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Children with leukemia treated with methotrexate (MTX) may develop MTX-induced leukoencephalopathy, which can present as seizures or focal neurological deficits. However, the precise pathophysiology has not been fully elucidated. Differences in cytokine/chemokine profiles in cerebrospinal fluid (CSF) between children with MTX-induced leukoencephalopathy and those with posterior reversible encephalopathy syndrome (PRES), an acute neurological condition associated with hypertension, were investigated. Interleukin (IL)-1β, 2, 4, 5, 6, 7, 8, 10, 12, 13, and 17, tumor necrosis factor-alpha, interferon-gamma, granulocyte monocyte colony-stimulating factor, granulocyte colony-stimulating factor, macrophage inflammatory protein-1β, and monocyte chemoattractant protein-1 concentrations were measured in CSF supernatants from 3 children with acute leukemia with MTX-induced leukoencephalopathy, 3 children with acute leukemia with PRES, 6 children with acute leukemia without neurological complications, and 8 children with acute encephalopathy. CSF IL-6 concentrations were higher in children with MTX-induced leukoencephalopathy than in children with acute leukemia with PRES, with acute leukemia without neurological complications, and with acute encephalopathy. We concluded that IL-6 may be involved in the pathogenesis of MTX-induced leukoencephalopathy.

Kawasaki disease is a systemic vasculitis of unknown etiology and is known to be associated with various digestive disorders, though only a few cases of intussusception associated with Kawasaki disease have been reported. The case of a 3-year-old boy with intussusception followed by Kawasaki disease is reported. The patient was admitted to our hospital due to severe abdominal pain. Because the target sign was seen on ultrasonography, intussusception was diagnosed, and hydrostatic reduction was performed. On the second day after admission, he developed a high-grade fever (38 oC) and an irregular rash on the whole body. On the fourth day after admission, his high-grade fever continued, and bilateral non-exudative conjunctivitis, erythema of the lips and oral mucosa, strawberry tongue, indurated edema of the dorsum of his hands and feet, and a diffuse erythema of his palms and soles appeared, and he was finally diagnosed as having Kawasaki disease. He was treated with intravenous immune globulin 2 g/kg, aspirin 30 mg/kg/day, and prednisolone 2 mg/kg/day. The high-grade fever, as well as the other clinical symptoms, resolved immediately after the start of treatment. There was no relapse of Kawasaki disease symptoms after initial treatment, and periungual desquamation was observed on the tenth day after admission. He was discharged on the 15th day and showed no abnormalities, such as coronary dilatation, three months after the onset of the symptoms of Kawasaki disease. Age distribution (≥ 3 years old vs < 3years old) between cases with intussusception and Kawasaki disease was clearly older than that with intussusception only. In addition, location of intussusception with Kawasaki disease was mainly colonic, not ileocolic. If intussusception precedes the appearance of the characteristic clinical symptoms of Kawasaki disease, the diagnosis of Kawasaki disease may be delayed. We must be aware of the diagnosis of Kawasaki disease in cases of intussusception in over three years old and colonic location of intussusception.

Effective leukemia treatment is seriously hampered by drug resistance, and the potential role of epigenetic mechanisms in cancer drug resistance has recently been investigated. With conventional anticancer drugs, including alkylating drugs, anti-metabolite drugs, topoisomerase inhibitors, and microtubule inhibitors-which have been available for half a century-drug resistance often develops because of decreased expression of target enzymes, in conjunction with increased expression of drug export pumps. Alterations of target gene expression and increased export pump function might be caused by epigenetic changes, such as alterations in methylation status, as well as by changes in histone acetylation status. In addition, newly developed anticancer drugs, including small-molecule drugs, such as kinase inhibitors, antibody drugs, and immune modulatory drugs, also resulted in development of drug resistance within 1 year, although these drugs showed significant effectiveness for patients resistant to conventional anticancer drugs. The resistant cells exhibited increased expression of bypass pathways, activation of downstream cascades, decreased expression of antigens of tumor cells, increased DNA repair activity, and increased expression of drug export pumps, which also suggests the presence of epigenetic changes. This article reviews drug resistance in cancer therapy and the possible roles of epigenetic mechanisms.

