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The pathogenesis of cyclophosphamide (CY)-induced cardiotoxicity remains unknown, and methods for its prevention have not been established. To elucidate the acute structural changes that take place in myocardial cells and the pathways leading to myocardial damage under high-dose CY treatments, we performed detailed pathological analyses of myocardial tissue obtained from C57BL/6J mice subjected to a high-dose CY treatment. Additionally, we analysed the genome-wide cardiomyocyte expression profiles of mice subjected to the high-dose CY treatment. Treatment with CY (400 mg/kg/day intraperitoneally for two days) caused marked ultrastructural aberrations, as observed using electron microscopy, although these aberrations could not be observed using optical microscopy. The expansion of the transverse tubule and sarcoplasmic reticulum, turbulence in myocardial fibre travel, and a low contractile protein density were observed in cardiomyocytes. The high-dose CY treatment altered the cardiomyocyte expression of 1210 genes (with 675 genes upregulated and 535 genes downregulated) associated with cell–cell junctions, inflammatory responses, cardiomyopathy, and cardiac muscle function, as determined using microarray analysis (|Z-score| > 2.0). The expression of functionally important genes related to myocardial contraction and the regulation of calcium ion levels was validated using real-time polymerase chain reaction analysis. The results of the gene expression profiling, functional annotation clustering, and Kyoto Encyclopedia of Genes and Genomes pathway functional-classification analysis suggest that CY-induced cardiotoxicity is associated with the disruption of the Ca2+ signalling pathway.

Abstract Background Anaplastic large cell lymphoma (ALCL) is a CD30-positive T-cell lymphoma, which is a rare type of non-Hodgkin lymphoma. ALCL rarely presents in the gastrointestinal tract, and the esophageal involvement in of ALCL is extremely rare. Case presentation An 11-year-old boy who complained of abdominal pain and cough was diagnosed with ALK-positive ALCL on the basis of systemic lymphadenopathy findings and immunohistochemistry results of pleural effusion. Although remission was observed after chemotherapy at 5 months after diagnosis, dysphagia persisted, and esophagoscopy revealed a severe stricture in the middle thoracic esophagus. At 9 months after diagnosis, allogeneic bone marrow transplantation was performed to ensure that complete remission was maintained; however, dysphagia and saliva retention did not improve. Approximately 10 months after diagnosis, esophagoscopy revealed a blind end in the middle thoracic esophagus, similar to that in congenital esophageal atresia. Subsequently, we performed minimally invasive subtotal esophagectomy under thoracoscopy and laparoscopy and gastric conduit reconstruction via the retrosternal route more than 2 years after allogeneic bone marrow transplantation. The final pathological diagnosis was esophageal atresia with esophagitis, with no malignancy. During postoperative evaluation, the patient required swallowing training for a few months, although no major complications were noted. Oral intake was possible, and complete remission was maintained at 14 month post-surgery. Conclusions Oncologists must consider the possibility of acquired esophageal cicatricial atresia as a complication during chemotherapy for ALCL. If esophageal obstruction or esophageal atresia occur and if remission is maintained, esophagectomy and esophageal reconstruction are useful treatment options for maintaining oral intake.

Innate immune activity plays an essential role in the development of Kawasaki disease (KD) vasculitis. Extracellular release of high mobility group box-1 (HMGB-1), an endogenous damage-associated molecular pattern protein that can activate the innate immune system and drive host inflammatory responses, may contribute to the development of coronary artery abnormalities in KD. Prednisolone (PSL) added to intravenous immunoglobulin treatment for acute KD may reduce such abnormalities. Here, we evaluate the dynamics of HMGB-1 and therapeutic effects of PSL on HMGB-1-mediated inflammatory pathways on KD vasculitis in vitro. Serum samples were collected prior to initial treatment from patients with KD, systemic juvenile idiopathic arthritis (sJIA), and from healthy controls (VH), then incubated with human coronary artery endothelial cells (HCAECs). Following treatment of KD serum-activated HCAECs with PSL or PBS as a control, effects on the HMGB-1 signaling pathway were evaluated. Compared to that from VH and sJIA, KD serum activation induced HCAEC cytotoxicity and triggered extracellular release of HMGB-1. KD serum-activated HCAECs up-regulated extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and, p38 phosphorylation in the cytoplasm and nuclear factor kappa B (NF-κB) phosphorylation in the nucleus and increased interleukin (IL)-1β and tumor necrosis factor (TNF)-α production. PSL treatment of KD serum-activated HCAECs inhibited extracellular release of HMGB-1, down-regulated ERK1/2, JNK, p38, and NF-κB signaling pathways, and decreased IL-1β and TNF-α production. Our findings suggest that extracellular HMGB-1 plays an important role in mediating KD pathogenesis and that PSL treatment during the acute phase of KD may ameliorate HMGB-1-mediated inflammatory responses in KD vasculitis.

