Cytological Assessment of Desmoplastic Malignant Pleural Mesothelioma in an Autopsy Case.

INTRODUCTION: Desmoplastic malignant pleural mesothelioma (DMPM) is a sarcoma-type mesothelioma, comprising approximately 5% of malignant pleural mesotheliomas. Although effusion cytology is commonly used as the primary diagnostic approach for mesothelioma, it may not be useful for DMPM because of the presence of desmoplasia and bland cellular atypia. We report a case, and previously undescribed cytological features, of DMPM that was diagnosed during autopsy. CASE PRESENTATION: A man in his 60s with a history of occupational asbestos exposure was referred to our hospital with right chest pain. A chest CT scan showed right pleural effusion. Thirteen months later, the patient died of respiratory failure. During autopsy, scrape-imprint smears were prepared and cytology of pleural effusions was performed. The scrape-imprint smear samples showed spindle cells with mild nuclear atypia and grooves with fibrous stroma. Pleural effusion cytology revealed spindle cells with mild nuclear atypia, as well as grooves with loose epithelial connections. Histological examination of the right pleura showed spindle cells proliferating with dense collagen fibers, as seen in the cytological samples, thus indicating a diagnosis of DMPM, which was confirmed by fluorescence in situ hybridization. CONCLUSION: Cytological procedures such as pleural effusion cytology and scrape-imprinting cytology may help in diagnosing rare tumors such as DMPM.

2-Deoxy-d-glucose induces deglycosylation of proinflammatory cytokine receptors and strongly reduces immunological responses in mouse models of inflammation.

Anti-proinflammatory cytokine therapies against interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1 are major advancements in treating inflammatory diseases, especially rheumatoid arthritis. Such therapies are mainly performed by injection of antibodies against cytokines or cytokine receptors. We initially found that the glycolytic inhibitor 2-deoxy-d-glucose (2-DG), a simple monosaccharide, attenuated cellular responses to IL-6 by inhibiting N-linked glycosylation of the IL-6 receptor gp130. Aglycoforms of gp130 did not bind to IL-6 or activate downstream intracellular signals that included Janus kinases. 2-DG completely inhibited dextran sodium sulfate-induced colitis, a mouse model for inflammatory bowel disease, and alleviated laminarin-induced arthritis in the SKG mouse, an experimental model for human rheumatoid arthritis. These diseases have been shown to be partially dependent on IL-6. We also found that 2-DG inhibited signals for other proinflammatory cytokines such as TNF-α, IL-1ß, and interferon -γ, and accordingly, prevented death by another inflammatory disease, lipopolysaccharide (LPS) shock. Furthermore, 2-DG prevented LPS shock, a model for a cytokine storm, and LPS-induced pulmonary inflammation, a model for acute respiratory distress syndrome of coronavirus disease 2019 (COVID-19). These results suggest that targeted therapies that inhibit cytokine receptor glycosylation are effective for treatment of various inflammatory diseases.

Crystalloid Granuloma of Parotid Gland: A Case Report With Review of the Literature.

Crystalloid granuloma (CG) of salivary gland is an extremely rare inflammatory disease, and only 6 cases have been reported in the English literature. CG is histologically characterized by a granulomatous reaction to amylase crystalloid deposition. A 73-year-old woman presented with a painful left neck mass. Computed tomography depicted a mass located in the lower pole of the left parotid gland, suspicious for a tumoral lesion. Preoperative fine needle aspiration cytology found amylase crystalloid deposition with a few inflammatory cells. Surgical sections of the mass revealed formation of a granuloma containing abundant eosinophilic but glassy and transparent amorphous crystalloids, suggestive of α-amylase crystalloid. No neoplastic elements were detected. The case was eventually diagnosed with CG in the parotid gland. Our findings suggest that when we identify amylase crystalloids in fine needle aspiration cytology smears from the salivary gland, CG should be considered even if neoplasm is clinically or radiographically suspected.

