Oxidative DNA damage induced by benz[a]anthracene metabolites via redox cycles of quinone and unique non-quinone

Benz[a]anthracene (BA) is one of the most abundant polycyclic aromatic hydrocarbons (PAHs) that are ubiquitous environmental pollutants. PAH carcinogenesis is explained by DNA adduct formation by PAH diol epoxide and oxidative DNA damage by PAH o-quinone. Benz[a]anthracene-trans-3,4-dihydrodiol (BA-3,4-dihydrodiol) is a minor metabolite but shows higher mutagenicity and tumorigenicity than parent BA. We confirmed that a BA o-quinone type metabolite, benz[a]anthracene-3,4-dione (BA-3,4-dione), induced oxidative DNA damage in the presence of cytochrome P450 reductase. Interestingly, we found that BA-3,4-dihydrodiol nonenzymatically caused Cu(II)-mediated DNA damage including 8-oxo-7,8-dihydro-2'-deoxyguanosine formation and the addition of NADH enhanced DNA damage. BA-3,4-dihydrodiol induced a double-base lesion of C and G at the 5'-ACG-3' sequence complementary to codon 273 of the human p53 tumor suppressor gene, which is known as a hotspot. The DNA damage was inhibited by catalase and bathocuproine, indicating the involvement of H(2)O(2) and Cu(I). Time-of-flight mass spectroscopic study suggested that BA-3,4-dihydrodiol undergoes Cu(II)-mediated autoxidation leading to the formation of its hydroxylated form of BA-3,4-dihydrodiol, capable of causing oxidative DNA damage. It is noteworthy that BA-3,4-dihydrodiol can nonenzymatically induce DNA damage more efficiently than BA-3,4-dione with metabolic activation. In conclusion, oxidative DNA damage induced by BA-3,4-dihydrodiol not only via quinone-type redox cycle but also via a new type of redox cycle participates in the expression of carcinogenicity of BA and BA-3,4-dihydrodiol.     

Antitumor properties of irinotecan-containing nanoparticles prepared using poly(DL-lactic acid) and poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)

Irinotecan-containing nanoparticles (NP) were prepared by coprecipitation with addition of water to acetone solution of poly(DL-lactic acid), poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) and irinotecan, and subsequent evaporation of organic solvent. NP were purified by gel filtration and used for experiments after condensation by evaporation. The obtained NP showed the drug content of 4.5% (w/w) and the mean particle diameter of 118 nm with the particle diameter distribution between 80-210 nm. When the antitumor effect was examined at a repeated dose of 20 mg irinotecan eq/kg for 3 d (3 x 20 mg/kg) using mice bearing Sarcoma 180 subcutaneously, only NP suppressed tumor growth significantly. After i.v. injection in rats, NP maintained irinotecan plasma concentration longer than CPT-11 aqueous solution. The present nanoparticle formation is suggested as a possibly useful dosage form of irinotecan against solid tumor.     

Antithrombin modulates the leukocyte-endothelial cell interaction in the staphylococcal enterotoxin B-challenged mouse

BACKGROUND: The beneficial effects of antithrombin on endotoxemia are well known. The purpose of this study was to examine the effects of antithrombin in a supertoxin-induced sepsis. METHODS: Mice were injected with staphylococcal enterotoxin B simultaneously with antithrombin. At 1 hour after injection, the mesenteric microcirculation was observed under intravital microscopy. In addition, humoral mediators were measured at the same time. RESULTS: The number of rolling leukocytes on the endothelium was significantly reduced in the treated mice (p < 0.01). The decrease of white blood cell and platelet counts was significantly inhibited in the treated animals (p < 0.01 for both). A comparison of the intercellular adhesion molecule-1 (p < 0.05), soluble tumor necrosis factor-alpha receptor (p < 0.05), and interleukin-6 (p < 0.01) levels showed less increase in the treated mice. CONCLUSION: Antithrombin showed a protective effects on the microcirculation of staphylococcal enterotoxin B-challenged mice by attenuating leukocyte-endothelial cell interaction. Suppression of adhesive molecule expression and cytokine production appears to play roles in this effect.     

