Roles of advanced glycation endproducts (AGE) and receptor for AGE on vascular smooth muscle cell growth.

Proliferation of vascular smooth muscle cells (VSMC) represents an essential event in the developement of diabetic atherosclerosis. Previous studies suggest that several cytokines and growth factors mediate the proliferation capability in VSMC from diabetic animals. In addition, advanced glycation end products (AGE) and receptor for AGE (RAGE) are important for pathologic features of diabetic complications. In the present study, we attempted to clarify the roles of AGE and RAGE in the proliferation of VSMC using streptozotocin (STZ)-treated rat sera and aortic SMC prepared from non-diabetic rats. AGE levels increased in the diabetic sera, which enhanced the growth of VSMC in proportion to their diabetic periods. AGE-bovine serum albumin (BSA) prepared in vitro also exhibited a stimulatory effect on VSMC growth. The endocytic uptake of AGE and enhanced RAGE expression in VSMC after culture with diabetic sera were observed. In addition, anti-AGE and anti-RAGE antibodies inhibited these stimulatory effects on VSMC growth. These findings suggest that AGE in diabetic rat sera may cause an enhanced effect on VSMC proliferation. However, the concentrations of AGE in diabetic sera were much lower than that of AGE-BSA which demonstrated a significant stimulatory effect on VSMC growth. The magnitude of the VSMC growth-enhancement by the diabetic sera was markedly greater than that by the AGE-BSA solution. In conclusion, the AGE-RAGE interaction in VSMC, in addition to growth factors induced by AGE, contributes to the stimulatory effect of diabetic sera on VSMC proliferation which can accelerate atherosclerosis.

Effects of the extracellular matrix on lumican expression in rat aortic smooth muscle cells in vitro.

Lumican is a small leucine-rich proteoglycan (SLRP), which contributes to cell migration, proliferation, tissue hydration, and collagen fibrillogenesis. Whether lumican is localized in rat aortic smooth muscle cells (SMCs) and what its relationships might be to other extracellular matrix components have not yet been elucidated. In this study, using reverse transcription-polymerase chain reaction (RT-PCR), competitive RT-PCR, and western blot, lumican messenger ribonucleic acid (mRNA) was expressed in cultured rat aortic SMCs. SMCs cultured in serum-free medium showed four bands at 68, 62, 50, and 37 kD. The 68 and 62 kD bands corresponded to proteoglycan, the 50 kD band to glycoprotein, and the 37 kD band to the core protein form of lumican. The relationships of lumican to fibronectin and laminin were also investigated. The lumican mRNA level in SMCs cultured on fibronectin was highest at day 1, but it increased at day 3 in SMCs cultured on laminin. On the fibronectin or laminin-coated plates, SMCs expressed only the 68 and 62 kD bands, corresponding to proteoglycan. Pretreatment with anti-beta1 integrin receptor antibody revealed a decrease in the proteoglycan forms of lumican protein and an additional two bands at 50 and 37 kD, indicating glycoprotein and the core protein of lumican. These results show that lumican was synthesized in cultured rat aortic SMCs as proteoglycan, glycoprotein, and core protein. The extracellular matrix (ECM) affected lumican protein production and restricted the lumican protein form to proteoglycan via the beta1 integrin receptor in SMCs.

Ebola hemorrhagic fever (EHF): mechanism of transmission and pathogenicity.

Hemorrhagic fevers represent a wide spectrum of viral infectious diseases, out-breaking mostly as epidemics, some of them being highly lethal. They range from those caused by bunyaviridae, associated with renal or pulmonary syndromes and those recently emerging and caused by the filoviridae family of thread-like viruses. Among the latter, Ebola hemorrhagic fever (EHF) bears the highest mortality and morbidity rates. One form of the disease has been documented only in monkeys. The human form, has occurred mainly in areas surrounding rain forests in central Africa. Patients present with signs of hemorrhagic diathesis, fever, diarrhea and neurological disorders, leading sometimes to confusion with local endemic diseases. Fatal victims of the disease die of dehydration. Poor hygienic conditions facilitate the spread of the virus. Biologically, the virus seems to target both the host blood coagulative and immune defense systems. Intensive epidemiologic search have failed to establish the definitive natural host of the virus. Twice, with a 19-year interval, major outbreaks have taken place in the Democratic Republic of the Congo. The second major outbreak in the northwestern city of Kikwit in April 1995 will serve here to elucidate the mechanism of the viral infection.

