The ten "hard" questions in pediatric functional constipation.

Functional constipation is a common problem in childhood and has a great impact on social, physical, and emotional functioning of affected children and their caregivers. No organic cause of the constipation can be found in approximately 95% of children, defining the "so-called" chronic functional constipation. Its prevalence has been reported to range from 0.7 to 29.6%, with a median of 12%. The diagnosis of functional constipation is exclusively clinical based on the pediatric diagnostic Rome criteria for functional gastrointestinal disorders and does not routinely require laboratory and/or radiological investigations. In case of alarm signs and symptoms that may suggest organic diseases, further investigations can be required. The therapeutic management is based on non-pharmacological and pharmacological approaches. Education, demystification of constipation and reward-based toilet training represent the cornerstones of nonpharmacological management. Disimpaction, maintenance treatment and weaning of medication are all elements of pharmacological treatment. Osmotic laxatives, mainly polyethylene glycol (PEG), are considered the first-choice laxative for both disimpaction and maintenance treatment. The aim of this review is to provide pediatric gastroenterologists with a practical tool to support the clinical and therapeutic management of children and adolescents affected by chronic functional constipation.

Diagnosis and management of anemia in pediatric inflammatory bowel diseases: Clinical practice guidelines on behalf of the SIGENP IBD Working group.

Anemia is one of the most frequent extra-intestinal manifestations of inflammatory bowel disease. Insidious onset, variability of symptoms and lack of standardized screening practices may increase the risk of underestimating its burden in children with IBD. Despite its relevance and peculiarity in everyday clinical practice, this topic is only dealt with in a few documents specifically for the pediatric field. The aim of the current guidelines is therefore to provide pediatric gastroenterologists with a practical update to support the clinical and therapeutic management of children with IBD and anemia. A panel of 19 pediatric gastroenterologists and 1 pediatric hematologist with experience in the field of pediatric IBD was agreed by IBD Working group of the Italian Society of Gastroenterology, Hepatology and Nutrition (SIGENP) to produce the present article outlining practical clinical approaches to the pediatric patient with IBD and anemia. The levels of evidence and recommendations have been defined for each part of the statement according to the GRADE system.

Induction of Remission With Exclusive Enteral Nutrition in Children With Crohn's Disease: Determinants of Higher Adherence and Response.

BACKGROUND: Exclusive enteral nutrition (EEN) is the first choice to induce remission and promote mucosal healing in pediatric Crohn's disease (CD). However, full adherence to EEN treatment may be problematic for children with CD. METHODS: The goal of the current multicenter retrospective study was to define predictive factors of nonadherence to treatment and nonremission at the end of induction treatment. Those data together were analyzed with the ultimate goal of trying to define an individualized induction treatment for children with CD. RESULTS: Three hundred seventy-six children with CD from 14 IBD pediatric referral centers were enrolled in the study. The rate of EEN adherence was 89%. Colonic involvement and fecal calprotectin >600 µg/g at diagnosis were found to be associated with a reduced EEN adherence. Exclusive enteral nutrition administered for 8 weeks was effective for inducing clinical remission in 67% of the total cohort. Factors determining lower remission rates were age >15 years and Pediatric Crohn's Disease Activity Index >50. CONCLUSION: Although EEN is extremely effective in promoting disease remission, several patients' related factors may adversely impact EEN adherence and response. Personalized treatments should be proposed that weigh benefits and risks based on the patient's disease location, phenotype, and disease activity and aim to promote a rapid control of inflammation to reduce long-term bowel damage.

Is Quarantine for COVID-19 Pandemic Associated with Psychological Burden in Primary Ciliary Dyskinesia?

BACKGROUND: Information on psychological impact of COVID-19 quarantine in primary ciliary dyskinesia (PCD), a chronic disorder with recurrent pulmonary exacerbations, is lacking. Psychological well-being was prospectively assessed during COVID-19 lockdown in Italy in a PCD population. METHODS: we recruited 27 PCD patients and 27 healthy controls. To assess psychological well-being, psychological general well-being index and parenting stress index-short questionnaires were administered to participants ≥15 years-old and to mothers of participants <15 years-old, respectively. The PCD exacerbations since outbreak onset and frequency of quarantine weekly chest physiotherapy were compared to the same period of 2019. OUTCOMES: 70% of PCD mothers and 90% of PCD patients did not show parental stress levels or distress levels, respectively, and these groups showed no significant difference in stress compared to controls. The PCD pulmonary exacerbations occurred less frequently and weekly chest physiotherapy sessions significantly increased compared to the same period during 2019 (p < 0.05). INTERPRETATION: During COVID-19 quarantine, a PCD population showed psychological well-being. Low exacerbation rate, explained by lower infectious exposure or improved compliance to chest physiotherapy, likely contributed to psychological well-being. Evaluating psychological burden and parental stress is a valuable tool for measuring the emotional impact of PCD and improving PCD medical care.

