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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.

L-asparaginase (L-Asp) is an important reagent for acute lymphoblastic leukemia because asparagine is required for the malignant growth of tumor cells, especially lymphoblastic leukemia cells. An allergic response to L-Asp is not unusual because L-Asp is derived from Escherichia coli and is often recognized as a foreign protein. The hypersensitivity induced by L-Asp is of the immediate type in most cases. We report on a 5-year-old girl who was hospitalized for precursor T-cell lymphoblastic leukemia. She was treated according to a Tokyo Children's Cancer Study Group protocol (TCCSG ALL L09-1603 HEX/BFM). During the intensification phase, blisters with erythema developed on the arm proximal to the catheter insertion site owing to a delayed-type hypersensitivity reaction caused by intravenous L-Asp administration. She was treated with additional methylprednisolone, tapered dexamethasone, and an antihistamine for the allergic reaction. No asparaginases other than E. coli L-Asp have been approved for use in Japan. Other asparaginases, such as polyethylene glycol L-Asp and Erwinia L-Asp should be quickly approved for use as alternative chemotherapy reagents in Japan.

We have investigated the possibility of overcoming the resistance of human brain tumour cells (HBT20) to etoposide by transferring the normal human topoisomerase IIα (H-topo II) gene into these cells. H-topo II in a mammalian expression vector containing a glucocorticoid-inducible mouse mammary tumour virus (MMTV) promoter was transfected into etoposide-resistant HBT20 cells (HBT20-hTOP2MAM). HBT20 cells transfected with pMAMneo vector alone served as control cells (HBT20-MAM). These were stable transfections. Following a 2 h dexamethasone treatment, H-topo II mRNA expression, protein production, etoposide-induced DNA-protein complex formation and sensitivity to etoposide were increased in HBT20-hTOP2MAM cells compared with control HBT20-MAM cells and with HBT20-hTOP2MAM cells not treated with dexamethasone. However, mRNA and protein levels and cell sensitivity returned to baseline when incubation with dexamethasone was continued for 24 h. This decrease from the 2 h values could not be explained by a loss of the MMTV promoter response to dexamethasone. (H-topo IIα promoter)-(chloramphenicol acetyltransferase) constructs containing regions -559–0 and -2400–0 were significantly down-regulated in HBT20-hTOP2MAM cells treated for 24 h with dexamethasone compared with dexamethasone-treated control cells. H-topo II mRNA stability after 24 h of dexamethasone treatment was not altered compared with that in control cells. Our data indicate that the exogenously produced H-topo II may have a negative-feedback effect on the endogenous topoisomerase II promoter, causing down-regulation of the endogenous gene.

The human brain tumour cell line HBT20 is intrinsically resistant to etoposide and does not express mdr-1 mRNA. These studies were conducted to determine whether transfecting a Drosophila (D) topoisomerase II (topo II) gene into HBT20 cells could increase their sensitivity to etoposide. A D-topo II construct in a pMAMneo vector under the control of a mouse mammary tumour virus (MMTV) promoter was transfected into HBT20 cells. The gene is inducible by dexamethasone (Dex). The growth rate of the transfected cells and percentage of the cells in G1, S and G2M was no different than the parental cells. Survival after etoposide exposure (10 microM x 2 h) was measured by colony formation. Parental cells and cells transfected by pMAMneo vector alone showed no enhanced etoposide sensitivity after 24 h of Dex stimulation. By contrast, D-topo II transfected cells were sensitised 3-fold when etoposide treatment was preceded by 24 h Dex stimulation. Northern blotting and Western blotting confirmed that Dex had induced D-topo II expression in the sensitised cells. However, in D-topo II-transfected cells increasing the duration of Dex stimulation to 48 h eliminated the sensitisation to etoposide although increased MMTV promoter activity and expression of the D-topo II gene persisted. Measurement of endogenous human topo-II mRNA and protein revealed a decrease after Dex exposure of greater than 24 h. At these distal times, the total cellular topo II levels (endogenous + exogenous) may be decreased, which may explain why increased sensitivity to etoposide could no longer be demonstrated. This model suggests that D-topo II gene transfection can sensitise de novo resistant HBT20 cells to etoposide but that the time frame of that sensitisation is limited. Images Figure 1 Figure 2 Figure 3 Figure 5

A cDNA encoding for human monocyte chemotactic and activating factor (MCAF) was ligated into the retroviral vector pLXSN. These pMCAF-LXSN and antisense p-antiMCAF-LXSN vectors were transfected into HBT20 and HBT28 human brain tumor cells. HBT28 cells constitutively express high amounts of MCAF, whereas HBT20 cells express much less MCAF. HBT20 cells transfected with pMCAF-LXSN (HBT20-MCAF) showed significantly higher MCAF mRNA expression and MCAF protein production than the HBT20-parent or HBT20 cells transfected with control vector (HBT20-LXSN). In contrast, supernatant from HBT28 cells transfected with p-antiMCAF-LXSN (HBT28-antiMCAF) contained less MCAF than HBT28-parent, HBT28-LXSN, and HBT28-MCAF cells. Activated human monocytes killed HBT20-MCAF cells more efficiently compared with HBT20-parent, HBT20-LXSN, and HBT20-antiMCAF cells (P< 0.02), whereas HBT28-antiMCAF cells were killed more efficiently by activated monocytes compared with HBT28-parent, HBT28-LXSN, and HBT28-MCAF cells (P< 0.05). Cultured supernatants from activated monocytes plus HBT20-MCAF cells or from activated monocytes plus HBT28-antiMCAF cells inhibited the growth of HBT20 and HBT28 cells, respectively. Altered MCAF expression can therefore enhance the ability of activated monocytes to kill brain tumor cells. This increased cytotoxicity is partially dependent upon the basal state of MCAF in the individual tumor cells.

