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.

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.

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.

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.

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.

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.

Microglial activation parallels system degeneration in progressive supranuclear palsy and corticobasal degeneration.

The role of microglia in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) is unknown. To address this issue we examined 10 cases of PSP, 5 cases of CBD, and 4 normal controls. Microglial and tau burdens were determined with image analysis on brain sections that had been immunostained with monoclonal antibodies to HLA-DR and phospho-tau. We found that microglial activation was greater in PSP and CBD than normal controls, and that the microglial burden correlated with the tau burden in most areas. There were distinct patterns of microglial activation and tau pathology in PSP and CBD, with PSP showing more pathology in infratentorial structures and CBD showing more pathology in supratentorial structures. These results support the notion that PSP and CBD are distinct clinicopathologic entities. Microglial activation was not well correlated with tau pathology in the brainstem of PSP, which suggests that brainstem pathology in PSP is not exclusively due to tau pathology. While the results do not necessarily support a direct causal link between microglial activation and neurodegeneration in PSP or CBD, they nevertheless suggest that microglia play a role in disease pathogenesis.

A qualitative and quantitative study of grumose degeneration in progressive supranuclear palsy.

Grumose degeneration (GD) of the dentate nucleus is a common feature in progressive supranuclear palsy (PSP), but its pathogenesis has not been well studied, and its clinical significance remains unknown. This report describes a quantitative study of GD in 9 cases of PSP using image analysis with single- and double-immunolabeling, as well as histochemical stains for myelin and axons. GD was associated with demyelination, axonal loss, glial tau pathology, and microgliosis in regions juxtaposed to the dentate nucleus (DN). Specifically, demyelination and microgliosis were prominent in the superior cerebellar peduncle (SCP), dentate hilus, and cerebellar hemispheric white matter. Tau pathology and microgliosis were less prominent in the DN itself. The degree of myelin loss correlated with the tau burden in the SCP. GAP-43, which is a phosphoprotein known to be involved in axonal growth and sprouting, was decreased in the DN of PSP, and the degree of GAP-43 loss correlated with severity of GD. These results suggest that GD may be related to progressive pathology in the dentatorubrothalamic tract as well as the cerebellar hemispheric white matter, and that GD may be a consequence of concurrent degeneration in both output from and input to the DN. The results further suggest a possible role for oligodendroglial and myelin pathology in the pathogenesis of PSP.

The effects of vinblastine on the expression of human immunodeficiency virus type 1 long terminal repeat.

Previous work by our group has demonstrated induction of the HIV-LTR following exposure of cells to various DNA-damaging agents such as ultraviolet (UV) light, cisplatin, and doxorubicin. The current experiments were designed to determine the relative effects of the anti-mitotic drug vinblastine on expression of the HIV-LTR. Using human cervical carcinoma (HeLa) cells stably transfected with the chloramphenicol acetyl transferase (CAT) reporter transcriptionally driven by the HIV-LTR promoter, we demonstrated a 9-10-fold induction at 48-72 h following vinblastine treatment. Previous experiments had demonstrated repression of cisplatin or doxorubicin-mediated HIV induction by treatment with salicylic acid. The vinblastine induction also was repressed by salicylic acid treatment, but not by treatment with indomethacin, suggesting a role for the NF kappa B pathway in the inductive response. When UV exposure was coupled to the vinblastine treatment, there was no additive or synergistic effect evident, suggesting similar paths of induction between the two agents. Northern blots demonstrated that these agents were operating at the level of transcription and that salicylic acid inhibited vinblastine-mediated induction of HIV-LTR-CAT mRNA only if administered at the same time as vinblastine; addition of salicylic acid 2 h later had no effect on transcript accumulation. All combinations of treatments with vinblastine and/or salicylic acid markedly reduced cell survival.

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.

The effects of histamine H3-receptor antagonists on amygdaloid kindled seizures in rats.

The effects of histamine H3-receptor antagonists, thioperamide, and clobenpropit on amygdaloid kindled seizures were investigated in rats. Both intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) injections of H3-antagonists resulted in a dose-related inhibition of amygdaloid kindled seizures. An inhibition induced by thioperamide was antagonized by an H3-agonist [(R)-alpha-methylhistamine] and H1-antagonists (diphenhydramine and chlorpheniramine). On the other hand, an H2-antagonist (cimetidine and ranitidine) caused no antagonistic effect. Metoprine, an inhibitor of N-methyltransferase was also effective in inhibiting amygdaloid kindled seizure, and this effect was augmented by thioperamide treatment.

Histaminergic mechanisms in amygdaloid-kindled seizures in rats.

The present study was undertaken to clarify the role of histaminergic neuron system on amygdaloid kindled seizures in rats. A significant decrease in histamine contents in the amygdala was observed after development of amygdaloid kindling. Histidine and metoprine inhibited amygdaloid kindled seizures at doses causing an increase in histamine contents of the brain. H1-antagonists (diphenhydramine and chlorpheniramine) attenuated histidine-induced inhibition of amygdaloid kindled seizures, however no significant antagonism was observed with H2-antagonists (zolantidine and ranitidine). The development of amygdaloid kindling was retarded by repeated administration of histidine. These findings suggest that histaminergic mechanisms play a suppressive role in amygdaloid kindled seizures through histamine H1-receptors.

Sporeamicin A, a new macrolide antibiotic. I. Taxonomy, fermentation, isolation and characterization.

Sporeamicin A, a novel antibiotic, was isolated from the culture filtrate of an actinomycete. The producing organism, strain L53-18, was taxonomically assigned as a species of the genus Saccaropolyspora. The antibiotic was extracted with chloroform and was then purified by crystallization. It was obtained as colorless prisms from ethanolic solutions. Sporeamicin A exhibited a strong UV absorption peak at 276 nm. The molecular formula of sporeamicin A was determined to be C37H63NO12.

Sporeamicin A, a new macrolide antibiotic. II. Structure determination.

Structure of a novel antibiotic, sporeamicin A (SRM-A), was determined by a combination of spectroscopic and X-ray crystallographic studies. SRM-A has a unique structure containing a 2,3-dihydro-3-oxofuran moiety as part of a 14-membered macrolide ring.

Sporeamicin A, a new macrolide antibiotic. III. Biological properties.

Sporeamicin A is a new erythromycin-type antibiotic isolated from a species of Saccharopolyspora. It was active in vitro against a wide variety of Gram-positive bacteria. In vitro studies indicated that the sporeamicin A was stable in the presence of human serum, although it was bound to serum proteins. Sporeamicin A was effective in the mouse protection test against Staphylococcus aureus, Streptococcus pyogenes and Streptococcus pneumoniae. Sporeamicin A attained higher plasma and tissue levels in the rat than did erythromycin stearate.