Expression and localization of basic fibroblast growth factor and its mRNA in solitary fibrous tumor.

Solitary fibrous tumors (SFTs) represent a distinct neoplasm that should be included in the differential diagnosis of spindle-cell neoplasms of the soft tissue. Basic fibroblast growth factor (bFGF or FGF-2) is a mitogenic and angiogenic polypeptide produced by diverse cell types, including the cells derived from normal tissue and neoplastic lesions. In this study, the expression of bFGF, vimentin, CD 34, c-kit (or CD 117), desmin, S-100 protein, and alpha-smooth muscle actin (alpha-SMA) in SFTs, hemangiopericytomas (HPC), gastrointestinal stromal tumors (GIST), and dermatofibrosarcoma protuberans (DFSP) were evaluated to assess their usefulness in the differential diagnosis of these lesions. The expression of bFGF mRNA was also examined in SFTs by in situ hybridization (ISH) using a digoxigenin-labeled bFGF oligonucleotide probe. All the SFTs, GISTs and DFSPs exhibited strong and diffuse immunoreactivity for CD34 and vimentin, and were completely negative for desmin, S-100 protein and alpha-SMA. The HPCs were positive for vimentin, but negative for CD34. In all the SFTs, strong and diffuse nuclear immunostaining was observed with bFGF antibody, contrasting with the negative staining observed in the majority of the HPCs, GISTs, and DFSPs. The bFGF mRNA was also expressed in the SFT cells. The constitutive expression of the bFGF in the SFT widens the spectrum of available markers for these tumors, providing a useful addition to their differential diagnosis in difficult cases, and contributing to the understanding of their histogenesis and molecular pathogenesis.

Expression of fibroblast growth factor (FGF)-10 in human colorectal adenocarcinoma cells.

Fibroblast growth factor (FGF) -10 (keratinocyte growth factor 2, KGF 2) is a new member of the FGF family that is mainly synthesized by mesenchymal cells and acts predominantly on epithelial cells in a paracrine manner. Its actions are dependent on its binding to the iiib isoform of the cell-surface FGF receptor 2 (FGFR2 iiib). FGF-10 is known to play an important role in fetal limb and lung development, skin wound healing and prostatic epithelial cell growth. In the present study, the expression of FGF-10 and FGFR2 iiib in five cultured human colorectal adenocarcinoma cell lines (COLO 205, DLD-1, HCT-15, SW 480 and WiDr) and the localization of FGF-10 messenger RNA (mRNA) and its protein in human colorectal cancer tissues from 10 patients were determined. All five colorectal cancer cell lines expressed FGF-10 mRNA and its protein. FGFR2 iiib mRNAs were expressed in these cells and the recombinant FGF-10 (1 ng/ml) increased the growth rate of COLO 205 cells. To determine the localization of FGF-10 protein and its mRNA in normal and cancerous human colorectal tissues, immunohistochemistry and in situ hybridization were performed. In normal colorectal tissues, FGF-10 and its mRNA were not detected. In contrast, moderate immunoreactivity was present in cancer cells in 5 of 10 colorectal cancer cases and mild immunoreactivity was recognized in adjacent fibroblasts. By using in situ hybridization, FGF-10 mRNA was observed in colorectal cancer cells and fibroblasts adjacent to cancer cells. These findings indicate that FGF-10 and its receptor, FGFR2 iiib expression in colorectal adenocarcinoma cells and FGF-10 may contribute to the growth of cells of this type.

Adenosine receptor antagonists cancelled the ischemic tolerance phenomenon in gerbil.