Background Therapeutic outcomes for childhood malignancy have dramatically improved. However, secondary malignancies are a major concern, as they greatly affect the quality of life of survivors. This retrospective study evaluated the cumulative incidence, clinical features, and outcomes of secondary malignancies at Nippon Medical School Hospital. Methods We examined data from 275 cases of primary childhood malignancy diagnosed between 1980 and 2014. Information regarding treatment of the primary malignancy, including irradiation dose, site, and cumulative dose of anticancer drugs, was assessed. We also collected data on secondary malignancy, including patient sex, age at diagnosis, malignancy site, time from primary to secondary malignancy, and outcomes. Results Secondary malignancies developed in 11 patients and included acute myeloid leukemia (AML) (4), meningioma (4), Ewing sarcoma (1), germ cell tumor (1), and malignant parotid gland tumor (1). The primary malignancies included acute lymphoblastic leukemia (ALL) (9), non-Hodgkin lymphoma (1) and brain tumor (1). In 7 of the 9 ALL patients, chemoradiotherapy was the primary treatment. The meningiomas and 1 solid tumor developed within the radiation field. All AMLs and meningiomas developed within 5 years and after 20 years, respectively, of the primary diagnosis. The 10- and 20-year cumulative incidence rates for secondary malignancy in our hospital were 1.9% and 5.8%, respectively. Conclusions Our results revealed that the type of secondary malignancy depends on the interval after the end of treatment for primary malignancy. Meningioma, notably, develops many years after completion of primary malignancy treatment. Early detection during long-term follow-up is therefore essential.

Drug resistance is a serious problem in leukemia therapy. A novel purine nucleoside analogue, nelarabine, is available for the treatment of children with T cell acute lymphoblastic leukemia. We investigated the mechanisms of drug resistance to nelarabine. Nelarabine-resistant cells were selected by stepwise and continuous exposure to nelarabine using the limiting dilution method in human B and T cell lymphoblastic leukemia cell lines. Expression analysis was performed using real-time polymerase chain reaction, and epigenetic analysis was performed using methylation-specific polymerase chain reaction and chromatin immunoprecipitation. The RNA expression level for deoxycytidine kinase (dCK) was decreased in nelarabine-resistant leukemia cells. There were no differences between the parental and nelarabine-resistant leukemia cells in the methylation status of the promoter region of the dCK gene. In the chromatin immune precipitation assay, decreased acetylation of histones H3 and H4 bound to the dCK promoter was seen in the nelarabine-resistant cells when compared to the parental cells. Furthermore, treatment with a novel histone deacetylase inhibitor, vorinostat, promoted the cytotoxic effect of nelarabine along with increased expression of the dCK gene, and it increased acetylation of both histones H3 and H4 bound to the dCK promoter in nelarabine-resistant leukemia cells. The combination index showed that the effect of nelarabine and vorinostat was synergistic. This study reports that nelarabine with vorinostat can promote cytotoxicity in nelarabine-resistant leukemia cells through epigenetic mechanisms.

Background Children who survive traffic accidents, and their parents, may develop post-traumatic stress disorder (PTSD) or related symptoms (depression or anxiety), which can hinder the children's development and the parents' ability to provide effective care. In Japan, the PTSD incidence rate following traffic accidents and its related factors remain unclarified. Method Participants were 79 children and 104 parents. The children were aged 3-18 years when injured. From August-December 2015, participants completed a self-reported questionnaire survey that comprised the 15-item Post-traumatic Stress Symptoms for Children and the Japanese version of the Impact of Event Scale-Revised. The children's Injury Severity Score (ISS) was also obtained from their medical records. Correlations, analyses of variance, and multiple regression analyses were conducted. Results Among the children and the parents, 10.2% and 22.1% were deemed to be at high risk of PTSD, respectively. Their stress scores were significantly positively correlated with each other and negatively correlated with children's age at the time of the accident. Parents who witnessed their children's accidents and those whose children were hospitalized were more stressed. Neither the children's nor the parents' risk for PTSD was associated with the ISS and the amount of time since the accident. Conclusions A system that simultaneously works with children and parents, to support both parties' psychological recovery is required. To ensure psychological care post-injury, it is necessary to evaluate PTSD risk, regardless of injury severity. Implementing preventive and early interventions can prove more valuable than awaiting natural recovery.

Background Since 2002, the Department of Pediatrics of Nippon Medical School Chiba Hokusoh Hospital has offered educational activities for children with short stature. We analyzed outcomes of growth hormone (GH) treatment for children with short stature treated at our hospital, particularly outcomes after the growth spurt. Methods We analyzed data from children aged 0 to 17 years who were treated with recombinant GH during the period from 2000 through 2016 and were followed for at least 2 years after the start of treatment. Results Among children with short stature, 85 had GH deficiency, 5 had Turner syndrome, 9 were small for gestational age, and 1 had Noonan syndrome. The outcomes of GH treatment was similar to those previously reported in Japan. Children with GH deficiency who started GH treatment before the growth spurt exhibited marked height catch-up until the second year, but the effect decreased after 3 years. The effect of treatment for GH deficiency that was started after the growth spurt continued for 4 to 5 years after the start of treatment. Conclusions Improvement in height standard deviation score was similar when treatment was started before and after the growth spurt.

