Association of non-steroidal anti-inflammatory drug use with encephalopathy development: An analysis using the United States Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) databases.

Encephalopathy is the most severe complication of various common infections, including influenza and herpes, and it often results in death or severe neurological disability. The risk factors for viral encephalopathy include non-steroidal anti-inflammatory drug (NSAID) use; however, studies on NSAID-related encephalopathy are limited. In this study, we aimed to investigate the characteristics of NSAID-related encephalopathy. We investigated the incidence of NSAID-related encephalopathy using data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) databases containing reports on spontaneous adverse effects (AEs) published by the Pharmaceuticals and Medical Devices Agency. We used these databases to detect AEs based on reported odds ratios. By separating suspicious drugs, concomitant drugs, and drug interactions involving NSAIDs, we investigated the relationship between encephalopathy pathology and AEs of NSAIDs. Significant encephalopathy signals were detected for loxoprofen and etodolac in the FAERS database and loxoprofen in the JADER database. In the JADER database, significant encephalopathy signals in loxoprofen-treated patients were detected in 70-79-year-old, ≥80-year-old, influenza viral infection, and herpes virus infection groups. Significant encephalopathy signals in patients with herpes virus infection were detected in the ≥80-year-old and loxoprofen-treated groups. Regarding the involvement of loxoprofen in the development of encephalopathy, the JADER database listed loxoprofen as a suspect drug, without indicating any concomitant drug interactions. In conclusion, our findings suggest that loxoprofen and etodolac may be associated with viral encephalopathy. Accordingly, prudence is recommended when using loxoprofen in older individuals with viral infections.

Development of LOX-1 Antibody Modified Immuno-liposomes as Drug Carriers to Macrophages in Atherosclerotic Lesions.

We developed a drug delivery system for atherosclerotic lesions using immuno-liposomes. We focused on enhancing the delivery efficiency of the liposomes to macrophages in atherosclerotic lesions by antibody modification of lectinlike oxidized low-density lipoproteins (LDL) receptor 1 (LOX-1). The cellular accumulation of the liposomes in foam cells induced by oxidized LDL (oxLDL) in Raw264 mouse macrophages was evaluated. The cellular accumulation of LOX-1 antibody modified liposomes in oxLDL-induced foam cells and untreated Raw264 cells was significantly higher compared with that of unmodified liposomes. The liposomes were also administered intravenously to Apoeshl mice as an atherosclerosis model. Frozen sections were prepared from the mouse aortas and observed by confocal laser microscopy. The distribution of LOX-1 antibody modified liposomes in the atherosclerotic regions of Apoeshl mice was significantly greater compared with that of unmodified liposomes. The results suggest that LOX-1 antibody modified liposomes can target foam cells in atherosclerotic lesions, providing a potential route for delivering various drugs with pharmacological effects or detecting atherosclerotic foci for the diagnosis of atherosclerosis.

Relationship between the administration of nicardipine hydrochloride and the development of delirium in patients on mechanical ventilation.

A history of hypertension is a known risk factor for delirium in patients in intensive care units, but the effect of antihypertensive agents on delirium development is unclear. Nicardipine, a calcium channel blocker, is widely used in ICU as a treatment agent for hypertensive emergency. This study investigated the relationship between the administration of nicardipine hydrochloride and delirium development in patients under mechanical ventilation. We conducted a medical chart review of 103 patients, who were divided into two groups according to the use of nicardipine hydrochloride. The prevalence of delirium was compared with respect to factors such as age, sex, laboratory data, and medical history, by multivariate analysis. 21 patients (20.4 %) were treated with nicardipine hydrochloride in 103 patients. The treatment and non-treatment groups differed significantly in age (72 vs. 65 years) and history of high blood pressure (57% vs. 11%). Multivariate analysis revealed that patients in the treatment group developed delirium significantly less often than those in the non-treatment group (19% vs. 48%). These results suggested that treatment of high blood pressure with nicardipine hydrochloride is a possible method for preventing the development of delirium.

Magnetic field shimming of a permanent magnet using a combination of pieces of permanent magnets and a single-channel shim coil for skeletal age assessment of children.

