Risk factors accelerating cerebral degenerative changes, cognitive decline and dementia

OBJECTIVES: Factors accelerating cerebral degenerative changes represent potentially modifiable risks for cognitive decline. Putative risk factors accelerating subtle cognitive decline and dementia were correlated with repeated measures of cerebral atrophy, CT densitometry, perfusions and cognitive testing among neurologically and cognitively normative ageing volunteers. METHODS: Two hundred and twenty-four normative subjects at increased risk for cognitive decline were admitted to the study. Mean entry age was 59. 5+/-15.8 years. Mean follow-up is 4.3+/-3.1 years. At follow-up, 22 developed subtle cognitive decline (deltaCCSE>/=-3), 19 became demented, eight with vascular type (VAD) and 11 with Alzheimer's type (DAT) and 183 remain cognitively unchanged. Standardized questionnaires, medical, neuropsychological, neurological and blood work examinations were obtained. Cerebral atrophy, tissue densities and perfusions were measured by xenon-enhanced CT. RESULTS: After age 60, cerebral atrophy, ventricular enlargement, polio- and leuko-araiosis geometrically increased as perfusions declined. Risk factors accelerating perfusional decline, cerebral atrophy, polio-araiosis and leuko-araiosis (thinning of grey-white matter densities) were: transient ischaemic attacks (TIAs), hypertension, smoking, hyperlipidemia, male gender. At age 71.5+/-11.9, subtle cognitive decline began, accelerated by TIAs, hypertension and heart disease. Leuko-araiosis began before cognitive decline. TIAs, hypertension and hyperlipidemia correlated with VAD. Excessive cortical perfusional decreases and cerebral atrophy correlated with cognitive decline. Family history of neurodegenerative disease correlated with DAT. CONCLUSION: TIAs, hypertension, hyperlipidemia, smoking and male gender accelerate cerebral degenerative changes, cognitive decline and dementia.     

Occurrence of the diffuse amyloid beta-protein (Abeta) deposits with numerous Abeta-containing glial cells in the cerebral cortex of patients with Alzheimer's disease

Diffuse amyloid beta-protein (Abeta) deposits with numerous glial cells containing C-terminal Abeta fragments occur in the cerebral cortex of patients with Alzheimer's disease. By using a panel of antibodies specific for various epitopes in the Abeta peptide, we have investigated the immunohistochemical nature of the diffuse Abeta deposits. The extracellular material contains Abeta with a C-terminus at residue valine40 (Abeta40) as well as residues alanine42/threonine43 (Abeta42). The N-termini include aspartate1, pyroglutamate3, and pyroglutamate11, with pyroglutamate3 being dominant. Microglia and astrocytes in and around these deposits contain intensely staining granules. Most of these granules are negative for antibodies to the N-terminally located sequences of Abeta. These include 6E10 (Abeta1-17), 6F/3D (Abeta8-17), and the N-terminal antibodies specific to aspartate1, pyroglutamate3, and pyroglutamate11. The C-termini of intraglial Abeta are comparable with those of the extracellular deposits. The microglia and astrocytes have quiescent morphology compared with those associated with senile plaques and other lesions such as ischemia. Complement activation in these deposits is not prominent and often below the sensitivity of immunohistochemical detection. Although factors which may cause this type of deposit remain unclear, lack of strong tissue responses suggests that these deposits are a very early stage of Abeta deposition. They were found only inconsistently and were absent in a number of cases examined in this study. Further analysis of these deposits might provide important clues regarding the accumulation and clearance of Abeta in Alzheimer's disease brain.     

Radiological states around the Kraton-4 underground nuclear explosion site in Sakha

A radiological survey around the site of Kraton-4, an underground nuclear explosion (Yield of 20 kt, depth of 560 m, 1978) in Sakha was carried out in March 1998. Gamma survey and in-situ spectroscopy on the ground exhibited quite normal levels: a dose rate of 0.022 microSv/h and Cs-137 surface contamination of less than 1.1 kBq/m2 around the hypocenter. The results suggested no remarkable leakage of radioactivity from the epicenter to the ground surface at least not for non-rare gas elements as of 1998.     

ATP-Dependent efflux of CPT-11 and SN-38 by the multidrug resistance protein (MRP) and its inhibition by PAK-104P

Non-P-glycoprotein-mediated multidrug-resistant C-A120 cells that overexpressed multidrug resistance protein (MRP) were 10.8- and 29. 6-fold more resistant to 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and SN-38, respectively, than parental KB-3-1 cells. To see whether MRP is involved in CPT-11 and SN-38 resistance, MRP cDNA was transfected into KB-3-1 cells. The transfectant, KB/MRP, which overexpressed MRP, was resistant to both CPT-11 and SN-38. 2-[4-Diphenylmethyl)-1-piperazinyl]ethyl-5-(trans-4,6-dimethyl-1,3 , 2-dioxaphosphorinan-2-yl)-2, 6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate P-oxide (PAK-104P) and MK571, which reversed drug resistance in MRP overexpressing multidrug-resistant cells, significantly increased the sensitivity of C-A120 and KB/MRP cells, but not of KB-3-1 cells, to CPT-11 and SN-38. The accumulation of both CPT-11 and SN-38 in C-A120 and KB/MRP cells was lower than that in KB-3-1 cells. The treatment with 10 microM PAK-104P increased the accumulation of CPT-11 and SN-38 in C-A120 and KB/MRP cells to a level similar to that found in KB-3-1 cells. The ATP-dependent efflux of CPT-11 and SN-38 from C-A120 and KB/MRP cells was inhibited by PAK-104P. DNA topoisomerase I expression, activity, and sensitivity to SN-38 were similar in the three cell lines. Furthermore, the conversion of CPT-11 to SN-38 in KB-3-1 and C-A120 cell lines was similar. These findings suggest that MRP transports CPT-11 and SN-38 and is involved in resistance to CPT-11 and SN-38 and that PAK-104P reverses the resistance to CPT-11 and SN-38 in tumors that overexpress MRP.     

