Comparison of endoscopic healing and durability between infliximab originator and CT-P13 in pediatric patients with inflammatory bowel disease.

Background and aims: Favourable clinical data were published on the efficacy of CT-P13, the first biosimilar of infliximab (IFX), in pediatric inflammatory bowel disease (IBD); however, few studies have compared the effect on endoscopic healing (EH) and drug retention rate between the IFX originator and CT-P13. Therefore, we aimed to compare EH and the drug retention rate between the IFX originator and CT-P13. Methods: Children with Crohn's disease (CD) and ulcerative colitis (UC)/IBD-unclassified (IBD-U) at 22 medical centers were enrolled, with a retrospective review conducted at 1-year and last follow-up. Clinical remission, EH and drug retention rate were evaluated. Results: We studied 416 pediatric patients with IBD: 77.4% had CD and 22.6% had UC/IBD-U. Among them, 255 (61.3%) received the IFX originator and 161 (38.7%) received CT-P13. No statistically significant differences were found between the IFX originator and CT-P13 in terms of corticosteroid-free remission and adverse events. At 1-year follow-up, EH rates were comparable between them (CD: P=0.902, UC: P=0.860). The estimated cumulative cessation rates were not significantly different between the two groups. In patients with CD, the drug retention rates were 66.1% in the IFX originator and 71.6% in the CT-P13 group at the maximum follow-up period (P >0.05). In patients with UC, the drug retention rates were 49.8% in the IFX originator and 56.3% in the CT-P13 group at the maximum follow-up period (P >0.05). Conclusions: The IFX originator and CT-P13 demonstrated comparable therapeutic response including EH, clinical remission, drug retention rate and safety in pediatric IBD.

Factors Associated with Reaching Mid-Parental Height in Patients Diagnosed with Inflammatory Bowel Disease in Childhood and Adolescent Period.

Background/Aims: The recent update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease initiative has added normal growth in children as an intermediate target in Crohn's disease and ulcerative colitis. We aimed to investigate factors associated with reaching mid-parental height (MPH) in patients diagnosed with inflammatory bowel disease in childhood and the adolescent period. Methods: This multicenter retrospective observational study included pediatric patients with inflammatory bowel disease that had reached adult height. Factors associated with reaching MPH were investigated by logistic regression analyses. Results: A total of 166 patients were included in this study (128 Crohn's disease and 38 ulcerative colitis). Among them, 54.2% (90/166) had reached their MPH. Multivariable logistic regression analysis revealed that height Z-score at diagnosis and MPH Z-score were independently associated with reaching MPH (odds ratio [OR], 8.45; 95% confidence interval [CI], 4.44 to 17.90; p<0.001 and OR, 0.11; 95% CI, 0.04 to 0.24; p<0.001, respectively). According to the receiver operating characteristic curve analysis, the optimal cutoff level of "height Z-score at diagnosis minus MPH Z-score" that was associated with reaching MPH was -0.01 with an area under the curve of 0.889 (95% CI [0.835 to 0.944], sensitivity 88.9%, specificity 84.2%, positive predictive value 87.0%, negative predictive value 86.5%, p<0.001). Conclusions: Height Z-score at diagnosis and MPH Z-score were the only factors associated with reaching MPH. Efforts should be made to restore growth in pediatric patients who present with a negative "height Z-score at diagnosis minus MPH Z-score."

Can red cell distribution width in very low birth weight infants predict bronchopulmonary dysplasia?

ABSTRACT: Red cell distribution width (RDW) is a useful marker for assessing the severity and prognosis of various diseases in adults. However, whether it is applicable to children, especially in newborns, has not been determined.This study aimed to investigate the RDW values of preterm infants and evaluate whether RDW values in the early days of life can predict bronchopulmonary dysplasia (BPD) development.One hundred and eight infants born at <30 weeks of gestation with a birth weight of <1500 g participated in this retrospective study. RDW values measured at birth, 7 days (D7), and 28 days (D28) after birth were reviewed. The changes in RDW values in the first month of life were analyzed, and we evaluated the relationship between RDW and BPD.The mean RDW values at birth, D7, D28 and the change from birth to D7 were 16.2 ±â€Š0.1%, 17.5 ±â€Š0.2%, 17.6 ±â€Š0.2% and 1.3 ±â€Š1.8%, respectively. RDW at birth was lower in the infants born at <28 weeks' gestational age than in those born at ≥28 weeks' gestational age (15.7 ±â€Š0.3 vs 16.4 ±â€Š0.2, P = .024). RDW values of both groups increased during the first week after birth and did not differ significantly at D7. The levels remained similar at 1 month of age. RDW at birth, D7, and D28 and the changes in RDW from birth to D7 were not correlated with the development of BPD independent of its severity.The usefulness of RDW as a predictor of BPD development remains questionable and requires further study.

