Despite the great importance of nonhematopoietic cells constituting the microenvironment for normal hematopoiesis, the cellular interactions between nonhematopoietic cells themselves are largely unknown. Using the Cre-loxP system in mice to inactivate Mind bomb-1 (Mib1), an essential component for Notch ligand endocytosis, here we show that the development of an MPD is dependent on defective Notch activation in the microenvironment. Our 2 independent Mib1 conditional knockout (CKO) mouse lines each developed a myeloproliferative disease (MPD), with gradual accumulations of immature granulocytes. The mutant mice showed hepatosplenomegaly, anemia, granulocytosis, and leukocyte infiltration in multiple organs and finally died at approximately 20 weeks of age. We were surprised to find that the transplantation of wild-type bone marrow cells into the Mib1-null microenvironment resulted in a de novo MPD. Moreover, by introducing the constitutively active intracellular domain of Notch1 in the Mib1-null background, we show that active Notch1 expression in the Mib1-null microen- IntroductionMaintenance of hematopoietic stem cells (HSCs) and regulation of their self-renewal and differentiation in vivo is thought to depend on their specific microenvironment, known as the HSC niche. [1][2][3] The bone marrow (BM) microenvironment mostly consists of mesenchymally originated cells, including osteoblasts, fibroblasts, adipocytes, and endothelial cells. 2,4 A subset of osteoblasts, sinusoid endothelial cells, and CXCL12-secreting reticular cells have been identified as the HSC niches, maintaining the quiescence of HSCs and regulating the proliferation, migration, and differentiation of HSCs. 1,2 The stem cell niches maintain stem cells during lifetime by preventing their depletion and overexuberant proliferation. 3 A variety of interactions between the BM microenvironment and hematopoietic cells in paracrine and juxtacrine manners, including stem cell factor/c-Kit, 5 Tie2/Angiopoietin-1, 6 CXCR4/ CXCL12, 7 and Notch signaling, [8][9][10][11][12] are believed to play a role in the maintenance of HSCs in the BM. In addition, cell extrinsic mediators, such as Wnt, Shh, and BMP, secreted by the niches can affect, at least in part, the cell cycle of HSCs through cell cycle regulators, including Bmi1, 13 p16 Ink4a /p19 Arf , 14,15 p21 cip1 , 16 and p18 Ink4c . 17 Thus, it is possible that the deregulation of HSCs by their niches could cause hematopoietic disorders.Notch signaling is thought to have a role in the maintenance of HSCs 12 and in lineage decisions at multiple stages of lymphopoiesis. 18 The activation of Notch signaling results in an increase of HSCs or progenitors, 10 whereas the inhibition of Notch signaling leads to the accelerated differentiation of HSCs and the depletion of HSCs. 9 Although the up-regulation of Jagged-1 (Jag1) on osteoblasts may expand HSCs, potentially through Notch activation, 8 the conditional inactivation of Jag1 does not affect HSC maintenance or hematopoiesis. 19 Because the BM microenvironmen...