Evaluation of preoperative portal embolization for safe hepatectomy,with special reference to assessment of nonembolized lobe function with 99mTc-GSA SPECT scintigraphy

BACKGROUND: Preoperative portal embolization (PE) is used to stimulate liver hypertrophy in the nonembolized lobe. We studied liver volume and function with computed tomography and technetium-99m-galactosyl human serum albumin ((99m)Tc-GSA) scintigraphy before PE and at 1 or 2 weeks after PE. METHODS: Right PE was performed in 30 patients. Morphologic and functional hypertrophy in the left lobe after PE was determined and related to the presence or absence of cholestasis, biliary drainage of the embolized lobe, and postoperative liver failure. RESULTS: The volume of the left lobe and (99m)Tc-GSA uptake increased rapidly for the first week after PE, but no significant increase was seen during the second week. Morphologic hypertrophy was less pronounced in patients with jaundice (P =.03). When PE was performed at a total bilirubin level above 2 mg/dL, the interval between PE and surgery was prolonged because of cholangitis and liver abscess formation. The net morphologic hypertrophy ratio was significantly higher in livers that had undergone left lobe drainage only (9.1% +/- 0.9%) compared with those in which there was drainage of the embolized lobes (5.7% +/- 0.9%; P =.03). The volume and (99m)Tc-GSA uptake of the left lobe in the second week after PE was significantly smaller in patients with postoperative liver failure (33.7% +/- 2.4% and 18.0% +/- 2.1%, respectively) than in patients without liver failure (46.2% +/- 1.4% and 38.4% +/- 2.3%; P =.003 and P =.01, respectively). CONCLUSION: In the nonembolized lobe, the functional increase in (99m)Tc-GSA uptake is more pronounced than suggested by the degree of morphologic hypertrophy. Whenever possible, biliary drainage should not be performed in the lobe undergoing hepatectomy. (99m)Tc-GSA SPECT scintigraphy is useful for the evaluation of postoperative liver failure.     

Structural and functional characterization of gastric mucosa and central nervous system in histamine H2 receptor-null mice

To examine the physiological role of the histamine H(2) receptor, histamine H(2) receptor-null mice were generated by homologous recombination. Histamine H(2) receptor-null mice, which developed normally and were fertile and healthy into adulthood, exhibited markedly enlarged stomachs and marked hypergastrinemia. The former was due to hyperplasia of gastric gland cells (small-sized parietal cells, enterochromaffin-like cells and mucous neck cells which were rich in mucin), but not of gastric surface mucous cells, which were not increased in number as compared with those in wild-type mice despite the marked hypergastrinemia. Basal gastric pH was slightly but significantly higher in histamine H(2) receptor-null mice. Although carbachol but not gastrin induced in vivo gastric acid production in histamine H(2) receptor-null mice, gastric pH was elevated by both muscarinic M(3) and gastrin antagonists. Thus, both gastrin and muscarinic receptors appear to be directly involved in maintaining gastric pH in histamine H(2) receptor-null mice. Interestingly, gastric glands from wild-type mice treated with an extremely high dose of subcutaneous lansoprazole (10 mg/kg body weight) for 3 months were very similar to those from histamine H(2) receptor-null mice. Except for hyperplasia of gastric surface mucous cells, the findings for gastric glands from lansoprazole-treated wild-type mice were almost identical to those from gastric glands from histamine H(2) receptor-null mice. Therefore, it is possible that the abnormal gastric glands in histamine H(2) receptor-null mice are secondary to the severe impairment of gastric acid production, induced by the histamine H(2) receptor disruption causing marked hypergastrinemia. Analyses of the central nervous system (CNS) of histamine H(2) receptor-null mice revealed these mice to be different from wild-type mice in terms of spontaneous locomotor activity and higher thresholds for electrically induced convulsions. Taken together, these results suggest that (1) gastrin receptors are functional in parietal cells in histamine H(2) receptor-null mice, (2) abnormal gastric glands in histamine H(2) receptor-null mice may be secondary to severe impairment of gastric acid production and secretion and (3) histamine H(2) receptors are functional in the central nervous system.     

Management of unresectable hilar bile duct cancer--preoperative diagnosis,treatment selection,and clinical outcome

BACKGROUND/AIMS: Hilar bile duct cancer progresses slowly but easily invades the nearby portal vein or hepatic artery. Thus, in some cases, curative resection is impossible, so we need to determine the best non-surgical treatments for this tumor. METHODOLOGY: We classified 98 patients with hilar bile duct cancer into 3 categories: a non-surgical group (34 cases), an exploratory laparotomy group (9 cases), and a surgical resection group (55 cases). Survival rates were examined in the light of clinical factors. RESULTS: In the non-surgical group, extensive vessel invasion was the most common reason for unresectability (13 cases), with broad biliary extension the second most common (11 cases). In the exploratory laparotomy group the most common reason for unresectability was severe vessel invasion (6 cases). Cumulative 1- and 2-year survival rates for patients with unresectable tumors without distant metastasis were 26.9% and 7.2%, respectively. One- and 2-year survival rates for patients with unresectable tumors and with total bilirubin of less than 2 mg/dL on discharge were 36.8% and 9.8%, respectively. The 1-year survival rate with placement of an expandable metallic stent was as high as 55.6%; without the stent it was 7.1% (P = 0.005). Radiation therapy gave a better prognosis than did no radiation (P = 0.01). CONCLUSIONS: Portal and arterial invasion were the principal reasons for unresectability. Use of an expandable metallic stent or radiation therapy, and a total bilirubin level of less than 2 mg/dL on discharge, were factors that enhanced survival in unresectable cases, but distant metastasis, dissemination, and poor general condition or liver function were negative factors for survival.     