Changing prevalence of Helicobacter pylori infection in children and adolescents.

Helicobacter pylori infection has declined over recent decades. However, its prevalence remains high, and nearly 50% of the global population has been infected. In Korea, seroprevalence has steadily decreased in adults, but the status of H. pylori infection in children is unknown. The current status or trend of H. pylori infection in children is important because it can help estimate H. pylori-related diseases including gastric cancer in later life. In this review, the authors discuss the change in H. pylori infection rate among children and adolescents based on literature reviews and our research.

A Case of Congenital Common Bile Duct Web Treated with Balloon Dilation under Endoscopic Retrograde Cholangiopancreatography in a Young Child.

Web in common bile duct (CBD web) is very rare. It is usually asymptomatic and detected incidentally during surgery for other causes in adults. It can be congenital or acquired, however congenital CBD web is extremely rare. Currently, despite its invasiveness and complications, endoscopic retrograde cholangiopancreatography (ERCP) is considered as a useful diagnostic and therapeutic modality in children with hepatobiliary pancreatic diseases as in adults. Herein we report a case of congenital CBD web presenting with acute pancreatitis and choledocholithiasis in a 4-year-old girl which was diagnosed and treated using balloon dilation under ERCP. After balloon dilation of the web, a common pancreatobiliary channel was observed. To the best of our knowledge, a case of congenital CBD web with pancreatobiliary junctional abnormality treated using ERCP in a child has not been reported to date.

Risk Factors and Effects of Severe Late-Onset Hyponatremia on Long-Term Growth of Prematurely Born Infants.

PURPOSE: Sodium is an essential nutritional electrolyte that affects growth. A low serum sodium concentration in healthy premature infants beyond 2 weeks of life is called late-onset hyponatremia (LOH). Here, we investigated the association between LOH severity and growth outcomes in premature infants. METHODS: Medical records of premature infants born at ≤32 weeks of gestation were reviewed. LOH was defined as a serum sodium level <135 mEq/L regardless of sodium replacement after 14 days of life. Cases were divided into two groups, <130 mEq/L (severe) and ≥130 mEq/L (mild). Characteristics and growth parameters were compared between the two groups. RESULTS: A total of 102 premature infants with LOH were included. Gestational age ([GA] 27.7 vs. 29.5 weeks, p<0.001) and birth weight (1.04 vs. 1.34 kg, p<0.001) were significantly lower in the severe group. GA was a risk factor of severe LOH (odds ratio [OR], 1.328, p=0.022), and severe LOH affected the development of bronchopulmonary dysplasia (OR, 2.950, p=0.039) and led to a poor developmental outcome (OR, 9.339, p=0.049). Growth parameters at birth were lower in the severe group, and a lower GA and sepsis negatively affected changes in growth for 3 years after adjustment for time. However, severe LOH was not related to growth changes in premature infants. CONCLUSION: Severe LOH influenced the development of bronchopulmonary dysplasia and developmental outcomes. However, LOH severity did not affect the growth of premature infants beyond the neonatal period.

Report: central diabetes insipidus and schwannoma in a male with X-linked congenital adrenal hypoplasia.

