Safety and efficacy of a probiotic-containing infant formula supplemented with 2'-fucosyllactose: a double-blind randomized controlled trial.

BACKGROUND: Human milk oligosaccharides (HMOs) have important and diverse biological functions in early life. This study tested the safety and efficacy of a starter infant formula containing Limosilactobacillus (L.) reuteri DSM 17938 and supplemented with 2'-fucosyllactose (2'FL). METHODS: Healthy infants < 14 days old (n = 289) were randomly assigned to a bovine milk-based formula containing L. reuteri DSM 17938 at 1 × 107 CFU/g (control group; CG) or the same formula with added 1.0 g/L 2'FL (experimental group; EG) until 6 months of age. A non-randomized breastfed group served as reference (BF; n = 60). The primary endpoint was weight gain through 4 months of age in the formula-fed infants. Secondary endpoints included additional anthropometric measures, gastrointestinal tolerance, stooling characteristics, adverse events (AEs), fecal microbiota and metabolism, and gut immunity and health biomarkers in all feeding groups. RESULTS: Weight gain in EG was non-inferior to CG as shown by a mean difference [95% CI] of 0.26 [-1.26, 1.79] g/day with the lower bound of the 95% CI above the non-inferiority margin (-3 g/day). Anthropometric Z-scores, parent-reported stooling characteristics, gastrointestinal symptoms and associated behaviors, and AEs were comparable between formula groups. Redundancy analysis indicated that the microbiota composition in EG was different from CG at age 2 (p = 0.050) and 3 months (p = 0.052), approaching BF. Similarly, between sample phylogenetic distance (weighted UniFrac) for BF vs EG was smaller than for BF vs CG at 3-month age (p = 0.045). At age 1 month, Clostridioides difficile counts were significantly lower in EG than CG. Bifidobacterium relative abundance in EG tracked towards that in BF. Fecal biomarkers and metabolic profile were comparable between CG and EG. CONCLUSION: L. reuteri-containing infant formula with 2'FL supports age-appropriate growth, is well-tolerated and may play a role in shifting the gut microbial pattern towards that of breastfed infants. TRIAL REGISTRATION: The trial was registered on ClinicalTrials.gov ( NCT03090360 ) on 24/03/2017.

Pathogenic correlation between mosaic variegated aneuploidy 1 (MVA1) and a novel BUB1B variant: a reappraisal of a severe syndrome.

BACKGROUND: The BUB 1 mitotic checkpoint serine/threonine kinase B (BUB1B) gene encodes a key protein in the mitotic spindle checkpoint, which acts as a surveillance mechanism, crucial for the maintenance of the correct chromosome number during cell deviation. Mutations of BUB1B gene are linked to mosaic variegated aneuploidy 1 (MVA1) syndrome, a rare autosomal recessive disorder characterized by widespread mosaic aneuploidies, involving different chromosomes and tissues. MVA1 is clinically characterized by intrauterine growth restriction, post-natal growth retardation, and severe neurologic impairment including microcephaly, developmental delay/intellectual disability, epileptic seizures, and generalized hypotonia. Malignancies are also serious sequelae associated with the disorder. We reported on a case of two-year-old Italian girl with MVA1 who shows severe neurologic impairment, microcephaly and epileptic seizures. MATERIALS AND METHODS: Clinical data collection and genetic diagnosis of the patient were assessed. Mutational analysis covers the chromosomal microarray analysis, the gene methylation pattern studied using the methylation-specific multiplex ligation-dependent probe amplification, and the family-based Whole Exome Sequencing (WES). A literature research based on reported cases of MVA and premature chromatid separation was also included. RESULTS: Karyotyping has revealed 12% of mosaics in the patient who carries a novel variant in BUB1B gene (c.2679A > T, p.Arg893Ser) detected by WES. Thirty-one cases of MVA1 including the present report, and four prenatally diagnosed cases with MVA1 were selected and inspected. CONCLUSION: Clinical and genetic findings reported in the girl strongly suggest a new MVA1 genotype-phenotype correlation and lead to a reappraisal of a severe syndrome. Diagnosis and in-depth follow-up provided worthwhile data.