We adopted a combination of pieces of permanent magnets and a single-channel (SC) shim coil to shim the magnetic field in a magnetic resonance imaging system dedicated for skeletal age assessment of children. The target magnet was a 0.3-T open and compact permanent magnet tailored to the hand imaging of young children. The homogeneity of the magnetic field was first improved by shimming using pieces of permanent magnets. The residual local inhomogeneity was then compensated for by shimming using the SC shim coil. The effectiveness of the shimming was measured by imaging the left hands of human subjects and evaluating the image quality. The magnetic resonance images for the child subject clearly visualized anatomical structures of all bones necessary for skeletal age assessment, demonstrating the usefulness of combined shimming.

CD5-positive diffuse large B-cell lymphoma: a retrospective study in 337 patients treated by chemotherapy with or without rituximab.

BACKGROUND: CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) shows poor prognosis and frequent central nervous system (CNS) relapses under anthracycline-containing chemotherapy. The aim of this study was to determine the prognosis and CNS relapse incidence of CD5+ DLBCL in the rituximab era. PATIENTS AND METHODS: We analyzed 337 patients with CD5+ DLBCL who received chemotherapy with (R-chemotherapy group; n = 184) or without (chemotherapy group; n = 153) rituximab. RESULTS: No significant difference was found in clinical background comparisons between the two groups. In the R-chemotherapy group, 60% of the patients were older than 65 years at diagnosis. Both the complete response rate and overall survival (OS) were significantly better in the R-chemotherapy group (P = 0.0003 and P = 0.002, respectively). Multivariate analysis confirmed that chemotherapy without rituximab was associated with unfavorable OS. However, the probability of CNS relapse did not differ between the two groups (P = 0.89). The CNS relapse was strongly associated with short OS (P < 0.0001). In the R-chemotherapy group, 83% of patients who experienced CNS relapse had parenchymal disease. CONCLUSIONS: Our results indicate that rituximab improves the OS of patients with CD5+ DLBCL but does not decrease the CNS relapse rate. More effective treatments with CNS prophylaxis are needed for CD5+ DLBCL patients.

Podoplanin is a potential marker for the diagnosis of ependymoma: a comparative study with epithelial membrane antigen (EMA).

Podoplanin is a mucin-type transmembrane sialoglycoprotein that is characteristically expressed in lymphatic endothelia. It is also expressed in the ependyma of the central nervous system as well as in ependymomas. Particularly, membrane-bound structures along the luminal surface, ring-like structures, and dot-like structures in the cytoplasm, all of which were originally reported for epithelial membrane antigen (EMA) immunohistochemistry in ependymoma, were also reported for podoplanin immunohistochemistry in ependymoma. This study was undertaken to evaluate podoplanin as compared with EMA as a marker of ependymoma. A total of 16 ependymomas (WHO Grade (G) II, 9 cases; GIII, 4; myxopapillary, 2; GIII clear cell, (1) were immunohistochemically studied using antibodies against podoplanin (clones D2-40 and NZ-1) as well as an antibody against EMA (clone E29). In all cases, D2-40 and NZ-1 excellently labeled linear signals along the luminal surface of ependymal canals/rosettes, dot-like structures, and/or ringlike structures, as did E29. These structures were generally more abundant in GII ependymomas than in GIII ependymomas. A semiquantitative analysis between the immunopositive structures of D2-40 or NZ-1 and E29 was conducted with a focus on the dot-like structures and the ring-like structures in the cases of GII and GIII ependymoma. The result showed that there was no statistical difference between D2-40 or NZ-1 and E29. Our study suggests that podoplanin is a potential marker for the diagnosis of ependymoma that corresponds to EMA. Anti-podoplanin antibodies and anti-EMA antibodies could cooperate with each other for the diagnostic immunohistochemistry of ependymoma.

Myeloablative cord blood transplantation for adults with hematological malignancies using tacrolimus and short-term methotrexate for graft-versus-host disease prophylaxis: single-institution analysis.

We studied clinical outcomes of 25 adult patients with hematological malignancies who underwent cord blood transplantation (CBT) after a myeloablative conditioning regimen, including high-dose cytosine arabinoside (CA) (8 g/m(2)), cyclophosphamide (CY) (120 mg/kg), and total-body irradiation (TBI) (12 Gy). For graft-versus-host disease (GVHD) prophylaxis, all patients received a combination of tacrolimus and short-term methotrexate (sMTX). Neutrophil engraftment was achieved in 20 of 25 patients. Of the 22 evaluable patients, 2 and 7 had grades I and II acute GVHD, respectively, and only 1 developed grade III acute GVHD after discontinuation of tacrolimus due to encephalopathy. Chronic GVHD developed in 13 of 19 evaluable patients, including 4 with the extensive type. However, the Karnofsky scores of survivors at 1 year after CBT were 90% or 100%. Eight of 25 patients died of nonrelapse causes (n = 4) and relapse/progressive disease (n = 4); 17 patients are currently alive with 15 free of disease at the present time (median follow-up, 24 months). The probability of disease-free survival at 2 years among patients with standard risk was 89% and that of high-risk patients was 30%. Transplantation-related mortality within 100 days was 12%. These results suggested that the CA/CY/TBI combination is a promising conditioning regimen for myeloablative CBT. Furthermore, tacrolimus and sMTX seemed to have suppressed severe acute GVHD and chronic GVHD, which may also contribute to the favorable results.

