A nationwide survey of pediatric acquired demyelinating syndromes in Japan.

OBJECTIVE: To investigate the clinical and epidemiologic features of pediatric acquired demyelinating syndromes (ADS) of the CNS in Japan. METHODS: We conducted a nationwide survey and collected clinical data on children with ADS aged 15 years or younger, who visited hospitals between 2005 and 2007. RESULTS: Among 977 hospitals enrolled, 723 (74.0%) responded to our inquiries and reported a total of 439 patients as follows: 244 with acute disseminated encephalomyelitis (ADEM), 117 with multiple sclerosis (MS), 14 with neuromyelitis optica (NMO), and 64 with other ADS. We collected and analyzed detailed data from 204 cases, including those with ADEM (66), MS (58), and NMO (10). We observed the following: (1) the estimated annual incidence rate of pediatric ADEM in Japan was 0.40 per 100,000 children (95% confidence interval [CI], 0.34-0.46), with the lowest prevalence in the north; (2) the estimated prevalence rate of MS was 0.69 per 100,000 children (95% CI, 0.58-0.80), with the lowest prevalence in the south; (3) NMO in Japan was rare, with an estimated prevalence of 0.06 per 100,000 children (95% CI, 0.04-0.08); and (4) the sex ratio and mean age at onset varied by ADS type, and (5) male/female ratios correlated with ages at onset in each ADS group. CONCLUSIONS: Our results clarify the characteristic clinical features of pediatric ADS in the Japanese population.

Analysis of MxA, IL-4, and IRF-1 genes in Filipino patients with subacute sclerosing panencephalitis.

BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a chronic and debilitating disease of the central nervous system caused by a latent measles virus infection. Three candidate genes, MxA, IL-4, and IRF-1 genes were shown to be associated with SSPE in Japanese patients. These genes have been suggested to play a role in the establishment of persistent viral infection in the central nervous system. SUBJECTS AND METHODS: Sixty Filipino SSPE patients and 120 healthy control subjects were included in the study. Single nucleotide polymorphisms at promoter regions ( IL-4-590C/T and MXA-88G/T) were screened using PCR-RFLP method. Genotyping was done for GT repeat polymorphism within intron 7 of IRF-1. RESULTS: The TT genotype of MXA, as well as the CT genotype of IL-4, were seen a little more frequently among the SSPE patients as compared to the control subjects. The values though, did not reach statistical significance. IRF-1 analysis did not differ between the two groups. CONCLUSION: Our study failed to demonstrate a significant association between IL-4, MXA, or IRF-1, and SSPE in the Filipino population. Our results might be explained by a greater contribution of environmental factors such as the socio-economic and nutritional factors in the susceptibility of Filipinos to SSPE other than genetic factors.

Persistent diffusion abnormalities in the brain stem of three children with mitochondrial diseases.

We report 2 children (patients 1 and 2) with Kearns-Sayre syndrome and 1 (patient 3) with Leigh syndrome, who underwent serial diffusion-weighted MR imaging (DWI) studies for 2.8 (patient 1), 4.2 (patient 2), and 1.0 years (patient 3). The DWI revealed the persistent hyperintense signals in the pontine and mesencephalic tegmenta. The apparent diffusion coefficient in the affected regions remained constantly low, suggesting that cytotoxic edema and spongiform degenerations may compose these brain stem lesions.

Functional MxA promoter polymorphism associated with subacute sclerosing panencephalitis.

BACKGROUND: The antivirally active MxA protein is induced by interferon (IFN) alpha/beta and inhibits the replication of single-stranded RNA viruses including measles virus (MV). The authors investigated whether the MxA gene contributed to the development of subacute sclerosing panencephalitis (SSPE) in Japanese individuals. METHODS: Single-nucleotide polymorphisms (SNP) in the promoter region of the MxA gene were screened, association studies were performed between two SNP and SSPE, and then a functional difference in the promoter activities of the two SNP was investigated by a dual luciferase reporter assay. RESULTS: Four SNP were found (-88 G/T, -123 C/A, -200 T/C, and -213 G/T), and SSPE patients exhibited a higher frequency of both the -88T allele and the -88TT genotype than controls (p = 0.040 and 0.003). The IFN-induced up-regulation of the MxA promoter activity of the sequence with -88T was found to be significantly higher than that with G. CONCLUSIONS: MxA promoter -88 G/T SNP may confer host genetic susceptibility to SSPE in Japanese individuals. The finding that homozygotes of the MxA -88T allele with a high MxA-producing capability were more frequently seen in SSPE patients suggests that the MxA protein promotes the establishment of persistent MV infection of neural cells.

Macrophage infiltration correlates with tumor stage and angiogenesis in human malignant melanoma: possible involvement of TNFalpha and IL-1alpha.

