Trisomy 22 Mosaicism from Prenatal to Postnatal Findings: A Case Series and Systematic Review of the Literature.

BACKGROUND: Among aneuploidies compatible with life, trisomy 22 mosaicism is extremely rare, and only about 25 postnatal and 18 prenatal cases have been described in the literature so far. The condition is mainly characterized by facial and body asymmetry, cardiac heart defects, facial dysmorphisms, growth failure, delayed puberty, and variable degrees of neurodevelopmental delay. PROBLEM: The scattered information regarding the condition and the dearth of data on its natural history and developmental outcomes restrict genetic counseling, particularly in prenatal settings. Moreover, a prompt diagnosis is frequently delayed by the negative selection of trisomic cells in blood, with mosaicism percentage varying among tissues, which often entails the need for further testing. Purpose/topic: The aim of our work is to provide assistance in prenatal and postnatal genetic counseling by systematically delineating the current knowledge of the condition. This entails defining the prenatal and postnatal characteristics of the condition and presenting novel data from three cases, both prenatally and postnatally. Additionally, we report the developmental outcomes observed in two new patients.

Mitochondrial Dysfunction Causes Cell Death in Patients Affected by Fragile-X-Associated Disorders.

Mitochondria are involved in multiple aspects of neurodevelopmental processes and play a major role in the pathogenetic mechanisms leading to neuro-degenerative diseases. Fragile-X-related disorders (FXDs) are genetic conditions that occur due to the dynamic expansion of CGG repeats of the FMR1 gene encoding for the RNA-binding protein FMRP, particularly expressed in the brain. This gene expansion can lead to premutation (PM, 56-200 CGGs), full mutation (FM, >200 CGGs), or unmethylated FM (UFM), resulting in neurodegeneration, neurodevelopmental disorders, or no apparent intellectual disability, respectively. To investigate the mitochondrial mechanisms that are involved in the FXD patients, we analyzed mitochondrial morphology and bioenergetics in fibroblasts derived from patients. Donut-shaped mitochondrial morphology and excessive synthesis of critical mitochondrial proteins were detected in FM, PM, and UFM cells. Analysis of mitochondrial oxidative phosphorylation in situ reveals lower respiration in PM fibroblasts. Importantly, mitochondrial permeability transition-dependent apoptosis is sensitized to reactive oxygen species in FM, PM, and UFM models. This study elucidated the mitochondrial mechanisms that are involved in the FXD phenotypes, and indicated altered mitochondrial function and morphology. Importantly, a sensitization to permeability transition and apoptosis was revealed in FXD cells. Overall, our data suggest that mitochondria are novel drug targets to relieve the FXD symptoms.

Italian guidelines for the management of irritable bowel syndrome in children and adolescents : Joint Consensus from the Italian Societies of: Gastroenterology, Hepatology and Pediatric Nutrition (SIGENP), Pediatrics (SIP), Gastroenterology and Endoscopy (SIGE) and Neurogastroenterology and Motility (SINGEM).

The irritable bowel syndrome (IBS) is a functional gastrointestinal disorder (FGID), whose prevalence has widely increased in pediatric population during the past two decades. The exact pathophysiological mechanism underlying IBS is still uncertain, thus resulting in challenging diagnosis and management. Experts from 4 Italian Societies participated in a Delphi consensus, searching medical literature and voting process on 22 statements on both diagnosis and management of IBS in children. Recommendations and levels of evidence were evaluated according to the grading of recommendations, assessment, development, and evaluation (GRADE) criteria. Consensus was reached for all statements. These guidelines suggest a positive diagnostic strategy within a symptom-based approach, comprehensive of psychological comorbidities assessment, alarm signs and symptoms' exclusion, testing for celiac disease and, under specific circumstances, fecal calprotectin and C-reactive protein. Consensus also suggests to rule out constipation in case of therapeutic failure. Conversely, routine stool testing for enteric pathogens, testing for food allergy/intolerance or small intestinal bacterial overgrowth are not recommended. Colonoscopy is recommended only in patients with alarm features. Regarding treatment, the consensus strongly suggests a dietary approach, psychologically directed therapies and, in specific conditions, gut-brain neuromodulators, under specialist supervision. Conditional recommendation was provided for both probiotics and specific fibers supplementation. Polyethylene glycol achieved consensus recommendation for specific subtypes of IBS. Secretagogues and 5-HT4 agonists are not recommended in children with IBS-C. Certain complementary alternative therapies, antispasmodics and, in specific IBS subtypes, loperamide and rifaximin could be considered.