BACKGROUND Juvenile xanthogranuloma (JXG) is the most common non-Langerhans cell histiocytosis in children. The mortality and morbidity of JXG with extracutaneous lesions remain unclear. METHODS Data of patients aged

Background Infantile aseptic meningitis is a rare infection of the central nervous system. Coxsackievirus B5 (CVB5) is an enterovirus that is sometimes associated with aseptic meningitis and encephalitis. Case presentation We report on three isolated infants with aseptic meningitis caused by CVB5 in the spring and summer of 2016 with nearly identical 404-bp CVB5 Viral Capsid Protein 1 (VP1) sequences. In addition, viral analysis of sewage samples from Chiba Prefecture in 2016 showed similar 404-bp CVB5 VP1 sequences from May to September 2016. Conclusion These results indicate that viral screening of sewage water may help detect occult outbreaks of viral infection, particularly for enterovirus strains.

We report on two siblings with early onset lysosomal acid lipase deficiency or Wolman disease. Their parents had a consanguineous marriage. The children showed evidence of abdominal distension and failed to thrive, despite having regular nutrition. At 3-4 months of age, their abdominal distension and jaundice progressed rapidly and they died of liver failure. Sebelipase alfa, a recombinant form of human lysosomal acid lipase has recently been used as an enzyme replacement therapy in patients with later-onset cholesteryl ester storage disease. Therefore, we investigated cases of lysosomal acid lipase deficiency in Japan and found that the number of cases was extremely low. Only 14 cases of Wolman disease and seven cases of cholesteryl ester storage disease were reported. As it is now possible to treat lysosomal acid lipase deficiency, it is important to increase awareness of this disease among pediatricians and doctors working in internal medicine.

The introduction of the Haemophilus influenzae type b (Hib) vaccine and the 7-valent pneumococcal conjugate vaccine (PCV7) has led to dramatic reductions in cases of invasive H. influenzae disease and invasive pneumococcal disease (IPD). After the introduction of the PCV7 and the 13-valent pneumococcal conjugate vaccine (PCV13), the number of children with IPD markedly decreased in our hospital. However, since 2015, three children with IPD have been admitted to our hospital. We analyzed the serotype, multilocus sequence type, and antimicrobial susceptibility of Streptococcus pneumoniae strains isolated in these newly diagnosed cases. The strains were serotypes 7F and 12F. In addition, we analyzed the incidence of invasive bacterial disease before and after the introduction of conjugate vaccines and found no change in the incidences. We found that cases of IPD and invasive H. influenzae disease clearly decreased following the introduction of the PCV7, the PCV13, and the Hib vaccine, as well as disease caused by antibiotic-resistant strains.

Zonisamide (ZNS) is an effective drug for not only motor symptoms but also non-motor symptoms in Parkinson's disease. However, the actions of ZNS as an anti-Parkinsonian drug are not well understood. To clarify the actions of ZNS in vivo, we administered ZNS to mice and examined the effects on neurotransmitter metabolism and behaviors, focusing on motor and non-motor symptoms. Administration of ZNS decreased dopamine (DA) turnover in various brain regions, including the striatum. In behavioral tests, ZNS enhanced locomotor activity and novelty seeking in the open field test, light-dark transition test, and the social interaction test. Consistent with these results of DA metabolism in ZNS-treated mice, monoamine oxidase activity was significantly inhibited by ZNS in primary neurons and astrocytes. Collectively, these data suggest that ZNS inhibits monoamine oxidase activity and decreases DA turnover, which increases locomotor activity and novelty seeking in mice. ZNS is potentially useful to improve not only motor symptoms but also neuropsychiatric non-motor symptoms such as apathy in PD.

Purpose: To examine the validity of our treatment strategy for spinal dural arteriovenous fistulae (SDAVF), based on the treatment results and the long-term outcome. Methods: This study included 50 SDAVF patients (38 men, 12 women, mean age 63.2 years) with progressive myelopathy. The treatment strategy involved embolization as the initial management tool and surgery if embolization was considered unsuitable. Their medical records were evaluated to identify the treatment results and functional outcomes. The mean follow-up period was 81.2 months (range 27 - 184 months). Results: Complete obliteration was achieved in 22 (71.0%) of 31 embolized patients and in 18 of 19 (94.7%) operated patients. The initial success rate was significantly lower in embolized- than operated patients. At the last follow-up, 33 of the 50 patients (66%) manifested improved gait and 16 (32%) improved micturition. The activity of daily living (ADL) was improved in 33 (66%). When we compared the rates of functional improvement at the last follow-up, there was no significant difference between patients treated initially by embolization or surgery. Conclusions: The long-term outcomes in SDAVF patients treated by multidisciplinary management with first-line embolization were comparable to those in earlier surgical series. However, our results were unable to demonstrate the superiority of endovascular embolization to surgical treatment for SDAVF. For the purpose of justifying endovascular embolization as a first-line treatment for SDAVF, it will be necessary to show further improvement in both the initial treatment success and the complication rates.