BackgroundAcute colonic pseudo-obstruction (ACPO) refers to dilatation of the colon and decreased bowel motility without evidence of mechanical obstruction. Neostigmine, an acetylcholinesterase inhibitor, has been used in patients in whom supportive therapy failed to resolve ACPO. Here, we report the results of administering neostigmine to treat ACPO in children with hematologic malignancies.MethodsBetween September 2005 and December 2009, 10 patients (8 male and 2 female) were diagnosed with ACPO at the Department of Pediatrics, Catholic University of Korea. Diagnosis of ACPO was based on typical clinical features as well as colonic dilatation found on abdominal CT imaging. Neostigmine was administered subcutaneously at a dosage of 0.01 mg/kg/dose (maximum 0.5 mg) twice daily for a maximum of 5 total doses. ACPO was determined to be responsive to neostigmine if the patient showed both stool passage and improvement of clinical symptoms.ResultsThe study group included 8 acute lymphoblastic leukemia patients, 1 patient with malignant lymphoma, and 1 patient with juvenile myelomonocytic leukemia. The median age at ACPO diagnosis was 8.5 years (range, 3-14). Overall, 8 patients (80%) showed therapeutic response to neostigmine at a median of 29 hours after the initial administration (range, 1-70). Two patients (20%) showed side effects of grade 2 or above, but none complained of cardiovascular symptoms that required treatment.ConclusionIn this study, ACPO was diagnosed most often in late-childhood ALL patients. Subcutaneous neostigmine can be used to effectively treat ACPO diagnosed in children with hematologic malignancies without major cardiovascular complications.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The analgesic and anti-inflammatory efficacy of dexibuprofen compared with ibuprofen in adults with osteoarthritis, rheumatoid arthritis and dental pain. WHAT THIS STUDY ADDS• Dexibuprofen is as effective and tolerable as ibuprofen, and a dose of 5 mg kg -1 of dexibuprofen would be sufficient to control fever caused by upper respiratory tract infection in children. AIMTo evaluate the antipyretic efficacy and tolerability of dexibuprofen compared with ibuprofen in children with fever caused by upper respiratory tract infection (URTI). METHODSThe study population consisted of children aged 6 months to 14 years. At the time of visit to the hospital, the children had fever; the cause of fever was determined to be URTI by a paediatrician based on history taking and physical examination. The study was a multicentre, randomized, double-blind, controlled parallel group, comparative, Phase 3 clinical trial, conducted at three hospitals. By using a computer-based random assignment program, the subjects were allocated to the following three groups: 5 mg kg -1 dexibuprofen group, 7 mg kg -1 dexibuprofen group, and 10 mg kg -1 ibuprofen group. RESULTSIn the clinical trial of the antipyretic action of dexibuprofen in patients with fever caused by URTI, there was no statistically significant difference in maximal decrease of temperature and mean time to become apyrexial among the 5 mg kg -1 dexibuprofen, 7 mg kg -1 dexibuprofen and 10 mg kg -1 ibuprofen groups (P > 0.05). There also was no significant difference in adverse drug reaction (P > 0.05). CONCLUSIONSDexibuprofen is as effective and tolerable as ibuprofen. A dose of 5 mg kg -1 and 7 mg kg -1 dexibuprofen in place of 10 mg kg -1 ibuprofen would be sufficient to control fever caused by URTI in children.

BackgroundAutoimmune cytopenia (AIC) is a rare complication of allogeneic hematopoietic cell transplantation (HCT). In this study, we reviewed the diagnosis, treatment and response to therapy for pediatric patients with post-HCT AIC at our institution.MethodsOf the 292 allogeneic HCTs performed from January, 2011 to December, 2015 at the Department of Pediatrics, The Catholic University of Korea, seven were complicated by post-HCT AIC, resulting in an incidence of 2.4%.ResultsAll seven patients with post-HCT AIC had received unrelated donor transplant. Six of seven patients had a major donor-recipient blood type mismatch. The subtypes of AIC were as follows: immune thrombocytopenia (ITP) 2, autoimmune hemolytic anemia (AIHA) 2, Evans syndrome 3. Median time from HCT to AIC diagnosis was 3.6 months. All but one patient responded to first line therapy of steroid±intravenous immunoglobulin (IVIG), but none achieved complete response (CR) with this treatment. After a median duration of treatment of 15.3 months, two patients with ITP achieved CR and five had partial response (PR) of AIC. Five patients were treated with rituximab, resulting in the following response: 2 CR, 2 PR, 1 no response (NR). Median time to response to rituximab was 26 days from first infusion. All patients are alive without event.ConclusionPost-HCT AIC is a rare complication that may not resolve despite prolonged therapy. Rapid initiation of second line agents including but not limited to B cell depleting treatment should be considered for those that fail to achieve CR with first line therapy.