The magnitude of CXCR4 signaling regulates resistance to quizartinib in FLT3/ITD+ cells via RUNX1.

CXCR4 antagonists sensitize FLT3/ITD+ AML cells to FLT3 inhibitors; however, CXCR4 signaling can induce apoptosis in AML cells, raising the question of whether CXCR4 signaling exerts divergent effects on FLT3/ITD+ cells. The present study investigated the paradoxical function of CXCR4 in resistance to FLT3 inhibitors. The FLT3 inhibitor quizartinib significantly decreased the number of FLT3/ITD+ Ba/F3 cells, whereas 1 ng/ml CXCL12 showed a significant protective effect against quizartinib. In contrast, CXCL12 over 100 ng/ml significantly decreased FLT3/ITD+ cell viability with concomitant downregulation of Runx1. Moreover, the survival of FLT3/ITD+ Ba/F3 or MOLM13 cells with low surface CXCR4 expression incubated with quizartinib was significantly enhanced by 100 ng/ml CXCL12; however, this protective effect of CXCL12 against quizartinib was barely detected in cells with high surface CXCR4 expression. Although silencing Runx1 downregulated CXCR4 expression, RUNX1 expression levels were significantly higher in CXCR4LOW FLT3/ITD+ Ba/F3 cells incubated with 100 ng/ml CXCL12 than in CXCR4HIGH cells, coincident with an increase in FLT3 phosphorylation. Silencing RUNX1 partially abrogated resistance to quizartinib in CXCR4LOW cells incubated with CXCL12, whereas ectopic RUNX1 significantly restored resistance in CXCR4HIGH cells. These results indicate that CXCR4 signaling of different magnitudes paradoxically regulates resistance to quizartinib in FLT3/ITD+ cells via RUNX1.

Clinical features and treatment strategies of febrile urinary tract infection caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae in children: a multicenter retrospective observational study in Japan.

OBJECTIVES: The incidence of infections caused by extended-spectrum beta-lactamase (ESBL)-producing bacteria has increased. This study aimed to clarify the risk factors and treatment strategies for febrile urinary tract infection (fUTI) caused by ESBL-producing bacteria in Japanese children. METHODS: A retrospective observational study was conducted in 21 hospitals among children aged <16 years diagnosed with an fUTI between 2008 and 2017. Clinical data of children with fUTI caused by ESBL-producing and non-ESBL-producing bacteria were compared. RESULTS: Of the 2049 cases of fUTI, 147 (7.2%) were caused by ESBL-producing bacteria. Children in the ESBL group were more likely to have a history of recent antibiotic use or prophylactic antibiotic use, and experience recurrent UTIs (P <0.001) compared with those in the non-ESBL group. Of the 124 cases of fUTI due to ESBL-producing bacteria that were reviewed, 20 and 100 had concordant and discordant antibiotic use, respectively, and four had unknown antibiotic susceptibility. The median time from the start of treatment to fever resolution was 24 hours and did not differ significantly by therapy group (P = 0.39). CONCLUSION: ESBL-producing bacteria should be considered in children with recurrent UTIs and recent antibiotic use. Most children with fUTI experience clinical improvement regardless of the choice of antibiotic.

Clinical characteristics of pediatric febrile urinary tract infection in Japan.

BACKGROUND: Febrile urinary tract infection (fUTI) is the most common serious bacterial infection in children. Despite this, there have been no studies examining the clinical features of pediatric fUTI in Japan. The purpose of this study was to describe the clinical characteristics of fUTI in Japanese children. METHODS: A multicenter, retrospective, observational study was conducted at 21 hospitals in Japan. Children under the age of 15 years who were diagnosed with fUTI between 2008 and 2017 were included. The diagnostic criteria were a temperature over 38 °C and the presence of a single bacterial pathogen in urine culture. Patient characteristics were obtained from medical records. RESULTS: In total, 2,049 children were included in the study. The median age was 5 months, and 59.3% were male. It was found that 87.0% of the males and 53.2% of the females were under 1 year of age. The main causative pathogens identified were Escherichia coli and Enterococcus spp., accounting for 76.6% and 9.8% of infections, respectively. CONCLUSIONS: There was a male predominance of fUTI in Japanese children, particularly in infants. Enterococcus spp. were the second most frequent causative pathogen; therefore, Gram staining of urine samples is strongly recommended before initiating antibiotic therapy.