We report a case of infantile acute monocytic leukemia associated with solid tumors in the skin. Light microscopy showed that the tumor cells were mainly spindle-shaped and arranged in tandem. Immunohistochemical staining showed that fibronectin was detected in the extracellular matrix (and partially on the surface of tumor cells), integrin alpha 5 beta 1 on the cell surface, and vinculin and actin were detected in the cytoplasm of the tumor cells. Electron microscopy showed that the tumor cells had perpendicular transmembranous fibrils and closely situated collections of cytoplasmic microfilaments beneath the cell membrane suggesting fibronexus-like structures. We conclude that the expression of fibronectin, integrin alpha 5 beta 1, vinculin, cytoplasmic actin and fibronexus-like structure in leukemic cells indicate these cells possess an adhesive function. The mechanism of formation of the extramedullary solid tumors in this patients involved these adhesion molecules of the tumor cells.

Effective leukemia treatment is seriously hampered by drug resistance. We previously showed that aberrant methylation of the topoisomerase IIα 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 IIα 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.

This communication reports on O2 reduction with a biocathode composed of poly(3-methylthiophene) (P3MT) and laccase based on direct electron transfer (DET). The biocathode was fabricated simply by adsorption of laccase on a P3MT film which was formed on a gold electrode by electrochemical polymerization. Properties of the biocathode were examined by measuring steady-state currents at an arbitrary potential in buffer solutions saturated with O2 or N2 at room temperature. Efficient O2 reduction was achieved with the biocathode, which was attributed to DET from the P3MT film to laccase. The biocathode gave the O2 reduction current density of -150μA/cm(2) at +0.40V (vs. Ag/AgCl). The onset potential of O2 reduction was +0.64±0.01V (vs. Ag/AgCl) at pH4.5. The O2 reduction current became maximum in the pH range 4.0-5.0. This pH dependency of the O2 reduction current is corresponding to that of the activity of native laccase. In addition, the O2 reduction current increased markedly with increasing amount of the charge passed through in the formation of the P3MT film.

Multi-detector-row CT angiography (MDCTA) is useful for diagnosis of spinal arteriovenous (AV) shunt. So we reported the role and pitfall of MDCTA based on our experience.From January 2007 to September 2011, 57 cases used MDCTA in our institution. We investigated 22 case of spinal dural AVF and 5 cases of epidural AVF.All cases were performed by Toshiba Aquilion 64. FOV was the whole spine, curved planar reconstruction along the spinal canal, sagittal and axial view obtained by multi-planar reconstruction.MDCTA detected dilated the perimedullary vein in all cases and identified the level of segmental artery matching the result of DSA in 16 cases of spinal dural AVF (73%) and 1 cases of epidural AVF (20%).MDCTA is useful for screening, and identifying the shunt point, but care needs to be taken concerning the particular pitfall of MDCTA.

Preoperative embolization for hypervascular tumors is typically performed using particle agents such as polyvinyl alcohol, gelfoam powder, and fibrin glue. Furthermore, n-butyl-2-cyanoacrylate (NBCA) is used in patients with cerebral arteriovenous malformation (AVM) or an AV shunt. However, few reports have described the efficacy of NBCA in treating hypervascular tumors. Here, we report cases of hypervascular tumors in which preoperative embolization was performed using NBCA. We also discuss the difference between the efficacy of a liquid agent and a particle agent for hypervascular tumor embolization. We analyzed 10 cases encountered at our institution since 2004 in which preoperative embolization was performed using NBCA. In all cases, NBCA was injected through the tumor-feeding artery. In eight of these cases, preoperative embolization decreased intraoperative bleeding and markedly reduced the tumor stain. In the remaining two cases, complications occurred but without any permanent sequel. Thus, NBCA is useful for preoperative embolization.

We report a case of vein of Galen aneurysmal malformation (VGAM) with a newly developed dural arteriovenous fistula (AVF) subsequent to successful embolization. A male neonate diagnosed as VGAM with prenatal ultrasonography and MRI presented severe cardiac and respiratory failure soon after birth. Five sessions of transarterial embolization using NBCA were performed during the first 6 months of his life. The shunt flow was effectively reduced and heart failure was resolved after the treatment. Follow-up angiography performed 2.5 years after the last embolization revealed complete obliteration of VGAM and newly developed small dural AVF on the wall of the thrombosed falcorial sinus. We believe that the dural AVF in this case was caused by local venous hypertension or induction of angiogenic factor during the thrombosing process of VGAM.

