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Although interleukin-33 (IL-33), a member of the IL-1 cytokine family, plays proinflammatory roles in immune cells as an "alarmin," little is known regarding the biological actions of IL-33 on vascular endothelial cells. To investigate the effects of IL-33 on vascular endothelial cells, we first screened the IL-33-regulated proteins in human umbilical vein endothelial cells (HUVECs) using a dot blot array and observed that IL-33 markedly increased growth-regulated oncogene-α (GRO-α), a chemokine that is also known as chemokine (C-X-C motif) ligand 1 (CXCL1). Real-time reverse transcription PCR and ELISA demonstrated that IL-33 induced GRO-α expression and secretion in HUVECs in a dose- and a time-dependent manner. Western immunoblot assay revealed that IL-33 activated the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun NH2-terminal kinase (JNK). In addition, translocation of nuclear factor-κB (NF-κB) p65 to the nucleus of HUVECs was observed by IL-33 stimulation. Furthermore, treatment with pharmacological inhibitors against ERK1/2 (PD98059), JNK (SP600125), or NF-κB (BAY11-7085) significantly suppressed IL-33-induced GRO-α gene expression and secretion from HUVECs. Moreover, immunohistochemical staining demonstrated that IL-33 and GRO-α coexpressed in the endothelium of human carotid atherosclerotic plaque. Taken together, the present study indicates that IL-33 localized in the human atherosclerotic plaque increases GRO-α mRNA expression and protein secretion via activation of ERK1/2, JNK, and NF-κB in HUVECs, suggesting that IL-33 plays an important role in the pathophysiology and development of atherosclerosis.

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We used a computational strategy, in vivo morphometry, to evaluate structural magnetic resonance (MR) images to investigate individual variations in the location of the central sulcus (CS). To locate the CS we identified six key points on individual brain images obtained from 40 normal subjects and measured the distances between these points along the brain circumference. We also analyzed the difference between the actual location of the CS and the location predicted by conventional estimation methods. Individual variation exceeded 2.7 cm for all measurements used to identify the location of the CS. The margin of error was approximately 2.7 cm even when the location of the CS was predicted by reported and commonly used methods. A "1 inch error" should be taken into consideration when the prediction relies solely on head circumference and surface measurements. Our results point to the importance of pre-surgical planning using individual brain images for each patient.

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Intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) play critical roles in mediating monocyte adhesion to the vascular endothelium and monocyte migration into the subendothelial regions of the vessels. Inasmuch as cardiotrophin-1 (CT-1), an IL-6-type cytokine, was expressed in human atherosclerotic plaque, we examined whether CT-1 induces monocyte adhesion and migration by stimulating gene and protein expressions of ICAM-1 and MCP-1 in human aortic endothelial cells (HAECs). Immunocytochemistry revealed that CT-1 increased intensity of ICAM-1 and MCP-1 immunoreactivity in HAECs. Adhesion assay and chemotaxis assay revealed that CT-1 increased human monocytic THP-1 cell adhesion to HAECs and promoted chemotaxis in THP-1 cells, which were attenuated by anti-ICAM-1 and anti-MCP-1 antibody, respectively. Western blot analysis showed that CT-1 increased phosphorylation of ERK1/2 MAP kinase, p38 MAP kinase, and Akt and that their inhibitors, PD-98059, SB-203580, and LY-294002, respectively, inhibited phosphorylation. RNase protection assay and ELISA demonstrated that CT-1 increased gene and protein expressions of ICAM-1 and MCP-1. EMSA revealed that CT-1 enhanced NF-kappaB DNA-binding activity. CT-1-mediated upregulation of ICAM-1 and MCP-1 was suppressed by PD-98059, SB-203580, LY-294002, and parthenolide. The present study demonstrates that CT-1 promotes monocyte adhesion and migration by stimulating ICAM-1 and MCP-1 through mechanisms that involve ERK1/2 MAP kinase, p38 MAP kinase, phosphatidylinositol 3-kinase, and NF-kappaB pathways and suggests that CT-1 plays an important role in the pathophysiology of vascular inflammation and atherosclerosis.

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Medulloblastomas are highly lethal tumors when they recur. Very few patients survive with conventional treatment. This report documents the preliminary study results of a treatment for recurrent medulloblastomas consisting of stereotactic radiation therapy (SRT) with chemotherapy. Four patients had local recurrence without apparent metastases and 8 patients had metastases with or without local recurrence. Twelve patients with 18 lesions underwent SRT as a single session (n=8) or in a hypofractionated manner (n=10) using a gamma knife or modified linear accelerator. All patients then received systemic chemotherapy. Five patients were treated with one to two sequential courses of high-dose chemotherapy with peripheral blood stem cell transplantation. The reduction in tumor size after SRT was often remarkable. Fourteen of 18 lesions treated disappeared 1-6 months after SRT. Two of 4 patients who had local recurrences without apparent metastasis at the time of SRT are alive without evidence of disease 70 and 72 months after SRT, respectively. In contrast, all 8 patients with metastasis had new lesions either in the spinal canal or on the surface of the brain outside the target area of SRT. Median progression-free survival and overall survival from the time of SRT were 9 and 19 months, respectively. The Kaplan-Meier estimates of PFS and overall survival at 3 years were 17 and 25%, respectively. One patient had brainstem edema after SRT causing bulbar palsy and quadriparesis. One patient died of toxicity of chemotherapy. Our experience suggests that local recurrence can be controlled by SRT with chemotherapy but survival of patients with metastases can not be improved effectively by SRT in conjunction with aggressive chemotherapy.

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Few autopsy cases of sudden death in renal transplant recipients have been reported in the literature. The present case was a 50-year-old female recipient of a living-related renal transplant, who died suddenly after a good post-transplant course of 14 years. The patient was admitted in December 2000 for detailed investigation for ascites, and died unexpectedly 1 month later. She complained of mild dyspnoea approximately 3 h before death. Detailed clinical and laboratory investigations after admission showed no malignant findings in the abdominal cavity. Postmortem pathological examination also showed no tumour in the abdominal cavity. Both lungs were pneumatized. Histopathological examinations revealed metastatic calcification. Calcification was observed in the heart, lungs, kidney graft and pancreas. Calcification in the heart was found in the central fibrous body surrounding the atrioventricular node and bundle of His, as well as in the origin of bifurcating bundle. In the myocardial fibres, fibre rupture and waviness were observed. Although these findings may indicate agonal changes, they might also be a consequence of sudden cardiac death. This patient was in a state of renal failure, which presumably caused metastatic calcification involving also the cardiac conduction system. This calcification might partially account for the sudden death.

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