Potential pathological role of single nucleotide polymorphism (c.787T>C) in alkaline phosphatase (ALPL) for the phenotypes of hypophosphatasia.

Hypophosphatasia (HPP; OMIM 241510, 241500, and 146300) is an inherited metabolic disease characterized by defects of bone and tooth mineralization, which is caused by loss-of-function mutations in the ALPL gene encoding tissue non-specific alkaline phosphatase (TNSALP). In the last three decades, several studies have focused on the genotype-phenotype correlation in hypophosphatasia (HPP). In particular, functional tests based on in vitro analysis for the residual enzymatic activities of mutations have revealed a clear but imperfect genotype-phenotype correlation, suggesting that multiple potential factors modulate the phenotype. One of the missense variants identified in the tissue non-specific alkaline phosphatase (ALPL) gene, c.787T>C, has been considered as a benign polymorphism in HPP; however, its pathogenicity and role in disease manifestation remain controversial. We here report our recent experience of three unrelated families harboring the c.787T>C variant, suggesting clinical implications regarding the controversial pathogenicity of c.787T>C. First, despite the lack of obvious clinical phenotypes, homozygous c.787T>C would decrease the serum level of ALP activity. Second, c.787T>C might deteriorate phenotypes of a patient harboring another ALPL variant, especially one that has thus far presumed to be benign, e.g., the c.1144G>A variant. These cases contribute to the recent advances in understanding HPP to facilitate clinical recognition of more subtle phenotypes, further providing insights into the pathogenesis of HPP.

Colonoscopic diagnosis and reduction of recurrent intussusception owing to Henoch-Schönlein purpura without purpura.

About 50-75% of patients with Henoch-Schönlein purpura (HSP) develop gastro-intestinal symptoms with surgical complications such as intussusception occurring in 0.7-13.6%. In 10-40% of patients, however, gastro-intestinal manifestations may precede the onset of purpura. In patients with gastro-intestinal tract involvement without purpura, confirming the diagnosis of HSP and determining the appropriate treatment remains difficult. A seven-year-old boy presented with recurrent intussusception owing to HSP without purpura. It was confirmed pathologically and treated via colonoscopy. Early colonoscopic intervention can contribute to the early diagnosis of HSP and its subsequent management by avoiding unnecessary surgical invasion.

Perinatal factors affecting growth and development at age 3 years in extremely low birth weight infants born small for gestational age.

Factors affecting growth and development in extremely low birth weight infants (ELBWIs) born small for gestational age (SGA) have not been precisely elucidated. We performed a retrospective analysis of ELBWIs born SGA who were treated in the neonatal intensive care unit of Kawaguchi Municipal Medical Centre, Japan. A total 244 ELBWIs were born from 2003 to 2010, and 31 were born with weight and height below the 10th percentile for their gestational age. Among the 31 ELBWIs born SGA, we excluded 9 who died before they reached 3 yr of age or who had severe developmental retardation. A total of 16 patients (weight, 510-998 g; GA, 28w0d-32w5d) who were followed until age 3 yr were eligible for our study. At age 3 yr, 94% and 88% of ELBWIs were above the -2 standard deviation (SD) for height and weight, respectively. A history of mechanical ventilation was associated with height. The average score of the full developmental quotient (DQ) was 85, and 63% (10/16) of ELBWIs scored more than 85. Lower Apgar score (≤ 7) was a risk factor for lower DQ scores in motor development and full development. Our study revealed that most ELBWIs born SGA were more than -2 SD below the mean for height and body weight.