Pretreatment of the brain with sublethal ischemia has been reported to induce neuronal resistance to otherwise lethal ischemia, a phenomenon designated as ischemic tolerance. The protective mechanisms of the phenomenon are not known yet, however, recent experimental data suggest the involvement of adenosine receptor activation in the acquisition of tolerance. In this study, the effect of theophylline, a non-selective adenosine receptor antagonist, and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an adenosine A1 receptor antagonist, were investigated to ascertain if these drugs could cancel the protective effect of ischemic tolerance in the gerbil. DPCPX or theophylline was administered at 3 h after a short preconditioning ischemia, and 21 h later animals were subjected to lethal ischemia of 5 min duration. DPCPX at a dose of 1.0 mg/kg (i.p) and theophylline at a dose of 20 mg/kg (i.p) significantly reduced the protective effect of preconditioning in the CA1 hippocampal neurons. These findings suggest the involvement of adenosine receptor activation for the development of ischemic tolerance phenomenon.

Vascular endothelial growth factor enhances glomerular capillary repair and accelerates resolution of experimentally induced glomerulonephritis.

Vascular endothelial growth factor (VEGF) regulates angiogenesis through endothelial cell proliferation and plays an important role in capillary repair in damaged glomeruli. We tested the hypothesis that VEGF might be beneficial in rats with severe glomerular injury in glomerulonephritis (GN) based on its angiogenic and vascular remodeling properties. Acute GN with severe glomerular destruction was induced in rats by injection of anti-Thy-1.1 antibody (day 0) and Habu-snake venom (day 1). Rats were intraperitoneally injected with recombinant human VEGF(165) (10 microg/100 g body wt/day) or vehicle from day 2 to day 9, and monitored changes in glomerular capillaries, development of glomerular inflammation, and progression to glomerular sclerosis after acute glomerular destruction in both groups. Rats that received anti-Thy-1.1 antibody and Habu-snake venom showed severe mesangiolysis and marked destruction of capillary network on day 2. VEGF was expressed on glomerular epithelial cells, proliferating mesangial cells, and some infiltrating leukocytes, and VEGF(165) protein levels increased in damaged glomeruli during day 5 to day 7. Normal, damaged, and regenerating glomerular endothelial cells expressed VEGF receptor flk-1. However, endothelial cell proliferation and capillary repair was rare in vehicle-treated rats with severe glomerular damage, which progressed to global sclerosis and chronic renal failure by week 8. In contrast, in the VEGF-treated group, VEGF(165) significantly enhanced endothelial cell proliferation and capillary repair in glomeruli by day 9 (proliferating endothelial cells: VEGF(165), 4.3 +/- 1.1; control, 2.2 +/- 0.9 cells on day 7, P < 0.001; and glomerular capillaries: VEGF(165), 24.6 +/- 4.8; control, 16.9 +/- 3.4 capillaries on day 7, P < 0.01). Thereafter, damaged glomeruli gradually recovered after development of capillary network by week 8, and significant improvement of renal function was evident in the VEGF-treated group during week 8 (creatinine: VEGF(165), 0.3 +/- 0.1; control, 2.6 +/- 0.9 mg/dl, P < 0.001; proteinuria: VEGF(165), 54 +/- 15; control, 318 +/- 60 mg/day, P < 0.001). We conclude that the beneficial effect of VEGF(165) in severe glomerular injury in GN emphasizes the importance of capillary repair in the resolution of GN, and may allow the design of new therapeutic strategies against severe GN.

Hepatocyte growth factor (HGF), HGF activator, and c-Met in synovial tissues in rheumatoid arthritis and osteoarthritis.