Purpose: Previous reports have suggested that endovascular parent artery occlusion is an effective and safe procedure for the treatment of vertebral artery dissection (VAD). However, the results of long-term outcomes are still unclear. This study reviewed the clinical and imaging outcomes of patients with VAD treated by endovascular internal trapping. Methods: A total of 73 patients were treated for VAD by endovascular internal trapping between March 1998 and March 2011. Patients were regularly followed up by magnetic resonance imaging, magnetic resonance angiography, and clinical examinations. Clinical outcomes were evaluated using the modified Rankin Scale. Results: Forty-five patients had ruptured VADs, and 28 had unruptured VADs. Clinical follow-up of at least 6 months data were obtained for 61 patients (83.6 %). The follow-up period ranged from 6 to 145 months (mean ± SD, 55.6 ± 8.9 months). Two patients with ruptured VADs had recurrence (2.74 %). Cranial nerve paresis (CNP) was observed in 6 patients (8.21 %), spinal cord infarction in 2 patients (2.74 %) and a perforating artery ischemia was diagnosed in 7 patients (9.59 %); all patients with CNP and 5 of the patients with partial Wallenberg syndrome experienced only temporary symptoms; 2 of the patients with partial Wallenberg syndrome had permanent neurological deficits. Despite their symptoms, most patients were in good general condition, as shown by their clinical scores. Conclusions: The results of this study have proven that endovascular internal trapping is a stable and durable treatment for closure of VADs. Recanalization is rather rare and occurred only in ruptured cases., both within 3 months after initial treatment without rupture. CNPs were observed in 8.21 %, perforating ischemia in 9.59 %, and spinal cord infarction in 2.74 %. The former two are temporary, while the last can be a factor that affect mRS. Patients rated their quality of life as good, as corroborated by their posttreatment clinical score. Endovascular internal trapping for VAD is a therapy with a satisfactory long-term outcome.

The authors reported a subclavian artery stenting (SAS) using gadolinium contrast medium. The patient was a 65-year-old female who presented dizziness and right upper extremity pain with movement. Digital subtraction angiography revealed right subclavian artery occlusion with subclavian steal phenomenon. We tried to treat this lesion using SAS. However, iodinated contrast medium caused the allergy in this patient and the treatment was discontinued. Therefore, SAS was performed with gadolinium contrast medium. Using gadolinium contrast medium, it is possible to confirm large arteries like innominate artery and subclavian artery. The stenting procedure was performed without complication. The usage of gadolinium contrast medium has the limit and some strategies are important to reduce the usage of gadolinium contrast medium in SAS. First, PercuSurge GuardWire® was placed in the right internal carotid artery to confirm the anatomy, to decide working angle, and to treat the common carotid artery in case of dissection. Second, a "U" shaped guide wire was placed in the distal end from the brachial artery. Guide wire from femoral side was able to pass the lesion at midpoint of the "U" shaped one. SAS using gadolinium contrast medium may be an alternative treatment if a patient with subclavian artery stenosis or occlusion is allergic to iodinated contrast medium.

Hemangioblastoma in the medulla oblongata is a relatively rare tumor. We present the case of a giant hemangioblastoma occurring in the dorsal medulla oblongata. A 33-year-old man with no neurological symptoms was diagnosed with a hemangioblastoma in the dorsal medulla oblongata, and opted for observation in the outpatient department. After 22 months of observation time, MRI scans showed rapid local tumor progression and obstructive hydrocephalus. At this point, he presented with mild dysphagia as a preoperative neurological deficit. Total surgical removal of the tumor was performed after temporary ventricle drainage and preoperative embolization of the feeding artery. Postoperatively, he became fully conscious but developed bulbar palsy followed by tracheostomy. During the 12 months of postoperative follow-up, severe dysphagia was still present.

We report a case of longstanding asymptomatic direct carotid-cavernous fistula (CCF) which caused fatal subarachnoid hemorrhage (SAH). A 91-year-old female with no history of previous head trauma and optic symptoms presented acute subarachnoid hemorrhage. Angiography revealed a left direct carotid-cavernous fistula draining only into the contralateral cavernous sinus with leptomeningeal venous reflux and small varix on the pontine bridging vein. The affected cavernous sinus was markedly dilated and there was no septum between the left cavernous sinus and the internal carotid artery. The patient underwent transvenous coil embolization for intercavernous sinus and leptomeningeal venous reflux was successfully obliterated and opacification of the varix was diminished. The past history of this patient and angiographical findings strongly suggest long standing asymptomatic CCF caused SAH.

Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) is a novel immune modulator that is now under investigation against metastatic melanoma and osteosarcoma. We have already reported that L-MTP-PE induced monocyte-mediated tumoricidal activity and up-regulation of the tumor necrosis factor and interleukin-1 (IL-1) in vivo and in vitro. We now demonstrate that L-MTP-PE also induces monocyte chemotactic and activating factor (MCAF) mRNA expression at both the transcriptional and post-transcriptional levels. Monocyte chemotactic activity was also present in the supernatants of L-MTP-PE-stimulated cells. In monocytes, the increased expression of MCAF was induced rapidly (by 2 h) but was short-lived. By 4 h, MCAF mRNA had decreased to background level. We found no change in MCAF mRNA levels in lymphocytes exposed to L-MTP-PE. We therefore conclude that L-MTP-PE selectively up-regulates MCAF expression in monocytes and that MCAF may play a role in the tumoricidal and immune-stimulating activity of L-MTP-PE.