Imaging findings of solitary uterine granulocytic sarcoma.

A 29-year old woman with a history of vaginal bleeding was referred to our hospital. Transvaginal ultrasonography revealed a hypervascular cervical mass and malignancy was suspected. Computed tomography (CT), magnetic resonance imaging, and 18-F-fluorodeoxyglucose positron emission tomography/CT were performed. She was finally diagnosed with granulocytic sarcoma based on pathological examination.

Spermatic cord tumor metastatic from stomach cancer 1 year after curative gastrectomy.

We report a case of advanced stomach cancer metastatic to the spermatic cord 1 year after curative distal gastrectomy. The patient underwent distal gastrectomy with D2 lymph node dissection. There was no metastasis to the liver or peritoneum, and cytologic examination of the peritoneal lavage fluid was negative for cancer cells (CY0). Histological examination revealed a moderately differentiated tubular adenocarcinoma that had penetrated the serosa (T4a). Postoperative staging was T4aN1M0, stage IIIA, according to the Japanese gastric carcinoma classification scale. One year after the operation, the patient was readmitted with right groin pain. Percutaneous fine needle aspiration biopsy of the inguinal tumor revealed a tubular adenocarcinoma. Extirpation of the inguinal tumor with wedge resection of the right iliac-femoral vein was performed. Pathological examination revealed a moderately differentiated tubular adenocarcinoma that had diffusely infiltrated the connective tissue surrounding the spermatic cord. Immunohistochemical studies showed the tumor cells were reactive for CK7 but not for CK20. These findings were consistent with the diagnosis of a spermatic cord tumor metastatic from a known gastric primary cancer. Laparoscopic exploration showed invagination of the peritoneum with small nodules from the median umbilical fold to the lateral umbilical fold and a markedly decreased distance between the folds. Pathological examination in this area revealed a tubular structure consisting of mesothelial cells within the cancer tissue which was associated with dense fibrosis, suggesting that the invagination of the peritoneum had been caused by minimal peritoneal metastasis.

Comparison of epirubicin-iodized oil suspension and emulsion for transcatheter arterial chemoembolization in VX2 tumor.

To compare the antitumor efficacy and safety of transcatheter arterial chemoembolization (TACE) by epirubicin suspension (epirubicin suspension: epirubicin-iodized oil mixture without solution) to that by epirubicin emulsion (epirubicin emulsion: epirubicin-iodized oil mixture with solution), the efficacy of treatment by administration of either an epirubicin suspension or emulsion was examined in an animal model. Changes in plasma epirubicin concentration were compared over 24 h immediately after treatment, and enhanced ultrasonographic and histopathological analysis subsequently conducted 7 days after treatment to determine the growth ratio and proportion of viable tumor cells. The growth ratio and proportion of viable tumor cells were found to be significantly lower in the suspension group than in the emulsion group while the plasma epirubicin concentration was found to be significantly higher in the suspension group than in the emulsion group. These results indicate that administration of an epirubicin suspension is a superior form of TACE compared to that of administration of an epirubicin emulsion.

Comparative study of cisplatin-iodized oil suspension and emulsion for transcatheter arterial chemoembolization of rabbit VX2 liver tumors.

