RPL26 variants: A rare cause of Diamond-Blackfan anemia syndrome with multiple congenital anomalies at the forefront.

PURPOSE: Diamond-Blackfan anemia syndrome (DBS) is a rare congenital disorder originally characterized by bone marrow failure with or without various congenital anomalies. At least 24 genes are implicated, the vast majority encoding for ribosomal proteins. RPL26 (ribosomal protein L26) is an emerging candidate (DBA11, MIM#614900). We aim to further delineate this rare condition. METHODS: Patients carrying heterozygous RPL26 variants were recruited. In one of them, erythroid proliferation and differentiation from peripheral blood CD34+ cells were studied by flow cytometry, and RPL26 expression by quantitative reverse transcription polymerase chain reaction and immunoblotting. RESULTS: We report on 8 affected patients from 4 families. Detailed phenotyping reveals that RPL26 is mainly associated with multiple congenital anomalies (particularly radial ray anomalies), albeit with variable expression. Mandibulofacial dysostosis and neural tube defects are potential features in DBA11, expanding the growing list of DBS abnormalities. In 1 individual, we showed that RPL26 haploinsufficiency was responsible for subclinical impairment in erythroid proliferation and enucleation. The absence of hematological involvement in 4 adults from this series contributes to the mounting evidence that bone marrow failure is not universally central to all DBS genes. CONCLUSION: We confirm RPL26 as a DBS gene and expand the phenotypic spectrum of the gene and the disease.

DNA methylation episignature, extension of the clinical features, and comparative epigenomic profiling of Hao-Fountain syndrome caused by variants in USP7.

PURPOSE: Hao-Fountain syndrome (HAFOUS) is a neurodevelopmental disorder caused by pathogenic variants in USP7. HAFOUS is characterized by developmental delay, intellectual disability, speech delay, behavioral abnormalities, autism spectrum disorder, seizures, hypogonadism, and mild dysmorphic features. We investigated the phenotype of 18 participants with HAFOUS and performed DNA methylation (DNAm) analysis, aiming to generate a diagnostic biomarker. Furthermore, we performed comparative analysis with known episignatures to gain more insight into the molecular pathophysiology of HAFOUS. METHODS: We assessed genomic DNAm profiles of 18 individuals with pathogenic variants and variants of uncertain significance (VUS) in USP7 to map and validate a specific episignature. The comparison between the USP7 cohort and 56 rare genetic disorders with earlier reported DNAm episignatures was performed with statistical and functional correlation. RESULTS: We mapped a sensitive and specific DNAm episignature for pathogenic variants in USP7 and utilized this to reclassify the VUS. Comparative epigenomic analysis showed evidence of HAFOUS similarity to a number of other rare genetic episignature disorders. CONCLUSION: We discovered a sensitive and specific DNAm episignature as a robust diagnostic biomarker for HAFOUS that enables VUS reclassification in USP7. We also expand the phenotypic spectrum of 9 new and 5 previously reported individuals with HAFOUS.

High flow nasal cannula versus standard low flow nasal oxygen during flexible bronchoscopy in children: A randomized controlled trial.

BACKGROUND: Hypoxemia is the most frequent complication of fiberoptic bronchoscopy (FB) in children. Guidelines recommend oxygen supplementation and conventional nasal prongs (NC) are used for this purpose. The aim of this study was to evaluate if the use of high-flow nasal cannula therapy (HFNC) in children undergoing FB result in a lower incidence of hypoxemia than standard oxygen administration. METHODS: Patients aged 1 month-16 years undergoing elective FB were included in a prospective randomized controlled, nonblinded, single-center clinical trial and randomly assigned to receive oxygen via NC or HFNC. Patients' baseline characteristics were recorded pre-bronchoscopy. The primary outcome was oxygen desaturation during the procedure defined as saturation less than 94%. RESULTS: An intention to treat analysis for 53 patients receiving NC and 51 receiving HFNC, showed HFNC patients were less likely to have hypoxemia than were NC patients (p = .011), with an absolute risk reduction of 0.27 (95% confidence interval [CI]: 0.08-0.45) and a number needed to treat of 3.75 (95% CI: 2.22-12.04). Moderate hypoxemia (SpO2 ≥ 90% and <94%, and <60 s) was observed significantly less often with HFNC than with NC (p = .012). Severe hypoxemia (SpO2 < 90% and >30 s) was not different between groups. Patients undergoing bronchoalveolar lavage (BAL) presented fewer desaturations with HFNC (p = .0003). CONCLUSIONS: HFNC offers optimized oxygenation during elective FB with a significant reduction in desaturations and can be considered for oxygen administration, especially when BAL is performed.