Shotgun Proteomics of Isolated Urinary Extracellular Vesicles for Investigating Respiratory Impedance in Healthy Preschoolers.

Urine proteomic applications in children suggested their potential in discriminating between healthy subjects from those with respiratory diseases. The aim of the current study was to combine protein fractionation, by urinary extracellular vesicle isolation, and proteomics analysis in order to establish whether different patterns of respiratory impedance in healthy preschoolers can be characterized from a protein fingerprint. Twenty-one 3-5-yr-old healthy children, representative of 66 recruited subjects, were selected: 12 late preterm (LP) and 9 full-term (T) born. Children underwent measurement of respiratory impedance through Forced Oscillation Technique (FOT) and no significant differences between LP and T were found. Unbiased clustering, based on proteomic signatures, stratified three groups of children (A, B, C) with significantly different patterns of respiratory impedance, which was slightly worse in group A than in groups B and C. Six proteins (Tripeptidyl peptidase I (TPP1), Cubilin (CUBN), SerpinA4, SerpinF1, Thy-1 membrane glycoprotein (THY1) and Angiopoietin-related protein 2 (ANGPTL2)) were identified in order to type the membership of subjects to the three groups. The differential levels of the six proteins in groups A, B and C suggest that proteomic-based profiles of urinary fractionated exosomes could represent a link between respiratory impedance and underlying biological profiles in healthy preschool children.

Ketogenic diet for infants with epilepsy: A literature review.

The ketogenic diet (KD) is an established, nonpharmacological treatment for drug-resistant epilepsy (DRE). Actually, KD and its variants have been shown to be elective and resolute for patients with glucose transporter type 1 (GLUT1) deficiency. The aim of this review was to study the use of KD and its variants in infancy, including the neonatal age, and demonstrate the safety and efficacy of this treatment in patients with the age of 0-23 months affected by DRE already subjected to pharmacological approach attempts. A literature search was conducted using PubMed as the medical database source. We used the age limit of 0-23 months, and we considered only articles published between the years 2015 and 2018, in light of increasing interest worldwide in the use of KD and its variants to manage DRE. We included 52 publications: 1 Cochrane study, 22 retrospective studies, 9 prospective studies, 4 randomized controlled trials (RCTs), 12 clinical cases, and 4 clinical reviews. Literature data showed that KD and its variants are safe and useful in patients with the age of 0-23 months with DRE. Classical KD is of first choice in the treatment of GLUT1 deficiency. Earlier introduction of KD in GLUT1 promises a better outcome and a decrease in seizure frequency in these patients.

West syndrome: a comprehensive review.

Since its first clinical description (on his son) by William James West (1793-1848) in 1841, and the definition of the classical triad of (1) infantile spasms; (2) hypsarrhythmia, and (3) developmental arrest or regression as "West syndrome", new and relevant advances have been recorded in this uncommon disorder. New approaches include terminology of clinical spasms (e.g., infantile (IS) vs. epileptic spasms (ES)), variety of clinical and electroencephalographic (EEG) features (e.g., typical ictal phenomena without EEG abnormalities), burden of developmental delay, spectrum of associated genetic abnormalities, pathogenesis, treatment options, and related outcome and prognosis. Aside the classical manifestations, IS or ES may present with atypical electroclinical phenotypes (e.g., subtle spasms; modified hypsarrhythmia) and may have their onset outside infancy. An increasing number of genes, proteins, and signaling pathways play crucial roles in the pathogenesis. This condition is currently regarded as a spectrum of disorders: the so-called infantile spasm syndrome (ISs), in association with other causal factors, including structural, infectious, metabolic, syndromic, and immunologic events, all acting on a genetic predisposing background. Hormonal therapy and ketogenic diet are widely used also in combination with (classical and recent) pharmacological drugs. Biologically targeted and gene therapies are increasingly studied. The present narrative review searched in seven electronic databases (primary MeSH terms/keywords included West syndrome, infantile spasms and infantile spasms syndrome and were coupled to 25 secondary clinical, EEG, therapeutic, outcomes, and associated conditions terms) including MEDLINE, Embase, Cochrane Central, Web of Sciences, Pubmed, Scopus, and OMIM to highlight the past knowledge and more recent advances.