Patients who have undergone cardiac surgery using prosthetic devices have an increased risk of developing prosthetic device-related infection and mediastinitis. However, accurate diagnosis of prosthetic device-related infection can be difficult to evaluate and treat with antibiotic therapy alone. In recent years, 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) has made promising contributions to detect infective endocarditis, pacemaker infections, or other inflammations. Nevertheless, 18F-FDG PET-CT for congenital heart disease (CHD) with device infection has been sparsely reported. We present an infantile girl diagnosed with pulmonary atresia with a ventricular septal defect who underwent replacement of the right ventricle-to-pulmonary artery (RV-PA) conduit for improvement cyanosis. She developed high fever and was diagnosed with mediastinitis and bacteremia by Pseudomonas aeruginosa (P. aeruginosa) on postoperative day 4. Mediastinal drainage and 6 weeks of antibiotic therapy improved her condition, but bacteremia flared up on postoperative day 56. Despite a long course of antibiotic therapy, she had two more recurrences of bacteremia with the detection of P. aeruginosa. Echocardiography and chest contrast CT showed no evidence of vegetation and mediastinitis. On postoperative day 115, 18F-FDG PET-CT revealed an accumulation on the RV-PA conduit (SUV max 3.4). Finally, she developed an infectious ventricular pseudo-aneurysm on postoperative day 129 and underwent aneurysm removal and RV-PA conduit replacement on postoperative day 136. Our case showed the importance of 18F-FDG PET-CT for diagnosing specific localization of prosthetic device-related infection which is hard to detect using other imaging techniques. It can be a useful diagnostic tool for infantile patients with CHD with cardiac prosthetic devices and improve subsequent clinical treatments.

Abstract Background The dose-limiting toxic effect of cyclophosphamide (CY) is cardiotoxicity. The pathogenesis of myocardial damage is poorly understood, and there is no established means of prevention. In previous studies, we suggested that for CY-induced cardiotoxicity, whereas acrolein is the key toxic metabolite, carboxyethylphosphoramide mustard (CEPM) is protective. We sought to verify that acrolein is the main cause of cardiotoxicity and to investigate whether aldehyde dehydrogenase (ALDH), which is associated with greater CEPM production, is involved in the protective effect for cardiotoxicity. We also evaluated the protective effect of N-acetylcysteine (NAC), an amino acid with antioxidant activity and a known acrolein scavenger. Methods H9c2 cells were exposed to CY metabolites HCY (4-hydroxy-cyclophosphamide), acrolein or CEPM. The degree of cytotoxicity was evaluated by MTT assay, lactate dehydrogenase (LDH) release, and the production of reactive oxygen species (ROS). We also investigated how the myocardial cellular protective effects of CY metabolites were modified by NAC. To quantify acrolein levels, we measured the culture supernatants using high performance liquid chromatography. We measured ALDH activity after exposure to HCY or acrolein and the same with pre-treatment with NAC. Results Exposure of H9c2 cells to CEPM did not cause cytotoxicity. Increased ROS levels and myocardial cytotoxicity, however, were induced by HCY and acrolein. In cell cultures, HCY was metabolized to acrolein. Less ALDH activity was observed after exposure to HCY or acrolein. Treatment with NAC reduced acrolein concentrations. Conclusions Increased ROS generation and decreased ALDH activity confirmed that CY metabolites HCY and acrolein are strongly implicated in cardiotoxicity. By inhibiting ROS generation, increasing ALDH activity and decreasing the presence of acrolein, NAC has the potential to prevent CY-induced cardiotoxicity.