OBJECTIVE: Hepatocyte growth factor (HGF) is a multifunctional polypeptide that has been implicated in cancer growth, tissue development, and wound repair. Its actions are dependent on activation by HGF activator (HGFA) and its binding to a specific HGF receptor (c-Met). We examined the role of HGF, HGFA, and c-Met in synovial tissues in rheumatoid arthritis (RA) and osteoarthritis (OA), and their localization and mRNA expression. METHODS: Immunohistochemical staining, Western blotting, RT-PCR, and in situ hybridization (ISH) for HGF, HGFA, and c-Met were performed on synovial tissue specimens from 10 patients with RA and 4 with OA, and 2 healthy controls. RESULTS: Immunohistochemical staining revealed that HGFA and c-Met were strongly expressed in fibroblasts, macrophages, endothelial cells, and synovial lining cells. HGF was expressed only faintly in macrophages and fibroblasts, and not at all in the endothelial cells of RA and OA synovial tissue. HGFA was detected near 73 and 34 kDa on Western blot analysis, corresponding to inactive and active HGFA, respectively. RT-PCR showed HGF, HGFA, and c-Met mRNA in RA, OA, and control synovial tissue. ISH and immunohistochemistry revealed mRNA expression for HGF, HGFA, and c-Met in the cell types mentioned above. CONCLUSION: HGFA, HGF, and c-Met mRNA are expressed in synovial tissue in RA and OA, and HGF is activated by HGFA and binds to c-Met on endothelial cells, inducing angiogenesis.

[Expression and intracytoplasmic signal transduction pathway of fibroblast growth factor (FGF)-10 in human cervical cancer cell lines].

Fibroblast growth factor (FGF) -10 is a new member of the FGF family initially reported in Japan. It is mainly synthesized by mesenchymal cells and acts on epithelial cells in a paracrine manner. FGF-10 actions are dependent on their binding to the iiib form of FGF receptor 2 (FGFR2) iiib, also known as keratinocyte growth factor receptor (KGFR). FGF-10 has high amino acid homology to keratinocyte growth factor (KGF) and plays an important role in fetal limb and lung development and skin wound healing. In the present study, the expression of FGF-10 and FGFR2 iiib messenger RNA (mRNA) in two different human uterine cervical cancer cell lines (CaSki and ME-180) were examined. Both CaSki and ME-180 cells expressed FGFR2 iiib mRNA, while only CaSki cells expressed FGF-10 mRNA and protein. Recombinant FGF-10 (1 ng/ml) increased the growth rate of ME-180 cells and also enhanced mitogen-activated protein kinase (MAPK) phosphorylation of the cells. These data indicate that FGF-10 may directly promote the growth of squamous cell cancer in the uterine cervix via the MAPK pathway.

Immunohistochemical expression of T, Tn and sialyl-Tn antigens and clinical outcome in human breast carcinoma.

BACKGROUND: The extent of expression of reactive T (Thomsen-Friedenreich), Tn and sialyl-Tn antigens has been assumed to predict carcinoma aggressiveness. We studied the expression of T, Tn and sialyl-Tn antigens in a relatively large cohort of breast carcinoma patients with known long-term outcome to assess the clinical and biological significance of these antigens. MATERIALS AND METHODS: T, Tn and sjalyl-Tn antigens were examined in 72 consecutive primary breast carcinomas by immunohistochemistry using well defined monoclonal antibodies and their semiquantitative values were correlated with established clinicopathologic prognostic parameters of the disease to determine their relationship with long-term clinical outcome. RESULTS: Of the 72 carcinomas, 63 (87.5%) each expressed T or Tn antigens, while 16 (22%) expressed sialyl-Tn antigens. Most carcinomas (81%) expressed more than one of the antigens simultaneously, being the most frequent combination T/Tn antigen expression. No significant correlation was noted between the expression of T, Tn and sialyl-Tn antigens (whether individually or in combination) and the prognostic parameters including patient age, disease stage, tumor size, lymph node status, nuclear and histologic grades, histologic types, hormone receptor status and menopausal status. Univariate survival analyses showed that disease stage, tumour size and lymph node metastasis were significant predictors of overall survival. Interestingly, a significant inverse correlation was found between the Tn antigen expression (p = 0.04), as well as the combined T/Tn (p = 0.03) and Tn/sialyl-Tn (p = 0.02) antigen expressions and long-term overall survival. In a multivariate Cox proportional hazard model, disease stage and a negative or low Tn antigen expression emerged as significant predictors of overall survival. CONCLUSION: Our data suggested that the expression of T, Tn and sialyl-Tn antigens does not appear to predict the outcome of patients with breast carcinoma in a long-term run. Moreover, the findings signified a potential value for a negative or low Tn antigen expression in prognostic stratification of breast carcinomas.

