Narrative review: Risk of eating disorders and nutritional deficiencies with dietary therapies for irritable bowel syndrome.

BACKGROUND AND AIMS: Dietary treatments are growing in popularity as interventions for chronic digestive conditions. Patients with irritable bowel syndrome (IBS) often change their eating behaviors to mitigate symptoms. This can occur under the direction of their physician, a dietitian, or be self-directed. Poorly implemented and monitored diet treatments occur frequently with considerable risks for negative consequences. We aim to review the literature related to dietary treatments and risks associated with nutritional deficiencies and disordered eating. METHODS: Searches were conducted from June to December 2020 on PubMed, MEDLINE, EMBASE, DARE and the Cochrane Database of Systematic Reviews using relevant keywords based on the Patient, Intervention, Comparator and Outcome (PICO) format. Studies included both adult and pediatric populations. Results are synthesized into a narrative review. RESULTS: While dietary approaches are efficacious in many research studies, their translation to clinical practice has been less clear. Patients with IBS are at risk for nutritional deficiencies, disordered eating, increased anxiety, and decreases in quality of life in both adult and pediatric groups. CONCLUSIONS: Physicians prescribing dietary treatment for IBS should be aware of nutritional and psychological risks and implement mitigation measures. These include using a combination of brief, validated questionnaires and clinical history, and collaboration with registered dietitians and/or psychologists. Recommendations for clinical decisions are provided.

In vivo targeting of miR-223 in experimental eosinophilic oesophagitis.

OBJECTIVES: Eosinophilic oesophagitis (EoE) is characterised by oesophageal inflammation, fibrosis and dysfunction. Micro (mi)-RNAs interfere with pro-inflammatory and pro-fibrotic transcriptional programs, and miR-223 was upregulated in oesophageal mucosal biopsy specimens from EoE patients. The therapeutic potential of modulating miR-223 expression in vivo has not been determined. We aimed to elucidate the relevance of oesophageal miR-223 expression in an in vivo model of EoE by inhibiting miR-223 tissue expression. METHODS: The expression of miR-223 and the validated miR-223 target insulin-like growth factor receptor 1 (IGF1R) protein was determined in our paediatric cohort of EoE patients. A murine model of Aspergillus fumigatus-induced EoE was employed, and oesophagi were assessed for miR-233, IGF1R, T lymphocyte type 2 (T2) cytokine expression and eosinophil infiltration. Mice were treated with antagomirs targeting miR-223 or resveratrol targeting its upstream regulator Midline-1(MID-1). RESULTS: There was an inverse relationship between an increased expression of miR-223 and a decreased IGF1R protein concentration in biopsy specimens from EoE patients. TNF-related apoptosis-inducing ligand deficiency, MID-1 inhibition and resveratrol treatment suppressed miR-223 expression. Furthermore, inhibition of miR-223 and treatment with resveratrol in the oesophagus resulted in an amelioration of EoE hallmark features including eosinophilic infiltration, oesophageal circumference and a reduction in T2 cytokine expression. CONCLUSION: miR-223 has a key role in the perpetuation of EoE hallmark features downstream of TNF-related apoptosis-inducing ligand and MID-1 in an experimental model. These studies highlight a potentially critical role of miRNA function in EoE aetiology. miR-223 expression in the oesophagus may be therapeutically modulated by resveratrol, providing a potential new therapeutic option to be explored in EoE patients for this increasingly prevalent condition.

Functional gastrointestinal disorders in children: What is new?

Abdominal pain-predominant functional gastrointestinal disorders encompass a group of chronic conditions featuring abdominal pain where no serious gastrointestinal or intra-abdominal pathology is present. The Rome IV classification system defines and categorises this group based on symptomatology as: functional dyspepsia, irritable bowel syndrome, functional abdominal pain - not otherwise specified and abdominal migraine. These conditions can impact the functioning of the child and family significantly and are challenging to manage. Although the causes of these conditions are not clear, recent years have seen an improved understanding of underlying pathophysiology and identification of effective management options for these conditions.

Sofosbuvir and Ribavirin Therapy for Children Aged 3 to <12 Years With Hepatitis C Virus Genotype 2 or 3 Infection.