Is Lactoferrin More Effective in Reducing Late-Onset Sepsis in Preterm Neonates Fed Formula Than in Those Receiving Mother's Own Milk? Secondary Analyses of Two Multicenter Randomized Controlled Trials.

BACKGROUND: Lactoferrin is the major antimicrobial protein in human milk. In our randomized controlled trial (RCT) of bovine lactoferrin (BLF) supplementation in preterm neonates, BLF reduced late-onset sepsis (LOS). Mother's own milk (MM) contains higher concentrations of lactoferrin than donor milk or formula, but whether BLF is more effective in infants who receive formula or donor milk is uncertain. AIM: To evaluate the incidence of LOS in preterm infants fed MM and in those fed formula and/or donor milk. STUDY DESIGN: This is a (A) post hoc subgroup analysis, in our RCT of BLF, of its effects in preterm infants fed MM, with or without formula, versus those fed formula and/or donor milk (no-MM) and (B) post hoc meta-analysis, in our RCT of BLF and in the ELFIN (Enteral Lactoferrin in Neonates) RCT, of the effect of BLF in subgroups not exclusively fed MM. RESULTS: (A) Of 472 infants in our RCT, 168 were randomized to placebo and 304 were randomized to BLF. Among MM infants, LOS occurred in 22/133 (16.5%) infants randomized to placebo and in 14/250 (5.6%) randomized to BLF (relative risk or risk ratio (RR): 0.34; relative risk reduction (RRR): 0.66; 95% confidence interval (95% CI) for RR: 0.18-0.64; p < 0.0008). Among no-MM infants, LOS occurred in 7/35 (20.0%) randomized to placebo and in 2/54 (3.7%) randomized to BLF (RR: 0.19; RRR: 0.81; 95% CI for RR: 0.16-0.96; p = 0.026). In multivariable logistic regression analysis, there was no interaction between BLF treatment effect and type of feeding (p = 0.628). (B) In 1,891 infants not exclusively fed MM in our RCT of BLF and in the ELFIN RCT, BLF reduced the RR of LOS by 18% (RR: 0.82; 95% CI: 0.71-0.96; p = 0.01). CONCLUSION: Adequately powered studies should address the hypothesis that BLF is more effective in infants fed formula or donor milk than those fed MM. Such studies should evaluate whether a specific threshold of total lactoferrin intake can be identified to protect such patients from LOS.

Exposure to Gastric Acid Inhibitors Increases the Risk of Infection in Preterm Very Low Birth Weight Infants but Concomitant Administration of Lactoferrin Counteracts This Effect.

OBJECTIVE: To investigate whether exposure to inhibitors of gastric acidity, such as H2 blockers or proton pump inhibitors, can independently increase the risk of infections in very low birth weight (VLBW) preterm infants in the neonatal intensive care unit. STUDY DESIGN: This is a secondary analysis of prospectively collected data from a multicenter, randomized controlled trial of bovine lactoferrin (BLF) supplementation (with or without the probiotic Lactobacillus rhamnosus GG) vs placebo in prevention of late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in preterm infants. Inhibitors of gastric acidity were used at the recommended dosages/schedules based on the clinical judgment of attending physicians. The distribution of days of inhibitors of gastric acidity exposure between infants with and without LOS/NEC was assessed. The mutually adjusted effects of birth weight, gestational age, duration of inhibitors of gastric acidity treatment, and exposure to BLF were controlled through multivariable logistic regression. Interaction between inhibitors of gastric acidity and BLF was tested; the effects of any day of inhibitors of gastric acidity exposure were then computed for BLF-treated vs -untreated infants. RESULTS: Two hundred thirty-five of 743 infants underwent treatment with inhibitors of gastric acidity, and 86 LOS episodes occurred. After multivariate analysis, exposure to inhibitors of gastric acidity remained significantly and independently associated with LOS (OR, 1.03; 95% CI, 1.008-1.067; P = .01); each day of inhibitors of gastric acidity exposure conferred an additional 3.7% odds of developing LOS. Risk was significant for Gram-negative (P < .001) and fungal (P = .001) pathogens, but not for Gram-positive pathogens (P = .97). On the test for interaction, 1 additional day of exposure to inhibitors of gastric acidity conferred an additional 7.7% risk for LOS (P = .003) in BLF-untreated infants, compared with 1.2% (P = .58) in BLF-treated infants. CONCLUSION: Exposure to inhibitors of gastric acidity is significantly associated with the occurrence of LOS in preterm VLBW infants. Concomitant administration of BLF counteracts this selective disadvantage. TRIAL REGISTRATION: isrctn.org: ISRCTN53107700.