Intravenous leiomyomatosis of the uterus with multiple pulmonary metastases associated with large bullae-like cyst formation.

We present a case of uterine intravenous leiomyomatosis associated with multiple pulmonary metastases with bullae-like cystic change. A 53-year-old woman who had undergone hysterectomy 5 years previously underwent an operation for multiple pulmonary nodules with bullae formation. After resection of several large bullae, a subsequent extirpation of the pulmonary nodules was performed, and a pathological examination showed multiple leiomyomatous nodules with occasional cystic change. A review of the previous slides of the uterus and immunohistochemical analysis of the proliferating ability using anti-Ki-67 and anti-proliferating cell nuclear antigen (PCNA) antibodies were performed. Proliferating cells of the uterus had very few mitotic figures for their high cellularity, and the labeling indices of Ki-67 and PCNA indicated very low levels in both uterine neoplasm and pulmonary nodules. From these findings, an intravenous leiomyomatosis associated with multiple pulmonary metastases was diagnosed.

3-D analysis of vascular and capsular invasion in thyroid follicular carcinoma.

To clarify the mechanism of vascular invasion (VI) and capsular invasion (CI) in thyroid follicular carcinoma (FC), 3-D reconstruction of tumor tissues, vessels and capsules was performed from serial sections in five FC and three follicular adenomas (FA). Outflow veins in the lesions were well developed under the capsule, narrowed just beneath the capsule, and dilated within the capsule. Both VI and CI were observed at the poststenotic intracapsular dilated part of outflow veins. The tumor tissue extended along the intracapsular horizontal veins which flowed in parallel with the capsule in VI, or along the vertical veins which directly flowed outside the capsule in CI. There was tumor tissue in the subendothelial layer of the outflow veins within the capsule. Intravascular tumor nests and nodular lesions within the capsule continued from the main tumors. It can be concluded from these results that most VI and CI may not be true invasions but pre-invasive lesions.

Expression of cathepsin B and cystatin C in human breast cancer.

Cathepsin B, which was originally found to be a lysosomal cysteine protease, is also an important matrix protease. In this study, we investigated the expression of cathepsin B and cystatin C, the strongest inhibitor of cathepsin B, and measured the relative amounts of each in human breast cancer tissues. Cystatin C expression relative to cathepsin B expression was found to be decreased. This finding could be associated with the looseness of cancerous interstitial tissue, which might play a role in cancer invasion and metastasis. This report documents the first simultaneous investigation of cathepsin B and cystatin C in breast cancer tissues.

Expression and localization of lumican in the ischemic and reperfused rat heart.

Lumican belongs to the small leucine-rich proteoglycan family and has an important role in the regulation of corneal and dermal collagen fiber assembly. Recently, lumican mRNA was found in the heart and its high expression was reported during wound healing of the cornea. In the present study, the expression and role of lumican in fibrosis of an ischemic and reperfused rat heart were examined. The expression level of lumican mRNA increased in the ischemic and reperfused rat heart and was highest on the fourth week. Lumican protein existed in the forms of core protein and proteoglycan in the control rat heart. The amount of lumican in the form of proteoglycan increased, and that as the form glycoprotein was newly detected in the ischemic and reperfused rat heart on the fourth week. In the control heart, lumican was weakly expressed in the collagen fibers of the perivascular area, but it was expressed strongly in many capillary endothelial cells in the ischemic lesion on day 1. After 3 days, lumican was localized in collagen fibers and in the fibroblasts of fibrotic lesions. A few myocardial cells close to the ischemic lesion expressed lumican mRNA. Lumican is considered to play an important role in the fibrillogenesis of the ischemic and reperfused rat heart.