The early-onset form of carnitine palmitoyltransferase (CPT) II deficiency has severe outcomes; patients typically die during the newborn period. We report a case of neonatal-onset CPT II deficiency with prolonged survival, exceeding 24 months. The patient was successfully treated by continuous hemodialysis (CHD), which enabled her to overcome repeated crises. We suggest that early intensive treatment, including CHD, is a key for prolonged survival in patients with neonatal-onset CPT II deficiency.

The pathogenesis of venous malformation needs to be clarified and, although various treatment modalities are available, an optimal treatment has not been established. A 19-year-old girl presented with venous malformation of the rectosigmoid colon. She showed severe anemia due to rectal hemorrhage; her hemoglobin (Hb) level was 4.9 g/dl. A large venous malformation connected to an internal hemorrhoid was evident by endoscopy. Neither surgical resection nor sclerotherapy was indicated because of high blood flow in the venous malformation. Octreotide was initiated. However, the bleeding continued and she required persistent blood transfusions. We started propranolol in the 5th week of hospitalization. Celecoxib, which was started for her knee pain was found to be predictably effective, and we administered it regularly. Propranolol and celecoxib were gradually increased, the rectal bleeding decreased, and her anemia improved. Five months after the initiation of propranolol and celecoxib, she could maintain Hb at 15 g/dl without transfusion. Propranolol can contract blood vessels and celecoxib can inhibit vascular endothelial growth factor (VEGF) to result in anti-angiogenesis. This combination therapy might be useful for controlling intractable venous malformation.

Immunohistochemistry (IHC) for detecting key signal molecules involved in programmed cell death (PCD) in archival human pathology specimens is fairly well established. Detection of cleaved caspase-3 in lymphocytes in rheumatoid arthritis (RA) and gastric surface foveolar glandular epithelia but not in synoviocytes in RA, gastric fundic glandular epithelia, or nasal NK/T-cell lymphoma (NKTCL) cells suggests anti-apoptotic mechanisms in cell differentiation and in oncogenesis such as the induction of survivin. Enzymatically pretreated and ultra-super sensitive detection of beclin-1 in synoviocytes in RA and gastric fundic glandular epithelia suggests enhanced autophagy. The deposition of beclin-1 in fibrinoid necrosis in RA and expression of beclin-1 in detached gastric fundic glandular cells suggest that enhanced autophagy undergoes autophagic cell death (ACD). NKTCL exhibited enhanced autophagy through LC3 labeling and showed densely LC3 labeled cell-debris in regions of peculiar necrosis without deposition of beclin-1, indicating massive ACD in NKTCL and the alternative pathway enhancing autophagy following autophagic vesicle nucleation. Autophagy progression was monitored by labeling aggregated mitochondria and cathepsin D. The cell-debris in massive ACD in NKTCL were positive for 8-hydroxydeoxyguanosine, suggesting DNA oxidation occurred in ACD. Immunohistochemical autophagy and PCD analysis in archival human pathology specimens may offer new insights into autophagy in humans.

Observed only after administration of high doses, cardiotoxicity is the dose-limiting effect of cyclophosphamide (CY). We investigated the poorly understood cardiotoxic mechanisms of high-dose CY. A rat cardiac myocardial cell line, H9c2, was exposed to CY metabolized by S9 fraction of rat liver homogenate mixed with co-factors (CYS9). Cytotoxicity was then evaluated by 3-(4,5-dimethyl-2-thiazolyl)¬2,5-diphenyl¬2H-tetrazolium bromide (MTT) assay, lactate dehydrogenase release, production of reactive oxygen species (ROS), and incidence of apoptosis. We also investigated how the myocardial cellular effects of CYS9 were modified by acrolein scavenger N-acetylcysteine (NAC), antioxidant isorhamnetin (ISO), and CYP inhibitor β-ionone (BIO). Quantifying CY and CY metabolites by means of liquid chromatography coupled with electrospray tandem mass spectrometry, we assayed culture supernatants of CYS9 with and without candidate cardioprotectant agents. Assay results for MTT showed that treatment with CY (125-500 μM) did not induce cytotoxicity. CYS9, however, exhibited myocardial cytotoxicity when CY concentration was 250 μM or more. After 250 μM of CY was metabolized in S9 mix for 2 h, the concentration of CY was 73.6 ± 8.0 μM, 4-hydroxy-cyclophosphamide (HCY) 17.6 ± 4.3, o-carboxyethyl-phosphoramide (CEPM) 26.6 ± 5.3 μM, and acrolein 26.7 ± 2.5 μM. Inhibition of CYS9-induced cytotoxicity occurred with NAC, ISO, and BIO. When treated with ISO or BIO, metabolism of CY was significantly inhibited. Pre-treatment with NAC, however, did not inhibit the metabolism of CY: compared to control samples, we observed no difference in HCY, a significant increase of CEPM, and a significant decrease of acrolein. Furthermore, NAC pre-treatment did not affect intracellular amounts of ROS produced by CYS9. Since acrolein seems to be heavily implicated in the onset of cardiotoxicity, any competitive metabolic processing of CY that reduces its transformation to acrolein is likely to be an important mechanism for preventing cardiotoxicity.

