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The human gastrointestinal (GI) tract hosts complex and dynamic populations of microorganisms (gut microbiota) in advantageous symbiosis with the host organism through sophisticated molecular cross-talk. The balance and diversification within microbial communities (eubiosis) are crucial for the immune and metabolic homeostasis of the host, as well as for inhibiting pathogen penetration. In contrast, compositional dysregulation of the microbiota (dysbiosis) is blamed for the determinism of numerous diseases. Although further advances in the so-called 'omics' disciplines are needed, dietary manipulation of the gut microbial ecosystem through biomodulators (prebiotics, probiotics, symbionts, and postbiotics) represents an intriguing target to stabilize and/or restore eubiosis. Recently, new approaches have been developed for the production of infant formulas supplemented with prebiotics (human milk oligosaccharides [HMOs], galacto-oligosaccharides [GOS], fructo-oligosaccharides [FOS]), probiotics, and postbiotics to obtain formulas that are nutritionally and biologically equivalent to human milk (closer to the reference).

During the complementary feeding period, any nutritional deficiencies may negatively impact infant growth and neurodevelopment. A healthy diet containing all essential nutrients is strongly recommended by the WHO during infancy. Because vegetarian diets are becoming increasingly popular in many industrialized countries, some parents ask the pediatrician for a vegetarian diet, partially or entirely free of animal-source foods, for their children from an early age. This systematic review aims to evaluate the evidence on how vegetarian complementary feeding impacts infant growth, neurodevelopment, risk of wasted and/or stunted growth, overweight and obesity. The SR was registered with PROSPERO 2021 (CRD 42021273592). A comprehensive search strategy was adopted to search and find all relevant studies. For ethical reasons, there are no interventional studies assessing the impact of non-supplemented vegetarian/vegan diets on the physical and neurocognitive development of children, but there are numerous studies that have analyzed the effects of dietary deficiencies on individual nutrients. Based on current evidence, vegetarian and vegan diets during the complementary feeding period have not been shown to be safe, and the current best evidence suggests that the risk of critical micronutrient deficiencies or insufficiencies and growth retardation is high: they may result in significantly different outcomes in neuropsychological development and growth when compared with a healthy omnivorous diet such as the Mediterranean Diet. There are also no data documenting the protective effect of vegetarian or vegan diets against communicable diseases in children aged 6 months to 2-3 years.

Several institutions propose responsive feeding (RF) as the caregivers' relational standard when nurturing a child, from breast/formula feeding onwards. Previous systematic reviews (SRs) on caregivers' feeding practices (CFPs) have included studies on populations from countries with different cultures, rates of malnutrition, and incomes, whereas this SR compares different CFPs only in healthy children (4-24 months) from industrialized countries. Clinical questions were about the influence of different CFPs on several important outcomes, namely growth, overweight/obesity, risk of choking, dental caries, type 2 diabetes (DM2), and hypertension. The literature review does not support any Baby Led Weaning's or Baby-Led Introduction to SolidS' (BLISS) positive influence on children's weight-length gain, nor their preventive effect on future overweight/obesity. RF-CFPs can result in adequate weight gain and a lower incidence of overweight/obesity during the first two years of life, whereas restrictive styles and coercive styles, two kinds of non-RF in CF, can have a negative effect, favoring excess weight and lower weight, respectively. Choking risk: failure to supervise a child's meals by an adult represents the most important risk factor; no cause-effect relation between BLW/BLISS/RF/NRCF and choking could be found. Risks of DM2, hypertension, and caries: different CFPs cannot be considered as a risky or preventive factor for developing these conditions later in life.

No consensus currently exists on the appropriate age for the introduction of complementary feeding (CF). In this paper, a systematic review is conducted that investigates the effects of starting CF in breastfed and formula-fed infants at 4, 4-6, or 6 months of age (i) on growth at 12 months of age, (ii) on the development of overweight/obesity at 3-6 years of age, (iii) on iron status, and (iv) on the risk of developing (later in life) type 2 diabetes mellitus (DM2) and hypertension. An extensive literature search identified seven studies that evaluated the effects of the introduction of CF at the ages in question. No statistically significant differences related to the age at which CF is started were observed in breastfed or formula-fed infants in terms of the following: iron status, weight, length, and body mass index Z-scores (zBMI) at 12 months, and development of overweight/obesity at 3 years. No studies were found specifically focused on the age range for CF introduction and risk of DM2 and hypertension. Introducing CF before 6 months in healthy term-born infants living in developed countries is essentially useless, as human milk (HM) and formulas are nutritionally adequate up to 6 months of age.

Adequate and balanced nutrition is essential to promote optimal child growth and a long and healthy life. After breastfeeding, the second step is the introduction of complementary feeding (CF), a process that typically covers the period from 6 to 24 months of age. This process is, however, still highly controversial, as it is heavily influenced by socio-cultural choices, as well as by the availability of specific local foods, by family traditions, and pediatrician beliefs. The Società Italiana di Pediatria Preventiva e Sociale (SIPPS) together with the Federazione Italiana Medici Pediatri (FIMP), the Società Italiana per lo Sviluppo e le Origine della Salute e delle Malattie (SIDOHaD), and the Società Italiana di Nutrizione Pediatrica (SINUPE) have developed evidence-based recommendations for CF, given the importance of nutrition in the first 1000 days of life in influencing even long-term health outcomes. This paper includes 38 recommendations, all of them strictly evidence-based and overall addressed to developed countries. The recommendations in question cover several topics such as the appropriate age for the introduction of CF, the most appropriate quantitative and qualitative modalities to be chosen, and the relationship between CF and the development of Non-Communicable Diseases (NCDs) later in life.

The complementary feeding (CF) period that takes place between 6 and 24 months of age is of key importance for nutritional and developmental reasons during the transition from exclusively feeding on milk to family meals. In 2021, a multidisciplinary panel of experts from four Italian scientific pediatric societies elaborated a consensus document on CF, focusing in particular on healthy term infants. The aim was to provide healthcare providers with useful guidelines for clinical practice. Complementary feeding is also the time window when iron deficiency (ID) and iron deficiency anemia (IDA) are most prevalent. Thus, it is appropriate to address the problem of iron deficiency through nutritional interventions. Adequate iron intake during the first two years is critical since rapid growth in that period increases iron requirements per kilogram more than at any other developmental stage. Complementary foods should be introduced at around six months of age, taking into account infant iron status.