AIM: To evaluate the antitumor effects and hepatotoxicity of transcatheter arterial chemoembolization (TACE) with cisplatin-iodized oil suspension and emulsion in a rabbit tumor model. METHODS: Transcatheter arterial chemoembolization was performed on 12 rabbits with hepatic VX2 tumors using a cisplatin suspension (1 mg/kg cisplatin and 0.1 mL/kg iodized oil, n = 6) or emulsion (1 mg/kg cisplatin, 0.1 mL/kg of iodized oil, and 0.1 mL/kg saline solution, n = 6). Time series changes in plasma platinum concentration were compared over 24 h. All rabbits were killed at 7 days after TACE, and the growth ratio and residual viable proportion of tumors were calculated on the basis of ultrasonographic and histopathological findings. Hepatotoxicity was also evaluated. Differences between the two groups were statistically assessed with the Mann-Whitney U-test. The animal care committee of our institute approved this study. RESULTS: Plasma platinum concentrations were significantly higher in the suspension group than in the emulsion group at 0.5-24 h after TACE (P < 0.05). Growth ratios (-24.6 ± 9.98% vs. 21.4 ± 8.87%, respectively; P = 0.004) and residual viable proportions of tumors (25.8 ± 5.02% vs. 51.1 ± 11.4%, respectively; P = 0.009) were significantly lower in the suspension group than in the emulsion group. Hepatotoxicity was transient in all rabbits. CONCLUSION: Cisplatin-iodized oil suspensions facilitated the slow release of cisplatin at the tumor border. A suspension is preferable to an emulsion for drug delivery and the antitumor effect during the treatment of VX2 liver tumors with TACE.

Overexpression of fibroblast growth factor receptor 4 in high-grade pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma.

The overexpression of fibroblast growth factor receptor (FGFR) 4 has been reported in various human cancers, but it has not been studied in pancreatic ductal adenocarcinoma (PDAC) or its precursor lesion, pancreatic intraepithelial neoplasia (PanIN). Moreover, there is controversy as to whether FGFR4 has a mitogenic role in carcinogenesis or other functions. Therefore, the expression and roles of FGFR4 in pancreatic cancer were investigated. Immunohistochemical staining was performed using an anti-FGFR4 antibody in PDAC and PanIN cases. The expression levels of FGFR4 mRNA and protein were investigated in PDAC cell lines by qRT-PCR and Western blot, respectively. Changes were analyzed in cell morphology, proliferation, migration, invasion and attachment in PDAC cell lines with or without the stimulation of FGFR4 by FGF19, as a known specific ligand. The changes in mRNA levels associated with transformation and tumorigenesis as a result of FGF19 administration were also evaluated. FGFR4 was expressed in 39 of 53 PDAC cases (73.6%) and its expression tended to be related to longer overall survival (P=0.068). Moreover, it was frequently expressed in high-grade PanIN lesions [10 of 11 lesions (90.9%)], whereas it was hardly expressed in low-grade PanIN lesions [1 of 10 lesions (10.0%)] (P=0.0003). FGFR4 stimulation of PDAC cells resulted in significantly increased cell adhesion to laminin and fibronectin (P<0.05) and decreased cell migration (P<0.05). The results of PCR array analysis indicated that this was a result of up-regulation of the integrin α4 family. In contrast, cell morphology or proliferation in PDAC cells was not affected. We showed that FGFR4 expression is markedly increased in high-grade PanIN and PDAC compared with that in normal and low-grade PanIN, and that FGFR4 stimulation by FGF19 of PDAC cells contributes to tumor suppression by increasing cell adhesion to extracellular matrix.

Expression of fibroblast growth factor receptor 2 IIIc in human uterine cervical intraepithelial neoplasia and cervical cancer.

Fibroblast growth factor receptors (FGFRs) 1-3 have IIIb and IIIc isoforms, and we reported that FGFR2 IIIb is highly expressed in cervical keratinizing squamous cell carcinoma (SCC). In this study, we determined the expression and roles of FGFR2 IIIc in cervical intraepithelial neoplasia (CIN) and cervical cancer. In CINs 1 and 2, FGFR2 IIIc was found to be localized at the basal to lower two-thirds of the squamous epithelium, whereas it was localized in most of the squamous epithelium, except for the superficial layer in CIN 3. In situ hybridization (ISH) analysis showed that the expression patterns of FGFR2 IIIc mRNA are similar to those of FGFR2 IIIc protein in CINs. The FGFR2 IIIc protein was detected in all invasive cervical cancer patients (29 cases) and its mRNA was found to be strongly expressed in the invasive front of cancer cell nests. FGFR2 IIIc cDNA was stably transfected into CaSki cells, which are derived from a cervical SCC. The growth rates of the CaSki cells were higher than those of Mock cells in vitro, and the CaSki cells tended to form larger subcutaneous tumors in nude mice. These findings suggest that FGFR2 IIIc plays important roles in carcinogenesis and growth of cervical cancer cells. Anti-FGFR2 IIIc therapies may represent therapeutic strategies for inhibiting the growth of CIN and cervical cancer.