BACKGROUND: DAX1 mutations are related to the X-linked form of adrenal hypoplasia congenita (AHC) in infancy and to hypogonadotropic hypogonadism (HH) in puberty. We report a male patient affected by X-linked AHC who presented with central diabetes insipidus and schwannoma in adulthood, which has not been described in association with AHC. CASE PRESENTATION: A 36-day-old male infant who presented with severe dehydration was admitted to the intensive care unit. His laboratory findings showed hyponatremia, hyperkalemia, hypoglycemia, and metabolic acidosis. After hormonal evaluation, he was diagnosed with adrenal insufficiency, and he recovered after treatment with hydrocortisone and a mineralocorticoid. He continued to take hydrocortisone and the mineralocorticoid after discharge. At the age of 17, he did not show any signs of puberty. On the basis of a GnRH test, a diagnosis of HH was made. At the age of 24, he was hospitalized with thirst, polydipsia and polyuria. He underwent a water deprivation test for polydipsia and was diagnosed with central diabetes insipidus. By quantitative polymerase chain reaction analysis, we identified a hemizygous frameshift mutation in DAX1 (c.543delA). CONCLUSIONS: We suggest that DAX1 mutations affect a wider variety of endocrine organs than previously known, including the posterior pituitary gland.

Chronic Gastric Volvulus as a Late Complication of Hepatectomy for Hepatoblastoma in a Child: A Case Report.

Gastric volvulus (GV) is an uncommon pathology, with 10-20% of cases occurring in children, typically before one year of age. It often occurs in people with congenital diaphragmatic hernias, intestinal malrotation, eventration of the diaphragm, paraesophageal hernias, wandering spleens, asplenism, or intra-abdominal adhesions. We report a rare case of chronic GV after left hemihepatectomy for hepatoblastoma in a child. The patient was a 9-year-old boy who complained of upper abdominal pain and postprandial upper abdominal distension for one year. At the age of 4 months, he was diagnosed with hepatoblastoma and had undergone left hemihepatectomy. The upper gastrointestinal contrast study revealed chronic organoaxial gastric volvulus. After a surgical procedure involving adhesiolysis and an anterior wall gastropexy, the patient improved and the symptoms resolved. Although GV is a rare disease, it should be suspected in a patient with a previous abdominal surgical history who is complaining of abdominal distension and pain.

Changes in the Treatment Strategies for Helicobacter pylori Infection in Children and Adolescents in Korea.

The policies developed for the treatment of Helicobacter pylori infection in adults may not be the most suitable ones to treat children and adolescents. Methods used to treat children and adolescents in Europe and North America may not be appropriate for treating children and adolescents in Korea due to differences in epidemiological characteristics of H. pylori between regions. Moreover, the agreed standard guidelines for the treatment of H. pylori infection in children and adolescents in Korea have not been established yet. In this study, the optimal treatment strategy for H. pylori infection control in children and adolescents in Korea is discussed based on these guidelines, and recent progress on the use and misuse of antimicrobial agents is elaborated. Non-invasive as well as invasive diagnostic test and treatment strategy for H. pylori infection are not recommendable in children aged less than ten years or children with body weight under 35 kg, except in cases of clinically suspected or endoscopically identified peptic ulcers. The uncertainty, whether enough antimicrobial concentrations to eradicate H. pylori can be maintained when administered according to body weight-based dosing, and the costs and adverse effects outweighing the anticipated benefits of treatment make it difficult to decide to eradicate H. pylori in a positive non-invasive diagnostic test in this age group. However, adolescents over ten years of age or with a bodyweight of more than 35 kg can be managed aggressively as adults, because they can tolerate the adult doses of anti-H. pylori therapy. In adolescents, the prevention of future peptic ulcers and gastric cancers is expected after the eradication of H. pylori. Bismuth-based quadruple therapy (bismuth-proton pump inhibitor-amoxicillin/tetracycline-metronidazole) with maximal tolerable doses and optimal dose intervals of 14 days is recommended, because in Korea, the antibiotic susceptibility test for H. pylori is not performed at the initial diagnostic evaluation. If the first-line treatment fails, concomitant therapy plus bismuth can be attempted for 14 days as an empirical rescue therapy. Finally, the salvage therapy, if needed, must be administered after the H. pylori antibiotic susceptibility test.

Monocyte Chemoattractant Protein (MCP)-1 in Rotavirus-Associated White Matter Injury in Newborns.