Recurrent respiratory infections (RRIs) are a common clinical condition in children, in fact about 25% of children under 1 year and 6% of children during the first 6 years of life have RRIs. In most cases, infections occur with mild clinical manifestations and the frequency of episodes tends to decrease over time with a complete resolution by 12 years of age. However, RRIs significantly reduce child and family quality of life and lead to significant medical and social costs.Despite the importance of this condition, there is currently no agreed definition of the term RRIs in the literature, especially concerning the frequency and type of infectious episodes to be considered. The aim of this consensus document is to propose an updated definition and provide recommendations with the intent of guiding the physician in the complex process of diagnosis, management and prevention of RRIs., (© 2021. The Author(s).)

Background: In 2019, a multidisciplinary panel of experts from eight Italian scientific paediatric societies developed a consensus document for the use of inhaled corticosteroids in the management and prevention of the most common paediatric airways disorders. The aim is to provide healthcare providers with a multidisciplinary document including indications useful in the clinical practice. The consensus document was intended to be addressed to paediatricians who work in the Paediatric Divisions, the Primary Care Services and the Emergency Departments, as well as to Residents or PhD students, paediatric nurses and specialists or consultants in paediatric pulmonology, allergy, infectious diseases, and ear, nose, and throat medicine., Methods: Clinical questions identifying Population, Intervention(s), Comparison and Outcome(s) were addressed by methodologists and a general agreement on the topics and the strength of the recommendations (according to the GRADE system) was obtained following the Delphi method. The literature selection included secondary sources such as evidence-based guidelines and systematic reviews and was integrated with primary studies subsequently published., Results: The expert panel provided a number of recommendations on the use of inhaled corticosteroids in preschool wheezing, bronchial asthma, allergic and non-allergic rhinitis, acute and chronic rhinosinusitis, adenoid hypertrophy, laryngitis and laryngospasm., Conclusions: We provided a multidisciplinary update on the current recommendations for the management and prevention of the most common paediatric airways disorders requiring inhaled corticosteroids, in order to share useful indications, identify gaps in knowledge and drive future research.

Hosting millions of microorganisms, the digestive tract is the primary and most important part of bacterial colonization. On one side, in cases of opportunistic invasion, the abundant bacterial population inside intestinal tissues may face potential health problems such as inflammation and infections. Therefore, the immune system has evolved to sustain the host-microbiota symbiotic relationship. On the other hand, to maintain host immune homeostasis, the intestinal microflora often exerts an immunoregulatory function that cannot be ignored. A field of great interest is the association of either microbiota or probiotics with the immune system concerning clinical uses. This microbial community regulates some of the host's metabolic and physiological functions and drives early-life immune system maturation, contributing to their homeostasis throughout life. Changes in gut microbiota can occur through modification in function, composition (dysbiosis), or microbiota-host interplays. Studies on animals and humans show that probiotics can have a pivotal effect on the modulation of immune and inflammatory mechanisms; however, the precise mechanisms have not yet been well defined. Diet, age, BMI (body mass index), medications, and stress may confound the benefits of probiotic intake. In addition to host gut functions (permeability and physiology), all these agents have profound implications for the gut microbiome composition. The use of probiotics could improve the gut microbial population, increase mucus-secretion, and prevent the destruction of tight junction proteins by decreasing the number of lipopolysaccharides (LPSs). When LPS binds endothelial cells to toll-like receptors (TLR 2, 4), dendritic cells and macrophage cells are activated, and inflammatory markers are increased. Furthermore, a decrease in gut dysbiosis and intestinal leakage after probiotic therapy may minimize the development of inflammatory biomarkers and blunt unnecessary activation of the immune system. In turn, probiotics improve the differentiation of T-cells against Th2 and development of Th2 cytokines such as IL-4 and IL-10. The present narrative review explores the interactions between gut microflora/probiotics and the immune system starting from the general perspective of a biological plausibility to get to the in vitro and in vivo demonstrations of a probiotic-based approach up to the possible uses for novel therapeutic strategies., Competing Interests: RF is the inventor of the patent N 0001425900, released on 17 November 2016 (Italy). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cristofori, Dargenio, Dargenio, Miniello, Barone and Francavilla.)

Objectives-Failure to thrive (FTT) in infants is characterized by growth failure. Although, cow's milk allergy (CMA) may have an impact on growth and leads to FTT, data are still limited. We focused on FTT as a possible clinical marker for an early diagnosis of CMA. The aim of the present study was to evaluate the implications of cow's milk hypersensitivity in infants with FTT and the growth catch-up after a cow's milk-free diet (CMFD). Methods-A cross-sectional study of all consecutive infants evaluated at the Pediatric Nutrition and Allergy Unit of the University Hospital of Bari (Italy) from January 2016 to April 2018 with a medical-driven diagnosis of FTT. Eligible infants were investigated for possible IgE mediated or non-IgE mediated CMA. Results-43 infants were included, mean age 5.7 months. 33/43 (77%) FTT presented a CMA related disease: 3/43 (7%) were diagnosed as presenting an IgE mediated CMA, 30 (93%) had a non IgE-mediated CMA, confirmed by the elimination diet for diagnostic purposes, that led to a significant improvement of symptoms and recrudescence after milk reintroduction. A total of 29 out of 30 patients (one patient was lost at follow-up) moved up to their original growth percentile after dietary changes. Growth z-scores were computed based on WHO anthropometric data. In 10 out of 43 patients (23%) were diagnosed with gastro-esophageal reflux disease (GERD). Conclusions-when evaluating an infant with FTT, physicians should include in their evaluation an extensive search for IgE mediated and non IgE mediated CMA. When in vivo and in vitro analysis are not conclusive, a 4- to 8-weeks trial of CMFD and a consecutive re-introduction of milk proteins may be helpful in less common diagnoses.

Background: There is no perfect agreement on how to perform an allergy workup in suspected beta-lactam (BL)-allergic children, since skin test (ST)-induced pain is often a limitation. The aim of the study was to assess the possibility of reducing the number of ST in children when performing a complete allergy workup for BL hypersensitivity reactions., Methods: A retrospective analysis of all patients referring to the Allergy Unit of the University Hospital of Montpellier (France) with positive responses in immediateand non-immediate-reading ST to a BL over a 16-year period was performed, to determine the positive predictive value (PPV) of ST. All pediatric patients with a suspected BL hypersensitivity were skin-tested with the suspected drug only, during the following 54 months., Results: A total of 319 patients reporting 328 BL reactions were included in the retrospective study. The PPV of ST for the reported drug was of 99.4%. Based on the results, the number of patients to include in the prospective study was estimated to be 101. In the prospective study, 229 children were included. We diagnosed a BL hypersensitivity in 12 children (5.2%): Diagnosis was reached in 6 (50.0%) through ST (delayed reading for all) and in 6 through drug provocation test (DPT)., Conclusion: ST with BL should therefore be performed as a screening test, before DPT, and testing only the suspected drug may be sufficient when dealing with children., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

