Osteosarcoma occurring in osteogenesis imperfecta

We describe a case history of a 24-year-old male with osteogenesis imperfecta (OI) who developed osteosarcoma of the left thigh. High-dose ifosfamide therapy caused marked tumor regression of multiple lung metastases. Immunohistochemically, the tumor cells were diffusely positive for the p53 protein. Mutation of the p53 gene was not detected by direct genomic sequencing of exons 4–8. The radiographic characteristics, including irregularly distributed osteolytic lesions and cortical discontinuity, should not be confused with hyperplastic callus formation, a benign process. A biopsy is critical to establish the differential diagnosis between osteosarcoma and common hyperplastic callus formation in OI; however, it must be applied with great care.     

Presence of apolipoprotein E on extracellular neurofibrillary tangles and on meningeal blood vessels precedes the Alzheimer β-amyloid deposition

The localization of apolipoprotein E (ApoE) has been examined immunohistochemically in the autopsied brains of middle-aged and old-aged control subjects, with and without amyloid protein (A) deposits, and of Alzheimer's disease patients. Senile plaques were consistently labeled with ApoE antiserum even in the very early stage of senile plaque formation seen in the fifth decade. In the cerebellar molecular layer, small dots of ApoE immunoreactivity, which were prominent in the Alzheimer's disease subjects, were observed in addition to immunoreactivity in diffuse plaques. ApoE antisera labeled all of the extracellular neurofibrillary tangles (NFT), whereas only a small minority of extracellular NFT were positive for A. A punctate pattern of ApoE immunoreactivity was seen at the media of the meningeal vessels lacking amyloid, when senile plaques were present in the nearby cortex. In the early stage of amyloid angiopathy, the distribution of ApoE immunoreactivity was much more extensive than that of A positivity. These findings suggest that ApoE accumulates in the early stage of senile plaque formation and, furthermore, that ApoE accumulation precedes A deposition in extracellular NFT and amyloid angiopathy.     

Bone marrow transplantation attenuates murine IgA nephropathy: role of a stem cell disorder

BACKGROUND: The pathogenesis of IgA nephropathy is still obscure. The aim of this study was to investigate whether the fundamental pathogenesis of IgA nephropathy lies in bone marrow stem cells (BMCs). METHODS: We used donors of two different strains for bone marrow transplantation (BMT) into mice with a high content of serum IgA (ddY strain, HIGA mice), a murine model of IgA nephropathy. One group (B6-->HIGA, N = 5) received BMCs of C57BL/6j (B6) mice, and the other (HIGA-->HIGA, N = 8) were reconstituted with BMCs of HIGA mice. RESULTS: Twenty-six weeks after BMT, in B6-->HIGA mice, mesangial deposits of IgA and C3 were statistically milder than those in HIGA-->HIGA mice. Light microscopic observations disclosed that glomerular sclerosis and mesangial matrix expansion in B6-->HIGA mice were decreased compared with those in HIGA-->HIGA mice. These B6-->HIGA mice also excreted less urinary albumin than HIGA-->HIGA mice. Furthermore, serum levels of IgA in B6-->HIGA mice were markedly lower than those in HIGA-->HIGA mice. Size analysis of serum IgA revealed that macromolecular IgA were notably lower in B6-->HIGA mice than in HIGA-->HIGA mice. CONCLUSIONS: Our results suggest that qualitative and quantitative changes of serum IgA are determined at the level of stem cells, and that BMT from normal donors can attenuate glomerular lesions in HIGA mice. This approach may offer a new avenue to study the pathogenesis of IgA nephropathy.     

Increased levels of urinary interleukin-6 in Kawasaki disease

Kawasaki disease (KD) often presents with abnormal urinary findings, such as aseptic pyuria, mild proteinuria and microscopic haematuria. In this study, we measured urinary interleukin-6 (IL-6) by a sensitive sandwich ELISA assay using mouse monoclonal antibodies against recombinant IL-6 to elucidate the role of IL-6 in the pathogenesis of renal lesions in KD. Serum IL-6 levels were increased in acute KD as well as in febrile controls. Importantly, urinary IL-6 levels were consistently elevated in patients with acute KD, but much lower in febrile controls. Urinary IL-6 levels returned steadily to normal during the convalescent phase. In addition to IL-6, urinary levels ofN-acetyl--d-glucosaminidase (NAG) and ₂-microglobulin (₂-mg) were also elevated during the acute phase of this disease. Eosinophils and macrophages were identifiable in urinary sediments from these patients. The increased levels of urinary IL-6 in combination with increased NAG and ₂-mg seemed to suggest the presence of certain renal parenchymal lesions with cellular infiltration during the acute phase of the disease. IL-6 may serve as clinically useful parameter for the detection and monitoring of the renal involvement in KD.     

Metabolism-based inactivation of neuronal nitric-oxide synthase by components of cigarette and cigarette smoke.