We examined whether macrophage infiltration is associated with angiogenesis in cutaneous melanoma. The numbers of macrophages and microvessels increased significantly with increasing depth of tumor and with tumor angiogenesis. Macrophage infiltration thus appeared to provide a useful diagnostic marker for the progression of cutaneous melanoma. We further examined whether human melanoma cells produce angiogenic factors in response to macrophage-derived cytokines, tumor necrosis factor alpha (TNFalpha) and interleukin-1 alpha (IL-1alpha). Treatment of melanoma cells with TNFalpha and IL-1alpha in vitro enhanced the production of interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF), and of basic fibroblast growth factor (bFGF) to a lesser degree, in human melanoma cells. Lipopolysaccharide (LPS)-activated human monocytes enhanced production of IL-8, VEGF, TNF alpha, as well as IL-1alpha, but not bFGF. Co-culture of human monocytes and human melanoma cells was also found to significantly enhance production of IL-8 and VEGF in the absence and presence of LPS, compared with either monocytes or melanoma cells alone. The production of IL-8 and VEGF from co-cultured melanoma cells and LPS-activated monocytes was blocked when anti-TNF-alpha antibody or anti-IL-1alpha antibody was co-administrated. This is direct evidence that production of the potent angiogenic factors IL-8 and VEGF from melanoma cells is up-regulated through TNFalpha and/or IL-1alpha secreted by activated monocytes/macrophages, influencing both tumor growth and angiogenesis in melanomas.

Biological implications of macrophage infiltration in human tumor angiogenesis.

Tumor angiogenesis is believed to be induced by increased production of angiogenic factors and decreased production of angiogenic inhibitors by cancer cells, vascular endothelial cells, and other stromal cell types. Most solid tumor cells are surrounded by stroma comprising interstitial connective tissue, blood vessels, fibroblastic cells, etc. Interaction between the stroma and malignant cells appears to have a critical role in the development of tumor neovasculature. We focused on macrophages, which demonstrate wide heterogeneity in biological function and have an essential role in tumor angiogenesis. Macrophages are terminally differentiated cells which produce a number of potent angiogenic cytokines and growth factors such as vascular endothelial growth factor, tumor necrosis factor-alpha, interleukin-8, and basic fibroblast growth factor. They also modulate events in the extracellular matrix through the secretion of extracellular matrix-degrading enzymes and -modulating enzymes. Thus macrophages could influence various stages of angiogenesis either positively or negatively. We found a close correlation between increased macrophage index, malignancy, and high vascular grade in malignant melanoma, and present a model for the possible involvement of activated macrophages in neovascularization in human malignant melanoma.

Novel biological functions of interleukin-4: formation of tube-like structures by vascular endothelial cells in vitro and angiogenesis in vivo.

The effect of interleukin-4 (IL-4) on angiogenesis was studied in vitro and in vivo. Human recombinant IL-4 significantly stimulated the formation of tube-like structures in collagen gels by bovine aortic endothelial cells as well as by human microvascular endothelial cells. Human recombinant IL-4 at 50-500 U/ml stimulated by about two- to threefold the formation of tubes by bovine aortic endothelial cells; the rate was comparable to that of basic fibroblast growth factor. Tube formation was almost completely inhibited by the addition of IL-4 receptor neutralizing antibody. Administration of rat recombinant IL-4 led to neovascularization when implanted in the rat cornea. Findings suggest that IL-4 may be a mediator of the immune system as well as an inducer of angiogenesis.

[Changes of periodontal vasculature and alveolar bone on the occlusal trauma].

Of the researches on periodontal diseases, the changes occurred in the vasculature of peridontal membrane and the surrounding alveolar bone there-to-fore attracts much attention. In order to induce an experimental occlusal trauma, composite resin was added on the occlusal surfaces of mandibular second and third premolars of dogs to raise the bite for a period of time, followed by injection of methacrylate resin (MERCOX) into inferior alveolar artery and dissolution of soft tissues by protainase and examined under the scanning electron microscope (SEM, JEOL 35 C). The results are as follows: After 14 days, a wide range of avascularized area was observed on resin cast of periodontal membrane. The surface of alveolar bone on which the vasculature disappeared did not show resorption process. However, the surface of alveolar bone next to the periodontal vasculature showed undergoing a direct bone resorption. After 30 days, the vasculature of periodontal membrane underwent a morphological change and turned out to appear as a mesh-like vascular network. Certain avascularized regions was observed over the alveolar bone on margin region and cervical region, and it was circumscribed by a vasculature with glomerule-like loops. This vasculature was suspected originating from underlying alveolar bone marrow and connected with the residual vasculature of periodontal membrane. After 60 days, vasculature of periodontal membrane facing teeth appeared quite resemblance with that of health periodontal membrane. Those next to the alveolar bone, however, showed enlargement. In this period, avascularized area was not observed. After 90 days, the vasculature in periodontal membrane lost its original two-layered arrangement and replaced by the irregular arrayed bundle-like vasculature. Longitudinally arrayed mesh like vasculature was observed in certain region of periodontal vasculature. After 180 days, bundle-like vessels arrayed as an ellipse pattern. Also, resorption process could be observed on the surface of alveolar bone and interradicular septum. Experimental study of occlusal trauma on dentition clearly indicated that teeth were showed a mobility in vertical direction and that the vasculature of periodontal membrane were showed depression and elongation for a period of time. It could not show an apposition where were showed by the experimental depression and elongation, so it was only showed the expansible periodontal membrane space by resorption of alveolar bone.