Allogeneic umbilical cord blood red cell concentrates: an innovative blood product for transfusion therapy of preterm infants.

BACKGROUND: Preterm infants often receive blood transfusions early in life. In this setting, umbilical cord blood (UCB) might be safer than adult blood (A) with respect to infectious and immunologic threats. OBJECTIVES: To evaluate, as a first objective, the feasibility of fulfilling transfusion needs of preterm infants with allogeneic UCB red blood cell (RBC) concentrates and, as a secondary objective, to assess the safety of allogeneic cord blood transfusions. METHODS: At the Neonatal Intensive Care Unit and the UNICATT Cord Blood Bank of 'A. Gemelli' Hospital in Rome, a prospective study was carried out over a 1-year period, enrolling newborns with gestational age ≤30 weeks and/or birth weight ≤1,500 g requiring RBC transfusions within the first 28 days of life. At first transfusion, patients were assigned to receive UCB-RBCs or A-RBCs depending on the availability of ABO-Rh(D)-matched UCB-RBC units. The same regimen (UCB-RBC or A-RBC units) was thereafter maintained, unless ABO-Rh(D)-matched UCB-RBC units were not available. RESULTS: Overall, 23 UCB-RBC units were transfused to 9 patients; the requests for UCB-RBC units were met in 45% of patients at the first transfusion and in 78% at the subsequent transfusions. At a median follow-up of 57 days (range 6-219), no acute or delayed transfusion-related adverse events occurred. Hematocrit gain after transfusion and time intervals between transfusions were similar in the UCB-RBC and A-RBC group, as well. CONCLUSIONS: Transfusing allogeneic UCB-RBC units in preterm infants appears a feasible and safe approach, although the transfusion needs of our study population were not completely covered. More data are necessary to validate this novel transfusion practice.

Working the endless puzzle of hereditary autoinflammatory disorders.

Hereditary autoinflammatory disorders encompass manifold dysfunctions of innate immunity caused by mutations in genes coding for the main characters of the inflammatory scene: most of these conditions have an early onset, ranging from the first days of life to the first decades, and include hereditary periodic fevers, NLRP-related diseases, granulomatous and pyogenic syndromes, which are basically characterized by upturned inflammasome activity and overproduction of bioactive interleukin (IL)-1ß and other proinflammatory cytokines. The discovery of a causative link between autoinflammation and IL-1ß release has improved our understanding of the intimate mechanisms of innate immunity, and has likewise led to the identification of extraordinary treatments for many of these disorders.

Renal failure of the surviving fetus after intrauterine death of the co-twin.

Twin pregnancies are considered at a higher risk for fetal mortality than singleton pregnancies. The antenatal death of one of the twins is associated with an increasing rate of cerebral impairment and lesions in other organs in the surviving fetus, especially if the pregnancy is monochorionic. We describe a case of isolate renal failure becoming evident gradually after birth in a surviving twin after the antenatal death of the co-twin. Considering the deleterious effects of vascular disruption in a surviving twin, our findings suggest careful investigation of renal function, even if no intrauterine signs of diminished renal function were previously detected.

Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells.

Regulation of tryptophan metabolism by indoleamine 2,3-dioxygenase (IDO) in dendritic cells (DCs) is a highly versatile modulator of immunity. In inflammation, interferon-γ is the main inducer of IDO for the prevention of hyperinflammatory responses, yet IDO is also responsible for self-tolerance effects in the longer term. Here we show that treatment of mouse plasmacytoid DCs (pDCs) with transforming growth factor-ß (TGF-ß) conferred regulatory effects on IDO that were mechanistically separable from its enzymic activity. We found that IDO was involved in intracellular signaling events responsible for the self-amplification and maintenance of a stably regulatory phenotype in pDCs. Thus, IDO has a tonic, nonenzymic function that contributes to TGF-ß-driven tolerance in noninflammatory contexts.

Is heel prick as safe as we think?