The most recent scientific evidence supports the consumption of cow's milk and dairy products as part of a balanced diet. However, these days, the public and practicing physicans are exposed to a stream of inconsistent (and often misleading) information regarding the relationship between cow's milk intake and health in the lay press and in the media. The purpose of this article, in this context, is to facilitate doctor-patient communication on this topic, providing physicians with a series of structured answers to frequently asked patient questions. The answers range from milk and milk-derived products' nutritional function across the life span, to their relationship with diseases such as osteoporosis and cancer, to lactose intolerance and milk allergy, and have been prepared by a panel of experts from the Italian medical and nutritional scientific community. When consumed according to appropriate national guidelines, milk and its derivatives contribute essential micro- and macronutrients to the diet, especially in infancy and childhood where bone mass growth is in a critical phase. Furthermore, preliminary evidence suggests potentially protective effects of milk against overweight, obesity, diabetes, and cardiovascular disease, while no clear data suggest a significant association between milk intake and cancer. Overall, current scientific literature suggests that an appropriate consumption of milk and its derivatives, according to available nutritional guidelines, may be beneficial across all age groups, with the exception of specific medical conditions such as lactose intolerance or milk protein allergy. Key teaching points: Milk and its derivatives contribute essential micro and macronutrients to the diet, when consumed according to appropriate national guidelines, especially in infancy and childhood where bone mass growth is in a critical phase. Preliminary evidence suggests potentially protective effects of milk against overweight, obesity, diabetes and cardiovascular disease No clear data are available about the association between milk intake and cancer. Current scientific literature suggests that an appropriate consumption of milk and its derivatives may be beneficial at all ages, with the exception of specific medical conditions such as lactose intolerance or milk protein allergy.

Recently, the interest in the human microbiome and its interplay with the host has exploded and provided new insights on its role in conferring host protection and regulating host physiology, including the correct development of immunity. However, in the presence of microbial imbalance and particular genetic settings, the microbiome may contribute to the dysfunction of host metabolism and physiology, leading to pathogenesis and/or the progression of several diseases. Celiac disease (CD) is a chronic autoimmune enteropathy triggered by dietary gluten exposure in genetically predisposed individuals. Despite ascertaining that gluten is the trigger in CD, evidence has indicated that intestinal microbiota is somehow involved in the pathogenesis, progression, and clinical presentation of CD. Indeed, several studies have reported imbalances in the intestinal microbiota of patients with CD that are mainly characterized by an increased abundance of Bacteroides spp. and a decrease in Bifidobacterium spp. The evidence that some of these microbial imbalances still persist in spite of a strict gluten-free diet and that celiac patients suffering from persistent gastrointestinal symptoms have a desert gut microbiota composition further support its close link with CD. All of this evidence gives rise to the hypothesis that probiotics might play a role in this condition. In this review, we describe the recent scientific evidences linking the gut microbiota in CD, starting from the possible role of microbes in CD pathogenesis, the attempt to define a microbial signature of disease, the effect of a gluten-free diet and host genetic assets regarding microbial composition to end in the exploration of the proof of concept of probiotic use in animal models to the most recent clinical application of selected probiotic strains.

The use of palm oil by the food industry is increasingly criticized, especially in Italy, for its purported negative effects on human health and environment. This paper summarizes the conclusions of a Symposium on this topic, gathered by the Nutrition Foundation of Italy, among experts representing a number of Italian Medical and Nutritional Scientific Societies. Toxicological and environmental issues were not considered. Participants agreed that: no evidence does exist on the specific health effects of palm oil consumption as compared to other saturated fatty acids-rich fats; the stereospecific distribution of saturated fatty acids in the triacylglycerol molecule of palm oil limits their absorption rate and metabolic effects; in agreement with International guidelines, saturated fatty acids intake should be kept <10% of total energy, within a balanced diet; within these limits, no effect of palm oil consumption on human health (and specifically on CVD or cancer risk) can be foreseen.

The aim of this paper is to discuss the current evidence regarding short and long-term health respiratory effects of nutrients and dietary patterns during the first 1000 days from conception. Population of interest included children from birth to two years and their mothers (during pregnancy and lactation). Studies were searched on MEDLINE® and Cochrane database, inserting individually and using the Boolean ANDs and ORs, 'nutrients', 'micronutrients', 'LC-PUFA', 'Mediterranean Diet', 'human milk', 'complementary food', 'pregnancy', 'respiratory disease', 'pulmonary disease', 'asthma', 'epigenetics', 'first 1000 days', 'maternal diet' and 'respiratory health'. All sources were retrieved between 01-09-2015 and 07-12-2016. While unhealthy maternal dietary patterns (high fat intake) during pregnancy can result in alteration of foetal lung development, with increased risk of respiratory disorders, Mediterranean diet has been associated with a lower risk of allergic sensitisation and allergic rhinitis. Breastfeeding has beneficial effects on respiratory infections while evidences about its protective effect on allergic disorders are unclear. During complementary feeding there is no evidence to avoid or encourage exposition to 'highly allergenic' foods to have modification of tolerance development. In children from birth to two years of age, Mediterranean diet has been associated with a lower risk of atopy, wheezing and asthma. Micronutrients, antioxidant and LCPUFA supplementation is not recommended and a whole food approach should be preferred, except for Vitamin D., (Copyright © 2017 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.)

Salicylic acid (SA), a phenolic compound produced by plants, may play a beneficial role on health. This pilot study evaluated whether there might be an association between serum SA and fruit and vegetable (FV) consumption in obese and normal-weight children. Thirty-four obese children (17 boys and 17 girls) and 34 normal-weight children were recruited. Dietary intake was evaluated by the 7-day dietary record. Serum SA was measured using gas chromatography-mass spectrometry method. FV intake in obese and normal-weight children was not different between groups (175.00 (97.66) g versus 192.29 (90.54) g, p = .455). Obese children had lower serum SA than normal-weight children [mean difference, -0.025; 95% CI (-0.044; -0.006) μmol/L]. Serum SA was not associated with daily intake of FV in obese (p = .111) and normal-weight (p = .092) children. Further studies are needed to evaluate the role of FV on serum SA, taking into account also the quantity and the type.