Background Acute encephalopathy includes rapid deterioration and has a poor prognosis. Early intervention is essential to prevent progression of the disease and subsequent neurologic complications. However, in the acute period, true encephalopathy cannot easily be differentiated from febrile seizures, especially febrile seizures of the complex type. Thus, an early diagnostic marker has been sought in order to enable early intervention. The purpose of this study was to identify a novel marker candidate protein differentially expressed in the cerebrospinal fluid (CSF) of children with encephalopathy using proteomic analysis. Methods For detection of biomarkers, CSF samples were obtained from 13 children with acute encephalopathy and 42 children with febrile seizure. Mass spectral data were generated by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) technology, which is currently applied in many fields of biological and medical sciences. Diagnosis was made by at least two pediatric neurologists based on the clinical findings and routine examinations. All specimens were collected for diagnostic tests and the remaining portion of the specimens were used for the SELDI-TOF MS investigations. Results In experiment 1, CSF from patients with febrile seizures (n = 28), patients with encephalopathy (n = 8) (including influenza encephalopathy (n = 3), encephalopathy due to rotavirus (n = 1), human herpes virus 6 (n = 1)) were used for the SELDI analysis. In experiment 2, SELDI analysis was performed on CSF from a second set of febrile seizure patients (n = 14) and encephalopathy patients (n = 5). We found that the peak with an m/z of 4810 contributed the most to the separation of the two groups. After purification and identification of the 4.8-kDa protein, a 4.8-kDa proteolytic peptide fragment from the neurosecretory protein VGF precursor (VGF4.8) was identified as a novel biomarker for encephalopathy. Conclusions Expression of VGF4.8 has been reported to be decreased in pathologically degenerative changes such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia, and encephalopathy. Thus, the VGF4.8 peptide might be a novel marker for degenerative brain conditions.

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.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.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 (onset30 days after HSCT) and 11 were classified as late-onset (onset30 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 (P0.05). The survival rate was significantly higher in patients with resolution of HLH than in those without resolution (59% vs. 14%, P0.05).These findings suggest that early-onset post-HSCT HLH is a specific entity of HLH, and appropriate diagnosis and prompt management need to be established.

In this report, the authors describe a 35-year-old male whose intracranial arteriovenous malformation (AVM) spontaneously disappeared about 2 years after successful living-donor liver transplantation for alcohol-induced liver cirrhosis. Preoperative screening MRI revealed intracranial arteriovenous malformation (AVM) around the midbrain. Cerebral angiography demonstrated that the AVM was fed by the paramedian mesencephalic arteries and was drained via the vein of Galen. He successfully underwent living-donor liver transplantation, and his postoperative course was uneventful. Follow-up MRI and MRA revealed spontaneous disappearance of the AVM 27 months after surgery. The authors discuss precisely the underlying mechanism of this rare phenomenon, based on thorough literature review.

Spinal dural arteriovenous fistula (SDAVF) in the sacral region is relatively rare and remains difficult to diagnose because of the uncommon origin of its feeder. It also has higher incidence of recurrence than usual thoraco-lumbar lesion and needs subsequent treatment. We reviewed 51 cases of SDAVF over the past 10 years. Especially in patients with sacral lesion, clinical features and the findings on spinal angiography were analyzed. Four patients (7.8%) had SDAVF in the sacral region. In all cases, SDAVF were supplied by the lateral sacral artery. Multiple feeders were observed in 3 (75%) out of 4 patients and 2 patients (50%) had multiple fistulas. Endovascular embolizations were performed in all patients, and neurological symptoms were improved in two patients (50%) and the other two were stabilized (50%). There was no recurrence during a follow-up period of 3 months to 8 years. We should keep in mind that SDAVF in the sacral region can have multiple shunts and feeders derived from the lateral sacral artery.

The mumps virus is frequently the causative agent in aseptic meningitis and mumps has still prevailed in Japan. We compared data obtained from patients with mumps meningitis and patients with aseptic meningitis caused by other viruses in order to identify mumps meningitis-specific cytokine/chemokine alterations in cerebrospinal fluid (CSF). We elucidated the cytokine/chemokine network based on the cytokine/chemokine profiles in CSF from children with mumps meningitis and meningitis due to other viral infections using multiplex cytokine measurement. Seventeen cytokines/chemokines, namely interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, granulocyte colony-stimulating factor (G-CSF), granulocyte monocyte colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1β (MIP-1β), were measured simultaneously in CSF supernatants from eight children with mumps meningitis, 11 children with other types of viral meningitis and eight children with fever without neurological complications such as convulsion. We found that IL-8, IL-10, IL-12, IL-13 and IFN-γ showed a statistically significant increase in CSF from mumps meningitis when compared to other types of viral meningitis and fever without neurological complications. Mumps meningitis may induce a distinct immunological response when compared with other types of viral meningitis.

Perimedullary arteriovenous fistula (AVF) is usually located on the surface of the spinal cord and is fed by the anterior spinal artery and/or the posterior spinal artery. We report a rare case of Conus perimedullary AVF with multiple shunt points including the cauda equina. A 68-year-old man presented with leg pain when walking long distances. Magnetic resonance imaging at the thoracic and lumbar level revealed multiple signal voids with marked cord signal change. Angiography showed the perimedullary AVF fed by the anterior spinal artery from the right T9 intercostal artery at the level of the conus medullaris and the fistula fed by the left lateral sacral artery from the left internal iliac artery at the level of the cauda equina. In the first surgery, we performed surgical interruption of feeding arteries from the filum terminale and coagulated AV shunt of the conus medullaris. However residual perimedullary AVF was found at the conus medullaris in the postoperative angiography. Secondary surgery was carried out to treat residual AVF. Follow-up angiography showed complete disappearance of all AVFs. Postoperatively, the patient`s symptoms were improved. Because the Conus perimedullary AVF has the characteristics of multiple feeding arteies, multiple shunt points, and complex venous drainage, it must be kept in mind that other fistula could exist in the cauda equina or filum terminale.