Purulent lymphadenitis is rare in newborn and is associated with prematurity and invasive procedure. Neonatal staphylococcal infections due to skin interruption during intramuscular vitamin K administration and national metabolic screening programme (heel prick or Guthrie card test) have been already previously described. This is a report of a premature infant who developed an inguinal adenitis as a result of late complications from heel pricks. The diagnosis was made on clinical grounds and confirmed by ultrasound scans. Staphylococcus aureus was isolated. Bacteremia did not occur and the lymphadenitis had a complete resolution with antimicrobial therapy. The heel prick is a well-established procedure in neonatal practice, nevertheless it is not risk-free. The attention to signs of infections is important to avoid complications such as purulent lymphadenitis, abscess formation and septicemia. Best practice prevention and control in minimising the risk of infections are the most important intervention to prevent this complication.

Metabotropic glutamate receptor-4 modulates adaptive immunity and restrains neuroinflammation.

High amounts of glutamate are found in the brains of people with multiple sclerosis, an inflammatory disease marked by progressive demyelination. Glutamate might affect neuroinflammation via effects on immune cells. Knockout mice lacking metabotropic glutamate receptor-4 (mGluR4) were markedly vulnerable to experimental autoimmune encephalomyelitis (EAE, a mouse model of multiple sclerosis) and developed responses dominated by interleukin-17-producing T helper (T(H)17) cells. In dendritic cells (DCs) from those mice, defective mGluR4 signaling-which would normally decrease intracellular cAMP formation-biased T(H) cell commitment to the T(H)17 phenotype. In wild-type mice, mGluR4 was constitutively expressed in all peripheral DCs, and this expression increased after cell activation. Treatment of wild-type mice with a selective mGluR4 enhancer increased EAE resistance via regulatory T (T(reg)) cells. The high amounts of glutamate in neuroinflammation might reflect a counterregulatory mechanism that is protective in nature and might be harnessed therapeutically for restricting immunopathology in multiple sclerosis.

Therapy of experimental type 1 diabetes by isolated Sertoli cell xenografts alone.

Type I diabetes mellitus is caused by autoimmune destruction of pancreatic beta cells, and effective treatment of the disease might require rescuing beta cell function in a context of reinstalled immune tolerance. Sertoli cells (SCs) are found in the testes, where their main task is to provide local immunological protection and nourishment to developing germ cells. SCs engraft, self-protect, and coprotect allogeneic and xenogeneic grafts from immune destruction in different experimental settings. SCs have also been successfully implanted into the central nervous system to create a regulatory environment to the surrounding tissue which is trophic and counter-inflammatory. We report that isolated neonatal porcine SC, administered alone in highly biocompatible microcapsules, led to diabetes prevention and reversion in the respective 88 and 81% of overtly diabetic (nonobese diabetic [NOD]) mice, with no need for additional beta cell or insulin therapy. The effect was associated with restoration of systemic immune tolerance and detection of functional pancreatic islets that consisted of glucose-responsive and insulin-secreting cells. Curative effects by SC were strictly dependent on efficient tryptophan metabolism in the xenografts, leading to TGF-beta-dependent emergence of autoantigen-specific regulatory T cells and recovery of beta cell function in the diabetic recipients.

IDO mediates TLR9-driven protection from experimental autoimmune diabetes.

Originally predicated on the recognition of an increasing prevalence of allergy, the hygiene hypothesis was later found to accommodate the contrasting epidemiologic trends in developed countries for infectious vs autoimmune diseases. Experimentally, reduced exposure to infections will increase the risk of disease in several models of experimental autoimmunity. Although TLRs were initially considered as stimulatory molecules capable of activating early defense mechanisms against invading pathogens, emerging data suggest that they can also exert a regulatory function. In the present study, we evaluated whether TLR3 and TLR9, recognizing microbial dsDNA and CpG-containing DNA sequences, respectively, play a role in the protection from experimental autoimmune diabetes induced in C57BL/6 mice by streptozotocin. In wild-type animals, the disease was accompanied by up-regulation of IDO in pancreatic lymph nodes and would be greatly exacerbated by in vivo administration of an IDO inhibitor. Conversely, administration of a CpG-containing oligodeoxynucleotide greatly attenuated the disease in an IDO-dependent fashion. TLR9-, but not TLR3-deficient mice developed a more robust disease, an event accompanied by lack of IDO induction in pancreatic lymph nodes. Thus, our data suggest that the TLR9-IDO axis may represent a valuable target in the prevention/therapy of type 1 diabetes.

Remifentanil analgosedation in preterm newborns during mechanical ventilation.