Currently, the only approved hepatitis C virus (HCV) treatment for children aged <12 years is pegylated interferon plus ribavirin. In an open-label study, we evaluated the safety and efficacy of sofosbuvir plus ribavirin for 12 weeks in children aged 3 to <12 years chronically infected with genotype 2 or for 24 weeks in patients with genotype 3. Patients aged 3 to <6 years weighing <17 kg received sofosbuvir 150 mg, and patients aged 3 to <6 years weighing ≥17 kg and all patients aged 6 to <12 years received sofosbuvir 200 mg once daily. Intensive pharmacokinetic sampling conducted in each age group confirmed the appropriateness of sofosbuvir doses. For all patients, ribavirin dosing was determined by baseline weight (up to 1,400 mg/day, two divided doses). The primary efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Fifty-four patients were enrolled (41 aged 6 to <12 years and 13 aged 3 to <6 years). Most were treatment naïve (98%) and infected perinatally (94%). All but one patient achieved SVR12 (53/54, 98%; 95% confidence interval, 90%-100%). The patient who did not achieve SVR12 was a 4-year-old who discontinued treatment after 3 days because of "abnormal drug taste." The most commonly reported adverse events in patients aged 6 to <12 years were vomiting (32%) and headache (29%), and those in patients aged 3 to <6 years were vomiting (46%) and diarrhea (39%). One 3-year-old patient had a serious adverse event of accidental ribavirin overdose requiring hospitalization for monitoring; this patient completed treatment and achieved SVR12. Conclusion: Sofosbuvir plus ribavirin was well tolerated and highly effective in children aged 3 to <12 years with chronic HCV genotype 2 or 3 infection.

Integrating psychosocial approaches into the management of childhood functional gastrointestinal disorders: a role for social work.

FGID is one of the most common pain conditions in children and adversely affects their functioning and quality of life. Recent approaches to the management of paediatric FGID recognise the importance of an integrated biopsychosocial approach. Unfortunately, research findings show that psychosocial factors are often not adequately addressed in the management of FGID in children. We recently conducted a survey of 327 paediatric doctors in Australia to investigate their approaches to managing two of the most common childhood FGID - functional abdominal pain (FAP) and irritable bowel syndrome (IBS). Findings provide important insights into paediatricians' perceptions of the role of psychosocial issues and interventions in these conditions. Implications for social work are discussed.

Functional gastrointestinal disorders in children and adolescents: Knowledge, practice and attitudes of Australian paediatricians.

AIM: To investigate paediatricians' understanding of, and approaches to, the diagnosis and treatment of functional abdominal pain (FAP) and irritable bowel syndrome (IBS) in children. METHODS: This study used an electronic survey of doctors subscribing to a popular Australian-based paediatrics email forum. Responses about investigation and management in two clinical vignettes were correlated with respondent demographic data, practice setting, attitudes and knowledge. RESULTS: The 327 respondents were mostly female (60.3%), aged <45 years (54.5%), general paediatricians (53.5%), working in public outpatient clinics (50.5%). Awareness of Rome III diagnostic criteria was low (37.2%) but associated with confidence in diagnosing FAP/IBS in the vignettes. Respondents who lacked confidence in diagnosing FAP/IBS requested more investigations (P < 0.05), although most acknowledged they would not be helpful. Most (70.5%) believed that families are unlikely to accept an FAP diagnosis without investigations requested. Fewer than 1 of 3 were aware of clear evidence for the effective therapy of FAP or IBS, although awareness did not influence management options selected. Two-thirds of respondents believe that FAP is a psychological rather than a medical problem, while few (8.8%) believe the same about IBS (P < 0.001). Parental pressure to find an immediate cure was cited as the most frequent challenge to successful management in both FAP (86.6%) and IBS (75.9%). CONCLUSIONS: Awareness of the Rome criteria was associated with greater confidence in diagnosing FAP and IBS. Attitudes to FAP and IBS being diagnoses of exclusion are prevalent among paediatricians and associated with more investigations requested. There is a lack of awareness of evidence-based therapies for FAP and IBS.

Differential regulation of two FLNA transcripts explains some of the phenotypic heterogeneity in the loss-of-function filaminopathies.