Olig2 and CD99 are useful negative markers for the diagnosis of brain tumors.

Olig2, a member of the group of basic helix-loop-helix transcription factors, is innately expressed in oligodendrocytes. In the neoplastic condition, Olig2 is widely expressed in astrocytomas and oligodendrogliomas, but its expression in ependymomas remains poorly documented. A total of 59 brain tumors including 16 ependymomas, 32 astrocytomas, and 11 oligodendrogliomas were immunohistochemically studied for the expression of Olig2 as well as other markers including epithelial membrane antigen (EMA) and CD99. In general, the Olig2-positive nuclei were only sparsely distributed in ependymomas; in contrast, they were very numerous in astrocytomas and oligodendrogliomas. Particularly in cases of glioblastoma or pilocytic astrocytoma that histologically mimicked ependymoma, the Olig2-positive nuclei were numerous as in conventional astrocytomas, which helped to differentiate them from ependymomas. The EMA-positive structures were helpful for the diagnosis of ependymoma, however, they were occasionally very modest and sparse on immunostained sections. A quantitative study showed that the Olig2-positive nuclei were much fewer in ependymomas than in astrocytomas and oligodendrogliomas. These results indicate that the Olig2-immunohistochemistry is useful and potentially more reliable than the EMA-immunohistochemistry for the diagnosis ofependymoma. CD99 is a cell surface antigen expressed in some tumors, most notably in Ewing's sarcomas. In our preliminary experiment, we noted the absence of CD99-immunoreactivity in a fraction of brain tumors with clear cell morphology, including oligodendroglioma, clear cell ependymoma, and pilocytic astrocytoma (the oligodendroglioma-like component). Thus, we investigated the expression of CD99 in an additional series of brain tumors with clear cell morphology, including oligoastrocytoma (7 cases), central neurocytoma (6), and dysembryoplastic neuroepithelial tumor (9). We found that the absence of CD99-immunoreactivity was dependent on clear cell morphology rather than on tumor entities. The CD99-immunohistochemistry is unique in that it is helpful for the diagnosis of clear cell brain tumors through the visualization of CD99-negative clear cells.

Pleomorphic xanthoastrocytoma: a comparative pathological study between conventional and anaplastic types.

AIMS: To facilitate the understanding and correct diagnosis of the anaplastic variant of pleomorphic xanthoastrocytoma (PXA). METHODS AND RESULTS: Twelve cases of PXA were divided into six conventional and six anaplastic types. Three anaplastic PXAs developed in recurrent tumours and three occurred as the primary tumour. Anaplastic PXAs were microscopically characterized by monotonous proliferation of atypical cells, increased mitotic activity, necrosis and microvascular proliferation. Characteristic features of conventional PXA are also variously included in all anaplastic PXAs. No remarkable differences were detected in the immunohistochemical profiles including the neuronal phenotype between the conventional and anaplastic types. Ki67 labelling indices of the anaplastic type were significantly higher than those of the conventional type, whereas p53 showed no difference. Immunohistochemical and fluorescence in situ hybridization analyses on epidermal growth factor receptor did not demonstrate overexpression or gene amplification. CONCLUSIONS: The anaplastic PXA, which occurs de novo or through recurrence, should be distinguished from glioblastoma by identifying the salient microscopic features of conventional PXA even in the anaplastic areas; and by demonstrating the expression of neuronal markers, in that the former is expected to have longer survival.

A neuroepithelial tumor showing combined histological features of dysembryoplastic neuroepithelial tumor and pleomorphic xanthoastrocytoma--a case report and review of the literature.