Early Identification of Prolonged QT Interval for Prevention of Sudden Infant Death.

Introduction: Long QT syndrome is the main arrhythmogenic disease responsible for sudden death in infants, especially in the first days of life. Performing an electrocardiogram in newborns could enable early diagnosis and adoption of therapeutic measures focused on preventing lethal arrhythmogenic events. However, the inclusion of an electrocardiogram in neonatal screening protocols still remains a matter of discussion. To comprehensively analyse the potential clinical value of performing an electrocardiogram and subsequent follow-up in a cohort of newborns. Methods: Electrocardiograms were performed in 685 neonates within the first week of life. One year follow-up was performed if QTc > 450 ms identified. Comprehensive genetic analysis using massive sequencing was performed in all cases with QTc > 470 ms. Results: We identified 54 neonates with QTc > 450 ms/ <470 ms; all normalized QTc values within 6 months. Eight cases had QTc > 480 ms at birth and, if persistent, pharmacological treatment was administrated during follow-up. A rare variant was identified as the potential cause of long QT syndrome in five cases. Three cases showed a family history of sudden arrhythmogenic death. Conclusions: Our prospective study identifies 0.14% of cases with a definite long QT, supporting implementation of electrocardiograms in routine pediatric protocols. It is an effective, simple and non-invasive approach that can help prevent sudden death in neonates and their relatives. Genetic analyses help to unravel the cause of arrhythmogenic disease in diagnosing neonates. Further, clinical assessment and genetic analysis of relatives allowed early identification of family members at risk of arrhythmias helping to adopt preventive personalized measures.

Therapeutic Effects of Catechins in Less Common Neurological and Neurodegenerative Disorders.

In recent years, neurological and neurodegenerative disorders research has focused on altered molecular mechanisms in search of potential pharmacological targets, e.g., imbalances in mechanisms of response to oxidative stress, inflammation, apoptosis, autophagy, proliferation, differentiation, migration, and neuronal plasticity, which occur in less common neurological and neurodegenerative pathologies (Huntington disease, multiple sclerosis, fetal alcohol spectrum disorders, and Down syndrome). Here, we assess the effects of different catechins (particularly of epigalocatechin-3-gallate, EGCG) on these disorders, as well as their use in attenuating age-related cognitive decline in healthy individuals. Antioxidant and free radical scavenging properties of EGCG -due to their phenolic hydroxyl groups-, as well as its immunomodulatory, neuritogenic, and autophagic characteristics, makes this catechin a promising tool against neuroinflammation and microglia activation, common in these pathologies. Although EGCG promotes the inhibition of protein aggregation in experimental Huntington disease studies and improves the clinical severity in multiple sclerosis in animal models, its efficacy in humans remains controversial. EGCG may normalize DYRK1A (involved in neural plasticity) overproduction in Down syndrome, improving behavioral and neural phenotypes. In neurological pathologies caused by environmental agents, such as FASD, EGCG enhances antioxidant defense and regulates placental angiogenesis and neurodevelopmental processes. As demonstrated in animal models, catechins attenuate age-related cognitive decline, which results in improvements in long-term outcomes and working memory, reduction of hippocampal neuroinflammation, and enhancement of neuronal plasticity; however, further studies are needed. Catechins are valuable compounds for treating and preventing certain neurodegenerative and neurological diseases of genetic and environmental origin. However, the use of different doses of green tea extracts and EGCG makes it difficult to reach consistent conclusions for different populations.

Toxic Elements in Traditional Kohl-Based Eye Cosmetics in Spanish and German Markets.

