Early-life fecal microbiome and metabolome dynamics in response to an intervention with infant formula containing specific prebiotics and postbiotics.

This study examined fecal metabolome dynamics to gain greater functional insights into the interactions between nutrition and the activity of the developing gut microbiota in healthy term-born infants. The fecal samples used here originate from a randomized, controlled, double-blind clinical study that assessed the efficacy of infant formula with prebiotics and postbiotics (experimental arm) compared with a standard infant formula (control arm). A group of exclusively breast-fed term infants was used as a reference arm. First, conventional targeted physiological and microbial measurements were performed, which showed differences in fecal Bifidobacterium levels and corresponding activity (e.g., lactate levels). Next, the overall fecal microbiota composition was determined by 16S rRNA gene amplicon sequencing. The microbiota composition profiles showed several bacterial groups in the experimental arm to be significantly different from the control arm and mostly closer to the levels observed in the reference arm. Finally, we applied an untargeted UPLC-MS/MS approach to examine changes in the fecal metabolome. Fecal metabolome profiles showed the most distinct separation, up to 404 significantly different metabolites, between the study arms. Our data reveal that infant formula with specific prebiotics and postbiotics may trigger responses in the intestinal microbiota composition that brings the ensuing fecal metabolite profile of formula-fed infants closer toward those observed in breast-fed infants. Furthermore, our results demonstrate a clear need for establishing an infant gut metabolome reference database to translate these metabolite profile dynamics into functional and physiologically relevant responses.NEW & NOTEWORTHY Untargeted metabolomics techniques can provide a "snapshot" of an ecosystem in response to environmental stimuli, such as nutritional interventions. Our analyses of fecal samples from infants demonstrate the potential of phenotyping by metabolomics while deciphering the complex interactions of early-life nutrition and gut microbiome development.

Prematurity With Extrauterine Growth Restriction Increases the Risk of Higher Levels of Glucose, Low-Grade of Inflammation and Hypertension in Prepubertal Children.

Introduction: An adipose tissue programming mechanism could be implicated in the extrauterine growth restriction (EUGR) of very preterm infants with morbidity in the cardiometabolic status later in life, as has been reported in intrauterine growth restriction. The aim of this study was to assess whether children with a history of prematurity and EUGR, but also with an adequate growth, showed alterations in the metabolic and inflammatory status. Methods: This was a case-control study. A total of 88 prepubertal children with prematurity antecedents were selected: 38 with EUGR and 50 with an adequate growth pattern (PREM group). They were compared with 123 healthy children born at term. Anthropometry, metabolic parameters, blood pressure (BP), C-reactive protein, hepatocyte growth factor (HGF), interleukin-6 (IL-6), IL-8, monocyte chemotactic protein type 1 (MCP-1), neural growth factor, tumour necrosis factor-alpha (TNF-α) and plasminogen activator inhibitor type-1 were analysed at the prepubertal age. Results: EUGR children exhibited higher BP levels and a higher prevalence of hypertension (46%) compared with both PREM (10%) and control (2.5%) groups. Moreover, there was a positive relationship between BP levels and values for glucose, insulin and HOMA-IR only in children with a EUGR history. The EUGR group showed higher concentrations of most of the cytokines analysed, markedly higher TNF-α, HGF and MCP-1 levels compared with the other two groups. Conclusion: EUGR status leads to cardiometabolic changes and a low-grade inflammatory status in children with a history of prematurity, and that could be related with cardiovascular risk later in life.

Neurotoxicity by mercury is not associated with autism spectrum disorders in Spanish children.