A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy.

Diseases associated with acquired or genetic defects in members of the chaperoning system (CS) are increasingly found and have been collectively termed chaperonopathies. Illustrative instances of genetic chaperonopathies involve the genes for chaperonins of Groups I (e.g., Heat shock protein 60, Hsp60) and II (e.g., Chaperonin Containing T-Complex polypeptide 1, CCT). Examples of the former are hypomyelinating leukodystrophy 4 (HLD4 or MitCHAP60) and hereditary spastic paraplegia (SPG13). A distal sensory mutilating neuropathy has been linked to a mutation [p.(His147Arg)] in subunit 5 of the CCT5 gene. Here, we describe a new possibly pathogenic variant [p.(Leu224Val)] of the same subunit but with a different phenotype. This yet undescribed disease affects a girl with early onset demyelinating neuropathy and a severe motor disability. By whole exome sequencing (WES), we identified a homozygous CCT5 c.670C>G p.(Leu224Val) variant in the CCT5 gene. In silico 3D-structure analysis and bioinformatics indicated that this variant could undergo abnormal conformation and could be pathogenic. We compared the patient's clinical, neurophysiological and laboratory data with those from patients carrying p.(His147Arg) in the equatorial domain. Our patient presented signs and symptoms absent in the p.(His147Arg) cases. Molecular dynamics simulation and modelling showed that the Leu224Val mutation that occurs in the CCT5 intermediate domain near the apical domain induces a conformational change in the latter. Noteworthy is the striking difference between the phenotypes putatively linked to mutations in the same CCT subunit but located in different structural domains, offering a unique opportunity for elucidating their distinctive roles in health and disease.

Congenital emphysematous lung disease associated with a novel Filamin A mutation. Case report and literature review.

BACKGROUND: Progressive lung involvement in Filamin A (FLNA)-related cerebral periventricular nodular heterotopia (PVNH) has been reported in a limited number of cases. CASE PRESENTATION: We report a new pathogenic FLNA gene variant (c.7391_7403del; p.Val2464Alafs*5) in a male infant who developed progressive lung disease with emphysematous lesions and interstitial involvement. Following lobar resection, chronic respiratory failure ensued necessitating continuous mechanical ventilation and tracheostomy. Cerebral periventricular nodular heterotopia was also present. CONCLUSIONS: We report a novel variant of the FLNA gene, associated with a severe lung disorder and PNVH. The lung disorder led to respiratory failure during infancy and these pulmonary complications may be the first sign of this disorder. Early recognition with thoracic imaging is important to guide genetic testing, neuroimaging and to define optimal timing of potential therapies, such as lung transplant in progressive lung disease.

High mobility group box 1 and markers of oxidative stress in human cord blood.

BACKGROUND: Parturition induces considerable oxidative stress and many inflammatory mediators, such as high mobility group box 1 (HMGB1), are involved from the beginning of the pregnancy to birth. The aim of the present study was to evaluate serum cord blood concentration of diacron-reactive oxygen metabolites (d-ROM), biological antioxidant potential (BAP), and HMGB1 to investigate the perinatal oxidative status of neonates and correlation with mode of delivery, as well as the influence of labor. METHODS: The subjects consisted of 214 neonates delivered at University Hospital "G. Martino", Messina, in a 6 months period. Venous blood samples were collected from the umbilical cord after cord separation. RESULTS: Umbilical cord venous blood HMGB1 was significantly higher in the spontaneous vaginal delivery (SVD) group than in the elective or emergency cesarean section (CS) group (P = 0.018). Regarding labor, there was no significant difference in HMGB1 concentration in umbilical vein blood between the spontaneous and induced labor groups (P = 0.250). Furthermore, d-ROM was significantly different between the SVD group and the elective or emergency CS group (P = 0.044). BAP concentration, however, was not significantly different, not even with regard to mode of labor. CONCLUSION: Oxidation is higher in newborns delivered by SVD than in those delivered by CS, and HMGB1 may be involved in the mechanisms of birth, and responsible for decidual modifications that lead to birth.