Inflammatory pseudotumor in the liver associated with intrahepatic bile duct stones mimicking malignancy.

We describe a 71-year-old man with an inflammatory tumor arising in segment 5 of the liver. The patient was admitted because of acute pain in the right upper quadrant of the abdomen and fever. Initial laboratory tests revealed the following: serum alkaline phosphatase concentration, 634 IU/L; serum gamma glutamic transpeptidase concentration, 1,378 IU/L; serum C-reactive protein concentration, 0.89 mg/dL; and total bilirubin concentration, 8.9 mg/dL. Abdominal ultrasonography, computed tomography (CT), and magnetic resonance imaging showed a mass, 3 cm in diameter, in segment 5 of the liver. Magnetic resonance cholangiopancreatography showed a lesion of moderate-to-high signal intensity on T2-weighted images of segment 5. Endoscopic retrograde cholangiopancreatography revealed a common bile duct stone. The intrahepatic bile ducts of segment 5 could not be visualized after the use of contrast material. Endoscopic sphincterotomy was performed to remove the common bile duct stone. Antibiotics were administered soon after stone removal, and fever gradually resolved. Positron emission tomography revealed hot spots in segment 5 of the liver. Three weeks after discharge, the patient was readmitted with an acute pain in the right upper quadrant of the abdomen. Abdominal ultrasonography, CT, and magnetic resonance imaging showed enlargement of this area. Inflammatory changes of segment 5 due to cholangitis with intrahepatic bile duct stones was diagnosed. Because malignant disease could not be completely ruled out, segment 5 of the liver was resected. Macroscopic examination of the resected specimen revealed a gray, fibrotic, solid tumor associated with intrahepatic bile duct stones. Microscopic examination of the tumor showed proliferation of spindle-shaped myofibroblastic cells in a mixed myxoedematous, dense fibrotic stroma, associated with infiltration by various acute and chronic inflammatory cells. The postoperative course was uneventful, and the patient was discharged on postoperative day 16.

Expression of keratinocyte growth factor and its receptor in human endometrial cancer in cooperation with steroid hormones.

The keratinocyte factor (KGF) and its receptor (KGFR) are implicated in tissue development and repair. We studied the expression and functions of KGF and KGFR in association with estrogen and progesterone in human endometrial tissues and cells. In non-cancerous human endometrial tissues in the secretory phase, a strong immunoreactivity of KGF in glands, stromal cells, and smooth muscle cells of spiral arteries was detected; however, in proliferative-phase tissues, the immunoreactivity of KGF or KGFR was weak or absent. Most of the 32 endometrioid adenocarcinoma cases showed positive KGF and KGFR stainings (90.6 and 71.9%, respectively). We then studied, using Ishikawa well-differentiated human endometrial cancer cell line that expresses estrogen receptor (ER) and progesterone receptor (PR), the expression of KGF and KGFR in conjunction with estrogen and progesterone, and observed that the KGFR expression of Ishikawa cells was upregulated by estrogen and that this upregulation was markedly enhanced by the coadministration of progesterone. We also observed that KGF administration to cells, with KGFR upregulated expression, stimulated ERK1/2 phosphorylation and cell adhesion to fibronectin. The implications of the hormone-stimulated KGF-KGFR expressions in the regulation of cell behavior associated with human endometrial cancer are discussed.

Defined localization of nestin-expressing cells in L-arginine-induced acute pancreatitis.