Loss-of-function mutations in the X-linked gene FLNA can lead to abnormal neuronal migration, vascular and cardiac defects, and congenital intestinal pseudo-obstruction (CIPO), the latter characterized by anomalous intestinal smooth muscle layering. Survival in male hemizygotes for such mutations is dependent on retention of residual FLNA function but it is unclear why a subgroup of males with mutations in the 5' end of the gene can present with CIPO alone. Here, we demonstrate evidence for the presence of two FLNA isoforms differing by 28 residues at the N-terminus initiated at ATG+1 and ATG+82 . A male with CIPO (c.18_19del) exclusively expressed FLNA ATG+82 , implicating the longer protein isoform (ATG+1 ) in smooth muscle development. In contrast, mutations leading to reduction of both isoforms are associated with compound phenotypes affecting the brain, heart, and intestine. RNA-seq data revealed three distinct transcription start sites, two of which produce a protein isoform utilizing ATG+1 while the third utilizes ATG+82 . Transcripts sponsoring translational initiation at ATG+1 predominate in intestinal smooth muscle, and are more abundant compared with the level measured in fibroblasts. Together these observations describe a new mechanism of tissue-specific regulation of FLNA that could reflect the differing mechanical requirements of these cell types during development.

Molecular and clinical characterization of a series of patients with childhood-onset lysosomal acid lipase deficiency. Retrospective investigations, follow-up and detection of two novel LIPA pathogenic variants.

BACKGROUND AND AIMS: Childhood/Adult-onset Lysosomal Acid Lipase Deficiency (LAL-D) is a recessive disorder due to loss of function variants of LAL, the enzyme which hydrolyses cholesteryl esters, derived from internalized apoB containing lipoproteins. The disease is characterized by multi-organ involvement including the liver, spleen, intestine and cardiovascular system. The aim of this study was the clinical and molecular characterization of 14 (13 unrelated) previously unreported patients with childhood-onset LAL-D. METHODS: Data collected included clinical and laboratory investigations, liver imaging, liver biopsy and LIPA gene analysis. The response to lipid-lowering medications, liver transplantation and enzyme replacement therapy (ERT) was reported for some patients. RESULTS: LAL-D was suspected at 4.4 ± 3.3 years of age for the presence of hepatomegaly, elevated serum transaminases and hypercholesterolemia, and was confirmed by liver biopsy/imaging and LAL assay. The follow up period ranged from 3 to 40 years (mean 7.8 ± 4.0 years in 13 cases). Patients treated with statins with or without ezetimibe showed 28% reduction of plasma LDL-cholesterol without a tangible effect on liver enzymes; some patients receiving ERT showed normalized lipoprotein profile and transaminase levels. The common c.894G > A variant was observed in homozygosity or compound heterozygosity in 10 patients. We found seven previously reported variants: p.(Trp140*), p.(Arg218*), p.(Gly266*), p.(Thr288Ile), p.(Leu294Ser), p.(His295Tyr) and p.(Gly342Arg) and two novel variants: p.(Asp345Asn), affecting the LAL catalytic triad, and c.229+3A > C, affecting splicing. Homozygosity for p.(Thr288Ile) or c.229+3A > C was associated with a severe phenotype. CONCLUSIONS: This study provides additional data on the features of childhood-onset LAL-D and describes two novel pathogenic variants of the LIPA gene.

Elevated Serum Tissue Transglutaminase Antibodies in Children With Eosinophilic Esophagitis.

OBJECTIVES: This study compared the clinical and histopathological characteristics of children with eosinophilic esophagitis (EoE) and elevated anti-transglutaminase (TTG Ab) with those with EoE and normal TTG Ab titres. METHODS: Single-center chart and blinded histopathological review of patients diagnosed with EoE for a 4-year period, who had esophageal and duodenal biopsies taken at time of endoscopy, and TTG Ab measured within 6 months of biopsy. Patients with histology-proven CD were excluded. RESULTS: Elevated TTG Ab was present in 19/34 (54%) of the study cohort, representing 23% of all patients diagnosed with EoE during the study period. Eight had titers >6× upper limit of normal (ULN) and 4 had >10× ULN. TTG Ab-positive patients were classified as having either potential CD with (n = 3, 16%) and without lymphocytic duodenosis (LD; n = 12, 63%), and no CD (n = 4, 21%) on human leukocyte antigen typing. There was an increase in duodenal eosinophils in patients with elevated TTG Ab (P = 0.01), which remained when patients with LD were excluded (P = 0.018). Of 19 patients with EoE and elevated TTG Ab, 5 responded to elimination diet involving exclusion of wheat, including 2 with a sole wheat trigger and TTG Ab >10× ULN that were CD-associated human leukocyte antigen-negative. CONCLUSIONS: Serum TTG Ab was elevated in almost one-quarter of our total EoE cohort, and at least 20% of these patients did not have potential CD, suggesting EoE is a heterogeneous disease with differing immune mechanisms activated in some patients. These findings also support routine esophageal biopsy during upper endoscopy in children with elevated TTG Ab.