Background: Liver involvement is a common manifestation of hereditary haemorrhagic telangiectasia (HHT). Although a number of studies have been carried out in adult patients, no study has ever been focused on investigating HHT-related hepatic involvement in paediatric patients. The present study aimed for the first time to systematically estimate the prevalence of HHT-associated liver involvement and to characterize HHT-associated hepatic angiodynamic features in paediatric age., Patients and Methods: The study was designed as a cross-sectional survey in an HHT paediatric cohort, subclassified as HHT1 and HHT2 according to the mutated gene. The evaluation of the angiodynamic profile was performed by duplex ultrasound examination. Investigation by multi-slice computed tomography (MSCT) or magnetic resonance angiography (MRA) was performed in patients >12 years., Results: MSCT/MRA examination disclosed silent hepatic involvement in 7/20 (35.0 %) children, and nodular regenerative hyperplasia in two cases. Diameter of common hepatic artery was significantly larger in HHT2 (0.45 ± 0.15 cm) compared to HHT1 (0.33 ± 0.09, p < 0.01) and control children (0.32 ± 0.08, p < 0.05). None of the patients had clinical manifestations of liver involvement. Angiodynamic profiles were different between paediatric and adult HHT patients., Conclusions: Liver involvement can be detected in paediatric HHT patients, albeit with a lower frequency compared to adults. Paediatric HHT2 children show a higher frequency of liver involvement and a trend to hepatic artery dilation when compared to HHT1 children.

Background: Probiotics have been observed to positively influence the host's health, but to date few data about the ability of probiotics to modify the gut microbiota composition exist., Aims: To evaluate the ability of Lactobacillus kefiri LKF01 DSM32079 (LKEF) to colonize the intestinal environment of healthy subjects and modify the gut microbiota composition., Methods: Twenty Italian healthy volunteers were randomized in pre-prandial and post-prandial groups. Changes in the gut microbiota composition were detected by using a Next Generation Sequencing technology (Ion Torrent Personal Genome Machine)., Results: L. kefiri was recovered in the feces of all volunteers after one month of probiotic administration, while it was detected only in three subjects belonging to the pre-prandial group and in two subjects belonging to the post-prandial group one month after the end of probiotic consumption. After one month of probiotic oral intake we observed a reduction of Bilophila, Butyricicomonas, Flavonifractor, Oscillibacter and Prevotella. Interestingly, after the end of probiotic administration Bacteroides, Barnesiella, Butyricicomonas, Clostridium, Haemophilus, Oscillibacter, Salmonella, Streptococcus, Subdoligranolum, and Veillonella were significantly reduced if compared to baseline samples., Conclusion: L. kefiri LKF01 showed a strong ability to modulate the gut microbiota composition, leading to a significant reduction of several bacterial genera directly involved in the onset of pro-inflammatory response and gastrointestinal diseases., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Childhood acute lymphoblastic leukaemia (ALL) survivors have an increased risk of metabolic and cardiovascular disease. We aimed to assess the presence of non-alcoholic fatty liver disease (NAFLD) in childhood ALL and if it is associated with early cardiovascular dysfunction., Methods: In total, 53 childhood ALL survivors and 34 controls underwent auxological evaluation, biochemical assay, liver, heart and vascular ultrasound study., Results: NAFLD was more frequent in ALL patients than in controls (39.6% vs 11.7%, P < 0.01). Patients with NAFLD were more obese and insulin resistant than patients without NAFLD. Flow-mediated dilatation and interventricular septum were lower in the ALL group than those in the control group (P < 0.001 for both). The patients with NAFLD showed lower left ventricular ejection fraction than those without NAFLD (P = 0.011). In ALL survivors, BMI-SDS and subcutaneous fat were the strongest predictors of NAFLD, whereas preperitoneal adipose tissue and C-reactive protein were the strongest predictors of left ventricular ejection fraction., Conclusions: Childhood ALL survivors had higher prevalence of NAFLD than healthy controls, which is associated with early left ventricular impairment. In the case of fatty liver, a comprehensive heart evaluation is mandatory. We strongly recommend to prevent visceral adiposity in ALL survivors, to search for metabolic syndrome or its components and to reinforce the need of intervention on diet and lifestyle during the follow-up of these patients., (© 2017 European Society of Endocrinology.)

Background: Allergic sensitization in children and allergic diseases arising therefrom are increasing for decades. Several interventions, functional foods, pro- and prebiotics, vitamins are proposed for the prevention of allergies and they can't be uncritically adopted., Objective: This Consensus document was developed by the Italian Society of Preventive and Social Paediatrics and the Italian Society of Paediatric Allergy and Immunology. The aim is to provide updated recommendations regarding allergy prevention in children., Methods: The document has been issued by a multidisciplinary expert panel and it is intended to be mainly directed to primary care paediatricians. It includes 19 questions which have been preliminarily considered relevant by the panel. Relatively to each question, a literature search has been performed, according to the Italian National Guideline Program. Methodology, and a brief summary of the available literature data, has been provided. Many topics have been analyzed including the role of mother's diet restriction, use of breast/formula/hydrolyzed milk; timing of introduction of complementary foods, role (if any) of probiotics, prebiotics, vitamins, exposure to dust mites, animals and to tobacco smoke., Results: Some preventive interventions have a strong level of recommendation. (e.g., the dehumidifier to reduce exposure to mite allergens). With regard to other types of intervention, such as the use of partially and extensively hydrolyzed formulas, the document underlines the lack of evidence of effectiveness. No preventive effect of dietary supplementation with polyunsaturated fatty acids, vitamins or minerals has been demonstrated. There is no preventive effect of probiotics on asthma, rhinitis and allergic diseases. It has demonstrated a modest effect, but steady, in the prevention of atopic dermatitis., Conclusions: The recommendations of the Consensus are based on a careful analysis of the evidence available. The lack of evidence of efficacy does not necessarily imply that some interventions may not be effective, but currently they can't be recommended.

Background: Functional gastrointestinal disorders (FGIDs) are chronic or recurrent gastrointestinal symptoms without structural or biochemical abnormalities. FGIDs are multifactorial conditions with different pathophysiologic mechanisms including altered motility, visceral hyperalgesia, brain-gut disturbance, genetic, environmental and psychological factors. Although in most cases gastrointestinal symptoms are transient and with spontaneous resolution in infancy multiple dietary changes and pharmacological therapy are often started despite a lack of evidence-based data. Our aim was to update and critically review the current literature to assess the effects and the clinical appropriateness of drug treatment in early (occurring in infants and toddlers) FGIDs., Methods: We systematically searched the Medline and GIMBE (Italian Group on Medicine Based on Evidence) databases, according to the methodology of the Critically Appraised Topics (CATs). We included reviews, clinical studies, and evidence-based guidelines reporting on pharmacological treatments. Systematic reviews and randomized controlled trials (RCTs) concerning pharmacologic therapies in children with early FGIDs were included, and data were extracted on participants, interventions, and outcomes., Results: We found no evidence-based guidelines or systematic reviews about the utility of pharmacological therapy in functional regurgitation, infant colic and functional diarrhea. In case of regurgitation associated with marked distress, some evidences support a short trial with alginate when other non pharmacological approach failed (stepped-care approach). In constipated infants younger than 6 months of age Lactulose is recommended, whilst in older ages Polyethylene glycol (PEG) represents the first-line therapy both for fecal disimpaction and maintenance therapy of constipation. Conversely, no evidence supports the use of laxatives for dyschezia. Furthermore, we found no RCTs regarding the pharmacological treatment of cyclic vomiting syndrome, but retrospective studies showed a high percentage of clinical response using cyproheptadine, propanolol and pizotifen., Conclusion: There is some evidence that a pharmacological intervention is necessary for rectal disimpaction in childhood constipation and that PEG is the first line therapy. In contrast, for the other early FGIDs there is a lack of well-designed high-quality RCTs and no evidence on the use of pharmacological therapy was found.