Ligamentous laxity in children with achondroplasia: Prevalence, joint involvement, and implications for early intervention strategies.

Achondroplasia (ACH), the most common form of skeletal dysplasia, is characterized by severe disproportionate short stature, rhizomelia, exaggerated lumbar lordosis, brachydactyly, macrocephaly with frontal bossing and midface hypoplasia. Ligamentous laxity has been reported as a striking feature of ACH, but its prevalence and characteristics have not been systematically evaluated yet. There is growing evidence that ligamentous laxity can be associated with chronic musculoskeletal problems and may affect motor development leading to abnormal developmental trajectories. This study aimed to assess the prevalence of ligamentous laxity in children with ACH through standardized tools, the Beighton scale and its modified version for preschool-age children. A total of 33 children (mean age 6.4 ± 3.2 years; age range 1-12.5 years) diagnosed with ACH by the demonstration of a pathogenic variant in the FGFR3 gene and 33 age- and sex-matched healthy controls were included in the study. Both ligamentous laxity assessment and neurological examinations were performed; medical history was also collected from caregivers. Children with ACH showed a 2 times higher risk of ligamentous laxity than the group without skeletal dysplasia (OR = 2.2; 95% CI = 1.0 to 4.7), with 55% of children meeting the diagnostic criteria for hypermobility. No significant difference in ligamentous laxity was observed between males and females. Joint involvement analysis revealed characteristic patterns, with knee hypermobility observed in 67% of patients, while rare was elbow hypermobility. Longitudinal assessments indicated a decreasing trend in ligamentous laxity scores over time, suggesting a potential decrease in hypermobility issues during adulthood. The findings of this study provide valuable insights into the prevalence and characteristics of ligamentous laxity in ACH. Implementation of standardized ligamentous laxity assessments might guide patients' follow-up and facilitate early interventions, helping to prevent pain and improve outcomes and quality of life for such patients. Further prospective studies are needed to explore the natural history of ligamentous laxity in ACH and investigate the potential impact of emerging pharmacological treatments upon hypermobility.

The Role of Diet and Nutritional Interventions for the Infant Gut Microbiome.

The infant gut microbiome plays a key role in the healthy development of the human organism and appears to be influenced by dietary practices through multiple pathways. First, maternal diet during pregnancy and infant nutrition significantly influence the infant gut microbiota. Moreover, breastfeeding fosters the proliferation of beneficial bacteria, while formula feeding increases microbial diversity. The timing of introducing solid foods also influences gut microbiota composition. In preterm infants the gut microbiota development is influenced by multiple factors, including the time since birth and the intake of breast milk, and interventions such as probiotics and prebiotics supplementation show promising results in reducing morbidity and mortality in this population. These findings underscore the need for future research to understand the long-term health impacts of these interventions and for further strategies to enrich the gut microbiome of formula-fed and preterm infants.

Diagnostic and therapeutic approach to children with chronic refractory constipation: Consensus report by the SIGENP motility working group.