BACKGROUND: The pathophysiological etiologies related with the development of Autism Spectrum Disorders (ASD) remain controversial. Different authors have studied neurotoxins such as mercury (Hg) and their relationship with ADS. The objective of this study was to assess the levels of Hg in hair in a group of ASD children (chronic exposure) and in urinary excretion (acute exposure), in comparison to a healthy group. METHODS: A case-control study was conducted in Spanish children. We compared 54 ASD children (aged 2-6) with no other associated pathology to a normally-developing control group (54 subjects). RESULTS: There were no differences in urine (p:0.631) and hair (p:1.000) samples percentages below the limits of detection between the control and the ASD groups, and also between patients in the regression ASD subgroup (AMR) (p:0.08) and the non-regression ASD subgroup (ANMR) (p:0.705). When the analysis was adjusted for age and sex, the differences between Hg levels maintained not significant. There were no correlations between Hg concentrations in the ASD group as a whole (p: 0.739), or when they were subdivided into ASD-AMR (p: 0.739) and ASD-ANMR (p: 0.363). CONCLUSIONS: The present study shows no evidence in our geographical area to support an association between mercury neurotoxicity and the etiopathogenesis of ASD.

Gastrointestinal Tolerance, Growth and Safety of a Partly Fermented Formula with Specific Prebiotics in Healthy Infants: A Double-Blind, Randomized, Controlled Trial.

This study evaluated the effect of a partly fermented infant formula (using the bacterial strains Bifidobacterium breve C50 and Streptococcus thermophilus 065) with a specific prebiotic mixture (short-chain galacto-oligosaccharides (scGOS) and long-chain fructo-oligosaccharides (lcFOS; 9:1)) on the incidence of gastrointestinal symptoms, stool characteristics, sleeping and crying behaviour, growth adequacy and safety. Two-hundred infants ≤28 days of age were assigned either to experimental infant formula containing 30% fermented formula and 0.8 g/100 mL scGOS/lcFOS or to non-fermented control infant formula without scGOS/lcFOS. A group of breastfed infants served as a reference. No relevant differences in parent-reported gastrointestinal symptoms were observed. Stool consistency was softer in the experimental versus control group with values closer to the breastfed reference group. Daily weight gain was equivalent for both formula groups (0.5 SD margins) with growth outcomes close to breastfed infants. No clinically relevant differences in adverse events were observed, apart from a lower investigator-reported prevalence of infantile colic in the experimental versus control group (1.1% vs. 8.7%; p < 0.02). Both study formulae are well-tolerated, support an adequate infant growth and are safe for use in healthy term infants. Compared to the control formula, the partly fermented formula with prebiotics induces stool consistencies closer to breastfed infants.

Cardiac Biomarkers of Low Cardiac Output Syndrome in the Postoperative Period After Congenital Heart Disease Surgery in Children.

INTRODUCTION AND OBJECTIVES: To assess the predictive value of atrial natriuretic peptide, ß-type natriuretic peptide, copeptin, mid-regional pro-adrenomedullin (MR-proADM) and cardiac troponin I (cTn-I) as indicators of low cardiac output syndrome in children with congenital heart disease undergoing cardiopulmonary bypass (CPB). METHODS: After corrective surgery for congenital heart disease under CPB, 117 children (aged 10 days to 180 months) were enrolled in a prospective observational pilot study during a 2-year period. The patients were classified according to whether they developed low cardiac output syndrome. Biomarker levels were measured at 2, 12, 24, and 48 hours post-CPB. The clinical data and outcome variables were analyzed by a multiple logistic regression model. RESULTS: Thirty-three (29%) patients developed low cardiac output syndrome (group 1) and the remaining 84 (71%) patients were included in group 2. cTn-I levels >14 ng/mL at 2hours after CPB (OR, 4.05; 95%CI, 1.29-12.64; P=.016) and MR-proADM levels>1.5 nmol/L at 24hours following CPB (OR, 15.54; 95%CI, 4.41-54.71; P<.001) were independent predictors of low cardiac output syndrome. CONCLUSIONS: Our results suggest that cTn-I at 2hours post-CPB is, by itself, an evident independent early predictor of low cardiac output syndrome. This predictive capacity is, moreover, reinforced when cTn-I is combined with MR-proADM levels at 24hours following CPB. These 2 cardiac biomarkers would aid in therapeutic decision-making in clinical practice and would also enable clinicians to modify the type of support to be used in the pediatric intensive care unit.