The authors present the case of a 61-year-old male with a de novo fusiform vertebral artery aneurysm, probably due to non-traumatic dissection. He underwent flow diversion therapy, using a double overlapping technique, because the origin of the contralateral vertebral artery was stenotic. Placement of two stents resulted in marked reduction of blood flow in the aneurysm. Postoperative course was uneventful. Follow-up 3D-CT angiography revealed a patent blood flow in the stent and a gradual progression of intra-aneurysmal thrombosis. Flow diversion therapy can potentially obliterate the complicated cerebral aneurysm with the preservation of blood flow in the parent artery, and would be one of the important therapeutic options in patients with complicated aneurysms in which conventional strategies such as neck clipping, endovascular coiling and parent artery occlusion are not feasible or contraindicated.

Liposomal muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) is a biological agent in phase I and II trials for osteosarcoma and melanoma. Its mechanism of action has been linked to its ability to activate monocyte tumoricidal function and to stimulate monocyte production of tumor necrosis factor (TNF) and interleukins(IL)-1, -6, and -8. Our ultimate goal is to combine L-MTP-PE with chemotherapy. The purpose of this study was to determine whether doxorubicin (Adriamycin) interfered with the ability of L-MTP-PE to activate monocyte cytokine production. Human monocytes were cultured with or without 5-500 ng/ml of Adriamycin for 3 h and washed before being exposed to 2 micrograms/ml L-MTP-PE for 16 h. Cultured supernatants were collected and assayed for TNF, IL-1, IL-6, and IL-8. The messenger RNA expression of IL-1 alpha, IL-1 beta, TNF alpha, IL-6, and IL-8 was quantified with northern blot analysis. Adriamycin did not suppress the up-regulation of any of these cytokines. We concluded that combination therapy with L-MTP-PE and Adriamycin is feasible and that this combination warrants further investigation in a clinical setting.

Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE), a new biologic response modifier, was designed to target the immunomodulator to monocytes and macrophages. Human monocytes/macrophages phagocytize L-MTP-PE, with subsequent upregulation of interleukin (IL)-1 alpha, IL-1 beta, IL-6, IL-8, tumor necrosis factor (TNF)-alpha, and monocyte chemotactic and activating factor genes and with the production and secretion of these cytokines in vitro. L-MTP-PE-activated macrophages kill tumor but not normal cells in vitro. Following i.v. infusion of L-MTP-PE into cancer patients, its uptake was demonstrated in liver, spleen, lung, and in and around metastases to lung. We also investigated whether L-MTP-PE therapy administered in a neoadjuvant setting could improve the disease-free interval in relapsed osteosarcoma patients with lung metastasis. Patients received either a 12- or 24-week course of L-MTP-PE after surgical removal of all metastases. Following L-MTP-PE infusion, induction of circulating TNF-alpha, IL-6, neopterin, and C-reactive protein was demonstrated. Disease-free intervals were calculated from the day of surgery to the day of relapse in each group and were compared with the disease-free interval for a historical control group. Those patients receiving 24 weeks of L-MTP-PE showed a significant (p < 0.03) prolongation in time to relapse. These data indicate that L-MTP-PE is an active agent against osteosarcoma and warrants further investigation in an adjuvant setting.

A case of a desmoplastic small cell tumor of the large omentum associated with gross ascites that occurred in a male adolescent is reported. Light microscopic studies revealed that the tumor cells were small and epithelioid in nature with eosinophilic hyaline material located in the perinuclear area. They were surrounded by rich desmoplastic and myxoidal stromal bands. Immunohistochemical staining revealed globoid perinuclear positivity for desmin. Vimentin, cytokeratin (AE3, CaM 5.2), epithelial membrane antigen, tissue polypeptide antigen, neuron-specific enolase, chromogranin A, endocrine granule constituent and synaptophysin were also positive in the cytoplasm. Electron microscopy revealed whorled intermediate filaments and some dense core granules in the cytoplasm. Bundles of microtubules in the cytoplasmic process and occasional cell junctions of zonulae adherentes in the tumor cells were also observed. DNA analysis of the tumor cells showed the three-fold amplification of the N-myc gene. Although desmoplastic small cell tumors showed a heterogeneous pattern with immunohistochemical studies, it is suggested that the tumor may originate from neurogenic cells.