Kohl is a traditional cosmetic widely used in Asia and Africa. In recent years, demand for kohl-based eyelids and lipsticks has increased in Europe, linked to migratory phenomena of populations from these continents. Although the European legislation prohibits the use of heavy metals in cosmetics due to the harmful effects to human health, particularly to pregnant women and children, these elements are still present in certain products. The European Union recommended levels are Pb < 20 ppm, As < 5 ppm, Cd < 5 ppm, Sb < 100 ppm, and Ni < 200 ppm. In Germany, levels are more restrictive: Pb < 2 ppm, As < 0.5 ppm, Cd < 0.1 ppm, Sb < 0.5 ppm, and Ni < 10 ppm. Here, we analyzed 12 kohl-based cosmetics in different presentations (powder, paste, and pencil) that were purchased in Spanish and German local shops. An inductively coupled plasma optical emission spectrophotometer was used to identify toxic elements and heavy metals. Levels of Pb ranged between 1.7 and 410,000 ppm in six of the study samples, four of which had levels above the recommended limit of at least two heavy metals. Arsenic (a carcinogenic element) values were within the range allowed by the EU in only 58% of the studied samples. Moreover, two products doubled this limit, reaching levels of 9.2 and 12.6 ppm. In one of the products, cadmium, related to toxic keratitis, was four times higher (20.7 ppm) than that allowed, while in two other products, these limits were doubled (11.8 and 12.7 ppm). Our results indicate the need to supervise the manufacture of kohl-based traditional products and the analysis of their composition prior distribution in European countries.

The effect of intestinal glucose load on neural regulation of food craving.

Objectives: Excess sugar consumption, particularly in the form of sweetened beverages, has been identified as a pivotal contributor to the epidemic of obesity and associated metabolic disorders. However, the impact of sugar-sweetened beverages on food craving is still inconclusive. Therefore, the present study aimed to specifically investigate the effects of an intestinal glucose load on neural processing of food cues. Methods: Using a single-blind fMRI design, 26 normal-weight women were scanned on two occasions, after receiving either a glucose or water infusion directly into the stomach using a nasogastric tube, without being aware of the type of infusion. Participants had to either view neutral and food images, or were asked to distract themselves from these images by solving an arithmetic task. Results: In response to viewing high-caloric food cues, we observed increased activation in reward-related brain areas. During food distraction, fronto-parietal brain regions were recruited, which are commonly related to attentional deployment and hedonic valuation. Furthermore, activity in the dorsolateral prefrontal cortex showed increased functional connectivity with the insula and was correlated with subjective craving levels to food cues. Despite an increase of blood glucose levels in response to the glucose compared to the water infusion, neither subjective food craving nor neural regulation of food craving showed significant differences. Conclusions: These findings support a decreased satiation effect of sweet beverages, as intestinal glucose ingestion and signalling showed no significant effect on cortical brain circuits associated with food craving. This trial was registered at clinicaltrials.gov as NCT03075371.

Probiotic Supplementation During the Perinatal and Infant Period: Effects on Gut Dysbiosis and Disease.

The perinatal period is crucial to the establishment of lifelong gut microbiota. The abundance and composition of microbiota can be altered by several factors such as preterm delivery, formula feeding, infections, antibiotic treatment, and lifestyle during pregnancy. Gut dysbiosis affects the development of innate and adaptive immune responses and resistance to pathogens, promoting atopic diseases, food sensitization, and infections such as necrotizing enterocolitis (NEC). Recent studies have indicated that the gut microbiota imbalance can be restored after a single or multi-strain probiotic supplementation, especially mixtures of Lactobacillus and Bifidobacterium strains. Following the systematic search methodology, the current review addresses the importance of probiotics as a preventive or therapeutic tool for dysbiosis produced during the perinatal and infant period. We also discuss the safety of the use of probiotics in pregnant women, preterm neonates, or infants for the treatment of atopic diseases and infections.

Neuroimaging of hypothalamic mechanisms related to glucose metabolism in anorexia nervosa and obesity.