[The protective effect of hepatocyte growth-promoting factor (pHGF) against carbon tetrachloride-induced acute liver injury in rats. II. Protective effects on cell membrane injury].

To examine the protective effects of hepatocyte growth-promoting factor (pHGF) against carbon tetrachloride (CCl4) -induced acute liver injury in rats, the pathological changes were observed by light and electron microcopy, and the serum GOT and GPT levels were measured. Acute liver injury was produced by the injection of CCl4 (2ml/kg BW) in two groups of animals, of which one received pHGF (300 microg/kg BW) via the tail vein after 4 hrs. In the group treated with CCl4 alone, serum GOT and GPT were significantly elevated (1280+/-228 and 187+/-73 IU/l, respectively) 6 hrs after injection, indicating the induction of liver injury by CCl4. They reached a peak (3836+/-654 and 1022+/-230 IU/l, respectively) at 48 hrs and declined thereafter, but did not completely recover after 72 hrs. PAS-negative cells were observed around the central veins after 6 hrs and most of the hepatocytes were PAS-negative at 12 hrs. PAS-positive cells began to appear and increased in number after 24 hrs. There were scarcely any PAS-negative cells remaining in the lobules after 72 hrs. In the group treated with CCl4 followed by pHGF, serum GOT and GPT levels were significantly lower than in the CCl4-treated group, and abundant PAS-positive hepatocytes were observed. Also, all hepatocytes were PAS-positive (as in normal liver) after 72 hrs. Administration of pHGF resulted in a decrease in the ultrastructural changes in rats with CCl4-induced liver injury such as vacuolation, cisternae formation and dilatation of the rough endoplasmic reticulum. These results suggest that pHGF acts to stabilize cell membranes, thereby providing protection against CCl4-induced hepatic injury.

[Blood vessels in normal and abnormal mitral valve leaflets].

UNLABELLED: The incidence and the distribution of blood vessels were examined in normal and abnormal mitral valve leaflets. MATERIALS AND METHODS: Normal valves were obtained from 12 autopsy cases without cardiovascular disease (8 men, 4 women, 33 to 93 years of age). Twenty-one abnormal valves were obtained at the time of mitral valve replacement (12 men, 9 women, 16 to 78 years of age). Clinical and pathological diagnoses were rheumatic valvular disease (RVD: n=8), floppy mitral valve (FMV: n=9), and healed infective endocarditis (HIE: n=4, 1 with RVD, 3 with FMV). The number of vessels was counted at the surgical excision line of the valvular rings by immunohistochemical study using Factor VIII related antigen and CD34. Histologic studies were also made at the 5 mm distal line from the ring in normal valves, and at the vertical line to the ring in abnormal valves. RESULTS: In normal valves, the number of vessels at the ring area, except in myocardial tissues that extended from the left atrium to the auricularis, ranged from 3 to 184. Vessels were also found at the 5 mm distal area from the ring in 6 valves out of 12. Vessels were mainly distributed near the commissure areas of the auricularis and/or the spongiosa and were extended with myocardial tissues. There was no difference in the number of vessels related to age or sex. In RVD, the number of vessels at the ring area ranged from 22 to 517 in 8 anterior leaflets (AML) and 2 to 151 in 5 posterior leaflets (PML). Many vessels also appeared in the distal spongiosa of the leaflets, and arterioles were frequently found in these areas. In FMV, a few (3 and 6) vessels were found in 2 leaflets (AML: 2/8, PML: 0/4). In HIE, the number of vessels was 216 in the case with RVD, and 3 to 110 in cases with FMV. CONCLUSION: At the ring area, normal mitral valve leaflets were supplied with nutrition from blood vessels that mainly extended from the left atrium with myocardial tissues. In RVD, the vessels branched from previously existing capillaries, extending to the distal area, and increased in number. Mechanical stress during opening and closing of the leaflets contributes to the arterialization of these vessels. In FMV, the number of capillaries, which is smaller than in normal valves, might be related to the progression of this disorder. In HIE with valvular disease, the number of vessels is related to the preexisting disease.