We herein report a case of severe aplastic anemia diagnosed in an 8-year-old girl with a previous diagnosis of autoimmune hepatitis. We found significantly increased CD8+ and CD68+ cell numbers in her bone marrow, which can induce severe organ damage, refractory to immunosuppressive therapy.

Spinal angiography is the gold standard for evaluation or diagnosis of spinal arteriovenous malformations (AVMs). However, some feeding arteries might be overlooked when multiple feeders exist. This study aimed to retrospectively review cases of spinal intra-dural AVMs, which were identified by three-dimensional digital subtraction angiography (3D-DSA), and attempted to estimate the number of feeding arteries. We retrospectively reviewed patients with spinal intra-dural AVMs who underwent 3D-DSA at Hokkaido University Hospital from January 2005 to December 2016. We selected 9 patients in whom we could obtain data of multi-planar reconstruction of 3D-DSA. We measured the computed tomography (CT) values of feeding arteries and draining veins. The CT values represented the averages of maximum CT values of 5 continuous axial slices. The ratio of the CT value of feeders to that of drainers (F/D ratio) was calculated. The correlation between the F/D ratio and the number of feeders was examined with Pearson’s correlation coefficient. The average number of feeders was 2.3 (1–4), and the number of feeders was significantly positively correlated with the F/D ratio (r = 0.855, P = .003). We conclude that the number of feeding arteries of spinal intra-dural AVMs can be estimated by using the F/D ratio obtained from 3D-DSA. These slides can be retrieved under Electronic Supplementary Material.

Bilateral complex vertebral artery aneurysms (BCoVAAns) have no established strategy of management. We retrospectively reviewed five consecutive patients with unruptured BCoVAAns between January 2006 and December 2012. Considering surgical risks of lower cranial nerve (LCN) injuries and eventual growth of an opposite side lesion after unilateral vertebral artery (VA) occlusion, we proposed a strategy of combined open and interventional treatment using revascularization. We applied the following several specific techniques: (1) proximal clipping and occipital artery-posterior inferior cerebellar artery (OA-PICA) and/or superficial temporary artery (STA)-superior cerebellar artery (SCA) bypasses; (2) Distal blood pressure, motor evoked potentials (MEPs), and somatosensory evoked potentials (SEPs) monitoring after parent artery temporary occlusion for safe permanent occlusion of the proximal portions of VA and PICA; (3) V3 to V4 bypass using radial artery (RA) graft with proximal clipping or trapping, two of them combined with OA-PICA bypass; (4) VA fenestration as an opportunity to preserve the flow of the parent artery. Two patients were treated bilaterally and 3 unilaterally, with modified Rankin scale assessed at 39 months postoperatively in average 0 in 2, 1 in 2, and 2 in 1, respectively, and the untreated opposite side lesions without regrowth or bleeding. Two patients with patent V3-RA-V4 bypass complained of dysphagia due to LCN palsies. One of them however suffered a cerebellar infarction due to occlusion of the OA-PICA bypass. When BCoVAAns require surgical treatment, revascularization or preservation of the VA should be considered at the first operation. By doing so, the opposite aneurysm can be effectively occluded by coil embolization, even with VA sacrifice if required.

Drug resistance remains a serious problem in leukemia therapy. Among newly developed nucleoside antimetabolites, clofarabine has broad cytotoxic activity showing therapeutic promise and is currently approved for relapsed acute lymphoblastic leukemia. To investigate the mechanisms responsible for clofarabine resistance, we established two clofarabine-resistant lymphoblastic leukemia cell lines from parental lines. To elucidate the mechanisms against clofarabine resistance in two newly established clofarabine-resistant cell lines, we measured the expression of export pumps multidrug resistance protein 1, multidrug resistance–associated protein 1, and ATP-binding cassette subfamily G member 2. There were no differences in the expression between clofarabine-sensitive and -resistant cell lines. Next, we determined expression of deoxycytidine kinase (dCK) , which phosphorylates clofarabine to exert cytotoxicity, in clofarabine-sensitive and -resistant cells. Clofarabine-resistant cells showed significantly decreased expression of dCK RNA when compared with sensitive cells. To elucidate the mechanisms of decreased dCK expression in clofarabine-resistant cells, we analyzed the methylation status of CpG islands of the dCK promoter and found no differences in methylation status between clofarabine-sensitive and -resistant cells. Next, we measured the acetylation status of histone and found that total histone acetylation, and histone H3 and H4 acetylation on chromatin immunoprecipitation assay were significantly decreased in resistant cells. Melatonin is an indolamine that functions in the regulation of chronobiological rhythms to exert cytotoxic effects. We examined the effects of melatonin in clofarabine-resistant cells and found that melatonin treatment led to significantly increased cytotoxicity with clofarabine in resistant cells via increased acetylation. Melatonin may be a useful candidate for overcoming clofarabine resistance in two newly established clofarabine resistant leukemia cell lines.