Constipation is a common problem in children, accounting for about 3% of all primary care visits and up to 25% of referrals to paediatric gastroenterologists. Although polyethylene glycol often proves effective, most children require prolonged treatment and about 50% of them have at least one relapse within the first 5 years after initial recovery. When conventional treatment fails, children are considered to have refractory constipation. Children with refractory constipation deserve specialist management and guidance. Over the last decades, there has been a remarkable increase in our knowledge of normal and abnormal colonic and anorectal motility in children, and a number of different techniques to measure transit and motility have been developed. The present review analyses the possible diagnostic investigations for children with refractory constipation, focusing on their actual indications and their utility in clinical practice. Moreover, we have also analytically reviewed medical and surgical therapeutic options, which should be considered in selected patients in order to achieve the best clinical outcome.

The pro-oncogenic protein IF1 does not contribute to the Warburg effect and is not regulated by PKA in cancer cells.

The endogenous inhibitor of mitochondrial F1Fo-ATPase (ATP synthase), IF1, has been shown to exert pro-oncogenic actions, including reprogramming of cellular energy metabolism (Warburg effect). The latter action of IF1 has been reported to be hampered by its PKA-dependent phosphorylation, but both reprogramming of metabolism and PKA-dependent phosphorylation are intensely debated. To clarify these critical issues, we prepared stably IF1-silenced clones and compared their bioenergetics with that of the three parental IF1-expressing cancer cell lines. All functional parameters: respiration rate, ATP synthesis rate (OXPHOS), and mitochondrial membrane potential were similar in IF1-silenced and control cells, clearly indicating that IF1 cannot inhibit the ATP synthase in cancer cells when the enzyme works physiologically. Furthermore, all cell types exposed to PKA modulators and energized with NAD+-dependent substrates or succinate showed similar OXPHOS rate regardless of the presence or absence of IF1. Therefore, our results rule out that IF1 action is modulated by its PKA-dependent phosphorylated/dephosphorylated state. Notably, cells exposed to a negative PKA modulator and energized with NAD+-dependent substrates showed a significant decrease of the OXPHOS rate matching previously reported inactivation of complex I. Overall, this study definitively demonstrates that IF1 inhibits neither mitochondrial ATP synthase nor OXPHOS in normoxic cancer cells and does not contribute to the Warburg effect. Thus, currently the protection of cancer cells from severe hypoxia/anoxia and apoptosis remain the only unquestionable actions of IF1 as pro-oncogenic factor that may be exploited to develop therapeutic approaches.

Validation and cross-cultural adaptation of the Italian version of the paediatric eating assessment tool (I-PEDI-EAT-10) in genetic syndromes.

BACKGROUND: The Pediatric Eating Assessment Tool (PEDI-EAT-10) is a reliable and valid tool for rapid identification of dysphagia in patients aged 18 months to 18 years. AIMS: To translate and adapt the PEDI-EAT-10 into the Italian language and evaluate its validity and reliability. METHODS & PROCEDURES: The translation and cross-cultural adaptation of the tool consisted of five stages: initial translation, synthesis of the translations, back translation, expert committee evaluation and test of the prefinal version. The internal consistency of the translated tool was analysed in a clinical group composed of 200 patients with special healthcare needs aged between 18 months and 18 years. They were consecutively enrolled at the Rare Disease Unit, Paediatrics Department, Fondazione Policlinico Agostino Gemelli-IRCCS, Rome. For test-retest reliability, 50 caregivers filled in the PEDI-EAT-10 questionnaire for a second time after a 2-week period. Construct validity was established by comparing data obtained from patients with data from healthy participants (n = 200). The study was approved by the local ethics committee. OUTCOMES & RESULTS: Psychometric data obtained from patients (104 M; mean age = 8.08 ± 4.85 years; median age = 7 years) showed satisfactory internal consistency (Cronbach's α = 0.89) and test-retest reliability (Pearson r = 0.99; Spearman r = 0.96). A total of 30% of children were classified as having a high risk of penetration/aspiration. The Italian PEDI-EAT-10 mean total score of the clinical group was significantly different from that resulting from healthy participants. CONCLUSIONS & IMPLICATIONS: The PEDI-EAT-10 was successfully translated into Italian, validated and found to be a reliable one-page rapid screening tool to identify dysphagia in children and adolescents with special needs. WHAT THIS PAPER ADDS: What is already known on the subject The PEDI-EAT-10 is a valid and reliable quick discriminative paediatric tool for identifying penetration/aspiration risks. What this paper adds to the existing knowledge In the present study we successfully translated and adapted the PEDI-EAT-10 into the Italian language. What are the potential or actual clinical implications of this work? This translation and adaptation increase access to valid feeding and swallowing assessment for children of Italian-speaking families. In addition, the I-PEDI-EAT-10 can suggest further assessment of patients' swallowing abilities.