Risk of coronary artery lesions in young infants with Kawasaki disease: need for a new diagnostic method.

AIM: To examine clinical characteristics of Kawasaki disease (KD) in infants younger than 3 months of age and to develop a method for detecting KD in febrile infants. METHOD: In a case-control study, we retrospectively collected clinical and laboratory data from 24 KD infants younger than 3 months of age out of 410 KD patients. We then compared younger infants with both older patients and febrile infants with respiratory syncytial virus (RSV) infection and urinary tract infections (UTI). RESULTS: The frequency of incomplete KD was higher in the younger group than in the control group (79% vs. 36%, P < 0.0001). Furthermore, before treatment, the incidence of coronary artery lesions (CAL) was significantly higher in the younger group (29% vs. 3.9%, P = 0.0001), resulting in a higher incidence of coronary artery sequelae (21% vs. 3.4%, P = 0.0023). Our results revealed that the serum N-terminal prohormone of brain natriuretic peptide (NT-proBNP) level of KD patients was higher than that of RSV and UTI patients (3110 ± 2076 vs. 698 ± 436, P = 0.0001; and 971 ± 589 pg/mL, P = 0.0002, respectively). Thus, NT-proBNP might be suitable as a diagnostic marker of KD in young infants (P = 0.0005, criterion values: 1555 pg/mL [sensitivity: 80%, specificity: 85%]). CONCLUSION: Kawasaki disease infants younger than 3 months of age appear to be at higher risk for incomplete KD and early-onset CAL prior to the appearance of coronary artery sequelae. We suggest performing an echocardiogram and evaluating NT-proBNP in young infants with fever that has lasted longer than 2 days, regardless of the presence or absence of manifestations associated with KD.

A case of a "wandering" mobile solitary fibrous tumor occurring in the pancreas.

A 73-year-old male with a complaint of abdominal discomfort was examined by abdominal ultrasonography and found to have a hypoechoic mass in the upper abdomen. On abdominal computed tomography (CT), there was a 5-cm, hypervascular mass between the stomach and aorta. Magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP) showed a homogeneous mass with hypointensity on T1-weighted images, accompanied by stenosis of the main pancreatic duct of the pancreatic head. On endoscopic ultrasonography, the mass was depicted as a round homogeneous, hypervascular mass attached to the pancreatic head. Surprisingly, the mass was located on the right side of the aorta on the second CT. Histological examination of the resected specimen showed that the lesion was composed of spindle cells with cord-like arrangement, the features of which were compatible with a mobile solitary fibrous tumor.

A Case of MECP2 Duplication Syndrome with Gonadotropin-Dependent Precocious Puberty.

BACKGROUND: MECP2 duplication syndrome, which is caused by duplication of part of the Xq28 region containing the MECP2 gene, causes intellectual disability and mild dysmorphic features in males. To date, precocious puberty has not been reported as a clinical feature of MECP2 duplication syndrome. METHODS: A 6-year-old male with severe intellectual disability was referred because of growth acceleration and precocious puberty. We checked his hormonal profile and conducted imaging studies and an array comparative genomic hybridization analysis. RESULTS: His bone age (9 years and 6 months) was accelerated, and the basal level of testosterone was 8.99 ng/ml. In a luteinizing hormone (LH)-releasing hormone (LHRH) stimulation test, LH increased from 3.69 to 9.32 IU/l, and follicle-stimulating hormone increased from 0.65 to 0.90 IU/l. Chest and abdominal CTs and a brain MRI did not reveal any abnormalities. Treatment with an LHRH analogue effectively suppressed the level of testosterone to <0.03 ng/ml, consistent with the diagnosis of gonadotropin-dependent precocious puberty (GDPP). We identified a duplication of the Xq28 locus including MECP2 in the patient. CONCLUSION: Precocious puberty is often a benign central process in girls, but it is rarely idiopathic in boys. The present case raises the possibility that GDPP is a novel clinical feature of MECP2 duplication syndrome.