Lung recruitment manoeuvres do not cause haemodynamic instability or oxidative stress but improve oxygenation and lung mechanics in a newborn animal model: an observational study.

BACKGROUND: Lung recruitment manoeuvres in neonates during anaesthesia are not performed routinely due to concerns about causing barotrauma, haemodynamic instability and oxidative stress. OBJECTIVE: To assess the influence of recruitment manoeuvres and positive end-expiratory pressure (PEEP) on haemodynamics, oxidative stress, oxygenation and lung mechanics. DESIGN: A prospective experimental study. SETTING: Experimental Unit, La Paz University Hospital, Madrid, Spain. ANIMALS: Eight newborn piglets (<48 h) with healthy lungs under general anaesthesia. INTERVENTIONS: The recruitment manoeuvres in pressure-controlled ventilation (PCV) were performed along with a constant driving pressure of 15 cmH2O. After the recruitment manoeuvres, PEEP was reduced in a stepwise fashion to find the maximal dynamic compliance step (maxCDyn-PEEP). Blood oxidative stress biomarkers (lipid peroxidation products, protein carbonyls, total glutathione, oxidised glutathione, reduced glutathione and activity of glutathione peroxidase) were analysed. MAIN OUTCOME MEASURES: Haemodynamic parameters, arterial partial pressure of oxygen (paO2), tidal volume (Vt), dynamic compliance (Cdyn) and oxidative stress biomarkers were measured. RESULTS: The recruitment manoeuvres did not induce barotrauma. Haemodynamic instability was not detected either in the maximum pressure step (overdistension step 5) or during the entire process. No substantial differences were observed in blood oxidative stress parameters analysed as compared with their baseline values (with 0 PEEP) or the values obtained 180 min after the onset of the recruitment manoeuvres (optimal PEEP). Significant maximal values were achieved in step 14 with an increase in paO2 (32.43 ±â€Š8.48 vs. 40.39 ±â€Š15.66 kPa; P = 0.037), Vt (47.75 ±â€Š13.59 vs. 73.87 ±â€Š13.56 ml; P = 0.006) and Cdyn (2.50 ±â€Š0.64 vs. 4.75 ±â€Š0.88 ml cmH2O; P < 0.001). Maximal dynamic compliance step (maxCdyn-PEEP) was 2 cmH2O. CONCLUSION: Recruitment manoeuvres in PCV with a constant driving pressure are a well tolerated open-lung strategy in a healthy-lung neonatal animal model under general anaesthesia. The recruitment manoeuvres improve oxygenation parameters and lung mechanics and do not cause barotrauma, haemodynamic instability or oxidative stress.

Interleukin-21 overexpression dominates T cell response to Epstein-Barr virus in a fatal case of X-linked lymphoproliferative syndrome type 1.

Interleukin-21 (IL-21) is a cytokine whose actions are closely related to B cell differentiation into plasma cells as well as to CD8(+) cytolytic T cell effector and memory generation, influencing the T lymphocyte response to different viruses. X-linked lymphoproliferative syndrome type 1 (XLP-1) is a primary immunodeficiency syndrome that is characterized by a high susceptibility to Epstein-Barr virus. We observed in a pediatric patient with XLP-1 that IL-21 was expressed in nearly all peripheral blood CD4(+) and CD8(+) T cells. However, IL-21 could not be found in the lymph nodes, suggesting massive mobilization of activated cells toward the infection's target organs, where IL-21-producing cells were detected, resulting in large areas of tissue damage.

Successful response to cidofovir of adenovirus hepatitis during chemotherapy in a child with hepatoblastoma.

BACKGROUND: Adenoviral infections are endemic in the pediatric population. Most of these infections are mild and self-limited in immunocompetent individuals. Although in profoundly immunocompromised hosts after solid organ or stem cell transplantation, adenovirus may cause fulminant hepatitis or other life-threatening infections, this is a rare complication in patients receiving standard chemotherapy. OBSERVATION: We report a case of severe adenovirus hepatitis in a 7-month-old child receiving induction chemotherapy for hepatoblastoma who fully recovered after treatment with cidofovir. CONCLUSIONS: To our knowledge, this is the first report documenting recovering of severe adenoviral hepatitis in a nontransplanted immunocompromised host.