Recent reports have suggested an association between rotavirus infection and a distinctive pattern of white matter injury (WMI) in neonates with seizures; however, the connection between the two is not fully understood. To evaluate the underlying mechanism, we profiled and compared eight cytokines (IL [interleukin]-1ß, IL-6, IL-8, IL-10, IFN-γ [interferon-γ ], MCP-1 [monocyte chemoattractant protein-1], MIP-1ß [macrophage inflammatory protein-1ß], and TNF-α [tumor necrosis factor-α]) in the cerebrospinal fluid (CSF) of 33 neonates with seizures who had no other well-known causes of seizures and 13 control patients (rotavirus-induced gastroenteritis but without seizures). Among the 33 neonates with seizures, 9 showed WMI and all were infected with rotavirus (R + W + ). Among the 24 patients without WMI, 11 were infected with rotavirus (R + W - ) and 13 were not (R - W - ).Only MCP-1 and MIP-1ß were different between the groups. MCP-1 was increased in R+ W+ compared with R + W- (p < 0.01), R - W- (p < 0.01), and control (p = 0.03) patients. MIP-1ß was decreased in R + W+ compared with R - W- (p < 0.01) and control (p < 0.01), but not R + W- (p = 0.23) patients. MCP-1 and MIP-1ß are C-C chemokines that recruit immune cells to the site of inflammation. Our pilot study suggests MCP-1-mediated monocyte recruitment may be linked with this complication caused by rotavirus.

Diagnosis of Helicobacter pylori Infection in Children and Adolescents in Korea.

Helicobacter pylori plays an important role in the pathogenesis of chronic gastritis, peptic ulcer disease, gastric cancer, and gastric mucosa-associated lymphoid tissue lymphoma. In Korea, the guidelines for the diagnosis and treatment of H. pylori infection in adults were revised in 2013. The European Helicobacter and Microbiota Study Group and Consensus panel released the fifth edition of the Maastricht Consensus Report for the management of H. pylori infection in 2015, and the European Society of Paediatric Gastroenterology, Hepatology and Nutrition and the North American Society of Paediatric Gastroenterology, Hepatology and Nutrition released the updated joint guidelines for children and adolescents in 2016. Considering these recommendations and recent progress in our research and that of other research teams, this study aimed to discuss the diagnostic strategies for H. pylori infection in children and adolescents.

A Pilot Study Evaluating Cerebral Vasculitis in Kawasaki's Disease.

Cerebral vasculitis is thought to be a possible underlying mechanism of severe neurological complications of Kawasaki's disease (KD), such as cerebral infarct or aneurysm rupture. To evaluate the intracranial inflammatory response in patients with acute-stage KD, we measured the levels of cytokines (interleukin [IL]-6 and tumor necrosis factor [TNF]-α) and pentraxin-3 (PTX3) in the cerebrospinal fluid of patients with KD (n = 7) and compared the levels to those of the age- and sex-matched febrile control patients (bacterial meningitis [n = 5], enteroviral meningitis [n = 10], nonspecific viral illness without central nervous system involvement [n = 10]). PTX3 and TNF-α were rarely detected and only in trace concentration in KD, and the levels of IL-6 were not different from those of nonspecific viral illnesses. These mediators are not established biomarkers for cerebral vasculitis but might reflect vascular inflammation in various diseases including KD. Therefore, intracranial inflammation including vasculitis seems to be insignificant in our patients with KD. However, our results might be attributed to the fact that these patients lacked any clinical signs of cerebral or coronary vessel involvement. None of them underwent brain imaging. To clarify this issue, further studies involving patients with neurologic symptoms and proven involvement of cerebral vessels are needed.

Characterizing antigenic determinants in Helicobacter pylori CagA capable of detecting serum antibodies in children.

Helicobacter pylori can persistently colonize the mucosa of the human stomach, resulting in gastric disorders. Endoscopic biopsy for rapid urease test and histopathologic examination are considered as the most accurate diagnostic methods for H. pylori infection. Serological methods are recommended for children because of invasiveness of the diagnosis mentioned above. Here, the cytotoxin-associated gene A protein (Cag A), as an immunodominant antigen, was subdivided to determine which regions harbor antigenicity for humans. CagA was divided into 17 overlapping fragments of ∼400 bp, which were used for the analysis of antigenic determinants. The partial proteins were subjected to immunoblot analysis using pooled serum samples from children with gastric symptoms. A partial recombinant CagA protein containing epitope regions (683-749 amino acids), which were identified in this study, was produced and used for the detection of anti-CagA antibodies and further investigated its serodiagnostic value for determination of H. pylori infection in children. The serum IgG reactivities from children with gastric symptoms were significantly three times more than that of serum samples from children with non-gastric symptoms (P < 0.005). Moreover, the serum IgG reactivities from children showing strong urease activity of gastric biopsies were significantly higher than those with moderate and weak urease activities (P < 0.05). Hence, the partial CagA is a candidate antigen for diagnosis of H. pylori infection.