Lower body weight and BMI at birth were associated with early adiposity rebound in 21-hydroxylase deficiency patients.

21-hydroxylase deficiency (21-OHD) is the most common type of congenital adrenal hyperplasia. In addition to the clinical problems caused by adrenal insufficiency and androgen excess, a risk for obesity and metabolic syndrome during young adulthood is a major ramification of the disease. Although glucocorticoid therapy is very likely to be one of the contributory factors, the precise causes of the metabolic status of adult 21-OHD patients remain to be clarified. Previously we reported that 21-OHD patients developed early onset AR, a condition which might create a risk for obesity and metabolic syndrome in adulthood. In order to elucidate the association between the onset of AR and factors during the fetal period to early infancy, we conducted a retrospective longitudinal analysis of 29 21-OHD patients (male: 14 cases, female: 15 cases, salt wasting type: 16, simple virilizing type: 13), who were identified by newborn screening and followed up at least until the age 10 years. Body size at birth, lower body weight, and lower BMI were found to precipitate the timing of AR. On the other hand, no significant association was observed between the timing of AR and sex, gestational age, treatment regimen (including cumulative dose of HDC), and disease severity (the type of the disease, the value of DHEA-S and 17-OHP). There are two points to consider: first, in 21-OHD patients treated with glucocorticoid substitution therapy, the risk for early AR cannot be reduced by adjusting the dose of glucocorticoid; second, fetal factors might affect the metabolic status of 21-OHD patients.

Dabigatran-induced esophagitis: The prevalence and endoscopic characteristics.

BACKGROUND AND AIM: There have been some descriptions of dabigatran-induced esophagitis in the literature. The aim of this study was to examine the prevalence and endoscopic characteristics of the disease. METHODS: We reviewed the endoscopic database and medical records of 91 patients with dabigatran internal use who underwent upper gastrointestinal endoscopy. The frequency of dabigatran-induced esophagitis and its endoscopic findings were retrospectively analyzed. In addition, the clinical characteristics were compared between patients with dabigatran-induced esophagitis and those without the disease. RESULTS: Dabigatran-induced esophagitis was found in 19 of 91 (20.9%) patients. Of the 19 patients with the esophagitis, 18 (94.7%) showed longitudinally sloughing epithelial casts in the mid and/or lower esophagus, which may be characteristic endoscopic findings of this disease. Symptomatic patients were more frequent in patients with dabigatran-induced esophagitis (68.4%) than those without (37.5%, P = 0.02). Other factors including age, gender, coexistence of hiatal hernia, gastroesophageal reflux disease, or concomitant other medications did not differ between the two groups. CONCLUSIONS: Dabigatran causes the esophageal mucosal injury in approximately 20% of patients. Longitudinally sloughing casts in the distal esophagus are characteristic of dabigatran-induced esophagitis.

Efficacy and safety of double-balloon endoscopy-assisted endoscopic papillary large-balloon dilatation for common bile duct stone removal.

BACKGROUND: Endoscopic retrograde cholangiopancreatography is difficult to perform in patients with gastrointestinal tract reconstruction. AIMS: To evaluate the efficacy and safety of double-balloon endoscopy-assisted endoscopic papillary large-balloon dilatation for common bile duct stones in patients with gastrointestinal tract reconstruction. METHODS: We conducted a retrospective case series with a comparison to historical controls. During the period 2009-2013, 11 postoperative patients underwent endoscopic papillary large-balloon dilatation (Group A). Procedure efficacy and safety were compared with patients who underwent endoscopic sphincterotomy without endoscopic papillary large-balloon dilatation, who served as historical controls (Group B). RESULTS: Group A consisted of 11 patients (63.6% males, mean age 78±10 years), and Group B consisted of 32 patients (78.1% males, mean age 75±7 years). The stone clearance rate was significantly higher in Group A than in Group B (100% vs. 65.6%, respectively; p<0.05). Median procedure time was significantly shorter in Group A than in Group B (54min vs. 102min, respectively; p<0.05), and the complication rate was not significantly different between groups (18% vs. 15.6%, respectively; p=0.586). CONCLUSION: Endoscopic papillary large-balloon dilatation may be an effective and safe treatment procedure in patients with gastrointestinal tract reconstruction.