Characterization of gliadin-specific Th17 cells from the mucosa of celiac disease patients.

OBJECTIVES: Celiac disease (CD) is a disorder characterized by a deregulated immune response to ingested wheat gluten and related cereal proteins in susceptible individuals. It has been considered that the onset of CD is mediated by a skewed Th1 response. However, the participation of Th17 cells in the pathogenesis of the disease, a key cell population in other autoimmune disorders, has not been studied in detail. We have investigated the presence of Th17 cells in the mucosa of active CD patients and their functional implications in the pathogenesis of the disease. METHODS: T cells obtained from duodenum biopsies from 15 untreated patients and 11 control individuals were characterized by flow cytometry, immunoassays, and real-time PCR. RESULTS: We found gliadin-specific CD4(+) interleukin (IL)-17A-producing T cells in the mucosa of CD patients with a phenotype consisting of TCR (T-cell receptor)αß(+) CD45RO(+) CD161(+) CCR6(+) (C-C chemokine receptor type 6) and IL-23R(+). Functional analysis showed that Th17 cells from CD patients are different from those of control individuals in terms of cytokines production. Th17 cells from CD patients, but not from controls, simultaneously express transforming growth factor-ß (TGFß). Th17 CD cells also produce interferon-γ (IFNγ), IL-21, and IL-22. The analysis of the transcription factors revealed a high expression of interferon regulatory factor-4 as a feature of gliadin-specific cells from CD patients with respect to controls. CONCLUSIONS: Gliadin-specific Th17 cells are present in the mucosa of CD patients having a dual role in the pathogenesis of the disease as they produce proinflammatory cytokines (such as IL-17, IFNγ, IL-21), mucosa-protective IL-22, and regulatory TGFß, which actively modulates IL-17A production by T cells in the celiac mucosa.

Oral phenylalanine loading test for the diagnosis of dominant guanosine triphosphate cyclohydrolase 1 deficiency.

OBJECTIVES: To evaluate the usefulness of Phe loading test in patients for the diagnosis of guanosine triphosphate cyclohydrolase 1 deficiency (GTPCH). DESIGN AND METHODS: We studied one family composed of 13 members harbouring the Q89X mutation in the GTPCH gene, a non-related pediatric patient with GTPCH deficiency and 8 pediatric controls. 100 mg/kg of L-phenylalanine was orally administered, and blood spot samples were taken at baselines 1, 2, 4 and 6 h post-load. RESULTS: Two out of 7 pediatric patients showed a phenylalanine/tyrosine ratio higher than the previously reported cut-off value of 5.25 at 4 h, while 6 of the 7 adult patients showed a higher value. The only adult patient with a phenylalanine/tyrosine ratio below 5.25 at 4 h was asymptomatic. CONCLUSIONS: A cut-off value of 5.25 seems reliable for interpreting Phe loading test in adult patients with GTPCH deficiency, although a lower value should be established for pediatric patients.

Descending necrotizing mediastinitis in early childhood: favorable outcome after aggressive treatment.

OBJECTIVE: To report a case of descending necrotizing mediastinitis (DNM), an unusual illness in childhood that develops as a complication of oropharyngeal infection. DESIGN: Descriptive case report. SETTING: Pediatric intensive care unit. PATIENT: A 19-month-old boy with a DNM that resulted from a pharyngeal abscess. INTERVENTIONS: Aggressive surgical debridement; intravenous therapy with broad-spectrum antibiotics. MEASUREMENTS AND MAIN RESULTS: Simple chest radiograph and computed tomographic scan, and routine culture were used to assess the patient. Administration of broad-spectrum antibiotics and surgical drainage resulted in clinical resolution of symptoms. CONCLUSIONS: An aggressive approach (broad-spectrum antibiotics and surgical debridement) can improve the prognosis of DNM in children.