From Feeding Challenges to Oral-Motor Dyspraxia: A Comprehensive Description of 10 New Cases with CTNNB1 Syndrome.

CTNNB1 syndrome is an autosomal-dominant neurodevelopmental disorder featuring developmental delay; intellectual disability; behavioral disturbances; movement disorders; visual defects; and subtle facial features caused by de novo loss-of-function variants in the CTNNB1 gene. Due to paucity of data, this study intends to describe feeding issues and oral-motor dyspraxia in an unselected cohort of 10 patients with a confirmed molecular diagnosis. Pathogenic variants along with key information regarding oral-motor features were collected. Sialorrhea was quantified using the Drooling Quotient 5. Feeding abilities were screened using the Italian version of the Montreal Children's Hospital Feeding Scale (I-MCH-FS). Mild-to-severe coordination difficulties in single or in a sequence of movements involving the endo-oral and peri-oral muscles were noticed across the entire cohort. Mild-to-profuse drooling was a commonly complained-about issue by 30% of parents. The mean total I-MCH-FS t-score equivalent was 43.1 ± 7.5. These findings contribute to the understanding of the CTNNB1 syndrome highlighting the oral motor phenotype, and correlating specific gene variants with clinical characteristics.

How pain affect real life of children and adults with achondroplasia: A systematic review.

The clinical features of achondroplasia can cause acute self-limited pain that can evolve into chronic pain. Pain causes a low quality of life, in terms of physical, emotional, social, and school functioning in both adult and children with achondroplasia. We conducted a systematic review according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement to describe prevalence, assessment tools, causes and management strategies of pain in this rare disease. We found that shoulder and knee pain is typically referred during infancy, while knee pain is generally referred around 5-6 years of age. The prevalence of general pain in adolescence can be as high as 90%. Chronic pain in the achondroplasia population increases with age, with up to 70% of adults reporting general pain and back pain. Recognizing the multiple determinants of acute and chronic pain in patients with achondroplasia may enable physicians to better understand and manage this burden, particularly with the advent of new drugs that may modify some of the striking features of achondroplasia.

Metabolic Profile of Patients with Smith-Magenis Syndrome: An Observational Study with Literature Review.

Background: Smith-Magenis syndrome (SMS) is caused by either interstitial deletions in the 17p11.2 region or pathogenic variants in the RAI1 gene and is marked by a distinct set of physical, developmental, neurological, and behavioral features. Hypercholesterolemia has been described in SMS, and obesity is also commonly found. Aim: To describe and characterize the metabolic phenotype of a cohort of SMS patients with an age range of 2.9-32.4 years and to evaluate any correlations between their body mass index and serum lipids, glycated hemoglobin (HbA1c), and basal insulin levels. Results: Seven/thirty-five patients had high values of both total cholesterol and low-density lipoprotein cholesterol; 3/35 had high values of triglycerides; none of the patients with RAI1 variants presented dyslipidemia. No patients had abnormal fasting glucose levels. Three/thirty-five patients had HbA1c in the prediabetes range. Ten/twenty-two patients with 17p11.2 deletion and 2/3 with RAI1 variants had increased insulin basal levels. Three/twenty-three patients with the 17p11.2 deletion had prediabetes. Conclusion: Our investigation suggests that SMS 'deleted' patients may show a dyslipidemic pattern, while SMS 'mutated' patients are more likely to develop early-onset obesity along with hyperinsulinism.