Early Posthepatoportoenterostomy Predictors of Native Liver Survival in Biliary Atresia.

OBJECTIVES: Most infants with biliary atresia (BA) require liver transplantation (LT) after hepatoportoenterostomy (HPE), including those who initially clear jaundice. The aim of the present study was to identify clinical and routine laboratory factors in infants with BA post-HPE that predict native liver survival at 2 years. METHODS: A retrospective cohort study was conducted in 217 patients with BA undergoing HPE in Sydney, Australia and Toronto, Canada between January 1986 and July 2009. Univariate and multivariate logistic regression using backwards-stepwise elimination identified variables at 3 months after HPE most associated with 2-year native liver survival. RESULTS: Significant variables (P < 0.05) on univariate analysis included serum total bilirubin (TB) and albumin at 3 months post-HPE, bridging fibrosis or cirrhosis on initial liver biopsy, ascites of <3 months post-HPE, type 3 BA anatomy, age at HPE of >45 days, change in length z scores within 3 months of HPE, and center. On multivariate analysis, TB (P < 0.0001) and albumin (P = 0.02) at 3 months post-HPE, and center (P = 0.0003) were independently associated with native liver survival. Receiver operating characteristic analysis revealed an optimal cut-off value of TB <74 µmol/L (4.3 mg/dL; area under the receiver operating characteristic curve 0.8990) and serum albumin level >35 g/L (3.5 mg/dL; area under the receiver operating characteristic curve 0.7633) to predict 2-year native liver survival. TB and albumin levels 3 months post-HPE defined 3 groups (1: TB ≤74 µmol/L, albumin >35 g/L; 2: TB ≤74 µmol/L, albumin ≤35 g/L; 3: TB >74 µmol/L) with distinct short- and long-term native liver survival rates (log-rank P < 0.001). Length z scores 3 months post-HPE were poorer for group 2 than group 1 (-0.91 vs -0.30, P = 0.0217) with similar rates of coagulopathy. CONCLUSIONS: Serum TB and albumin levels 3 months post-HPE independently predicted native liver survival in BA when controlling for center. Serum albumin level <35 g/L in infants with BA who were no longer jaundiced at 3 months post-HPE was a poor prognostic indicator. Poorer linear growth and absence of significant coagulopathy suggest a role for early aggressive nutritional therapy in this group.

Differences in Outcomes between Early and Late Diagnosis of Cystic Fibrosis in the Newborn Screening Era.

OBJECTIVES: To evaluate children with cystic fibrosis (CF) who had a late diagnosis of CF (LD-CF) despite newborn screening (NBS) and compare their clinical outcomes with children diagnosed after a positive NBS (NBS-CF). STUDY DESIGN: A retrospective review of patients with LD-CF in New South Wales, Australia, from 1988 to 2010 was performed. LD-CF was defined as NBS-negative (negative immunoreactive trypsinogen or no F508del) or NBS-positive but discharged following sweat chloride < 60 mmol/L. Cases of LD-CF were each matched 1:2 with patients with NBS-CF for age, sex, hospital, and exocrine pancreatic status. RESULTS: A total of 45 LD-CF cases were identified (39 NBS-negative and 6 NBS-positive) with 90 NBS-CF matched controls. Median age (IQR) of diagnosis for LD-CF and NBS-CF was 1.35 (0.4-2.8) and 0.12 (0.03-0.2) years, respectively (P <.0001). Estimated incidence of LD-CF was 1 in 45 000 live births. Compared with NBS-CF, LD-CF had more respiratory manifestations at time of diagnosis (66% vs 4%; P <.0001), a higher rate of hospital admission per year for respiratory illness (0.49 vs 0.2; P = .0004), worse lung function (forced expiratory volume in 1 second percentage of predicted, 0.88 vs 0.97; P = .007), and higher rates of chronic colonization with Pseudomonas aeruginosa (47% vs 24%; P = .01). The LD-CF cohort also appeared to be shorter than NBS-CF controls (mean height z-score -0.65 vs -0.03; P = .02). CONCLUSIONS: LD-CF, despite NBS, seems to be associated with worse health before diagnosis and worse later growth and respiratory outcomes, thus providing further support for NBS programs for CF.