Adhesion molecules involved in pleural dissemination of esophageal cancer cells

Pleural dissemination is a common cause of recurrence after surgery of patients with esophageal cancer. Very little is known about the biochemical processes involved in the initial attachment of cancer cells to pleural mesothelial cells. The authors conducted in vitro and in vivo studies to assess the role of adhesion molecules in this process, using 2 cell lines derived from human esophageal cancer. TE-1 cells, which pronouncedly express CD44H, adhered to the monolayers of mesothelial cells more firmly than T.Tn cells. On the other hand, the adhesion of TE-I cells to mesothelial cells was markedly inhibited by antibodies to CD44H or the beta(1) integrin subunit, and more strongly blocked by using a combination of the two antibodies. These antibodies inhibited the dissemination of TE-1 cells in the pleural cavity of nude mice. The findings suggest that CD44 and integrin play important roles in the initial attachment of esophageal cancer cells to mesothelial cells.     

Chronic hypertension induced by streptozotocin in rats

Summary An intravenous injection of 40 or 65 mg/kg streptozotocin induced not only diabetes but also severe hypertension in rats. Whereas the hyperglycemia developed fully within a few days after the injection of streptozotocin, the hypertension progressively advanced and reached maximum level several weeks after the treatment and lasted more than 20 weeks. Twenty mg/kg streptozotocin did not induce hyperglycemia but significantly increased blood pressure several weeks after the treatment. Arrest of growth, polyuria, glycosuria, hyperlipemia and lenticular cataracts developed in the animals treated with 40 or 65 mg/kg streptozotocin, but in none of the animals treated with 20 mg/kg. In histological examinations in the 24th week after the treatment, degranulation and necrosis in the pancreatic -cells, and vacuolization and deposition of PAS-positive materials in the renal proximal tubules were found in the animals treated with 40 or 65 mg/kg streptozotocin.     

Fibroblast-mediated collagen gel contraction does not require fibronectin-alpha 5 beta 1 integrin interaction.

Fibroblasts cultured within free-floating collagen gels can bind to and reorganize the surrounding collagen fibrils into a more dense and compact arrangement. Collagen gel contraction provides an in vitro model for studying fibroblast-collagen interactions important in wound healing, fibrosis, scar contraction, and connective tissue morphogenesis. We have assessed the role of fibronectin and its interaction with the alpha 5 beta 1 "high affinity" fibronectin-specific integrin receptor in collagen gel contraction. A variety of agents, which specifically inhibit fibronectin-alpha 5 beta 1 interactions, were tested for their abilities to inhibit fibroblast-mediated collagen gel contraction. These included anti-alpha 5 beta 1 monoclonal antibodies, the synthetic peptide GRGDSP, the cell adhesive fragment of fibronectin, and an antibody against the cell adhesive region of fibronectin. None of these agents inhibited collagen gel contraction. Therefore, it is concluded that fibronectin-alpha 5 beta 1 interactions are not necessary for collagen gel contraction. However, collagen gel contraction is dependent on a member or members of the beta 1 subfamily of integrin matrix receptors. A polyclonal antiserum and a monoclonal antibody, both directed against the beta 1 subunit of integrin matrix receptors, inhibited the spreading of fibroblasts in the collagen gel and inhibited collagen gel contraction. This study demonstrates that fibroblast-mediated collagen gel contraction is independent of fibronectin-alpha 5 beta 1 interactions but dependent on an interaction of beta 1 integrin matrix receptors with collagen fibers.     

A cancer-prone case with a background of methylation of p16 tumor suppressor gene.

PURPOSE AND EXPERIMENTAL DESIGN: To date, the presence of p16 gene promoter methylation associated with loss of protein expression has been demonstrated frequently in digestive tract cancers. In this study, we tested for the methylation status of p16 promoter in normal tissue specimens using the methylation-specific PCR technique to examine whether p16 methylation already existed in the background of tumors. RESULTS: Aberrant promoter methylation of p16 gene was detected in 1 of 40 esophageal and 1 of 69 gastric and no colorectal epithelium specimens, and these 2 specimens were derived from the same patient. We also found the same methylation change in both tumor and blood cell DNA. CONCLUSION: These results suggested that the p16 gene was inactivated by methylation in normal background cells of this patient and that other additional factors may promote tumor development in his esophageal and gastric tissues.     

Tumor-specific Activation of Mitogen-activated Protein Kinase in Human Colorectal and Gastric Carcinoma Tissues

To search for the signaling events in colorectal carcinoma relevant to its tumorigenesis, we investigated the activity of mitogen-activated protein kinase (MAPK) in human colorectal carcinoma tissues and paired normal tissues. Of 64 cases examined, approximately 75% (48 cases) showed tumor-specific activation of MAPK by in situ kinase renaturation assay, as well as in vitro kinase assay with immunoprecipitated MAPK. In addition, tumor-specific activation of MAPK was associated with the activation of MAPK kinase in the cases we examined. However, no clear correlation of MAPK activation with lymph node involvement, metastatic rate, stage, histological classification, age or sex was observed. These results suggest that the MAPK pathway is involved in colorectal tumor development, but its activation alone is not sufficient for malignant conversion. In contrast to colorectal carcinoma, gastric carcinoma tissues showed a lower rate of MAPK activation, suggesting that the signaling pathway activated in colorectal carcinoma tissues may differ in part from that of gastric carcinoma.