Surgical anatomy of the inferior vena cava ligament

BACKGROUND/AIMS: The inferior vena cava ligament is a fibrous membrane located around the inferior vena cava. Few reports exist on the ligament's location, attachment to the liver, or the inferior vena cava. METHODOLOGY: We obtained 16 specimens of human liver and inferior vena cava from cadavers. The inferior vena cava ligament was photographed and then dissected for histological examination. Relationships among the ligament, inferior vena cava, and liver were examined microscopically. The numbers and diameters of veins, arteries, and lymph vessels at least 1 mm in diameter were recorded. RESULTS: The cranial margin of the inferior vena cava ligament was ended in a blind loop. The cranial portion above the mid-portion of the Spiegel lobe was thicker than the caudal portion. The ligament was attached to the right and left hepatic veins. The mean length of the right side of the inferior vena cava ligament was 37.0 mm and the mean width 15.6 mm. The inferior vena cava ligament had a mean thickness of 0.8 mm (thin end) and 2.5 mm (thick end). Although the inferior vena cava ligament was usually tightly continuous with the liver capsule, microscopically the attachment between the ligament and the inferior vena cava was loose. The mean number and diameter of veins in the inferior vena cava ligament was 1.0 and 1.4 mm, respectively. The mean number and diameter of arteries was 0.2 and 2.4 mm, respectively. The mean number and diameter of lymphatic vessels was 2.8 and 1.7 mm, respectively. CONCLUSIONS: After dissection of the inferior vena cava ligament, major hepatic veins can be dissected extrahepatically. Because the ligament is wider caudally, the forceps should be inserted caudocranially during separation. Since both the number and diameters of lymphatic vessels in the ligament are large, the ligament should be ligated and cut.     

Non-perforating pericardial rupture causing cardiac tamponade

A 51-year-old auto truck driver was transferred to our hospital after crashing. He had a severe pain on the left anterior chest wall with high central venous pressure of 30 cm H(2)O. Surveillance of the chest revealed cardiac tamponade and the right seventh rib fracture with left pleural effusion. Pericardiotomy through median sternotomy led to extrusive bloody pericardial effusion. Non-perforating pericardial laceration at the site of the adjoining muscular structure of the diaphragm was repaired with direct suture closure. His postoperative course was uneventful.     

Immunological responses in acute low-tone sensorineural hearing loss and Ménière's disease

OBJECTIVE: The autoimmune response appears to play an important role in some types of acute sensorineural hearing loss. Endolymphatic hydrops associated with fluctuating hearing loss has also been suggested to be caused by an immunological mechanism. Acute low-tone hearing loss (ALHL) associated with Ménière's disease (MD) is characterized by fluctuating hearing loss, and its etiology is thought to involve endolymphatic hydrops. The aim of this study was to attempt to determine the etiology of ALHL in MD. MATERIAL AND METHODS: A flow cytometer was used to analyze intracellular cytokine levels in peripheral blood from 19 patients with ALHL and 26 patients with MD and the data compared to those obtained from age- and gender-matched healthy volunteers. RESULTS: The patients with ALHL showed significantly increased levels of Th1 subsets (interferon-gamma-producing helper T cells) as compared to those in normal controls. The levels of Th2 (IL-4-producing helper T cells) subsets did not differ from those in the control group and thus Th1 predominated in ALHL patients. The patients with MD showed significantly increased natural killer cell activity but no Th1 dominance. These patients had no obvious systemic or local disease except in the inner ear. CONCLUSION: An abnormality of the Th1/Th2 balance in ALHL and increased natural killer cell activity in MD are thought to relate to inner ear disorder. These results are consistent with the possibility that the etiology of ALHL and MD involves an immune response.     

Intraocular hemangiopericytoma. A case report

A 55-year-old man presented with a smoothly elevated solid choroidal mass with choroidal detachment in the temporal region of the left eye. Both fluorescein and indocyanine green angiography suggested a vascularized lesion such as an angioma. However, radiographic examination revealed a solid, circumscribed, dome-shaped mass. During a 3-month observation, the mass gradually enlarged and invaded the iris. The possibility of malignant melanoma could not be ruled out. Due to rapid and continued growth of the tumor, the eye was enucleated. Histopathologic examination revealed proliferation of spindle-shaped cells surrounding reticulin-positive vessels, which is characteristic of hemangiopericytoma. To our knowledge, this is only the fourth reported case of intraocular hemangiopericytoma and the first diagnosed in a male patient.