The microbial communities that reside in the human gut (microbiota) and their impact on human health and disease are nowadays one of the most exciting new areas of research. A well-balanced microbial intestinal colonization in early postnatal life is necessary for the development of appropriate innate and adaptive immune responses and to establish immune homeostasis later in life. Although the composition and functional characteristics of a 'healthy' gut microbiota remain to be elucidated, perturbations in the microbial colonization of an infant's gastrointestinal tract have been associated with an increased risk of short- and long-term immunologically mediated diseases. Emerging evidence suggests that gut microbiota biomodulators, such as probiotics, prebiotics, synbiotics, and postbiotics may support disease prevention in infants who tend to have a delayed and/or aberrant initial colonization with reduced microbiota diversity (delivery by caesarean section, premature delivery, and excessive use of perinatal antibiotics). Under these dysbiosis conditions probiotics could act as 'surrogate' colonizers to prevent immune-mediated diseases. This review focuses on the influence of delivery mode on the colonization of the infant gastro-intestinal tract. In particular, it examines the manipulation of the gut microbiota composition through the use of gut microbiota biomodulators, in the management of aberrant initial gut colonization and subsequent consequences for the health of the offspring., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Research findings are inconsistent about improvement of specific cardio-metabolic variables after lifestyle intervention in obese children. The aim of this trial was to evaluate the effect of a 1-year intervention, based on normocaloric diet and physical activity, on body mass index (BMI), blood lipid profile, glucose metabolism and metabolic syndrome. Eighty-five obese children aged ≥6 years were analyzed. The BMI z-score was calculated. Fasting blood samples were analyzed for lipids, insulin and glucose. The homeostatic model assessment of insulin resistance (HOMA-IR) was calculated and insulin resistance was defined as HOMA-IR >3.16. HOMA-β%, quantitative insulin sensitivity check index and triglyceride glucose index were calculated. The metabolic syndrome was defined in accordance with the International Diabetes Federation criteria. At the end of intervention children showed a reduction (mean (95% CI)) in BMI z-score (-0.58 (-0.66; -0.50)), triglycerides (-0.35 (-0.45; -0.25) mmol/L) and triglyceride glucose index (-0.29 (-0.37; -0.21)), and an increase in HDL cholesterol (0.06 (0.01; 0.11) mmol/L). Prevalence of insulin resistance declined from 51.8% to 36.5% and prevalence of metabolic syndrome from 17.1% to 4.9%. Nutritional-behavioral interventions can improve the blood lipid profile and insulin sensitivity in obese children, and possibly provide benefits in terms of metabolic syndrome.

Unlabelled: Cervical lymphadenopathy is a common disorder in children due to a wide spectrum of disorders. On the basis of a complete history and physical examination, paediatricians have to select, among the vast majority of children with a benign self-limiting condition, those at risk for other, more complex, diseases requiring laboratory tests, imaging and, finally, tissue sampling. At the same time, they should avoid expensive and invasive examinations when unnecessary. The Italian Society of Preventive and Social Pediatrics, jointly with the Italian Society of Pediatric Infectious Diseases, the Italian Society of Pediatric Otorhinolaryngology, and other Scientific Societies, issued a National Consensus document, based on the most recent literature findings, including an algorithm for the management of cervical lymphadenopathy in children., Methods: The Consensus Conference method was used, following the Italian National Plan Guidelines. Relevant publications in English were identified through a systematic review of MEDLINE and the Cochrane Database of Systematic Reviews from their inception through March 21, 2014., Results: Basing on literature results, an algorithm was developed, including several possible clinical scenarios. Situations requiring a watchful waiting strategy, those requiring an empiric antibiotic therapy, and those necessitating a prompt diagnostic workup, considering the risk for a severe underling disease, have been identified., Conclusion: The present algorithm is a practice tool for the management of pediatric cervical lymphadenopathy in the hospital and the ambulatory settings. A multidisciplinary approach is paramount. Further studies are required for its validation in the clinical field.

Background: Several guidelines for the management of respiratory tract infections in children are available in Italy, as well as in other European countries and the United States of America. However, poor adherence to guidelines and the sustained inappropriate use of antibiotics have been reported. In the outpatient setting, almost half of antibiotics are prescribed for the treatment of common respiratory tract infections. In Italy the antibiotic prescription rate is significantly higher than in other European countries, such as Denmark or the Netherlands, and also the levels of antibiotic resistance for a large variety of bacteria are higher. Therefore, the Italian Society of Preventive and Social Paediatrics organised a consensus conference for the treatment of respiratory tract infections in children to produce a brief, easily readable, evidence-based document., Methods: The conference method was used, according to the National Institute of Health and the National Plan Guidelines. A literature search was performed focusing on the current guidelines for the treatment of airway infections in children aged 1 month-18 years in the ambulatory setting., Results: Recommendations for the treatment of acute pharyngitis, acute otitis media, sinusitis, and pneumonia have been summarized. Conditions for which antibiotic treatment should not be routinely prescribed have been highlighted., Conclusion: This evidence-based document is intended to accessible to primary care pediatricians and general practice physicians in order to make clinical practice uniform, in accordance with the recommendations of the current guidelines., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Aims: Insulin resistance (IR) impairs cellular response to insulin due to a dysfunction in glucose metabolism, associated with an increased cardiovascular risk. The aim of our study was to investigate the relationship among homeostasis model assessment index (HOMA index), endothelial function and vascular morphology in order to better stratify cardiovascular risk in children and adolescents., Methods: A total of 150 children and adolescents (55 pre-pubertal, mean age 10.4 ± 3.1 years) were enrolled. Anthropometric [body mass index (BMI), waist circumference (WC)], laboratory [blood lipids, inflammatory markers, insulinemia, glycemia], HOMA index and ultrasound parameters [flow-mediated dilatation (FMD), common carotid intima-media thickness (cIMT) and antero-posterior diameter of infra-renal abdominal aorta (APAO)] were assessed., Results: cIMT was positively related to age (r=0.274, p<0.01), BMI (r=0.318, p<0.01), WC (r=0.315, p<0.01) and triglycerides (r=0.230, p<0.01). APAO measurements showed a linear positive correlation with age (r=0.435, p<0.01), BMI (r=0.505, p<0.01), WC (r=0.487, p<0.01), triglycerides (r=0.280, p<0.01), C-reactive protein (r=0.209, p<0.05), fasting insulin (r=0.378, p<0.01) and HOMA index (r=0.345, p<0.01). FMD was inversely related to age (r=-0.251, p<0.01), rough BMI (r=-0.318, p<0.01), WC (r=-0.340, p<0.01), fasting insulin (r=-0.281, p<0.01) and HOMA index (r=-0.282, p<0.01). Multiple regression analysis found no influence of HOMA index on APAO and cIMT. HOMA index was an independent predictor for brachial artery FMD worsening after the statistical adjustment., Conclusion: HOMA index increase induced a worsening in endothelial function since childhood., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Obstructive sleep apnea syndrome (OSAS) in children can induce endothelial dysfunction, a well-known early marker of atherosclerosis. The study aimed to evaluate a link among endothelial function (measured by flow-mediated vasodilation (FMD)), obesity (evaluated by body mass index (BMI)), and sleep disordered breathing (SDB), assessed with apnoea/hypopnoea index (AHI), in a paediatric population. We demonstrated that our little OSAS patients showed an impaired endothelial function as compared to controls. In particular, the higher the AHI, the worst the FMD values and thus the endothelial function. Although the population sample is small, this study demonstrated that OSAS could impair endothelial function and worsen cardiovascular risk profile since childhood.