Methemoglobinemia Associated with Late-Onset Neonatal Sepsis: A Single-Center Experience.

OBJECTIVE: Methemoglobinemia (MetHb) is a rare congenital or acquired cause of infantile cyanosis. We examined the role of MetHb in a neonatal intensive care unit (NICU). STUDY DESIGN: A retrospective observational study was conducted reviewing blood gas analyses of hospitalized newborns over a 2-year period. MetHb-positive patients (MetHb >1.8%) were matched with a control group for gestational age, weight, disease, and illness severity at admission. Maternal, neonatal, clinical, and laboratory parameters were collected and analyzed in both groups. RESULTS: MetHb incidence was 6%. The mean MetHb in the case group was 7.2%, and the first positive samples were observed at a mean of 22 days of life, 6 days prior to clinical or culture-proven sepsis. We identified low maternal age (31 vs. 34 years; p = 0.038), sepsis (90 vs. 45%; p = 0.022), and protracted parenteral nutrition (46 vs. 23 days; p = 0.013) as risk factors for MetHb, and early minimal enteral feeding as protective factor (12th vs. 9th day; p = 0.038). CONCLUSION: MetHb has a high occurrence in NICU and can be a helpful prognostic indicator of an infectious process. Understanding and prompt identification of MetHb can allow pediatricians to implement a life-saving therapy.

Intestinal Involvement in Kawasaki Disease.

OBJECTIVES: To describe a case of Kawasaki disease with intestinal involvement and to analyze other published reports to define clinical characteristics, diagnostic issues, and therapeutic approaches of gastrointestinal involvement in Kawasaki disease. STUDY DESIGN: A computerized search without language restriction was conducted using PubMed and SCOPUS. An article was considered eligible for inclusion in the systematic review if it reported data on patient(s) with intestinal involvement in Kawasaki disease. Our case was also included in the analysis. RESULTS: Thirty-three articles reporting 48 cases of Kawasaki disease with intestinal involvement were considered. Fever, abdominal pain, and vomiting were the most frequent symptoms observed and typical Kawasaki disease signs and symptoms appeared after intestinal complaints in all cases. Plain radiographs, ultrasonography, and computed tomography showed pseudo-obstruction as the most frequent sign of gastrointestinal involvement; 25 patients underwent surgery. Cardiac involvement was documented in 21 cases. All but three patients received medical treatment with immunoglobulin intravenous or aspirin. The outcome was good in 28 patients; 7 patients showed persistence of coronary artery abnormalities; 1 patient developed cyanosis, and later, left hand and forefoot gangrene; 3 patients died. CONCLUSIONS: The diagnosis and treatment of Kawasaki disease might be delayed if intestinal symptoms appear before the characteristic clinical features of Kawasaki disease, thus, increasing the risk of cardiac complications. Furthermore, patients may undergo unnecessary invasive procedures. Pediatricians and pediatric surgeons, therefore, should consider Kawasaki disease among diagnoses in children with fever, abdominal symptoms, and radiologic findings of pseudo-obstruction.

SLIT's Prevention of the Allergic March.