TRAIL deficiency and PP2A activation with salmeterol ameliorates egg allergen-driven eosinophilic esophagitis.

Food antigens are common inflammatory triggers in pediatric eosinophilic esophagitis (EoE). TNF-related apoptosis-inducing ligand (TRAIL) promotes eosinophilic inflammation through the upregulation of the E3 ubiquitin ligase Midline (MID)-1 and subsequent downregulation of protein phosphatase 2A (PP2A), but the role of this pathway in EoE that is experimentally induced by repeated food antigen challenges has not been investigated. Esophageal mucosal biopsies were collected from children with EoE and controls and assessed for TRAIL and MID-1 protein and mRNA transcript levels. Wild-type and TRAIL-deficient (Tnfsf10-/-) mice were administered subcutaneous ovalbumin (OVA) followed by oral OVA challenges. In separate experiments, OVA-challenged mice were intraperitoneally administered salmeterol or dexamethasone. Esophageal biopsies from children with EoE revealed increased levels of TRAIL and MID-1 and reduced PP2A activation compared with controls. Tnfsf10-/- mice were largely protected from esophageal fibrosis, eosinophilic inflammation, and the upregulation of TSLP, IL-5, IL-13, and CCL11 when compared with wild-type mice. Salmeterol administration to wild-type mice with experimental EoE restored PP2A activity and also prevented esophageal eosinophilia, inflammatory cytokine expression, and remodeling, which was comparable to the treatment effect of dexamethasone. TRAIL and PP2A regulate inflammation and fibrosis in experimental EoE, which can be therapeutically modulated by salmeterol.

Outcomes in infants listed for liver transplantation: A retrospective cohort study using the United Network for Organ Sharing database.

LT in neonates and young infants can be challenging due to a variety of factors. To describe the waitlist mortality rates and outcomes of patients listed and transplanted as infants identified from the UNOS database. Infants listed for LT between January 1985 and September 2010 were identified from the UNOS database. Mortality on the waitlist as well as outcomes post-LT was compared between infants aged ≤60 days (Group 1), 61-179 days (Group 2), and 180-364 days (Group 3). Of 6763 infants listed for LT (Group 1 n = 496, Group 2 n = 2404, Group 3 n = 3863), mean age at listing was 196 ± 87 days (Group 1, 29 ± 16 days; Group 2, 132 ± 32 days; Group 3, 257 ± 52 days). Waitlist mortality was highest in Group 1 (Group 1 vs. 3 HR 3.01, 95% CI 2.19-4.15, Group 2 vs. Group 3 HR 0.82, 95% CI 0.66-1.03). One- and five-yr graft survival was 59.6% and 42% (Group 1), 66% and 45% (Group 2), and 66.8% and 41% (Group 3) (one-yr survival p = 0.20; five-yr survival p = 0.19). Infants listed for LT at age ≤60 days had greater waitlist mortality risk than older infants. Infants undergoing LT at age ≤60 days had similar rates of patient and graft survival to older infants.

Predicting severe acute pancreatitis in children based on serum lipase and calcium: A multicentre retrospective cohort study.

OBJECTIVE: This study aims to identify predictors of severe paediatric AP based on laboratory trends and peak/trough values on day 2 (D2) after presentation. The performance of identified predictors was first assessed and then combined with the previously validated sensitive predictor serum lipase ≥7 times the upper limit of normal (× ULN) on day 1 (D1). METHODS: A retrospective review of children with AP (January 2000-July 2011) was performed at three tertiary referral hospitals (two in Australia, one in the Netherlands). Trends of candidate predictors were analysed using the percentage change from D1 to D2 or peak/trough values within 48 h after presentation. RESULTS: 175 AP episodes (including 50 severe episodes [29%]) were identified. Serum lipase ≥50% decrease on D2 (sensitivity 73%, specificity 54%) and calcium trough ≤2.15 mmol/L within 48 h (sensitivity 59%, specificity 81%) were identified as statistically significant predictors for severe AP. By combining the newly identified predictors with the previously validated predictor serum lipase ≥7× ULN on D1 (sensitivity 82%, specificity 53%), specificity improved to predict severe AP on D2 with the addition of: (i) serum lipase ≥50% decrease (sensitivity 67%, specificity 79%), or (ii) trough calcium ≤2.15 mmol/L (sensitivity 46%, specificity 89%). CONCLUSIONS: Serum lipase and calcium, may be helpful in predicting severity of paediatric AP. There may be a clinical role on D1 for using serum lipase ≥7× ULN (high sensitivity), and on D2 for combining D1 serum lipase ≥7× ULN with calcium trough ≤2.15 mmol/L within 48 h (high specificity) to help predict severe paediatric AP.