The discovery and SAR study of a new series of soluble and highly potent phosphodiesterase (PDE) 7 inhibitors are described herein. We explored a new lead compound with improved solubility, which led to the discovery of a 2-(4-pyridylamino)thieno[3,2-d]pyrimidin-4(3H)-one series. The introduction of 3-piperidines at the 7-position resulted in the significant enhancement of PDE7 activity. In particular, compound 32 also showed strong PDE7 inhibitory activity; good selectivity against PDE3, 4, and 5; and good aqueous solubility.

Involvement of iron in the development of neurodegenerative disorders has long been suggested, and iron that cannot be stored properly is suggested to induce iron toxicity. To enhance iron uptake and suppress iron storage in neurons, we generated transgenic (Tg) mice expressing iron regulatory protein 2 (IRP2), a major regulator of iron metabolism, in a neuron-specific manner. Although very subtle, IRP2 was expressed in all regions of brain examined. In the Tg mice, mitochondrial oxidative insults were observed including generation of 4-hydroxynonenal modified proteins, which appeared to be removed by a mitochondrial quality control protein Parkin. Inter-crossing of the Tg mice to Parkin knockout mice perturbed the integrity of neurons in the substantia nigra and provoked motor symptoms. These results suggest that a subtle, but chronic increase in IRP2 induces mitochondrial oxidative insults and accelerates neurodegeneration in a mouse model of Parkinson's disease. Thus, the IRP2 Tg may be a useful tool to probe the roles of iron-induced mitochondrial damages in neurodegeraration research.

Bacterial infections often cause fatal systemic infections in patients with primary immunodeficiency. To prevent unfortunate results, the selection, dose, and dosage of antibiotics are extremely important. Here, we report a case of Wiskott-Aldrich syndrome in a patient undergoing peritoneal dialysis because of chronic renal failure in whom methicillin-resistant Staphylococcus aureus sepsis developed. Because of the primary disease and complications, teicoplanin was the only chosen anti-S. aureus drug to prevent side effects. We used parameter estimation and dosage adjustment from a therapeutic drug monitoring simulation software program to overcome the challenges with teicoplanin treatment.

Background The goal of treatment for spinal arteriovenous lesions is to completely obliterate the shunt. In our institution, intraoperative digital subtraction angiography and intraarterial injection of contrast agent have been used to accurately identify the site of arteriovenous shunts. We describe the intraoperative digital subtraction angiography and intraarterial dye injection procedures and how they may improve surgical outcomes. Methods We retrospectively investigated 22 patients with intradural arteriovenous lesions (n = 19) or spinal dural arteriovenous fistulas (n = 3). A microcatheter was used during the procedures to avoid catheter migration. Results There were 29 procedures performed. To support the surgical procedures, indigo carmine was used 17 times and indocyanine green was used 12 times. There were no complications associated with these procedures. The indocyanine green procedure required a lower concentration of dye in the artery than in the vein to clarify the shunt point and visualized complex lesions more clearly. These methods allowed surgeons to orientate the complex vessel structure. Conclusions Intraoperative digital subtraction angiography and intraarterial dye injection are useful tools for management of spinal arteriovenous lesions.

In acute encephalopathy, deterioration of the condition can be rapid, and early intervention is essential to prevent progression of the disease. However, in the acute period, differentiating acute encephalopathy from febrile seizures is difficult. Thus, an early diagnostic marker has been sought to enable early intervention. Proton nuclear magnetic resonance ((1)H NMR) spectroscopy is used to study the chemical characteristics of biological fluids such as cerebrospinal fluid (CSF). The purpose of this study was to ascertain if pattern recognition of (1)H NMR spectra could differentiate CSF obtained from patients with acute encephalopathy and febrile seizures.CSF was obtained from patients with acute encephalopathy (n = 4), complex febrile seizures (n = 9), and simple febrile seizures (n = 9).NMR spectra of CSF did not visually differ across the three groups. Spectral data were analyzed by partial least squares discriminant analysis and visualized by plotting the partial least squares scores of each sample. The three patient groups clustered separately on the plots.In this preliminary study, we were able to visualize different characteristics of CSF obtained from patients with acute encephalopathy and simple and complex febrile seizures using pattern recognition analysis of (1)H NMR data.