Vitamin C induces apoptosis in AGS cells via production of ROS of mitochondria.

It has been demonstrated that vitamin C exhibits anti-cancer activity in various tumor cell lines; however, its specific mechanism of action remains unknown. Although the diagnosis and therapy of cancer patients have markedly improved in recent years, safer and more cost-effective treatments are still required. Therefore, the present study examined the effect of vitamin C on the induction of cell death in gastric cancer and its underlying mechanism of action. It was observed that the cytotoxicity of vitamin C on the human gastric cancer cell line AGS is dependent on the apoptotic pathway, including caspase cascades, but not on the necroptotic pathway. It was demonstrated that the vitamin C-induced calcium influx and ROS generation have critical roles in the induction of apoptosis. Furthermore, vitamin C treatment depleted adenosine triphosphate (ATP) production in AGS cells, and the autophagy pathway may be involved in this process. Taken together, the current study suggests that a high dose of vitamin C may induce gastric cancer cell apoptosis through the dysfunction of mitochondria, including calcium influx, reactive oxygen species generation and ATP depletion.

Clinical and ABCB11 profiles in Korean infants with progressive familial intrahepatic cholestasis.

AIM: To investigate clinical profiles and mutations of ABCB11 in Koreans with progressive familial intrahepatic cholestasis 2 and review the differences between Koreans and others. METHODS: Of 47 patients with neonatal cholestasis, five infants had chronic intrahepatic cholestasis with normal γ-glutamyl transpeptidase. Direct sequencing analyses of ABCB11, including exons and introns, were performed from peripheral blood. RESULTS: Living donor-liver transplantation was performed in four patients because of rapidly progressive hepatic failure and hepatocellular carcinoma. Three missense mutations were found in two patients: compound heterozygous 677C>T (S226L)/3007G>A (G1003R) and heterozygous 2296G>A (G766R). The mutations were located near and in the transmembranous space. CONCLUSION: Alterations in the transmembrane of the bile salt export pump in the Korean infants were different from those previously reported in Chinese, Japanease, Taiwanese, and European patients.

Limitations of urease test in diagnosis of pediatric Helicobacter pylori infection.

The diagnosis of Helicobacter pylori (H. pylori) infection is usually based on the results of urease test and histology. The urease test known as a simple and cheap method does not need special skills to perform or to read the result. The time needed for the test to turn positive depends on the concentration of bacteria, and the accuracy is up to the density of H. pylori density in the biopsy sample, which is generally lower in children than adolescents and adults. Therefore, there are debates about the sensitivity of the urease test in children. The reason for lower sensitivity of the urease test in children was not identified, but might be related to the low density and patchy distribution of bacteria. In this review, we discuss the limitations of the urease test in children according to age, histology, number of biopsy samples, and biopsy site. In children under 5 years old, the differences in positivity rate when the urease test used one or three biopsy samples, and samples from the antrum or the gastric body, were larger than those in children aged 5-15 years. Thus, three or more biopsy samples from both the antrum and body would improve the sensitivity of H. pylori infection diagnosis in children under 5 years old.

Suppurative meckel diiverticulum in a 3-year-old girl presenting with periumbilical cellulitis.

Meckel diverticulum (MD) is one of the most common congenital gastrointestinal anomalies and occurs in 1.2-2% of the general population. MD usually presents with massive painless rectal bleeding, intestinal obstruction or inflammation in children and adults. Suppurative Meckel diverticulitis is uncommon in children. An experience is described of a 3-year-old girl with suppurative inflammation in a tip of MD. She complained of acute colicky abdominal pain, vomiting and periumbilical erythema. Laparoscopic surgery found a relatively long MD with necrotic and fluid-filled cystic end, which was attatched to abdominal wall caused by inflammation. Herein, we report an interesting and unusual case of a suppurative Meckel diverticulitis presenting as periumbilical cellulitis in a child. Because of its varied presentations, MD might always be considered as one of the differential diagonosis.