A neuroepithelial tumor showing combined histological features of dysembryoplastic neuroepithelial tumor (DNT) and pleomorphic xanthoastrocytoma (PXA) is described. The patient was a 60-year-old male with a long-standing temporal lobe tumor and seizures. After a long, dormant period, the tumor, which had been localized in the left uncus, re-grew rapidly and extended into the subarachnoidal space and brain stem. The post-operative specimens disclosed two distinct components: an intra-cortical, cystic lesion containing mucinous materials and an extra-cortical, nodular lesion involving the leptomeninges. The former contained oligodendroglia-like small, round cells placed along axonal processes, plus mature neurons situated against mucinous materials (DNT-like component, WHO Grade I). The latter contained spindle and/or pleomorphic cells expressing glial fibrillary acidic protein, having bizarre nuclei and atypical mitotic figures. A reticulin network was developed among the tumor cells (PXA-like component, WHO Grade III). This case illustrates an unusual composite brain tumor, combined DNT and PXA.

Evaluation of a fully automated system (RAISUS) for rapid identification and antimicrobial susceptibility testing of Staphylococci.

RAISUS is a system for rapid bacterial identification and antimicrobial susceptibility testing. RAISUS and VITEK showed 97.8% and 75.9% agreement in identification of 45 Staphylococcus aureus strains and 58 coagulase-negative staphylococci (CoNS), respectively, and RAISUS and CLSI (formerly NCCLS) methods showed 87.2% and 87.9% agreement in the MICs for S. aureus and CoNS, respectively. RAISUS provided these data within 3.75 h, suggesting its utility for clinical bacteriological laboratories.

Increased circulating endothelial progenitor cells in patients with bacterial pneumonia: evidence that bone marrow derived cells contribute to lung repair.

BACKGROUND: Tissue repair often occurs in organs damaged by various inflammatory diseases including pneumonia. Inflammatory stimuli induce a rapid and massive release of inflammatory cells from the bone marrow. Recent studies have suggested that bone marrow cells have the potential to differentiate into a variety of cell types. It has been shown that administration of lipopolysaccharide (LPS) to murine lungs induces a rapid release of endothelial progenitor cells (EPCs) into the circulation, and that bone marrow derived progenitor cells including EPCs contribute to lung repair after lung injury in mice. This study was undertaken to investigate the mobilisation of EPCs in humans following acute pneumonia. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood taken from 23 patients with pneumonia during both the acute and convalescent phase. 1x10(6) PBMCs were plated on fibronectin coated culture slides and cultured in culture medium for endothelium. The numbers of EPCs were counted 8 days after plating. RESULTS: The number of circulating EPCs significantly increased in patients with pneumonia (p<0.0001). Patients with low EPC counts tended to have persistent fibrotic changes in their lungs even after their recovery from pneumonia. CONCLUSIONS: Inflammatory stimuli induce a rapid release of EPCs into the circulation in humans. A sufficient number of EPCs is necessary for proper lung repair following bacterial pneumonia.

Hemodynamic infarction of the spinal cord: involvement of the gray matter plus the border-zone between the central and peripheral arteries.

OBJECTIVE: Hemodynamic infarction of the spinal cord that affected an 81-year-old female having a dissecting aortic aneurysm is presented. During the graft replacement operation, systemic hypotension occurred and the patient was subsequently complicated with paraplegia of the lower limbs. The patient died 2 weeks after the surgery due to gastrointestinal bleeding. An autopsy, which did not include the brain, was performed and the spinal cord was sampled. The aim of this report is to describe the pathologic profile of the spinal cord of the patient, and to gain insight into the pathogenesis of the lesion. METHODS: Histochemical and immunohistochemical methods were employed to study the spinal cord ranging from the lower thoracic to sacral segments. RESULTS: The whole central areas of the spinal cord showed coagulation and/or liquefaction necroses, while the white matter on the circumference of the cord remained unaffected, thus exhibiting a 'ring-like' appearance. CONCLUSION: This case is an example of hemodynamic infarction of the spinal cord involving the gray matter that is supplied by the central artery, plus the border-zone that is supplied by both the central and peripheral arteries. The former is probably associated with selective vulnerability of the gray matter to ischemia, while the latter is probably associated with intrinsic vulnerability of the border-zone to systemic hypotension or low blood-flow states.

Lipomatous primitive neuroectodermal tumor with a glioblastoma component: a case report.