PURPOSE OF REVIEW: The progression of atopic disorders from atopic dermatitis in infants to allergic rhinitis and asthma in children, adolescents, and adults defines the allergy march. Allergen immunotherapy is the only causal treatment altering the immunological mechanism underlying the allergic diseases. The sublingual administration route is more acceptable than the subcutaneous one in pediatric age. RECENT FINDINGS: Several studies show the efficacy and safety profile of sublingual immunotherapy (SLIT) for the treatment of respiratory allergy diseases, but few data are available on its effect of primary and secondary prevention of allergic disease. The purpose of this manuscript is to review the latest studies addressing the effect of SLIT on the development of new sensitizations in not sensitized or already sensitized patients and progression of the allergy march.

Effects of Infant Formula With Human Milk Oligosaccharides on Growth and Morbidity: A Randomized Multicenter Trial.

OBJECTIVES: The aim of the study was to evaluate the effects of infant formula supplemented with 2 human milk oligosaccharides (HMOs) on infant growth, tolerance, and morbidity. METHODS: Healthy infants, 0 to 14 days old, were randomized to an intact-protein, cow's milk-based infant formula (control, n = 87) or the same formula with 1.0 g/L 2'fucosyllactose (2'FL) and 0.5 g/L lacto-N-neotetraose (LNnT) (test, n = 88) from enrollment to 6 months; all infants received standard follow-up formula without HMOs from 6 to 12 months. Primary endpoint was weight gain through 4 months. Secondary endpoints included additional anthropometric measures, gastrointestinal tolerance, behavioral patterns, and morbidity through age 12 months. RESULTS: Weight gain was similar in both groups (mean difference [95% confidence interval] test vs control: -0.30 [-1.94, 1.34] g/day; lower bound of 95% confidence interval was above noninferiority margin [-3 g/day]). Digestive symptoms and behavioral patterns were similar between groups; exceptions included softer stool (P = 0.021) and fewer nighttime wake-ups (P = 0.036) in the test group at 2 months. Infants receiving test (vs control) had significantly fewer parental reports (P = 0.004-0.047) of bronchitis through 4 (2.3% vs 12.6%), 6 (6.8% vs 21.8%), and 12 months (10.2% vs 27.6%); lower respiratory tract infection (adverse event cluster) through 12 months (19.3% vs 34.5%); antipyretics use through 4 months (15.9% vs 29.9%); and antibiotics use through 6 (34.1% vs 49.4%) and 12 months (42.0% vs 60.9%). CONCLUSIONS: Infant formula with 2'FL and LNnT is safe, well-tolerated, and supports age-appropriate growth. Secondary outcome findings showing associations between consuming HMO-supplemented formula and lower parent-reported morbidity (particularly bronchitis) and medication use (antipyretics and antibiotics) warrant confirmation in future studies.

Genotyping and Antifungal Susceptibility of Dipodascus capitatus Isolated in a Neonatal Intensive Care Unit of a Sicilian Hospital.

In August 2015, Dipodascus capitatus was isolated from two patients admitted to the neonatal intensive care unit. Nosocomial acquisition of the fungus was suspected and epidemiological studies were undertaken. The patients were simultaneously hospitalized, and the comparison of the two isolates by two independent molecular typing methods have confirmed clonal dissemination of a single strain of D. capitatus. Antimicrobial susceptibility testing was useful for identifying the appropriated antifungal therapy in micafungin. To our knowledge these are the first described cases of neonatal D. capitatus infection and also the first report of successful treatment by micafungin.

The Child Health Care System in Italy.

Pediatric care in Italy has been based during the last 40 years on the increased awareness of the importance of meeting the psychosocial and developmental needs of children and of the role of families in promoting the health and well-being of their children. The pediatric health care system in Italy is part of the national health system. It is made up of 3 main levels of intervention: first access/primary care, secondary care/hospital care, and tertiary care based on specialty hospital care. This overview will also include a brief report on neonatal care, pediatric preventive health care, health service accreditation programs, and postgraduate training in pediatrics. The quality of the Italian child health care system is now considered to be in serious danger because of the restriction of investments in public health caused both by the 2008 global and national economic crisis and by a reduction of the pediatric workforce as a result of progressively insufficient replacement of specialists in pediatrics.