BACKGROUNDGiven the heightened tolerance to self-starvation in anorexia nervosa (AN), a hypothalamic dysregulation of energy and glucose homeostasis has been hypothesized. Therefore, we investigated whether hypothalamic reactivity to glucose metabolism is impaired in AN.METHODSTwenty-four participants with AN, 28 normal-weight participants, and 24 healthy participants with obesity underwent 2 MRI sessions in a single-blind, randomized, case-controlled crossover study. We used an intragastric infusion of glucose and water to bypass the cephalic phase of food intake. The responsivity of the hypothalamus and the crosstalk of the hypothalamus with reward-related brain regions were investigated using high-resolution MRI.RESULTSNormal-weight control participants displayed the expected glucose-induced deactivation of hypothalamic activation, whereas patients with AN and participants with obesity showed blunted hypothalamic reactivity. Furthermore, patients with AN displayed blunted reactivity in the nucleus accumbens and amygdala. Compared with the normal-weight participants and control participants with obesity, the patients with AN failed to show functional connectivity between the hypothalamus and the reward-related brain regions during water infusion relative to glucose infusion. Finally, the patients with AN displayed typical baseline levels of peripheral appetite hormones during a negative energy balance.CONCLUSIONThese results indicate that blunted hypothalamic glucose reactivity might be related to the pathophysiology of AN. This study provides insights for future research, as it is an extended perspective of the traditional primary nonhomeostatic understanding of the disease.FUNDINGThis study was supported by a grant from the DFG (SI 2087/2-1).

Assessment of portable oxygen concentrators in infants undergoing hypoxic challenge testing. A randomised controlled crossover trial.

AIM: Due to reduced PaO2 , aircrafts at cruising altitudes are pressurised to a cabin altitude of 2438 m, equivalent to breathing FiO2 0.15. Portable oxygen concentrators (POCs) are approved for onboard oxygen supply with lack of evidence, especially in infants. We assessed POCs (continuous-flow cPOC vs. pulsed-flow pPOC) under simulated altitude conditions performing Hypoxic Challenge Testing (HCT). METHODS: In a randomised controlled crossover trial, we included patients <1 year born prematurely. In incidents of hypoxia (SpO2  ≤ 85%), oxygen was administered through POC. In patients with a positive hypoxia reversal, HCT was repeated 24 hours later. If hypoxia occurred during the second testing, oxygen was given using the alternative POC. RESULTS: We randomised 26 patients; 22 patients received allocated intervention (4 dropped out). Mean gestational age 30.4 weeks, mean corrected age 38.2 weeks. Both POCs achieved immediate hypoxia reversal in all cases (SpO2 cPOC/pPOC 98%/99.4% (95%CI -2.91, 0.01)) without any adverse events. No significant difference was observed in patients with BPD. CONCLUSION: Both POCs generated sufficient oxygen to reverse HCT induced hypoxia. Although pPOCs are not recommended in paediatric age, our data suggest their effectiveness even in neonates without any associated adverse events. Future research on pPOCs safety is required to establish recommendations for their use.

The Evolving Microbiome from Pregnancy to Early Infancy: A Comprehensive Review.

Pregnancy induces a number of immunological, hormonal, and metabolic changes that are necessary for the mother to adapt her body to this new physiological situation. The microbiome of the mother, the placenta and the fetus influence the fetus growth and undoubtedly plays a major role in the adequate development of the newborn infant. Hence, the microbiome modulates the inflammatory mechanisms related to physiological and pathological processes that are involved in the perinatal progress through different mechanisms. The present review summarizes the actual knowledge related to physiological changes in the microbiota occurring in the mother, the fetus, and the child, both during neonatal period and beyond. In addition, we approach some specific pathological situations during the perinatal periods, as well as the influence of the type of delivery and feeding.

Impact of Nicotine Replacement and Electronic Nicotine Delivery Systems on Fetal Brain Development.