The "FEEDS (FEeding Eating Deglutition Skills)" over Time Study in Cardiofaciocutaneous Syndrome.

Feeding, eating and deglutition difficulties are key concerns in patients with cardiofaciocutaneous syndrome (CFCS). This study intends to quantify the development of feeding skills from birth to adulthood in patients with CFCS. Twenty-seven patients (eight males; mean age: 16.7 ± 8.3 years; median age: 15 years, age range: 1.5-38 years) with molecularly confirmed clinical diagnosis of CFCS were prospectively recruited from the Rare Disease Unit, Paediatrics Department, Fondazione Policlinico Agostino Gemelli-IRCCS, Rome, Italy, over a one-year period. Pathogenic variants along with key information regarding oro-motor features were collected. Sialorrhea was quantified using the Drooling Quotient 5. Feeding abilities were screened using the Italian version of the Montreal Children's Hospital Feeding Scale (I-MCH-FS). The oral sensory processing section of the Sensory Profile completed the assessment. Mild-to-profuse drooling was experienced by 25% of patients, and food taste selectivity was a constant during infancy (65%), with persistence even beyond adolescence. Nineteen percent of participants with long-term enteral feeding dependency had BRAF, KRAS and MAP2K1 mutations. These findings document that mealtime challenges in CFCS do not remain restricted only to the paediatric age, and that supportive care until adulthood plays a key role.

Bladder and bowel dysfunction in Down syndrome with neural tube defect: case report and review of the literature.

BACKGROUND: Down syndrome is a genetic disorder caused by trisomy of chromosome 21 and characterized by an increased risk of multiorgan involvement. In Down syndrome children, functional constipation and lower urinary tract infections have been described, together with higher risk for incontinence and delayed sphincter control. At present, to our knowledge, no clear association between Down syndrome, Bladder Bowel Dysfunction and neural tube defects has been previously described. CASE PRESENTATION: We describe two female patients with Down syndrome presenting Bladder Bowel Dysfunction in association with neural tube defects, who both underwent personalized multidisciplinary intervention and pelvic floor rehabilitation, with good clinical outcomes. CONCLUSION: At present, no screening program has been established in order to rule out neural tube defects or neurogenic urinary anomalies in Down syndrome patients presenting bowel and/or bladder dysfunction. In our opinion, presence of spinal abnormalities, despite rare, may be contribute to urinary symptoms and should be ruled out in patients presenting progressive or persistent Bladder Bowel Dysfunction. Early diagnosis and management of spinal cord defects associated with neurogenic urinary dysfunction may allow to prevent possible complications.

Acrodermatitis enteropathica during parenteral nutrition: a pediatric case report.

Background and aim Acrodermatitis enteropathica is a rare disorder characterized by the triad composed by dermatitis, alopecia and diarrhoea. Its acquired form can be caused by inadequate zinc intake, malabsorptive processes, excessive renal or intestinal loss. A rare cause of acquired zinc deficiency is iatrogenic nutritional deficiency due to parenteral nutrition. The diagnosis can be really difficult because the early clinical signs are non-specific and patient's eventual comorbidities can often mask symptoms. Methods: A 5-years-old child affected by several comorbidities, consequent to C. Koseri meningo-encephalitis occurred in the neonatal period, was admitted to Pediatric ward for acute pancreatitis and  had been fed via total parenteral nutrition for one month. Symptoms started approximately 15 days after the start of a  standardized parenteral nutrition mixture. The child presented with diarrhoea, alopecia and erythematous bullous skin lesions, distributed predominantly in acral and periorificial sites and not responsive to topical treatments. Zinc serum dosage were very low (10 µg/dL, with normal values 68-107 µg/dL). Clinical improvement was very fast after oral zinc supplementation (5mg/daily), with a rapid regularisation in the intestinal habits and re-epithelialization of the skin lesions. Results and Conclusions: Trace elements are an essential component of parenteral nutrition. The supplementation of trace elements is an important part of the parenteral nutrition prescription. Even few days of zinc shortage, especially in frail patients, may cause a severe dermatitis that can be easily prevented. Despite its rarity, acrodermatitis enteropathica should be strongly considered in the differential diagnosis of skin lesions for these patients.