Objective: To estimate target of treatment for long-term efficacy of the first biologic agent used to treat polyarticular juvenile idiopathic arthritis (pJIA). Methods: A retrospective cohort of patients with pJIA treated at six medical institutions in Japan between 1 March 2005 and 31 October 2014 was identified. The patients were divided by 2-year treatment periods with the first biologic agent into continuous treatment group and switching group. Three markers were examined: matrix metalloproteinase-3 (MMP-3), erythrocyte sedimentation rate (ESR), and disease activity score (DAS) 28-ESR. Results: Thirty-two pJIA patients (8 boys, 24 girls) from 43 recruited patients were included in this study. The treatment periods with the first biologic agent in continuous treatment group (24 patients, 75%) was 40 months (median, range 24-119) and switching group (8 patients; 25%) was 9.5 months (median, 6-18). Markers [odds ratio (95% confidence interval)] at 3 months were MMP-3 [1.02 (0.99-1.05), p = .219], ESR [1.00 (0.78-1.30), p = .998], and DAS28-ESR [13.9 (2.08-409.82), p = .035]. The cut-off point for DAS28-ESR at 3 months to distinguish the two groups was 2.49 (sensitivity, 87.5%; specificity, 87.5%). Conclusion: DAS28-ESR of 2.49 at 3 months after initiating the first biologic agent can be a target of sustained treatment in pJIA patients. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to evaluate the usefulness of S100A12 and vascular endothelial growth factor (VEGF) for predicting the stability of remission for discontinuing methotrexate (MTX) and/or biological agents in Japanese patients with oligo/polyarticular juvenile idiopathic arthritis (JIA). Methods: Forty-four patients with oligo/polyarticular JIA who received MTX with or without biological agents were enrolled. Serum concentration of both S100A12 and VEGF were simultaneously evaluated by ELISA in active and in remission phase determined by activity markers including DAS-28. Results: S100A12 and VEGF were correlated with DAS-28. Of the 22 patients with oligo/polyarticular JIA in clinical remission, 13 patients with low S100A12 and VEGF concentrations could discontinue treatment without relapse over 2 years. However, nine patients without low S100A12 and VEGF concentrations relapsed afterwards, even though they had been in clinical remission. The cut-off levels of S100A12 and VEGF for division into two groups of the maintenance remission and relapse groups were 177 ng/ml and 158 pg/ml, respectively. Conclusions: S100A12 and VEGF are useful markers for assessing disease activity of oligo/polyarticular JIA in remission phase. These markers should be kept low when clinicians consider tapering or discontinuing treatments in oligo/polyarticular JIA patients. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the safety and effectiveness of hepatitis B virus (HBV) vaccination in patients with juvenile idiopathic arthritis (JIA) controlled by treatment. Methods: Among 49 patients with juvenile idiopathic arthritis (JIA) at the outpatient clinic of Kagoshima University Hospital, we enrolled 25 who were controlled by treatment. All children were unimmunized and were vaccinated against HBV according to the schedule. Their responses to the vaccine and vaccine adverse events were examined during their visits. Results: Nineteen of the 25 patients with JIA controlled by treatment developed effective antibody responses (76%). All eight patients with JIA below 10 years of age achieved seroconversion. The seroconversion was not influenced by biologics. Five adverse events were observed (6.7%). The rate of all adverse events did not surpass that of a previous report, and all adverse events were immediately resolved. None of the patients with JIA experienced a flareup or clinical deterioration related to the vaccination. Conclusions: HBV vaccination is safe and effective. Pediatric rheumatologists should consider HBV vaccination for unimmunized patients with JIA, because the response to HBV vaccine might be influenced by age, and children have a higher risk for potential HBV infection than adults. [ABSTRACT FROM AUTHOR]