Maternal tobacco smoking during pregnancy remains a major public health issue. The neurotoxic properties of nicotine are associated with fetal neurodevelopmental disorders and perinatal morbimortality. Recent research has demonstrated the effects of nicotine toxicity on genetic and epigenetic alterations. Smoking cessation strategies including nicotine replacement therapy (NRT) and electronic nicotine delivery systems (ENDS) show lack of clear evidence of effectiveness and safety in pregnant women. Limited trials using randomized controls concluded that the intermittent use formulation of NRT (gum, sprays, inhaler) in pregnant women is safe because the total dose of nicotine delivered to the fetus is less than continuous-use formulations (transdermal patch). Electronic nicotine delivery systems (ENDS) were hyped as a safer alternative during pregnancy. However, refill liquids of ENDS are suspected to be cytotoxic for the fetus. Animal studies revealed the impact of ENDS on neural stem cells, showing a similar risk of pre- and postnatal neurobiological and neurobehavioral disorders to that associated with the exposure to traditional tobacco smoking during early life. There is currently no clear evidence of impact on fetal brain development, but recent research suggests that the current guidelines should be reconsidered. The safety of NRT and ENDS is increasingly being called into question. In this review, we discuss the special features (pharmacodynamics, pharmacokinetics, and metabolism) of nicotine, NRT, and ENDS during pregnancy and postnatal environmental exposure. Further, we assess their impact on pre- and postnatal neurodevelopment.

Serum concentrations of IGF-I/IGF-II as biomarkers of alcohol damage during foetal development and diagnostic markers of Foetal Alcohol Syndrome.

Foetal Alcohol Syndrome (FAS) is the most deleterious health effect derived from alcohol consumption during pregnancy and is placed at the end of the Foetal Alcohol Spectrum Disorders (FASD). Few studies have proposed potential molecular biomarkers of physical and neurological damage associated with prenatal alcohol exposure. We prospectively recruited 55 children from 8 to 12 years old, with a prenatal assessment for ethanol exposure using meconium analysis of fatty acid ethyl esters (FAEE). The control group was established for FAEE < 2 nmol/g (n = 31) and a Prenatal Ethanol Exposure (PEE) group for FAEEs > 2 nmol/g (n = 33). Moreover, 98 children adopted from Eastern European Countries (EEC) were also recruited to evaluate FASD diagnosis comprising 31 cases with complete FAS, 42 with partial FAS, 6 with ARBD and 5 with ARND. Serum values of IGF-I and IGF-II for all children recruited were determined by immunoassay. Anthropometric and neurocognitive evaluation showed severe impairments in FAS children, moderate effects in PEE and no harmful effects in the control group with no prenatal exposure to alcohol. Analysis of IGF-I and IGF-II serum concentrations revealed that FASD from EEC as well as PEE children showed significantly lower concentrations of both IGF-I and IFG-II than the control group and reference values. Moreover, Spearman correlations showed a significant effect of IGF-I on anthropometric measurements in girls, whereas IGF-II affected the neuropsychological variables in both genders. These findings validate the use of growth factors IGF-I and IGF-II as surrogate biomarkers of damage induced by prenatal exposure to ethanol and could be used in the diagnosis of foetal alcohol spectrum disorders.

Non-instrumented DNA isolation, amplification and microarray-based hybridization for a rapid on-site detection of devastating Phytophthora kernoviae.

A rapid and simple instrument-free detection system was developed for the identification of the plant pathogen Phytophthora kernoviae (P. kernoviae). The on-site operable analysis steps include magnetic particle based DNA isolation, helicase-dependent amplification (HDA) and chip-based DNA hybridization. The isothermal approach enabled the convenient amplification of the yeast GTP-binding protein (Ypt1) target gene in a miniaturized HDA-zeolite-heater (HZH) by an exothermic reaction. The amplicon detection on the chip was performed under room temperature conditions ­ either by successive hybridization and enzyme binding or by a combined step. A positive signal is displayed by enzymatically generated silver nanoparticle deposits, which serve as robust endpoint signals allowing an immediate visual readout. The hybridization assay enabled the reliable detection of 10 pg µL(-1) target DNA. This is the first report of an entirely electricity-free, field applicable detection approach for devastating Phytophthora species, exemplarily shown for P. kernoviae.