Prevalence of Non-erosive Esophageal Phenotypes in Children: A European Multicenter Study.

Background/Aims: Since available data on pediatric non-erosive esophageal phenotypes (NEEPs) are scant, we investigated their prevalence and the phenotype-dependent treatment response in these children. Methods: Over a 5-year period, children with negative upper endoscopy, who underwent esophageal pH-impedance (off-therapy) for persisting symptoms not responsive to proton pump inhibitor (PPI)-treatment, were recruited. Based on the results of acid reflux index (RI) and symptom association probability (SAP), patients were categorized into: (1) abnormal RI (non-erosive reflux disease [NERD]), (2) normal RI and abnormal SAP (reflux hypersensitivity [RH]), (3) normal RI and normal SAP (functional heartburn [FH]), and (4) normal RI and not-reliable SAP (normal-RI-not otherwise-specified [normal-RI-NOS]). For each subgroup, treatment response was evaluated. Results: Out of 2333 children who underwent esophageal pH-impedance, 68 cases, including 18 NERD, 14 RH, 26 FH, and 10 normal-RI-NOS were identified as fulfilling the inclusion criteria and were analyzed. Considering symptoms before endoscopy, chest pain was more reported in NERD than in other cases (6/18 vs 5/50, P = 0.031). At long-term follow-up of 23 patients (8 NERD, 8 FH, 2 RH, and 5 normal-RI-NOS): 17 were on PPIs and 2 combined alginate, 1 (FH) was on benzodiazepine + anticholinergic, 1 (normal-RI-NOS) on citalopram, and 3 had no therapy. A complete symptom-resolution was observed in 5/8 NERD, in 2/8 FH, and in 2/5 normal-RI-NOS. Conclusions: FH may be the most common pediatric NEEP. At long-term follow-up, there was a trend toward a more frequent complete symptom resolution with PPI-therapy in NERD patients while other groups did not benefit from extended acid-suppressive-treatment.

Cross-cultural adaptation and validation of the Italian version of the Montreal Children's Hospital Feeding Scale in a special healthcare needs population.

BACKGROUND: The Montreal Children's Hospital Feeding Scale (MCH-FS) allows paediatricians and other health care professionals to identify feeding difficulties among children. AIM: To translate and adapt the MCH-FS into Italian, and to evaluate the validity and reliability of this Italian version of the Montreal Children's Hospital Feeding Scale (I-MCH-FS). METHODS & PROCEDURES: A total of 150 children with special healthcare needs were admitted to the Rare Disease Unit of the Paediatrics Department at the Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy, between March 2021 and March 2022 (74 males; mean age = 3.85 ± 1.96 years; median age = 4 years; age range = 6 months-6 years and 11 months) and 150 healthy participants (83 males; mean age = 3.5 ± 1.98 years; median age = 3 years; age range = 6 months-6 years and 11 months) were included in the study, which was approved by the local ethics committee. The original version of the MCH-FS was translated and cross-cultural adapted through five stages: (1) initial translation, (2) synthesis of the translations, (3) back translation, (4) expert committee and (5) test of the prefinal version. Test-retest reliability and internal consistency were assessed using Pearson r, Spearman r and Cronbach's alpha, respectively. Construct validity was established by comparing data obtained from patients with those of healthy participants using the Mann-Whitney U-test. OUTCOMES & RESULTS: A Pearson r of 0.98, a Spearman r of 0.95 and Cronbach's alpha value of 0.86 were obtained. In the clinical group, 40.6% children were classified as having feeding disorders (n = 61), while in the normative group 4.7% were diagnosed with feeding problems (n = 7). Mean total score of the clinical group was significatively different from the normative's. CONCLUSIONS & IMPLICATIONS: The I-MCH-FS is a valid and reliable one-page, quick screening tool used to identify feeding disorders among children with special needs in outpatient paediatric setting. WHAT THIS PAPER ADDS: What is already known on the subject The MCH-FS is a valid and reliable parent-report measure aimed at discriminating between children presenting or not feeding disorders. What this paper adds to existing knowledge This paper presents the translation and cross-cultural adaptation of the scale into the Italian language. What are the potential or actual clinical implications of this work? The Italian version of the MCH-FS can be used in the special healthcare needs population.