Allergic infants have an unusual gastrointestinal microbiota with low numbers of Bifidobacterium/Lactobacilli and high levels of Clostridium, staphylococci and Escherichia coli. Hydrolyzed formula used to treat these infants is deprived of lactose that instead may influence the gut microbial composition. The aim of the present study is to investigate the influence of lactose on the composition of the gut microbiota and metabolome of infants with cow's milk allergy. Infants prospectively enrolled received an extensively hydrolyzed formula with no lactose for 2 months followed by an identical lactose-containing formula for an additional 2 months. Healthy, age-gender-matched infants were used as controls. The following determinations were performed before and after the introduction of lactose in the diet: enumeration of cells present in the feces using FISH, counts of viable bacterial cells and gas-chromatography mass spectrometry/solid-phase microextraction analysis. The addition of lactose to the diet significantly increases the counts of Bifidobacteria and lactic acid bacteria (p < 0.01), decreases that of Bacteroides/clostridia (p < 0.05) reaching counts found in healthy controls; lactose significantly increases the concentration of total short-chain fatty acids (p < 0.05). The addition of lactose to an extensively hydrolyzed formula is able to positively modulate the composition of gut microbiota by increasing the total fecal counts of Lactobacillus/Bifidobacteria and decreasing that of Bacteroides/Clostridia. The positive effect is completed by the increase of median concentration of short chain fatty acids, especially for acetic and butyric acids demonstrated by the metabolomic analysis., (© 2012 John Wiley & Sons A/S.)

Probiotics (bacteria or yeasts) were defined by the Food Agricultural Organization (FAO) and the World Health Organization (WHO) joint report as live microorganisms which when administered in adequate amounts (in food or as a dietary supplement) confer a health benefit on the host. The best-demonstrated potential clinical benefits of probiotic agents, specifically in the pediatric population, are in the prevention and management of acute diarrhea, antibiotic associated diarrhea, and evidence is mounting on their potential benefits in atopic disease, inflammatory bowel conditions, and necrotizing enterocolitis. Their beneficial effects seem to be strain specific, thus, pooling data from different strains may result in misleading conclusions. Because there was no international consensus on methodology to assess efficiency and safety of probiotics, in 2001 the FAO/WHO undertook work to compile and evaluate the scientific evidence on functional and safety aspects of probiotics. International criteria have been developed to formulate unequivocal criteria for probiotic bacterial strains and products that contain them. More recently, the European Food Safety Authority (EFSA) highlighted as critical factors for probiotic health claim submissions genetic typing, internationally recognised naming protocols and evidence of consistency in the final product.

Background: The association of obesity with sleep-associated respiratory disturbances, which has traditionally been described as a problem in adults, actually originates in childhood. We sought an association between sleep-disordered breathing (SDB) and overweight and/or obesity in a large cohort of school- and preschool-aged children in Southern Italy., Methods: One thousand two hundred seven children (612 girls and 595 boys; mean age 7.3 years) were screened by self-administered questionnaires. According to answers, subjects were divided into three groups: nonsnorers (NS), occasional snorers (OS), and habitual snorers (HS). All HS, who also failed an oximetry study at home, underwent polysomnographic monitoring for the definition of SDB. BMI was calculated according to Italian growth charts., Results: A total of 809 subjects (67.0%) were eligible for the study. Of them, 44 subjects (5.4%) were classified as HS, 138 (17.0%) as OS, and 627 (77.5%) as NS. Fourteen subjects (1.7%) were given a diagnosis of obstructive sleep apnea syndrome (OSAS). Sixty-four subjects (7.9%) were defined as obese, 121 (14.9%) as overweight, and 624 (77.2%) as normal weight. The frequency of HS was significantly higher in obese subjects than in overweight and normal-weight subjects (12.5% vs 5.8% vs 4.6%, respectively; P = .02), whereas the frequency of OSAS was 1.6% in normal-weight, 1.6% in overweight, and 3.1% in obese subjects (P = not significant)., Conclusions: Our findings in a large sample of Italian children suggest that obesity is associated with snoring.

The purpose of our study was to verify the efficacy of prolonged cycles of 1% topical cyclosporine in improving severe form of vernal keratoconjunctivitis (VKC) in childhood and investigate for factors affecting the response to therapy. We conducted an open trial involving 197 children with severe VKC, who received topical cyclosporine 1% for 4 months. Ocular subjective symptoms (SS) and objective signs (OS) were scored in all children at entry, 2 wks and 4 months. Skin prick tests and microscope endothelial cells evaluation were also performed; serum immunoglobulin E and cyclosporine levels were assessed. The mean score values for severity of SS and OS were significantly decreased after 2 wks and 4 months, compared with those at entry (p < 0.001) in all children. Cyclosporine serum levels were neither detectable at the end of therapy, nor were endothelial corneal cells damaged. Patients who started the therapy at the beginning of the disease and/or received long-term regimen of treatment with cyclosporine had a faster improvement of ocular signs and symptoms, compared with all other patients. Our findings suggest that 1% cyclosporine concentration administrated topically at the beginning of the disease and for a long-term period might be the most effective treatment to control symptoms and local inflammation in severe forms of VKC in childhood.