AIM: To assess efficacy of remifentanil in preterm newborns during mechanical ventilation. METHODS: Remifentanil was administered by continuous intravenous infusion to provide analgesia and sedation in 48 preterm infants who developed respiratory distress and required mechanical ventilation. We examined the doses needed to provide adequate analgesia, extubation time after the discontinuation of opioid infusion, the presence of side effects and safety of the use. RESULTS: Remifentanil provided adequate analgesia, with a significant reduction of NIPS and COMFORT score since 1 h after starting the infusion of remifentanil. The drug was initially administered at a dose of 0.075 microg/kg/min, but in 73% of newborns the latter had to be increased; at a dose of 0.094 +/- 0.03 (mean +/- standard deviation) microg/kg/min, 97% of the newborns received adequate analgesia and sedation. The time elapsed between the discontinuation of remifentanil infusion and extubation was 36 +/- 12 min. Treatment was started between the 1st and the 17th day of life. The mean duration of therapy was 5.9 +/- 5.7 days. No side effects on the respiratory or cardiovascular system were observed. CONCLUSION: Remifentanil is a manageable and effective opioid in the newborn undergoing mechanical ventilation, though randomized controlled trials and information about long-term outcomes are necessary.

Neonatal colour Doppler ultrasound study: normal values of abdominal blood flow velocities in the neonate during the first month of life.

BACKGROUND: Doppler US to measure abdominal blood flow velocities (ABFV) is increasingly used to investigate intestinal haemodynamics in several clinical conditions in neonates. Studies that provide reference values of ABFV during the entire neonatal period are currently lacking. OBJECTIVE: To make available normal reference values of ABFV and Doppler indices in the coeliac trunk and superior mesenteric artery during the first month of life in term and healthy preterm infants. MATERIALS AND METHODS: ABFV were obtained with colour Doppler US in 69 neonates (12 term, 57 preterm) divided into four gestational age groups (25-28 weeks, 29-32 weeks, 33-36 weeks, and 37-41 weeks). RESULTS: ABFV increased with increasing gestational and postnatal age. We also provide normal reference values of ABFV and Doppler indices to compare with measurements of abdominal blood flow changes during the neonatal period for diagnostic, therapeutic and prognostic purposes. CONCLUSION: These longitudinal reference values provide a useful tool for assessing possible alteration in ABFV secondary to neonatal pathologies.

SOCS3 drives proteasomal degradation of indoleamine 2,3-dioxygenase (IDO) and antagonizes IDO-dependent tolerogenesis.

Despite their common ability to activate intracellular signaling through CD80/CD86 molecules, cytotoxic T lymphocyte antigen 4 (CTLA-4)-Ig and CD28-Ig bias the downstream response in opposite directions, the latter promoting immunity, and CTLA-4-Ig tolerance, in dendritic cells (DCs) with opposite but flexible programs of antigen presentation. Nevertheless, in the absence of suppressor of cytokine signaling 3 (SOCS3), CD28-Ig-and the associated, dominant IL-6 response-become immunosuppressive and mimic the effect of CTLA-4-Ig, including a high functional expression of the tolerogenic enzyme indoleamine 2,3-dioxygenase (IDO). Here we show that forced SOCS3 expression antagonized CTLA-4-Ig activity in a proteasome-dependent fashion. Unrecognized by previous studies, IDO appeared to possess two tyrosine residues within two distinct putative immunoreceptor tyrosine-based inhibitory motifs, VPY(115)CEL and LLY(253)EGV. We found that SOCS3-known to interact with phosphotyrosine-containing peptides and be selectively induced by CD28-Ig/IL-6-would bind IDO and target the IDO/SOCS3 complex for ubiquitination and subsequent proteasomal degradation. This event accounted for the ability of CD28-Ig and IL-6 to convert otherwise tolerogenic, IDO-competent DCs into immunogenic cells. Thus onset of immunity in response to antigen within an early inflammatory context requires that IDO be degraded in tolerogenic DCs. In addition to identifying SOCS3 as a candidate signature for mouse DC subsets programmed to direct immunity, this study demonstrates that IDO undergoes regulatory proteolysis in response to immunogenic stimuli.

Cutting edge: Autocrine TGF-beta sustains default tolerogenesis by IDO-competent dendritic cells.

CD8(-) and CD8(+) dendritic cells (DCs) are distinct subsets of mouse splenic accessory cells with opposite but flexible programs of Ag presentation, leading to immunogenic and tolerogenic responses, respectively. In this study, we show that the default tolerogenic function of CD8(+) DCs relies on autocrine TGF-beta, which sustains the activation of IDO in response to environmental stimuli. CD8(-) DCs do not produce TGF-beta, yet externally added TGF-beta induces IDO and turns those cells from immunogenic into tolerogenic cells. The acquisition of a suppressive phenotype by CD8(-) DCs correlates with activation of the PI3K/Akt and noncanonical NF-kappaB pathways. These data are the first to link TGF-beta signaling with IDO in controlling spontaneous tolerogenesis by DCs.