A case of extracerebellar lipomatous primitive neuroectodermal tumor (PNET) with glioblastoma multiforme (GBM) areas is reported. A 44-year-old woman who had been on antipsychotic agents for schizophrenia complained of hemiparesis and drowsiness. She deteriorated progressively and died 3 months later. The autopsy revealed a huge, ill-defined tumor located from right basal ganglia to brain stem. Microscopically, the tumor consisted of three distinct components: clusters of small primitive cells consistent with PNET, mature lipoma-like islands, and a GBM-like component. Neuronal differentiation in PNET areas was confirmed by the presence of Homer Wright rosette, synaptophysin-positive fibrillary background, and ultrastructural demonstration of neuritic processes. Lipoma-like areas composed of lipidized cells containing large lipid droplets were intimately intermingled and closely related with PNET areas. Furthermore, GBM areas were, although predominantly located in the brain stem, often blended with the previous two components. This component was characterized by glial fibrillary acid protein immunoreactivity of atypical tumor cells and the presence of necrosis and endothelial proliferation. PNET areas with lipomatous differentiation in the present tumor may suggest the morphological and histogenetic similarity to liponeurocytoma, although the neuronal element in the former was anaplastic. The association with a GBM component makes the present tumor a unique, and, to our knowledge, previously unrecognized lesion.

Effects of losartan in combination with or without exercise on insulin resistance in Otsuka Long-Evans Tokushima Fatty rats.

Hypertension often complicates type 2 diabetes mellitus, and angiotensin converting enzyme inhibitor treatment has been shown to improve insulin resistance in such cases. However, the effect of angiotensin II type-1 (AT(1)) receptor antagonists on insulin resistance is still controversial. To gain further information on this effect, we examined the effect of losartan on insulin resistance in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus. Losartan administration alone lowered systolic blood pressure, but did not improve oral glucose tolerance test or insulin resistance in OLETF rats. However, the administration of losartan with exercise significantly improved both systolic blood pressure and insulin resistance relative to control OLETF rats. On the other hand, losartan treatment, regardless of exercise, increased glucose uptake in excised soleus muscle and fat cells. To explore the beneficial effect of losartan on skeletal muscle glucose uptake, we examined intracellular signaling of soleus muscle. Although Akt activity and glucose transporter type 4 (GLUT4) expressions were not affected by losartan with or without exercise, extracellular signal-regulated kinase (ERK1/2) and p38 mitogen-activated protein (MAP) kinase activities were increased by both interventions. These results indicate that angiotensin AT(1) receptor antagonist improved local insulin resistance, but not systemic insulin resistance. These findings may explain the controversy over the effect of angiotensin AT(1) receptor antagonists on insulin resistance in clinical use. The enhancing effect of angiotensin AT(1) receptor antagonist on skeletal muscle glucose uptake may be attributable to MAP kinase activation or other mechanisms rather than phosphatidylinositol 3-kinase activation.

Clinical effect of irinotecan in advanced and metastatic breast cancer patients previously treated with doxorubicin- and docetaxel-containing regimens.

BACKGROUND: Previous phase II trials in Japan suggested that irinotecan was a promising agent for advanced or metastatic breast cancer pretreated with anthracycline. However, irinotecan has not yet been evaluated in the salvage setting for breast cancer pretreated with both anthracycline and taxane, which are two active agents for breast cancer. METHODS: The efficacy and safety of irinotecan were retrospectively evaluated in patients with breast cancer who had previously been treated with both doxorubicin and docetaxel. From 1996 to 1999, irinotecan was administered to 20 patients, all with a performance status of <2. Irinotecan treatment was repeated in approximately 6 week cycles consisting of the administration of irinotecan once weekly for 4 weeks followed by a 2 week rest. The median dose of irinotecan administered was 100 mg/m(2) weekly. The median number of irinotecan cycles given was 1 (range: 1-8 cycles). The median total dose was 388 mg/m(2) (range: 50-2400 mg/m(2)). RESULTS: Performance status declined to >3 after treatment with irinotecan in four patients. Two patients had grade 3 leukopenia; three had grade 3 anemia and one had a creatinine elevation of grade 4. The objective response rate for all patients was 5.0% (95% CI: 0-15.5%). The median time to progression and overall survival were 35 days (range: 17-285 days) and 124 days (range: 17-667 days), respectively, since the start of the administration of irinotecan. CONCLUSIONS: Salvage chemotherapy with irinotecan may be inactive against advanced and metastatic breast cancer pretreated with doxorubicin and docetaxel. We will evaluate irinotecan for advanced and metastatic breast cancer patients as first- or second-line chemotherapy combined with anthracycline or taxane.