Background Despite several advances in the treatment of Epstein–Barr virus (EBV) in recent years, patients with Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) do not always show satisfactory outcomes. We here conducted a nationwide survey in Japan to identify prognostic factors of EBV-HLH in children with this disease in an effort to improve the management and the outcomes of these patients. Procedure Between January 2003 and June 2008, we enrolled 98 children younger than 18 years of age who were diagnosed with EBV-HLH. We then studied the clinical characteristics and laboratory findings at the time of diagnosis with the aim to identify prognostic factors for EBV-HLH. Results The mean age of onset of EBV-HLH was 3.9 ± 2.8 years. Most of our patients presented with fever, hepatosplenomegaly, lymphadenopathy, and hemophagocytosis of bone marrow. Sixty-two percent of patients showed T cell clonality, and 97% had EBV infection in either T or natural killer cells. Most patients (60%) were treated with a multi-agent chemotherapeutic regimen, including corticosteroid, etoposide, and cyclosporine. After initial treatment, 90.3% of patients were in remission, and 7 patients (8.2%) experienced recurrence of EBV infection. Among several prognostic factors, patients with both hyperbilirubinemia (>1.8 mg/dl) and hyperferritinemia (>20,300 ng/ml) at the time of diagnosis had significantly poorer outcomes than those with low serum bilirubin and ferritin levels. Conclusions These findings suggest that the therapeutic strategy for children with EBV-HLH could be tailored according to the laboratory findings at diagnosis. Pediatr Blood Cancer 2014;61:1257–1262. © 2014 Wiley Periodicals, Inc.

Background: We sometimes treat children with acute lymphoblastic leukemia in whom neutrophil function is impaired at diagnosis. Transmission electron microscopy enables more accurate assessment by providing greater morphological detail. Using transmission electron microscopy we have found 2 types of neutrophils in the peripheral blood of children: 1 amoeboid neutrophils which are characterized as amoeboid cells with pseudopodia and few granules and 2 round neutrophils with many granules at different stages and glycogen particles. Aim: To assess the pathological role of amoeboid neutrophils we investigated amoeboid neutrophils in the peripheral blood of children with leukemia. Methods: Amoeboid neutrophils were examined in peripheral blood from 12 children with acute B‑cell precursor lymphoblastic leukemia (BCP‑ALL. Eight childre nw ith short stature served as healthy control subjects. Results: The percentage of amoeboid neutrophils (per total neutrophil count at onset or relapse of BCP‑ALL was significantly higher than at remission. Children with short stature showed a lower percentage of amoeboid neutrophils than did children with acute leukemia. Conclusion: The presence of fewer intracellular granules in amoeboid neutrophils suggests lower neutrophil activity. These results indicate that amoeboid neutrophils in patients with BCP‑ALL have lower function at onset and relapse. (J Nippon Med Sch 2014; 81: 78―83

Although thrombotic thrombocytopenic purpura (TTP) is rare, early diagnosis and treatment are important for decreasing the mortality rate. Acquired vitamin B12 deficiency is frequently overlooked because of its rarity in developed countries, particularly in children and adolescents. The hematological changes in vitamin B12 deficiency present as megaloblastic anemia, increased lactate dehydrogenase, vasoconstriction, increased platelet aggregation, and abnormal activation of the coagulation followed by microangiopathy as well as neutropenia and thrombocytopenia. We report herein the case of a 15-year-old girl who had been neglected, which might have caused pseudo-TTP through malnutrition, particularly vitamin B12 deficiency. When we encounter cases of TTP in children, clinicians must be aware of the possibility of malnutrition, particularly with vitamin B12 deficiency, even in developed countries, and investigate the cause of malnutrition including neglect.

Objective: Isolated accessory nerve palsy due to intracranial disorders is uncommon because intracranial accessory nerve injury usually occurs in case of a skull base tumor or trauma, resulting in one of multiple cranial nerve palsies. We report a very rare case of isolated accessory nerve palsy due to a large thrombosed aneurysm of the intracranial vertebral artery. Full recovery was achieved after surgery. Case Report: A patient complaining of transient numbness in the right side was referred to our hospital. An MRI indicated a large thrombosed aneurysm of the right vertebral artery. The aneurysm severely compressed the medulla oblongata. First, the proximal vertebral artery (VA) was clipped with an aneurysm clip to reduce the pressure inside the aneurysm. However, cerebral angiography revealed a partial recanalization of the right VA. The patient then underwent coil embolization of the right VA just proximal to the aneurysm clip. Subsequently, the right VA was completely obliterated. The patient was discharged without any neurological deficit. Two weeks later, however, she complained of right shoulder pain. Physical and neurological examinations demonstrated atrophy of the right trapezius and sternocleidomastoid muscle, leading to a deepening of the right supraclavicular fossa. The symptoms were considered to result from the right isolated accessory nerve palsy. Follow-up MRI showed that the VA aneurysm gradually decreased in size over a period of several months. At the same time, her symptoms disappeared completely. Conclusion: We should keep in mind that isolated accessory nerve palsy can be caused by a large or giant vertebral aneurysm.