OBJECTIVE: Nestin is a stem cell marker originally described as an intermediate filament protein expressed in neuroepithelial stem cells. In the pancreas, a small number of nestin-expressing cells, which are believed to represent either stem cells or progenitor cells, are known to be present in islets, as well as in some stellate cells, pericytes, and endothelial cells. We monitored pancreatic nestin expression to delineate the location of stem cells/progenitor cells in the pancreas after L-arginine-induced pancreatitis. METHODS: Male Wistar rats received 2 intraperitoneal injections of L-arginine, each consisting of 250 mg/100 g of body weight, and were killed 3, 6, and 12 hours and 1, 4, 7, and 14 days later. RESULTS: Serum amylase and lipase levels increased after L-arginine injection, maximal levels occurring at 3 and 12 hours postinjection, respectively. Six hours after L-arginine injection, interstitial edema was observed in the pancreas, whereas on day 4 postinjection, there was severe pancreatic necrosis. Neovascularization and ductal-ductular proliferation were also present in the pancreas. Immunohistochemical analysis revealed increased Ki-67 labeling in acinar cells and capillary endothelial cells. Immunoblotting using antinestin antibody revealed increased nestin expression after L-arginine injection. In the control rat pancreas, nestin immunoreactivity was detected in a few capillary endothelial cells in some islets. After L-arginine injection, nestin was expressed in proliferating capillary endothelial cells, in stellate cells surrounding ductular structures and in submesothelial cells. CONCLUSIONS: Transient nestin expression occurs in specific cell types during the proliferative stage after recovery from L-arginine-induced pancreatitis and may represent the contribution of stem cells and/or progenitor cells to the regenerative capacity of the pancreas.

Characteristic localisation of denatured high-density lipoprotein (HDL) at the periphery of a lipid core in human atherosclerotic lesions.

AIMS: High-density lipoprotein (HDL) has been reported to efflux cholesterol (Chl) from the cell membrane, and the physiological balance between the influx and efflux of Chl is important in the formation of atherosclerotic lesions. METHODS: In order to clarify these mechanisms in atherosclerotic lesions, the ratios of areas of apoprotein A-I (apo A-I)-positive areas were determined using a fluorescence polarisation microscope coupled to a spectrometer. RESULTS: According to the staining patterns of apo A-I, atherosclerotic lesions are classified into three types, namely, focal dense area (FA), diffuse dense area (DA) and shading area (SA). In FA, protein was prominent and lipid was minimal in the intercellular space of degenerated cells in the thickened intima. In DA, the protein and lipid were co-localised. In SA, at the periphery of lipid core, more lipids were present than protein. In the developed lesions, FA and SA were statistically bigger than those in the early lesions. CONCLUSIONS: These results suggest that an effective micro-solubilisation mechanism in FA may result in a low lipid content. Moreover, accumulated HDL may alter the relationship between various lipid vesicles and crystals in the extracellular matrix, and be an additional factor for the fragility of atheromatous plaques at the periphery of the lipid core.

Pathogenesis and protection of ischemia and reperfusion injury in myocardium.