Immunohistochemical Expressions of MUC2, MUC5AC, and MUC6 in Normal, Helicobacter pylori Infected and Metaplastic Gastric Mucosa of Children and Adolescents.

OBJECTIVES: The aim of this study was to investigate expression of gastric mucins in children and adolescents and to assess their relations with age and Helicobacter pylori (H. pylori) infection. METHODS: Gastric biopsies were collected from 259 pediatric and adulthood patients with gastrointestinal symptoms among all of patients undergone gastroduodenoscopy from 1990 to 2004 at Gyeongsang National University hospital and assorted based on H. pylori infection, age, and intestinal metaplasia as follows; H. pylori infection before 5 years of age or not, H. pylori infection between 5 and 9 years of age or not, H. pylori infection between 10 and 14 years of age or not, H. pylori infection between 20 and 29 years of age or not and intestinal metaplasia between 21 and 35 years of age. Total 810 tissue slides from the subjects were examined regarding expressions of Mucin2 (MUC2), Mucin5AC (MUC5AC), and Mucin6 (MUC6) in nine groups using immunohistochemical stains. A semiquantitative approach was used to score the staining extent of tissue slide. RESULTS: Increased expressions of MUC2, MUC5AC, and MUC6 were noted in intestinal metaplasia compared with subjects infected with H. pylori between 20 and 29 years. Gastric expressions of MUC5AC were decreased in older than 5 years with H. pylori compared with in older than 5 years without H. pylori (p < .001). Expressions of MUC2 and MUC6 did not change significantly by H. pylori status. Some nuclear expressions of MUC2 and MUC6 were noted in children without intestinal metaplasia. CONCLUSIONS: MUC5AC might be affected by chronic H. pylori infection. In addition to biomarkers for intestinal metaplasia or prognostic factors for gastric cancer in adults, MUC2 and MUC6 in children might have an another role, based on ectopic gastric nuclear expressions of MUC2 and MUC6 in children without intestinal metaplasia.

Association between Gastric pH and Helicobacter pylori Infection in Children.

PURPOSE: To assess gastric pH and its relationship with urease-test positivity and histological findings in children with Helicobacter pylori infection. METHODS: Fasting gastric juices and endoscopic antral biopsy specimens were collected from 562 children and subjected to the urease test and histopathological examination. The subjects were divided into 3 age groups: 0-4, 5-9, and 10-15 years. The histopathological grade was assessed using the Updated Sydney System, while the gastric juice pH was determined using a pH meter. RESULTS: The median gastric juice pH did not differ significantly among the age groups (p=0.655). The proportion of individuals with gastric pH >4.0 was 1.3% in the 0-4 years group, 6.1% in the 5-9 years group, and 8.2% in 10-15 years (p=0.101). The proportions of moderate and severe chronic gastritis, active gastritis, and H. pylori infiltration increased with age (p<0.005). Urease-test positivity was higher in children with hypochlorhydria (77.8%) than in those with normal gastric pH (31.7%) (p<0.001). Chronic and active gastritis were more severe in the former than the latter (p<0.001), but the degree of H. pylori infiltration did not differ (20.9% vs. 38.9%; p=0.186). CONCLUSION: Gastric pH while fasting is normal in most children regardless of age. Urease-test positivity may be related to hypochlorhydria in children, and hypochlorhydria is in turn related to H. pylori infection.

Denys-Drash syndrome, septated vagina and low level of anti-Mullerian hormone in male neonate.

There is a wide variety of genital abnormalities observed in patients with Denys-Drash syndrome (DDS). WT1 is thought to influence the genes related to genital development and mutations in this gene have been associated with DDS. DDS should be considered in the differential diagnosis of newborns with genital anomalies. In contrast to other conditions with 46,XY disorders of sex development, individuals with DDS often have duplicated genital organs (a double vagina, cervix or uterus). A double uterus has not yet been reported with 1390G>A (Arg464 Asn) mutation. However, duplicated genitals have been reported with other genetic mutations in patients with DDS. The duplicated genitals in DDS may be associated with low anti-Mullerian hormone (AMH) secretion. Measurement of the AMH levels may add to our understanding of variations in genital development and their abnormalities in disorders such as DDS. In conclusion, this is first case of low level of AMH and double uterus in 1390G>A (Arg464 Asn) mutations of DDS male.