What to Expect of Feeding Abilities and Nutritional Aspects in Achondroplasia Patients: A Narrative Review.

Achondroplasia is an autosomal dominant genetic disease representing the most common form of human skeletal dysplasia: almost all individuals with achondroplasia have identifiable mutations in the fibroblast growth factor receptor type 3 (FGFR3) gene. The cardinal features of this condition and its inheritance have been well-established, but the occurrence of feeding and nutritional complications has received little prominence. In infancy, the presence of floppiness and neurological injury due to foramen magnum stenosis may impair the feeding function of a newborn with achondroplasia. Along with growth, the optimal development of feeding skills may be affected by variable interactions between midface hypoplasia, sleep apnea disturbance, and structural anomalies. Anterior open bite, prognathic mandible, retrognathic maxilla, and relative macroglossia may adversely impact masticatory and respiratory functions. Independence during mealtimes in achondroplasia is usually achieved later than peers. Early supervision of nutritional intake should proceed into adolescence and adulthood because of the increased risk of obesity and respiratory problems and their resulting sequelae. Due to the multisystem involvement, oral motor dysfunction, nutrition, and gastrointestinal issues require special attention and personalized management to facilitate optimal outcomes, especially because of the novel therapeutic options in achondroplasia, which could alter the progression of this rare disease.

The mitochondrial inhibitor IF1 binds to the ATP synthase OSCP subunit and protects cancer cells from apoptosis.

The mitochondrial protein IF1 binds to the catalytic domain of the ATP synthase and inhibits ATP hydrolysis in ischemic tissues. Moreover, IF1 is overexpressed in many tumors and has been shown to act as a pro-oncogenic protein, although its mechanism of action is still debated. Here, we show that ATP5IF1 gene disruption in HeLa cells decreases colony formation in soft agar and tumor mass development in xenografts, underlining the role of IF1 in cancer. Notably, the lack of IF1 does not affect proliferation or oligomycin-sensitive mitochondrial respiration, but it sensitizes the cells to the opening of the permeability transition pore (PTP). Immunoprecipitation and proximity ligation analysis show that IF1 binds to the ATP synthase OSCP subunit in HeLa cells under oxidative phosphorylation conditions. The IF1-OSCP interaction is confirmed by NMR spectroscopy analysis of the recombinant soluble proteins. Overall, our results suggest that the IF1-OSCP interaction protects cancer cells from PTP-dependent apoptosis under normoxic conditions.

Role of inflammation in pediatric irritable bowel syndrome.

BACKGROUND: IBS affects a large number of children throughout the world and is thought to be the result of disturbed neuroimmune function along with the brain-gut axis. Although the underlying pathophysiologic mechanisms are not clear, the role of low-grade inflammation and mucosal immune activation in IBS symptom generation has become evident also in subsets of pediatric patients. Animal models provided meaningful insight in the causal relationship between abnormal mucosal immune activation and changes in gastrointestinal (GI) sensory-motor function. Likewise, the development of long-standing GI symptoms fulfilling the current criteria for functional GI disorders after infection gastroenteritis and in patients with IBD or celiac disease in remission further supports this hypothesis. Immune activation, its impact on gut sensory-motor function, and potential implications for symptom generation emerged in both children and adults with IBS. PURPOSE: The aim of this review is to summarize the main evidence on the presence of low-grade inflammation and immune activation in children with IBS, its possible role in symptom generation, and its potential implication for new therapeutic strategies.