The important factors that influence the progress of ischemic cardiac lesion are blood flow condition and abnormal cardiac metabolism. Myocardial ischemia is promoted by either an increase in oxygen demand or a shortage of oxygen supply. The Na(+)-Ca(++) ion exchange mechanism is very important for myocardial contraction and cell damage. Na(+)-K(+)ATPase and Ca(++)ATPase are enzyme histochemically localized in subsarcolemmal cisterns, sarcolemmal reticulum and capillary endothelium, and keep myocardial function. These ATPases are impaired by anoxia, superoxides and free radicals. The reduction of O(2) results in the production of superoxides as well as hydrogen peroxide (H(2)O(2)). H(2)O(2) is highly diffusible and induces cell damage. H(2)O(2) appears to affect not only lipids but also intramembranous proteins embedded in the cell membrane. The hydroxyl radical (OH) also participates in lipid hyperoxidation. In the pathogenesis of ischemic and/or reperfused heart disease, ischemia induces rapid or gradual changes in all membrane systems and causes reversible or irreversible injury including necrotic and apoptotic cell death. Advanced glycation end products (AGEs) accumulation induced by diabetic conditioning is an etiologic factor inducing cardiomyopathy. The AGEs protein affects cell changes such as increased number, transformation, functional disturbance and cytokine elimination. In coronary arteries, the migration of smooth muscle cells caused by the taking up of AGEs proteins through the receptor (RAGE), and cytokine discharge are suggested. AGEs accumulation may induce diabetic macroangiopathy through RAGE, and the increase in the level of RAGE expression by endothelial cells could be a reason that diabetes mellitus accelerates atherosclerosis. On the other hand, we also reported that hyperglycemia was a promoting factor of ischemic heart injury in diabetic animals. Ischemic preconditioning is a useful phenomenon that limits myocardial damage. We foused on protein kinase C (PKC), mitogen-activated protein kinase (MAPK) and mitochondrial ATP-dependent potassium (mitoK(ATP)) channel as mediator or end which effector are necessary for adaptation. The opening of the mitoK(ATP) channel induces the depolarization of mitochondria, reducing Ca(++)overload during reperfusion. The regeneration of myocardial cells is confirmed using embryonic stem cells. Myocardial cells that exhibit self-pulsation are generated from mesenchymal stem cells in mesodermal tissues of the bone marrow.

Expression of keratinocyte growth factor receptor (KGFR/FGFR2 IIIb) in vascular smooth muscle cells.

Keratinocyte growth factor receptor (KGFR), also known as fibroblast growth factor receptor (FGFR)2 IIIb, is located in many types of epithelial cells and is activated by four known ligands (FGF-1, FGF-3, FGF-7 (also known as KGF) and FGF-10) that are predominantly synthesized by mesenchymal cells. In the early stage of atherosclerosis, vascular smooth muscle cells (VSMC) transform from a contractile to a synthetic phenotype, proliferate and migrate into the intima. Previously, FGF-7 mRNA expression was reported in VSMC, but KGFR mRNA was not detected. In the present study, we attempted to determine whether KGFR is localized in VSMC cultured from rat aorta and VSMC in human normal and atherosclerotic coronary arteries. Expression of KGFR mRNA and its protein was detected in cultured rat VSMC by reverse transcription-polymerase chain reaction and western blot analysis, respectively. Immunohistochemically, KGFR was localized in the VSMC of the outer layer of the media in normal human coronary arteries. Furthermore, it was localized in the VSMC of the media and thickened intima of atherosclerotic arteries. Recombinant FGF-7 and/or FGF-10 proteins stimulated the growth of cultured rat VSMC. These findings indicate that KGFR localized in VSMC may contribute to the proliferation of VSMC in normal and atherosclerotic arteries.

Clinical application of a CT-guided lung biopsy system: core needle biopsy at the IVR center.

Prior reports of CT-guided lung biopsy of the small lung nodules of less than 2 cm have been unsatisfactory. In January 1998, we began a preliminary study of CT-guided lung biopsy in our conventional CT room. With the basic results achieved, we constructed a novel CT-guided lung biopsy system. Together with Hitachi Corporation we have developed CT, the Radix Prima, exclusive for interventional procedures especially for CT-guided lung biopsy. As reconstruction delay time of the procedures has been shortened from 1.0 sec. to 0.6 sec., real time CT fluoroscopy monitoring is possible on the Cathode Ray Tube (CRT) monitor in the CT room, very closed to the patient. Multiple confirmations of the tip of the biopsy needle have been possible with this specially equipped CT. A semi-automatic-type needle have been selected for reliable biopsy, because the old fully-automatic-type needle was very heavy and easily misfired. Multiple punctures have been also used, because single punctures have a greater risk of obtaining inadequate specimens. In our clinical study at our IVR center, the subjects comprised 41 patients (26 males, 15 females, ranging in age from 34 to 79, mean 64 years old). The mean nodule diameter was 1.9 cm, the mean distance from skin surface to lesion was 5.5 cm, and the mean number of punctures was 3.0. The biopsy results included 23 malignancies. In 13 patients the results were benign tumors or specific inflammation. In 4 patients the results were nonspecific inflammation. In only 1 patient was the specimen inadequate. There was no false negative. The correct rate of benign/malignant diagnoses was 98%. A complication of pneumothorax was observed in 22 patients, but all were improved by conservative treatment. Pulmonary hemorrhage was observed in 21 patients, 7 of whom also had hemoptysis. Each of these patients also responded to conservative treatment from specialist medical staff at the IVR center. The 98%accuracy of our results indicates that multiple punctures using a semi-automatic-type biopsy needle and multiple confirmations of the needle tip on our method of real time CT fluoroscopy are extremely important for CT-guided lung biopsy of small lung nodules of less than 2 cm.