This paper shows the concept of the support effect about the pre-installed cable bolt and reports the justice based on the local examination. On the large sectional tunnel of the cracking rock mass, we take the pre-installed cable bolt instead of rock bolt. Because the axial stiffness and the bond strength of the pre-installed cable bolt are smaller than them of the rock bolt, the axial force of the pre-installed cable bolt spreads and becomes relatively equal. Moreover, by analyzing the bond strength of the cable bolt on the mass, the authors show that the occurrence mechanism of support effect is different and classified into three types.

A 60-year-old woman presented with a spinal dural arteriovenous fistula (SDAVF) located in the lower cervical region, which had been asymptomatic for 56 months after the initial detection. She underwent embolization of the SDAVF when she became symptomatic, but her neurological recovery was only partial. Cervical SDAVF is rare but sometimes discovered in an asymptomatic state. The natural history and validity of preventive treatment for asymptomatic SDAVF have not been fully established. Her unfavorable outcome demonstrates the potential advantages of adequate treatment at an early stage even for asymptomatic SDAVF.

Effective leukemia treatment is seriously hampered by drug resistance. We previously showed that aberrant methylation of the topoisomerase II α gene causes altered gene expression and acquired drug resistance in etoposide‐resistant leukemia cells. In this study, we analyzed the genome‐wide methylation status in resistant leukemia cells. We used MX2, which is a morpholino anthracycline derivative that functions as a topoisomerase II α inhibitor. We established a human myelogenous leukemia cell line (K562/P) and a related cell line with resistance to MX2 (K562/MX2). Using these cell lines, we investigated the genome‐wide methylation status, compared expression profiles with a microarray, and analyzed the data using Gene Ontology and key node analysis. We demonstrate that the MX2‐resistant cell line was globally hypermethylated. Gene Ontology analysis identified genes involved in the immunological response and gene silencing that were responsible for methylation‐related altered gene expression in drug‐resistant cells. Key node analysis showed that p38α mitogen‐activated protein kinase was a novel enzyme involved in MX2‐related resistance. p38 kinase activity in resistant cells was increased compared to MX2‐sensitive parent cells. Blocking p38α activity using inhibitors and p38α knock down with small interfering RNA restored the sensitivity to MX2 in resistant cells with a decrease in p38 kinase activity as well as decreased expression of p38α mRNA and phosphorylated p38α protein. These findings may lead to a new strategy for treatment of drug‐resistant leukemia cells.

Painful peripheral neuropathy has been correlated with various voltage-gated sodium channel mutations in sensory neurons. Recently Nav1.9, a voltage-gated sodium channel subtype, has been established as a genetic influence for certain peripheral pain syndromes. In this study, we performed a genetic study in six unrelated multigenerational Japanese families with episodic pain syndrome. Affected participants (n = 23) were characterized by infantile recurrent pain episodes with spontaneous mitigation around adolescence. This unique phenotype was inherited in an autosomal-dominant mode. Linkage analysis was performed for two families with 12 affected and nine unaffected members, and a single locus was identified on 3p22 (LOD score 4.32). Exome analysis (n = 14) was performed for affected and unaffected members in these two families and an additional family. Two missense variants were identified: R222H and R222S in SCN11A. Next, we generated a knock-in mouse model harboring one of the mutations (R222S). Behavioral tests (Hargreaves test and cold plate test) using R222S and wild-type C57BL/6 (WT) mice, young (8-9 weeks old; n = 10-12 for each group) and mature (36-38 weeks old; n = 5-6 for each group), showed that R222S mice were significantly (p < 0.05) more hypersensitive to hot and cold stimuli than WT mice. Electrophysiological studies using dorsal root ganglion neurons from 8-9-week-old mice showed no significant difference in resting membrane potential, but input impedance and firing frequency of evoked action potentials were significantly increased in R222S mice compared with WT mice. However, there was no significant difference among Nav1.9 (WT, R222S, and R222H)-overexpressing ND7/23 cell lines. These results suggest that our novel mutation is a gain-of-function mutation that causes infantile familial episodic pain. The mouse model developed here will be useful for drug screening for familial episodic pain syndrome associated with SCN11A mutations., 乳幼児期に特異的な手足の痛み発作を起こす病気を見つけ原因を解明 －この病気を小児四肢疼痛発作症と命名－. 京都大学プレスリリース. 2016-05-27.

