hospitalization days, and the total cost comparing to the control group in children with suspected CNS infection. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature

Serum lipids in preterm infants fed a formula supplemented with nucleotides

Background: The effect of dietary nucleotides on lipid metabolism has been the subject of clinical studies with conflicting results. We measured serum triglycerides, total cholesterol (total-C), and lipoprotein cholesterol levels (HDL-C, LDL-C, and VLDL-C) in preterm neonates fed formula with and without nucleotide supplements. Methods: This prospective, randomized, controlled study included 150 healthy preterm neonates (gestational age, 33.0 +/- 1.9 weeks) matched for gestational age, birth weight, and gender. Subjects were assigned at birth to receive either a standard milk formula supplemented with nucleotides (group F-NT) or the same formula without nucleotides (group F). Serum was obtained before discharge (29.1 +/- 10.0 days of life) and triglycerides, total-C, and HDL-C were determined enzymatically. LDL-C and VLDL-C were estimated by the Friedewald formula. For statistical analysis t test, Mann Whitney-U test, two-way ANOVA, and chi(2) test were used, as appropriate. The influence of several factors on serum lipid levels was evaluated by linear regression analysis. Results: Serum triglycerides, total-C, and VLDL-C levels did not differ between groups. HDL-C levels (median; 25th-75th percentiles) were significantly higher (P &lt; 0.001) in group F-NT (48.0 mg/dL; 40.5-57.0 mg/dL) than in group F (34.5 mg/dL; 27.2-44.0 mg/dL). On the contrary, LDL-C levels (median; 25th-75th percentiles) were significantly lower (P &lt; 0.001) in group F-NT (39.0 mg/dL; 26.0-54.0 mg/dL) than in group F (65.0 mg/dL; 41.0-73.0 mg/dL). In the multiple regression analysis, nucleotide supplementation was identified as one of the controlled independent factors influencing serum HDL-C and LDL-C levels. Conclusions: Preterm neonates fed from birth with formula supplemented with nucleotides have significantly higher HDL-C and lower LDL-C serum levels than do neonates fed unsupplemented formula. The clinical relevance of these results remains to be elucidated