A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency.

BACKGROUND: Lysosomal acid lipase is an essential lipid-metabolizing enzyme that breaks down endocytosed lipid particles and regulates lipid metabolism. We conducted a phase 3 trial of enzyme-replacement therapy in children and adults with lysosomal acid lipase deficiency, an underappreciated cause of cirrhosis and severe dyslipidemia. METHODS: In this multicenter, randomized, double-blind, placebo-controlled study involving 66 patients, we evaluated the safety and effectiveness of enzyme-replacement therapy with sebelipase alfa (administered intravenously at a dose of 1 mg per kilogram of body weight every other week); the placebo-controlled phase of the study was 20 weeks long and was followed by open-label treatment for all patients. The primary end point was normalization of the alanine aminotransferase level. Secondary end points included additional disease-related efficacy assessments, safety, and side-effect profile. RESULTS: Substantial disease burden at baseline included a very high level of low-density lipoprotein cholesterol (≥190 mg per deciliter) in 38 of 66 patients (58%) and cirrhosis in 10 of 32 patients (31%) who underwent biopsy. A total of 65 of the 66 patients who underwent randomization completed the double-blind portion of the trial and continued with open-label treatment. At 20 weeks, the alanine aminotransferase level was normal in 11 of 36 patients (31%) in the sebelipase alfa group and in 2 of 30 (7%) in the placebo group (P=0.03), with mean changes from baseline of -58 U per liter versus -7 U per liter (P<0.001). With respect to prespecified key secondary efficacy end points, we observed improvements in lipid levels and reduction in hepatic fat content (P<0.001 for all comparisons, except P=0.04 for triglycerides). The number of patients with adverse events was similar in the two groups; most events were mild and were considered by the investigator to be unrelated to treatment. CONCLUSIONS: Sebelipase alfa therapy resulted in a reduction in multiple disease-related hepatic and lipid abnormalities in children and adults with lysosomal acid lipase deficiency. (Funded by Synageva BioPharma and others; ARISE ClinicalTrials.gov number, NCT01757184.).

Health-related quality of life in long-term survivors of paediatric liver transplantation.

BACKGROUND: Long-term survival after paediatric liver transplantation is now the rule rather than the exception. Improving long-term outcomes after transplantation must consider not only the quantity but also the quality of life years restored. OBJECTIVES: To characterize health-related quality of life (HRQOL) of LT recipients ≥15 years after paediatric LT. METHODS: Recipients of a paediatric LT performed before December 1996 in a single institution with continuous follow-up at either the paediatric or adult partner centre were identified. Patients with severe developmental or neurological impairment were excluded. HRQOL was assessed using the Pediatric Quality of Life Inventory 4.0, the Medical Outcomes Study Short Form-36 version 2 and the Pediatric Liver Transplant Quality of Life Tool. RESULTS: A total of 27 (67% male) subjects (mean age 24.3±6.7 years [median 23.2 years; range 16.6 to 40.3 years]) participated. The median age at transplant was 1.7 years (range 0.5 to 17.0 years). Seven (26%) participants underwent retransplantation. Seventeen (63%) participants were engaged in full-time work/study. Mean Short Form-36 version 2 scores included physical (49.6±11.1) and mental (45.3±12.5) subscale scores. The mean score for the disease-specific quality of life tool for paediatric liver transplant recipients (the Pediatric Liver Transplant Quality of Life Tool) was 64.70±15.2. The physical health of the young adults strongly correlated with level of involvement in work/study (r=0.803; P<0.05). CONCLUSIONS: The self-reported HRQOL of participants <18 years of age was comparable with a standardized healthy population. In contrast, participants between 18 and 25 years of age had HRQOL scores that were more similar to a group with chronic illness. Participants engaged in full-time work/study experienced enhanced physical health.