We report a case in which a 2-year-old girl who underwent a right middle and lower lung lobectomy for congenital cystic adenomatoid malformation suffered massive bleeding and developed acute respiratory distress syndrome (ARDS) during the operation. She was ventilated with a high level of F(I)O(2) (0.75-1.0), PEEP (10-20 cmH(2)O), and PIP (33-55 cmH(2)O) to maintain SPO(2) (90%). Following transfer to the ICU, continuous hemodialysis was introduced to reduce excessive blood volume. However, pulmonary oxygenation did not improve, and marked subcutaneous emphysema occurred on postoperative day 3 (POD 3). We introduced venovenous (V-V) extracorporeal membrane oxygenation (ECMO) to rest the lung, and V-V ECMO was changed to right and left atrial ECMO because of unsatisfactory oxygen support on POD 23. A CT scan showed almost the entire lung had collapsed, even though we had administered diuretics, steroids, nitric oxide, sivelestat, and surfactant for ARDS. We applied high-frequency oscillatory ventilation (HFOV) with a mean airway pressure of 20 cmH(2)O, frequency of 9.2 Hz, and amplitude of 38 cmH(2)O on POD 45. The collapsed lung was then gradually recruited, and pulmonary oxygenation improved (P/F ratio = 434). ECMO was successfully weaned on POD 88. The patient required a tracheostomy, but she was able to function without a ventilator on POD 142. Although HFOV has failed to show a mortality benefit in ARDS patients, the unique lung recruitment by HFOV can be a useful therapeutic option for severe ARDS patients in combination with sufficient lung rest produced by ECMO.

Cat-scratch disease is the most common form of Bartonella henselae infection. Although reports have shown that CSD is relatively common, they have not shown the prevalence of seropositivity for Bartonella henselae in cases of cervical lymphadenitis and Kawasaki disease, which are relatively common diseases in children.We evaluated the presence of immunoglobulin (Ig) G- and IgM-class antibodies against Bartonella henselae in children with cervical lymphadenitis, Kawasaki disease, and infectious diseases without lymphadenopathy in a semi-rural area in Japan.We found that the positivity rate for the IgG antibody against Bartonella henselae in patients with cervical lymphadenitis who owned cats or dogs was significantly higher than that in patients with Kawasaki disease and infectious diseases without lymphadenopathy. However, the average age of children with cervical lymphadenitis did not significantly differ when compared to those with other infectious diseases.Our serological study showed that Bartonella henselae infection may contribute to the etiology of cervical lymphadenitis in children.

本研究では拘束圧力下における地盤と構造物の相互作用に関する一つの問題として水平荷重を受ける杭の深部をとりあげ, この領域では地盤は水平面内の二次元的挙動を示すという仮定のもとに模型実験を実施した. その結果, この領域において杭前面地盤に発生するせん断帯の形状, ひずみ分布および地盤反力特性を把握することができた.

Bacterial meningitis has a poor prognosis and neurologic complications. The present study aimed to investigate the cytokine/chemokine network in cerebrospinal fluid (CSF) from children with bacterial meningitis and aseptic meningitis. Interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, interferon-gamma, tumor necrosis factor-alpha, granulocyte colony-stimulating factor, granulocyte monocyte colony-stimulating factor, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1beta, were measured simultaneously in CSF supernatants. We found that, IL-17 was significantly elevated in CSF with bacterial meningitis. We believe that IL-17 plays a key role in neutrophil infiltration into CSF and neuronal protection in bacterial meningitis.

BACKGROUND: The current study aimed to evaluate the efficacy of superselective high-dose cisplatin infusion with concomitant radiotherapy (RADPLAT) for previously untreated patients with advanced cancer of the nasal cavity and paranasal sinuses. METHODS: Between October 1999 and December 2006, 47 patients were given superselective intra-arterial infusions of cisplatin (100-120 mg/m2 per week) with simultaneous intravenous infusions of thiosulfate to neutralize cisplatin toxicity and conventional external-beam radiotherapy (65-70 grays). RESULTS: There were 7 patients (14.9%) diagnosed with T3, 22 (46.8%) with T4a, and 18 (38.3%) with T4b disease. During the median follow-up period of 4.6 years, the 5-year local progression-free survival rate was 78.4% for all patients (n = 47), 69.0% for patients with T4b disease (n = 18), and 83.2% for patients with

The authors reported three cases of high flow arteriovenous fistula (AVF) associated with hereditary haemorrhagic telangiectasia (HHT). The first case was a 9-month-old boy who presented with subarachnoid hemorrhage (SAH). Digital subtraction angiography (DSA) revealed a perimedullary AVF at the cervical spine and the fistula was successfully interrupted by transarterial embolization with no additional neurological deficits. The second case was his mother, a 29-year-old women. She also had history of epistaxis, so imaging screens of her central nervous system (CNS) were undertaken. MRI showed a giant intracerebral varix associated with a high-flow pial AVF. This patient was treated by surgery and postoperative CT angiography showed extinction of AVF completely. The third case was an 8-year-old girl with a family history of HHT. She presented with gradual progression of paraparesis, sensory disturbance in the bilateral lower extremities and bladder dysfunction. MRI disclosed a perimedullary AVF with a large varix at the L3/4 level. The AVF was successfully interrupted by transarterial embolization with platinum coils. Post-embolization DSA showed complete disappearance of the AVF. The existence of HHT must always be considered a possibility when AVF of the CNS is diagnosed.

A 7-year-old boy with dysmorphic features was found to have a recombinant chromosome 18, rec(18), resulting from meiotic recombination of a maternal pericentric inversion, inv(18) (p11.2q21.3), as defined by high-resolution banding. He was trisomic for the long arm (q21.3-qter) and monosomic for the short arm (p11.2-pter) of chromosome 18. His clinical features were compared with those in other rec(18) cases, and also those in monosomy 18p, trisomy 18qter and full trisomy 18 syndromes. The risk of recombinant formation for inv(18) carriers was also discussed.