Expression of lumican in thickened intima and smooth muscle cells in human coronary atherosclerosis.

Lumican is a member of a small leucine-rich proteoglycan family. Members of this family play an important role in cell migration and proliferation during embryonic development, tissue repair, and tumor growth. Lumican is reported to be overexpressed during the wound-healing process in the cornea and ischemic and reperfused heart. Recently, we found that lumican mRNA and its protein are expressed in cultured vascular smooth muscle cells (VSMCs) from the rat aorta. However, the expression and role of lumican in human atherosclerotic tissues are not clearly elucidated. In the present study, we aimed to clarify whether lumican is expressed in VSMCs and its localization in human coronary atherosclerotic tissues. The lumican protein and its mRNA were expressed in a small number of VSMCs in the media of normal coronary artery, but the lumican protein was not localized in the medial stroma. In contrast, the lumican protein and its mRNA were expressed in most of VSMCs that migrated into the thickened intima, but not in infiltrating foamy macrophages. The lumican protein was prominently localized in the thickened intimal stroma. The lumican protein and its mRNA were also expressed in VSMCs in the inner layer of the media and its protein was localized in medial stromal tissues. These findings indicate that the lumican protein is mainly synthesized by intimal and medial VSMCs in coronary atherosclerosis and that lumican contributes to collagen fibrillogenesis of coronary atherosclerosis.

Ultrastructural changes and immunohistochemical localization of advanced glycation end products in the heart of streptozotocin-treated Mongolian gerbils.

This study was designed to clarify the developing mechanism of cardiomyopathy and vasculopathy in streptozotocin-treated Mongolian gerbils. Twenty male Mongolian gerbils (MG; 10-12 weeks old) were used, and 150 mg/kg of streptozotocin (STZ) was injected into the left femoral vein. Six control male MG were injected intravenously with normal saline. The animals showed severe hyperglycemia (up to 330 +/- 96.4 mg/dl) by 1 week after streptozotocin administration. At 1 week after STZ treatment, cardiomyocytes revealed no significant change, but unclear striated structures were demonstrated in cardiomyocytes at 4 weeks. After 1 year, anisocytosis was observed, and in the perinuclear region granular components were stained positively with periodic acid-Schiff reagent. Ultrastructurally, at 4 weeks and 1 year after STZ treatment, cardiomyocytes were irregular in size, and oval amorphous and lysosomal electron-dense bodies were observed in perinuclear and cytoplasmic regions. In coronary arteries, endothelial and medial cells revealed increased vesicles and intercellular collagen fibrils. Capillaries showed slight swelling of endothelial cells associated with the lamellar thickening of basement membrane and collagen fibrils in the perivascular regions. Immunohistochemically, advanced glycation end products (AGE) were observed in the cytoplasm of vascular and heart cells, and ultrastructurally the reaction products were demonstrated in the endoplasmic reticulum and lysosomes of cardiomyocytes and vascular cells in the STZ-treated Mongolian gerbils. AGE may play an important role not only in angiopathy but also in cardiomyopathy of STZ-treated Mongolian gerbils after STZ treatment.