The effect of granulocyte and monocyte adsorptive apheresis on serum cytokine levels in patients with ulcerative colitis.

BACKGROUND: Granulocyte and monocyte adsorptive apheresis (GMA) with an Adacolumn has been reported to be effective as induction therapy in ulcerative colitis (UC). However, the effects of GMA on serial changes in cytokine levels have not been well characterized. We therefore, investigated cytokine levels in UC patients before and after treatment with GMA. A total of 16 patients with active UC, 10 men, and six women, mean age, 42.6 years were included. Fourteen patients had total colitis and two patients had left-sided colitis. The study included nine patients with a chronic intermittent course, six with a chronic continuous course and one with a single episode. The duration of each GMA session was 60 min at a flow rate of 30 mL/min as per study protocol. Serum levels of 17 cytokines were determined simultaneously using a Bio-Plex suspension array system before and after treatment with GMA. Serum interleukin (IL)-10 and macrophage inflammatory protein-1ß levels were increased significantly in UC patients after GMA treatment compared to pre-treatment levels (P < 0.05). In particular, GMA treatment caused a significant increase in serum IL-10 levels compared to pre-treatment in patients with total colitis or with a chronic intermittent UC course. In conclusion, this investigation showed that GMA was associated with a marked increase in serum level of the anti-inflammatory cytokine, IL-10. The rise in circulating IL-10 is interesting, and potentially a significant factor in the efficacy of GMA in patients with inflammatory bowel diseases.

Unusual Manifestation of Gastric Helicobacter pylori Infection.

Infection with Helicobacter pylori (HP) is common in many parts of the world. While most patients are asymptomatic, it causes peptic ulcer disease and malignancy in some of them. Other rare conditions have occasionally been reported in association with this infection. We report a case of hypertrophic gastropathy caused by HP in a 52-year-old asymptomatic patient. He was found to have marked enlargement of the gastric mucosal folds on radiological imaging and endoscopy. A gastric mucosal biopsy showed HP colonization associated with neutrophilic inflammation. After exclusion of neoplasia, other infections and infiltrative disorders, HP was thought to be the cause of the gastric fold hypertrophy. The patient responded well to HP eradication therapy, with normalization of the gastric mucosal folds. HP infection should be considered in the differential diagnosis of hypertrophic gastropathy and treated accordingly.

Peripheral Blood CD64 Levels Decrease in Crohn's Disease following Granulocyte and Monocyte Adsorptive Apheresis.

Granulocyte and monocyte adsorptive apheresis (GMA) is reportedly useful as induction therapy for Crohn's disease (CD). However, the effects of GMA on CD64 have not been well characterized. We report here our assessment of CD64 expression on neutrophils before and after treatment with GMA in two patients with CD. The severity of CD was assessed with the CD activity index (CDAI). The duration of each GMA session was 60 min at a flow rate of 30 ml/min as per protocol. CD64 expression on neutrophils was measured by analyzing whole blood with a FACScan flow cytometer. In case 1, CD64 levels after each session of GMA tended to decrease compared to pretreatment levels, whereas in case 2, CD64 levels dropped significantly after treatment. The CDAI decreased after GMA in both cases 1 and 2. A significant correlation was noted between CDAI scores and CD64 levels in both cases. In conclusion, GMA reduced blood CD64 levels, which would be an important factor for the decrease of CDAI scores.