A 9-month-old boy was transferred to our institute after suffering sudden seizure and loss of consciousness followed by cardiopulmonary arrest. Neurological examination on admission revealed deep coma and tetraparesis. Brain computed tomography revealed diffuse intracranial subarachnoid hemorrhage (SAH), whereas brain magnetic resonance (MR) angiography showed no intracranial abnormalities. MR imaging of the spine demonstrated a remarkable flow void extending from C3 to T1. Digital subtraction angiography revealed a perimedullary arteriovenous fistula (AVF) fed by the left thyrocervical trunk, associated with a varix and a dilated perimedullary vein. He had hypoxic encephalopathy due to transient cardiopulmonary arrest, and remained in the intensive care unit for 2 months. Thereafter, he was transferred to the pediatric ward, where his general condition improved, and after 7 months underwent embolization of the AVF to prevent further SAH. The perimedullary AVF was successfully interrupted by transarterial embolization with n-butyl-2-cyanoacrylate and platinum coils, and no additional neurological deficits developed. Post-embolization MR imaging showed loss of the flow void. The favorable outcome demonstrates the importance of spinal cord imaging in infants with SAH without other intracranial abnormalities to detect the presence of perimedullary AVF. Perimedullary AVFs in children are often associated with huge fistulas and varices, so are good candidates for endovascular surgery.

Paraspinal arteriovenous fistulas (AVFs), with the fistulas draining into the epidural veins alone, are relatively rare and few cases have been reported until now. We reported a case of cervical paraspinal AVFs draining only into the epidural venous plexus without reflux into the intradural venous system. The patient showed myelopathy due to direct compression of the spinal cord by a large varix. A 57-year-old man presented with gait disturbance. Neurological findings on admission revealed that tetraparesis, sensory disturbance of four extremitas below the C5 level and bladder bowel dysfunction. Magnetic resonance imaging and computed tomography at the cervical level disclosed remarkable compression of the spinal cord by a large venous pouch at the C6 level. Digital subtraction angiography (DSA) revealed paraspinal arteriovenous fistulas fed by bilateral C6 radicular arteries, the right ascending cervical arteries, and the right deep cervical artery in the right C6 intervertebral foramen. Three-staged transarterial embolization was performed by selective catheterization of the multiple feeders with n-butylcyanoacrylate, followed by transvenous embolization. During transvenous embolization, motor evoked potential (MEP) monitoring was performed. After retrograde catheterization of the epidural venous plexus, the large varix was occluded with Guglielmi detachable coils. The AV fistulas were completely occluded without any change in MEP monitoring during the procedure. The patient's gait improved well after the procedure and follow up DSA six months later showed no recurrence of the paraspinal AVFs.

Leucine-rich repeat kinase 2 (LRRK2) is a key molecule in the pathogenesis of familial and idiopathic Parkinson’s disease (PD). We have identified two novel LRRK2-associated proteins, a HECT-type ubiquitin ligase, HERC2, and an adaptor-like protein with six repeated Neuralized domains, NEURL4. LRRK2 binds to NEURL4 and HERC2 via the LRRK2 Ras of complex proteins (ROC) domain and NEURL4, respectively. HERC2 and NEURL4 link LRRK2 to the cellular vesicle transport pathway and Notch signaling, through which the LRRK2 complex promotes the recycling of the Notch ligand Delta-like 1 (Dll1)/Delta (Dl) through the modulation of endosomal trafficking. This process negatively regulates Notch signaling through cis-inhibition by stabilizing Dll1/Dl, which accelerates neural stem cell differentiation and modulates the function and survival of differentiated dopaminergic neurons. These effects are strengthened by the R1441G ROC domain-mutant of LRRK2. These findings suggest that the alteration of Notch signaling in mature neurons is a component of PD etiology linked to LRRK2., Author Summary LRRK2 is linked to autosomal dominant late-onset Parkinson’s disease, suggesting that LRRK2 gain-of-function mutations lead to age-dependent degeneration of the midbrain dopaminergic neurons. In this study, we describe two novel LRRK2-associated proteins HERC2 and NEURL4, which are a ubiquitin ligase and an adaptor-like protein, respectively. HERC2 and NEURL4 direct LRRK2 to Notch signaling pathway, in which the LRRK2-NEURL4-HERC2 complex promotes the recycling of the Notch ligand Delta-like 1 (Dll1)/Delta (Dl) through the modulation of endosomal trafficking. As a result, the amounts of Dll1/D1 on the plasma membrane are increased, which affects negatively Notch signaling through cis-inhibition. The effect is enhanced by a Parkinson’s-disease associated mutation of LRRK2. Inhibition of Notch signaling in adult dopaminergic neurons impairs its functions and survival. These findings indicate a possible link between Notch pathway and Parkinson’s disease.

BACKGROUND The clinical features of patients with anaphylactoid purpura who were admitted to the National Tosei Hospital over the past 15 years were investigated to confirm whether the prognosis of renal involvement had improved. RESULTS Of the 107 patients admitted to hospital, 43 (40.2%) had urinary abnormalities. The patients with renal involvement were older (P < 0.05) compared to patients without nephritis. Over the last 5 years (1991-95), the duration of urinary abnormalities was significantly shorter than in the period from 1981 to 1990 (P < 0.05). CONCLUSIONS The duration of the urinary abnormality of nephritis complicating anaphylactoid purpura appears to be changing.