The natural history of allergic disease and its potential for prevention merit close examination because of the explosive worldwide increase in the prevalence and morbidity of atopic disorders. In infants from ''high-risk'' families (i.e. those with one or two parents and/or a sibling with food allergy, eczema, asthma or allergic rhinitis) food allergen avoidance has been advocated as means of preventing the development of atopic disease. The aim of this review was to evaluate the allergy preventive potential of partially or extensively hydrolyzed formulas. When breast-feeding is not possible or supplemental feeding is needed, infants from atopic families should be given a hydrolyzed infant formula for the first 6 month of life. High-risk infants without a history of eczema in a primary relative will receive the protective effect from the less expensive partial hydrolyzed formula (p-HF); whereas those infants who have first-degree relatives with eczema should receive the extensively hydrolyzed formula (e-HF).

Background: Several studies report an inhibitory effect of probiotics on Helicobacter pylori., Aim: To test whether Lactobacillus reuteri ATCC 55730 reduces H. pylori intragastric load in vivo, decreases dyspeptic symptoms, and affects eradication rates after conventional treatment., Materials and Methods: In a double-blind placebo-controlled study, 40 H. pylori-positive subjects were given L. reuteri once a day for 4 weeks or placebo. All underwent upper endoscopy, (13)C-urea breath test, and H. pylori stool antigen determination at entry and (13)C-urea breath test and H. pylori stool antigen (used as both qualitative and semiquantitative markers) after 4 weeks of treatment. Sequential treatment was administered subsequently to all., Results: In vivo, L. reuteri reduces H. pylori load as semiquantitatively assessed by both (13)C-urea breath test delta-value and H. pylori stool antigen quantification after 4 weeks of treatment (p < .05). No change was shown in patients receiving placebo. L. reuteri administration was followed by a significant decrease in the Gastrointestinal Symptom Rating Scale as compared to pretreatment value (p < .05) that was not present in those receiving placebo (p = not significant). No difference in eradication rates was observed., Conclusions: L. reuteri effectively suppresses H. pylori infection in humans and decreases the occurrence of dyspeptic symptoms. Nevertheless, it does not seem to affect antibiotic therapy outcome.

Evidence on the efficacy of standardised phytoterapic extracts for the prevention of recurrent respiratory tract infections (RRTIs) in children is reviewed. Echinacea extracts are widely used in European countries and in the United States as immune-stimulating agents. However, further prospective, appropriately powered clinical studies are required to confirm their benefits in reducing duration and severity of RRTIs.

Background: Helicobacter pylori eradication fails in about 25-30% of children, particularly because of the occurrence of resistance to antibiotics and side-effects., Aim: To determine whether adding the Lactobacillus reuteri to an anti-H. pylori regimen could help to prevent or minimize the gastrointestinal side-effects burden in children., Methods: Forty H. pylori-positive children (21 males; median age: 12.3 years) were consecutively treated with 10-day sequential therapy [omeprazole + amoxycillin for 5 days, and omeprazole + clarithromycin + tinidazole for other 5 days] and blindly randomized to receive either L. reuteri ATCC 55730 (10(8) CFU) or placebo. All children completed the Gastrointestinal Symptom Rating Scale (GSRS) at entry, during and after treatment. H. pylori status was assessed after 8 weeks by (13)C-urea breath test., Results: Overall, in all probiotic supplemented children when compared with those receiving placebo there was a significant reduction of GSRS score during eradication therapy (4.1 +/- 2 vs. 6.2 +/- 3; P < 0.01) and at the end of follow-up (3.2 +/- 2 vs. 5.8 +/- 3.4; P < 0.009). Overall, children receiving L. reuteri report less symptoms than those receiving placebo., Conclusion: L. reuteri is capable of reducing frequency and intensity of antibiotic-associated side-effects during eradication therapy for H. pylori.

Recent studies have shown that the pH of exhaled breath condensate (EBC) could be predictive of asthma exacerbation. Moreover, it has been documented that both allergic rhinitis and atopic dermatitis constitute risk factors for the occurrence of asthma in a progression of disease known as atopic march. The aim of our study was to establish if condensate pH could be used as a valuable mean of monitoring of asthma in atopic children. We studied 34 atopic children with acute asthma, 70 with stable asthma, 35 children with allergic rhinitis, and 17 with atopic dermatitis. Thirty healthy children were used as controls. All children underwent skin prick tests and lung function tests. Exhaled breath condensate samples were collected with a condensing device and de-aerated with argon. The pH of EBC was measured using a pH meter. Children with acute asthma were treated with inhaled steroids and bronchodilators. We found that the pH of condensate in patients with acute asthma was lower than that of patients with stable asthma, rhinitis, and controls (7.25 vs. 7.32, p < 0.05; 7.25 vs. 7.48, p < 0.02; 7.25 vs. 7.78, p < 0.0001, respectively). Patients with stable asthma, rhinitis, and eczema had also lower pH than that of controls (7.32, 7.48, and 7.44 vs. 7.78; p < 0.0001, p < 0.006, p < 0.04, respectively). Patients with acute asthma normalized their pH after treatment (7.82 vs. 7.25; p < 0.0001). Finally, patients with acute asthma showed a positive correlation between pH and lung functional parameters (forced expiratory volume in 1 s; r = 0.39, p = 0.04). Our study shows that EBC pH measurement may be a promising marker for assessing airway inflammation and monitoring response to anti-inflammatory treatment in asthmatic children. Furthermore, we report the first evidence of airways acidification in children with allergic rhinitis and atopic dermatitis. Therefore, EBC pH assessment may be useful in the evaluation of progression of the atopic march toward the development of asthma later in life. Further studies are recommended in order to confirm this indication.

Background & Aims: The currently recommended first-line eradication treatment of Helicobacter pylori in children is usually successful in about 75%. Recently, in adults, a novel 10-day sequential treatment has achieved an eradication rate of 95%. The aim of the study was to assess the H pylori eradication rate of the sequential treatment regimen compared with conventional triple therapy in children., Methods: Seventy-eight consecutive children with H pylori infection were randomized to receive either sequential treatment (omeprazole plus amoxicillin for 5 days, followed by omeprazole plus clarithromycin plus tinidazole for another 5 days) (n = 38; 15 boys [39.5%]; median age, 11.0 years [range, 3.3-16 years]) or triple therapy (omeprazole, amoxicillin, and metronidazole) for 1 week (n = 37; 15 boys [40.5%]; median age, 9.9 years [range, 4.3-16 years]). H pylori infection was based on 2 out of 3 positive tests results: 13C-urea breath test, rapid urease test, and histologic analysis. Eradication was assessed by 13C-urea breath test 8 weeks after therapy., Results: Seventy-four patients completed the study. H pylori eradication was achieved in 36 children receiving sequential treatment (97.3%; 95% confidence interval, 86.2-99.5) and 28 children receiving triple therapy (75.7%; 95% confidence interval, 59.8-86.7) (P < .02). Compliance with therapy was good (>95%) in all., Conclusions: Our study shows, for the first time in children, that 10-day sequential treatment achieves a higher eradication rate than standard triple therapy, which is consistent with the results of adult studies.