Evaluation of myc and chromosome 8 copy number in colorectal cancer using interphase cytogenetics.

To reveal the significance of genetic abnormalities of the c-myc gene, 56 colorectal tumors (43 colorectal carcinomas, 5 recurrent or metastatic tumors, and 8 adenomatous polyps) were analyzed using fluorescence in situ hybridization (FISH). Two probes specific for c-myc and the chromosome 8 centromere were used for dual color FISH. In each case, 100-200 nuclei were observed for signals from the probes. The percent of nuclei with c-myc amplification (PMA) was defined as the proportion of nuclei representing the ratio of c-myc/chromosome 8 >1.0, and the percent of nuclei with the greater number of c-myc (PGNM) was defined as the proportion of nuclei representing the ratio of c-myc/chromosome 8 > or =2.0. Low level amplification was defined as a case with PMA > or =10% and PGNM <10%. High level amplification was defined as a case with PGNM > or =10%. While adenomatous polyps and in situ carcinomas showed no c-myc amplification, the low level amplification and high level amplification of c-myc were observed in 48.8% (21/43) and 20.9% (9/43) of primary colorectal carcinomas. In addition, the group including cases of stage IIIb and IV exhibited significantly higher average copy numbers of c-myc (CN-myc), PMA and PGNM than the other group of earlier stages. FISH was thought a useful cytogenetic method to detect genetic abnormalities in solid tumors. It was shown that the c-myc gene amplification identified using FISH was associated with the aggressiveness of colorectal carcinoma.

Localization of extracellular matrix and mitogen-activated protein kinase (MAPK) in aorta of streptozotocin treated Mongolian gerbils.

To evaluate the relationship among the extracellular matrix (ECM) and mitogen-activated protein kinase (MAPK) family for the vascular damages in hyperglycemia, we injected Mongolian gerbils intravenously with 150 mg/kg streptozotocin (STZ) and observed over the next one year the resulting aortic changes by immunohistochemical techniques. After STZ treatment, hyperglycemia was confirmed. At 4 weeks after STZ administration morphological observation revealed increased stromal components among the vascular smooth muscle cells (SMCs). Immunohistochemically, extracellular matrices such as fibronectin and laminin were localized in the aorta at 4 weeks and one year after STZ administration. The reaction products of MAPK in vascular SMCs were more increased at one year than at 4 weeks after STZ administration. After STZ administration, the increase of ECM and MAPK was observed in the aorta, which suggests these factors play important roles in the pathogenesis of macrovasculopathy in diabetes mellitus.

Alpha-synuclein-positive structures in cases with sporadic Alzheimer's disease: morphology and its relationship to tau aggregation.

Alzheimer's disease (AD) and Parkinson's disease share common clinical and pathological features. In this study, we examined the relationship between AD pathology and alpha-synuclein aggregation. The frequency and distribution of alpha-synuclein-positive structures were systematically investigated in 27 cases with sporadic AD by alpha-synuclein immuno-histochemistry. Thirteen (48.2%) of 27 cases had various alpha-synuclein-positive structures as well as Lewy bodies. The frequency and density of senile plaques and neurofibrillary tangles were not significantly different between cases with alpha-synuclein structures and those without. alpha-Synuclein-positive structures were found most frequently in the amygdala. The alpha-synuclein-positive inclusions that are different from Lewy bodies were observed at the highest rate in the hippocampus. The discovery of alpha-synuclein as the constituent of Lewy bodies facilitated the detection of Lewy-related structures even in AD cases with widespread and numerous neurofibrillary tangles. alpha-Synuclein-positive inclusions except for Lewy bodies are exposed, and the distribution of them indicates that Lewy body formation may be influenced by the degree of tau aggregation. This study also supports the suggestion that cases with AD pathology can be classified into two groups according to the existence or absence of alpha-synuclein aggregation.