Background and Purpose: To discuss and summarize the strategies and complications of endovascular embolization for aneurysms of the posterior cerebral artery (PCA). Methods: Data of patients with PCA aneurysms treated by an endovascular procedure were analyzed retrospectively (n = 21). Twenty patients with aneurysms were treated by detachable coil embolization, and 1 patient was treated with n-butyl cyanoacrylate. Of the 21 aneurysm embolization cases, 9 were treated by parent artery occlusion (PAO), and 12 were treated by selective occlusion of the aneurysm (SOA). Results: All 12 aneurysms treated by SOA showed complete occlusion. Two aneurysms became recanalized 6 months after the first embolization and were then re-embolized; complete healing was observed on follow-up angiography. All patients showed acceptable outcomes without any procedural complications, except 1 patient who died 2 days after treatment. PAO resulted in 100% occlusion of all aneurysms. Cerebral infarction was noted in most patients (78%). However, the area of infarction was small. Permanent neurological deficit was observed in 2 patients (22%), but their condition was not critical. Conclusions: Aneurysm embolization with SOA is well indicated for saccular aneurysms with well-defined necks, whereas PAO carries a risk of ischemic complications. Although the PCA is rich in collateral circulation, ischemic complications were noted in most patients after PAO, and it was difficult to predict occurrence of these complications. However, the area of cerebral infarction tended to be small, and the neurological deficits observed were not critical.

Background Hemophagocytic lymphohistiocytosis (HLH) is associated with hypercytokinemia in children. Although HLH can be also observed after hematopoietic stem cell transplantation (HSCT), the incidence and clinical features of HLH after HSCT remain obscure. Procedure The clinical features of HLH after HSCT (post-HSCT HLH) were investigated in children with malignancies, immune deficiencies, or aplastic anemia. The HLH/Langerhans Cell Histiocytosis (LCH) Committee of the Japanese Society of Pediatric Hematology (JSPH) sent questionnaires to hospitals with JPSH members asking for details of cases in which HLH occurred after HSCT between 1998 and 2008. Results Among 42 children who were diagnosed with post-HSCT HLH between 1998 and 2008 in Japan, 37 fulfilled our inclusion criteria; of these, 26 were classified as early-onset (onset 30 days after HSCT). In the early-onset group, the presence of respiratory symptoms, high levels of total bilirubin, and triglycerides at onset and the lack of control of GVHD with tacrolimus were significantly associated with non-resolution of HLH (P

The present study aimed to elucidate the possible role of High Mobility Group Box 1 (HMGB1), which is a candidate prognostic marker in diseases that combine inflammation and tissue injury, in acute encephalopathy. HMGB1 in cerebrospinal fluid (CSF) obtained on admission from eight children with acute encephalopathy, and 16 children with febrile seizure, eight children with bacterial/aseptic meningitis, and eight children with fever without neurological symptoms were analyzed using enzyme-linked immunosorbent assay (ELISA). We found no increase in HMGB1 in CSF from acute encephalopathy or in CSF from febrile seizure or fever without neurological complications at early time points, while marked elevation of HMGB1 was seen in CSF from bacterial and aseptic meningitis. In conclusion, HMGB1 is a poor disease marker for acute encephalopathy.

Ferritin is a cytosolic protein that stores excess iron, thereby protecting cells from iron toxicity. Ferritin-stored iron is believed to be utilized when cells become iron deficient; however, the mechanisms underlying the extraction of iron from ferritin have yet to be fully elucidated. Here, we demonstrate that ferritin is degraded in the lysosome under iron-depleted conditions and that the acidic environment of the lysosome is crucial for iron extraction from ferritin and utilization by cells. Ferritin was targeted for degradation in the lysosome even under iron-replete conditions in primary cells; however, the mechanisms underlying lysosomal targeting of ferritin were distinct under depleted and replete conditions. In iron-depleted cells, ferritin was targeted to the lysosome via a mechanism that involved autophagy. In contrast, lysosomal targeting of ferritin in iron-replete cells did not involve autophagy. The autophagy-independent pathway of ferritin delivery to lysosomes was deficient in several cancer-derived cells, and cancer-derived cell lines are more resistant to iron toxicity than primary cells. Collectively, these results suggest that ferritin trafficking may be differentially regulated by cell type and that loss of ferritin delivery to the lysosome under iron-replete conditions may be related to oncogenic cellular transformation.