Osteonecrosis of the femoral head (ONF) is a necrosis due to disruption of the blood flow. The disease often occurs in association with corticosteroid treatment. The pathology of corticosteroid-induced ONF is unclear, although abnormalities in the coagulation and fibrinolytic systems or in the lipid metabolism have been reported to be involved. We examined the relationships between development of ONF and genetic variations and plasma level of lipoprotein(a) (Lp(a)), which is closely involved in the coagulation and fibrinolytic systems and lipid metabolism.The study population consisted of 112 renal transplant patients undergoing corticosteroid treatment. Their apolipoprotein (a) [apo(a)] isoform was determined by Western blotting, and patients were classified into low molecular weight (LMW) or high molecular weight (HMW) groups. The plasma Lp(a) level was measured. Patients were also examined for 3 single-nucleotide polymorphisms (SNP), -773 (G/A), +93 (C/T), and +121 (G/A). Relationships between these 3 genetic factors of Lp(a) and ONF development were examined using statistical methods including multivariate analysis.A strong relationship was observed between the apo(a) molecular weight phenotype and ONF development, with an increased risk of ONF development for the LMW group (adjusted odds ratio 5.75, 95% CI 1.76-18.74, p = 0.0038). No significant relationships were observed between ONF and plasma Lp(a) level and SNP.Apo(a) molecular weight phenotype would be a useful predictor of ONF that develops after corticosteroid treatment.

We describe an uncircumcised male infant treated for urinary tract infection who exhibited multiple hormonal and electrolyte abnormalities consistent with a diagnosis of transient pseudohypoaldosteronism. Successful treatment of the urinary tract infection was accompanied by the resolution of all hormonal and electrolyte abnormalities, including hyperaldosteronemia, hyperreninemia, hyponatremia and hyperkalemia. Radiographic examination revealed marked left dilatation of the renal pelvis and hydroureter but no vesicoureteral reflux. Owing to the possibilities of future renal scarring, decreased renal function, and hypertension, evaluation of urinary tract malformation and appropriate hormonal studies should be performed in infants with urinary tract infection and hyperkalemia.

We report on a 13‑year‑old girl with a solid cystic tumor of the pancreas. She was referred to our hospital with abdominal pain in the left upper quadrant. Physical examination revealed a firm mass in the abdomen. Ultrasonography showed a clearly demarcated round mass with a mixture of solid and cystic components. Computed tomography confirmed that the mass measured 5 � 5 cm with low density in the cystic region and soft‑tissue density in the solid region. Magnetic resonance also showed a clearly demarcated mass with a solid portion of low intensity on T1‑weighted images and high intensity on T2‑weighted images. We diagnosed a solid and cystic tumor of the pancreas and subsequently performed distal pancreatectomy. A firm well‑encapsulated tumor was found in the pancreas tail. The cut surface of the tumor consisted of a solid area with hemorrhage and a cystic area. Light microscopy of the tumor confirmed small neoplastic cells. Pathological diagnosis was solid pseudopapillary tumor (solid cystic tumor of the pancreas. Surgery was successful and the postoperative course was uneventful. (J Nippon Med Sch 2006; 73: 231―234

Neurocutaneous melanosis (NCM) is a rare congenital disease characterized by the presence of large or multiple congenital melanocytic nevi and benign or malignant melanocytic tumors of the leptomeninges [2] with high risk of melanoma development [1]. Acute disseminated encephalomyelitis (ADEM) is an uncommon monophasic inflammatory demyelinating disease that usually presents in children and young adults [3]. Here, we report a boy aged 10 years and 7 months with NCM complicated by ADEM.

A 13-year old boy with acute lymphoblastic leukemia had bilateral paresis of the upper extremities and aphasia 1 week after high dose methotrexate and triple intrathecal therapy (methotrexate, cytarabin, hydrocortisone). The stroke-like neurological symptoms disappeared on the third day. T2-weighted magnetic resonance imaging showed hyperintensities of white matter on the second day. Despite resolution of the neurological symptoms, magnetic resonance images were still abnormal 3 years after the attack. Methotrexate has been considered to be responsible for ischemic damage to oligodendroglial cells, resulting in demyelination. The changes are occasionally prolonged without persistent neurologic symptoms.

This paper details the design and evaluation of the Delphian Desktop, a mechanism for online spatial prediction of cursor movements in a Windows-Icons-Menus-Pointers (WIMP) environment. Interaction with WIMP-based interfaces often becomes a spatially challenging task when the physical interaction mediators are the common mouse and a high resolution, physically large display screen. These spatial challenges are especially evident in overly crowded Windows desktops. The Delphian Desktop integrates simple yet effective predictive spatial tracking and selection paradigms into ordinary WIMP environments in order to simplify and ease pointing tasks. Predictions are calculated by tracking cursor movements and estimating spatial intentions using a computationally inexpensive online algorithm based on estimating the movement direction and peak velocity. In testing the Delphian Desktop effectively shortened pointing time to faraway icons, and reduced the overall physical distance the mouse (and user hand) had to mechanically traverse.