Objectives: To establish the rate of Helicobacter pylori reinfection in children from an H. pylori high prevalence area, possible clinical features predictive of reinfection and the usefulness of re-treatment., Methods: 65 consecutive children attending the authors' department between 1998 and 2000 who had proven successful H. pylori eradication were enrolled; 52 took part. Patients and family members were invited to undergo C-urea breath testing and to complete a simple questionnaire regarding symptoms and socioeconomic status. Patients with H. pylori reinfection were offered treatment; eradication was assessed by C-urea breath test 8 weeks after completion of treatment., Results: Of 52 children, 15 (28.8%) were H. pylori positive. Variables predictive of reinfection were age at primary infection and presence of an infected sibling. Although reinfected children were more frequently symptomatic than non-reinfected patients, no specific symptom was associated with reinfection. Of the nine re-treated patients who returned 8 weeks after completing therapy, the bacterium was eradicated in five (56%)., Conclusions: The 12.8% per year reinfection rate in childhood at 2 years that we observed should prompt a re-evaluation of H. pylori status even after a successful eradication. Living in an H. pylori high prevalence area increases the annual risk of reinfection by approximately fourfold over the annual risk in H. pylori low prevalence areas.

Background: The etiology of chronic urticaria (CU) in childhood often remains unrecognized. Recently, in adults it has been shown that approximately 40% of patients with CU have autoimmune urticaria (AU); however, no data are available in children., Objective: To determine the prevalence and possible risk factors for AU in children with CU., Methods: Ninety-three consecutive children (52 male; median age, 7.8 years) with CU were evaluated for AU by means of autologous serum skin test (ASST) in all and serum-induced basophil histamine release (HR-urticaria test) in 52. All other known causes of CU were excluded as appropriate., Results: A cause for CU was identified in 44 children (47%), whereas 49 (53%) remained idiopathic. ASST and HR-urticaria test had positive results in 22 of 49 (45%) and in 16 of 31 (52%) children with idiopathic CU compared with 1 of 44 (2%) and 5 of 21 (24%) with CU of a known cause, respectively ( P <.00001; P=.09). Sensitivity, specificity, and positive and negative predictive values of the ASST for diagnosing AU are 78%, 85%, 74%, and 88%. The prevalence of AU in childhood is 31% (15/52; 95% CI, 24%-51%). None of the variables studied were predictive for development of AU., Conclusion: Our results demonstrate for the first time that children have the same ability as adults to produce functionally active autoantibodies directed against IgE or IgE receptor and that AU occurs in children in as many as 30% of cases. The addition of screening for AU dramatically decreases the rate of the idiopathic form from 52% to 20%.

Phyto-oestrogens are non-steroidal plant-derived compounds that possess oestrogenic activity and act as selective oestrogen receptor modulators (SERMs). Among the dietary oestrogens, the isoflavone class enjoy a wide-spread distribution in most of the members of the Leguminosae family, including such prominent high-content representatives as soybean. Phyto-oestrogen research has grown rapidly in recent years owing to epidemiological studies suggesting that diets rich in soy may be associated with potential health benefits. There is a paucity of data on endocrine effects of soy phytochemicals during infancy, the most sensitive period of life for the induction of toxicity. The safety of isoflavones in infant formulas has been questioned recently owing to reports of possible hormonal effects. Infants fed soy formula receive high levels of phyto-oestrogens in the form of isoflavones (genistein, daidzein and their glycosides). To date, no adverse effects of short- or long-term use of soy proteins have been observed in humans and exposure to soy-based infant formulas does not appear to lead to different reproductive outcomes than exposure to cow milk formulas. Soy formula seems to be a safe feeding option for most infants. Nevertheless, much closer studies in experimental animals and human populations exposed to phyto-oestrogen-containing products, and particularly soy-based infant formulas, are necessary.

In recent years it has become accepted that healthy human intestinal microflora may play an important part in priming the infants' systemic and mucosal immunity. Dietary modulation of the gut microbiota is a topical area of nutritional sciences and the main focus of many current functional foods such as non-digestible oligosaccharides (NDOs). Fructo-oligosaccharides (FOS) and trans-beta-galacto-oligosaccharides (TOS) have been claimed to benefit the health of the colon by selectively stimulating the growth of bifidobacteria and lactobacilli (prebiotic effect). It could be of clinical interest to manipulate colonic flora because it is supposed that specific bacteria in the gut microbial microflora could promote potentially antiallergenic processes and play a key part in atopic disease prevention. Supporting this view is the finding that analysis of the composition of the intestinal bacterial populations showed different microbial patterns between healthy and allergic individuals. Assuming that non-digestible TOS and FOS can affect the intestinal ecosystem beneficially, the opportunity for gut flora manipulation arises in bottle-fed infants. New preterm and term infant milk formulas, supplemented with a mixture of TOS and FOS as prebiotic ingredients induced a significantly higher colonization of bifidobacteria and lactobacilli. In the future, selective manipulation of the intestinal microbiota might be an approach to novel prophylactic and therapeutic intervention strategies of atopy, by redirecting allergic Th-2 responses in favour of Th-1 responses.

A major complication of cholestasis is fat malabsorption related to decreased intestinal bile acids, which leads to malnutrition and fat-soluble vitamin deficiency. The impaired excretion of bile acids leads to a low intraluminal micellar concentration that causes long-chain triglyceride lipolysis and absorption to be ineffective. Medium-chain triglycerides (MCTs) are more readily absorbed when there are low concentrations of bile acids and therefore are a good source of fat calories; MCTs can be administered as MCT-containing formulas. In those children who are unable to take sufficient calories by mouth, it is important to start nocturnal enteral feeding to improve nutritional status. In infants with cholestasis, the absorption of fat-soluble vitamins (A, D, E and K) that require bile acids is also impaired, and supplementation is mandatory. Vitamin K deficiency may be responsible for hypoprothrombinaemia, which may lead to bleeding diathesis, Vitamin K (phytomenadione) should therefore be promptly administered intravenously, at a dose of 1 mg. Chronic vitamin E (alpha-tocopherol) deficiency is associated with a progressive neuromuscular syndrome that can cause cerebellar ataxia, areflexia and peripheral neuropathy. Supplements are given orally in doses of 3-5 times the normal requirement if cholestasis is incomplete. In complete cholestasis, supplements must be given intramuscularly at monthly intervals. In infants who fail to thrive, dietary supplements of carbohydrate polymers and MCTs are required.