Background: Kawasaki disease (KD) is an acute febrile vasculitis in childhood. Currently, treatment with 2 g/kg of intravenous immunoglobulin (IVIG) is recommended. Previously we had encountered a patient with KD who showed persistent fever and a severe eruption after IVIG treatment. Using a drug-induced lymphocyte stimulation test (DLST), he was positive for an immunoglobulin product. The aim of this study was to clarify the importance of a positive value for the DLST for immunoglobulin products in KD patients. Methods: Subjects were 30 confirmed KD patients treated with IVIG at the Kagoshima Medical Association Hospital. DLST values were compared between patients with additional events and those without additional events using the stimulation index (SI = value of 3H-thymidine absorption with antigen/without antigen). Additional events were defined as symptoms observed after IVIG that were considered unexplainable by the symptoms of KD alone. Results: DLST results were evaluated in 13 patients with additional events and 17 patients without additional events. Elevated DLST values were observed not only in patients with additional events but also in those without additional events. Elevated SI values were observed in the initial 14 days after IVIG and the SI values in this period were significantly higher than those after day 14 (initial 14 days, n = 20, 194 ± 112%; after day 14, n = 10, 117 ± 66%, p = 0.010). Conclusions: Elevated SI values of DLST for immunoglobulin products are not related with additional events. Our results show they may represent one of the immunological abnormalities of KD. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The aberrant induction of proinflammatory cytokines is considered to be crucial in the pathogenesis of systemic juvenile idiopathic arthritis and adult‐onset Still's disease. Interleukin‐18 (IL‐18) in particular has been reported to be a candidate for the key cytokine in both diseases; however, the origin of IL‐18 is unclear. To clarify the origin, we investigated specimens from various organs obtained during autopsy of a child with systemic JIA and macrophage activation syndrome, using immunohistochemical staining. Our results showed a high number of cells expressing IL‐18 in the bone marrow but not in the other organs. This finding suggests that bone marrow is the origin of increased serum IL‐18 and raises the possibility that other proinflammatory cytokines are also induced by IL‐18 in bone marrow in this disease. Bone marrow may be an essential organ in the pathogenesis of systemic JIA. [ABSTRACT FROM AUTHOR]

Introduction We report the case of a patient who developed symptoms of acute cerebellar ataxia (ACA) after administration of the human papilloma virus (HPV)-16/18 vaccine. Patient and Method This patient developed symptoms of ACA, including nausea, vertigo, severe limb and truncal ataxia, and bilateral spontaneous continuous horizontal nystagmus with irregular rhythm, 12 days after administration of the HPV-16/18 AS04- adjuvanted cervical cancer vaccine. After this, the patient received methylprednisolone pulse and intravenous immunoglobulin (IVIG) therapies as well as immunoadsorption plasmapheresis. Results Severe ACA symptoms did not improve after methylprednisolone pulse and IVIG therapies, but the patient recovered completely after immunoadsorption plasmapheresis. Conclusion This temporal association strongly suggests that ACA was induced by the vaccination. [ABSTRACT FROM AUTHOR]

Abstract  We report herein of a 6-year-old boy with descending necrotizing mediastinitis (DNM) secondary to retropharyngeal abscess, who was successfully treated by the administration of antibiotics. DNM is very rare in children, and surgical drainage of the mediastinum is recommended in adult patients. DNM should be recognized as a severe complication of an oropharyngeal infection in children, and early and accurate diagnosis is important in ensuring appropriate clinical management. [ABSTRACT FROM AUTHOR]

Abstract  We describe a case of an 11-year-old girl who presented with osteomyelitis of the vertebrae and right femur due to Bartonella henselae. Her only symptom was prolonged fever without focal pain. Magnetic resonance imaging (MRI) and nested polymerase chain reaction (PCR) were useful for the diagnosis. Osteomyelitis due to B. henselae should be considered in cases of prolonged fever of unknown origin. [ABSTRACT FROM AUTHOR]