It has been shown that administration of cigarette smoke to rats leads to loss of neuronal nitric-oxide synthase (nNOS) activity and nNOS protein in penile tissue. The exact mechanism for this loss of activity and protein is not known. In the current study, we investigated whether extracts prepared from cigarette smoke or from the cigarette itself could directly inhibit nNOS activity. We discovered that the cigarette smoke extract and the cigarette extract cause a time-, concentration-, and calmodulin-dependent inactivation of nNOS in an in vitro system containing the purified enzyme. L-Arginine, but not D-arginine, protects nNOS from this time-dependent inactivation, suggesting an active site directed event. The kinetics of inactivation are consistent with the metabolism-based or suicide inactivation of nNOS. Based on studies with other metabolism-based inactivators, this cigarette-mediated inactivation may render nNOS more susceptible to proteasomal degradation and thereby may explain the loss of nNOS protein in vivo. The component(s) responsible for nNOS inactivation is not volatile, is not retained by a 3,000 molecular weight cut-off membrane, binds to activated charcoal, and is highly water-soluble under both acidic and basic conditions. The discovery of a direct inactivation of nNOS by an organic, cationic compound(s) present in tobacco and tobacco smoke provides a basis for further study of not only the mechanisms responsible for the biological effects of tobacco but also a search for a potentially novel inactivator of nNOS.     

Significant antitumoral activity of cationic multilamellar liposomes containing human IFN-beta gene against human renal cell carcinoma.

PURPOSE: Immunotherapy is the most effective treatment against metastatic renal cell carcinoma (RCC). However, the response rate is approximately 15%. More effective therapy is, therefore, needed for patients with metastatic RCC. We then examined the antitumor effect of cationic multilamellar liposome containing human IFN-beta (huIFN-beta) gene (IAB-1) against RCC. EXPERIMENTAL DESIGN: Concentrations of huIFN-beta protein were measured by ELISA. The cytotoxicity of IAB-1 against human RCC (NC65, ACHN, and freshly isolated RCC cells), prostate and bladder cancer cell lines, and renal proximal tubule endothelial cells (RPTEC5899) was examined by the colorimetric method using tetrazolium salt. Apoptosis was assessed by the acridine-orange staining. For in vivo study, we used NC65 cells inoculated into severe combined immunodeficiency mouse. RESULTS: The RCC cells treated with IAB-1 secreted significant amounts of huIFN-beta protein continuously. Drastic in vitro cytotoxic effect of IAB-1 against RCC was observed. In contrast, treatment with 1000 IU/ml recombinant huIFN-beta protein resulted in weak cytotoxicity. The cytotoxic effect against prostate and bladder cancer cell lines was less than that against RCC. Furthermore, no significant cytotoxicity was observed in RPTEC5899 cells. Apoptosis was observed in the cells treated with IAB-1, but recombinant huIFN-beta failed to induce apoptosis. The size of NC65 tumors transfected with IAB-1 in mice was significantly smaller than that receiving injection of empty liposome or recombinant huIFN-beta protein. CONCLUSION: These findings indicate that IAB-1 may have an antitumor activity against human RCC by inducing apoptosis, suggesting its potential clinical application for gene therapy against RCC.     

Alteration of p53 Clonality Accompanying Colorectal Cancer Progression

The aim of this study was to clarify whether or not the status of gene alteration is heterogeneous in intramucosal carcinoma and homogeneous within invasive carcinoma. We selected 10 colorectal carcinoma cases (1 mucosal, 5 submucosal and 4 advanced carcinomas including 2 cases with lymph node metastasis) and analyzed the p53 gene sequence. Six colorectal cancers in this study showed heterogeneity in p53 mutations in cells from the intramucosal part. In the invasive part of a carcinoma, p53 mutation status was homogeneous intratumorally in all cases. These data indicate that, in regard to p53 gene alterations, colorectal cancers can be composed of various subclones when limited to the mucosa, but clonal selection occurs when one of these subclones commences invasion to the submucosa, generating a monoclonal invasive carcinoma.     

Carcinoma of the cervix: Value of dynamic magnetic resonance imaging in assessing early stromal invasion

Background The purpose of this study was to assess the accuracy of contrast-enhanced magnetic resonance imaging (dynamic MR imaging) in the evaluation of preinvasive and early invasive cancer of the cervix. Methods Twenty-nine women with untreated squamous cell carcinoma of the cervix with either no stromal invasion or early stromal invasion underwent pretreatment MR imaging and dynamic MR imaging within 4 weeks of surgical evaluation. The images were evaluated for tumor detection and compared with results of histologic examination of the surgical specimens. Results The lesions in 17 cases with histologically proven stromal invasion of 4 mm or greater were detected with dynamic MR imaging, whereas lesions in only 8 of these cases were detected with T2 imaging. In 9 cases with stromal invasion between 4.0 mm and 5.0 mm, lesions were represented as early phase focal enhancement on dynamic MR images, but not detected on T2-weighted images. In the 12 cases with less than 4 mm stromal invasion, no lesions were visualized on either T2-weighted images or dynamic MR images, except in 1 case of glandular involvement without stromal invasion that appeared as enhancement on early-phase dynamic MR imaging. Conclusion Dynamic MR imaging detected more lesions of early stromal invasion in pretreatment imaging for cervical cancer than nonenhanced MR imaging.