HISTORIQUE: La survie à long terme après une transplantation du foie (TF) en pédiatrie est maintenant la règle plutôt que l'exception. Il faut tenir compte à la fois de la quantité et de la qualité des années de vie récupérées dans l'amélioration des résultats après la TF. OBJECTIFS: Caractériser la qualité de vie liée à la santé (QdVLS) des greffés du foie de 15 ans et plus après une TF en pédiatrie. MÉTHODOLOGIE: Les chercheurs ont dépisté des greffés du foie opérés avant décembre 1996 dans un seul établissement et recevant un suivi continu au centre pédiatrique ou au centre partenaire pour adultes. Les patients ayant une grave atteinte développementale et neurologique étaient exclus. La QdVLS était évaluée au moyen de l'inventaire de la qualité de vie en pédiatrie 4.0, de la version 2 du formulaire court sur les résultats médicaux en 36 questions et de l'outil sur la qualité de vie des greffés du foie en pédiatrie. RÉSULTATS: Au total, 27 sujets (67 % d'hommes, âge moyen de 24,3±6,7 ans [médiane de 23,2 ans; plage de 16,6 à 40,3 ans]) ont participé. Ils avaient un âge médian de 1,7 an au moment de la transplantation (plage de 0,5 à 17,0 ans). Sept participants (26 %) ont dû subir une autre transplantation. Dix-sept participants (63 %) travaillaient ou étudiaient à temps plein. La version 2 du formulaire court en 36 questions incluait des scores de sous-échelle physique (49,6±11,1) et mentale (45,3±12,5). Le score moyen pour l'outil de qualité de vie propre à la maladie (outil de qualité de vie des greffés du foie en pédiatrie) était de 64,70±15,2. La santé physique des jeunes adultes était fortement corrélée avec le taux d'investissement dans le travail ou l'étude (r=0,803, P<0,05). CONCLUSIONS: La QdVLS autodéclarée des participants de moins de 18 ans était comparable à celle d'une population en santé standardisée. En revanche, les participants de 18 à 25 ans avaient un score de QdVLS qui ressemblait davantage à celui d'un groupe ayant une maladie chronique. Les participants qui s'investissaient dans un emploi ou des études à temps plein présentaient une meilleure santé physique.

TNF-related apoptosis-inducing ligand (TRAIL) regulates midline-1, thymic stromal lymphopoietin, inflammation, and remodeling in experimental eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is an inflammatory disorder of the esophagus defined by eosinophil infiltration and tissue remodeling with resulting symptoms of esophageal dysfunction. TNF-related apoptosis-inducing ligand (TRAIL) promotes inflammation through upregulation of the E3 ubiquitin-ligase midline-1 (MID1), which binds to and deactivates the catalytic subunit of protein phosphatase 2Ac, resulting in increased nuclear factor κB activation. OBJECTIVE: We sought to elucidate the role of TRAIL in EoE. METHODS: We used Aspergillus fumigatus to induce EoE in TRAIL-sufficient (wild-type) and TRAIL-deficient (TRAIL(-/-)) mice and targeted MID1 in the esophagus with small interfering RNA. We also treated mice with recombinant thymic stromal lymphopoietin (TSLP) and TRAIL. RESULTS: TRAIL deficiency and MID1 silencing with small interfering RNA reduced esophageal eosinophil and mast cell numbers and protected against esophageal circumference enlargement, muscularis externa thickening, and collagen deposition. MID1 expression and nuclear factor κB activation were reduced in TRAIL(-/-) mice, whereas protein phosphatase 2Ac levels were increased compared with those seen in wild-type control mice. This was associated with reduced expression of CCL24, CCL11, CCL20, IL-5, IL-13, IL-25, TGFB, and TSLP. Treatment with TSLP reconstituted hallmark features of EoE in TRAIL(-/-) mice and recombinant TRAIL induced esophageal TSLP expression in vivo in the absence of allergen. Post hoc analysis of gene array data demonstrated significant upregulation of TRAIL and MID1 in a cohort of children with EoE compared with that seen in controls. CONCLUSION: TRAIL regulates MID1 and TSLP, inflammation, fibrosis, smooth muscle hypertrophy, and expression of inflammatory effector chemokines and cytokines in experimental EoE.