Attenuation of lipopolysaccharide-induced acute lung injury after (pro)renin receptor blockade.

PURPOSE/AIM: We performed a randomized, prospective animal study to investigate whether inhibiting the renin-angiotensin system with a (pro)renin receptor blocker (PRRB) prevents acute lung injury (ALI) in a rodent model. MATERIALS: We used Thirty-six male Sprague-Dawley rats. We administered lipopolysaccharide (LPS; 2 mg/kg) intratracheally with or without PRRB pretreatment (1 mg/kg/d). METHODS: We performed bronchoalveolar lavage (BAL) and lung removal at 4 h after LPS administration and measured levels of inflammatory cytokines, high mobility group box 1 (HMGB-1) protein, and total protein in bronchoalveolar lavage fluid (BALF). Myeloperoxidase (MPO) activity was detected in lung tissue homogenates using a sensitive ELISA. We performed hematoxylin and eosin staining and immunohistochemical staining for nonproteolytically activated prorenin in the left lung. RESULTS: The PRRB decreased leukocyte counts and total protein, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-2, IL-6, and IL-10 levels in the BALF and MPO activity in lung tissue. The PRRB reduced interstitial edema, hemorrhage, and the neutrophil count in the lung tissues. Consistent with the reduction in lung tissue damage, immunohistochemical staining showed that the PRRB decreased the amount of nonproteolytically activated prorenin. CONCLUSIONS: The PRRB blocked LPS-induced inflammatory response in the lung and protected against ALI. Therefore, it is a potential therapeutic agent for preventing ALI.

Percutaneous endoscopic gastrostomy for decompression of malignant bowel obstruction.

BACKGROUND: Previous reports on percutaneous endoscopic gastrostomy (PEG) for bowel decompression have included a relatively small number of patients and the details of post-procedural outcomes and complications are lacking. The aim of the present study was to evaluate the outcomes and safety of PEG for bowel decompression in a relatively large number of patients with malignant bowel obstruction. PATIENTS AND METHODS: Over a 10-year period, 76 patients with malignant bowel obstruction were referred to the main referral cancer center in Shizuoka prefecture for PEG to obtain decompression. The method for gastrostomy was carried out by the pull-method, the modified introducer method and the percutaneous endoscopic gastrojejunostomy method. Patient demographics, procedural success, complications, elimination of nasal intubation, and survival were reviewed. RESULTS: Successful placement was achieved in 93% of patients (71/76). Procedure-related complications occurred in 21% ofpatients (15/71), of which the majority involved stomal leakage (eight patients), and wound infection (six patients). There were no procedure-related deaths. Among the 55 patients who required nasal intubation before PEG, a trans-gastrostomy intestinal tube was inserted in 16 patients. The need for further nasal intubation was eliminated in 96% of the patients (53/55). The median survival time was 63 days (range, 8-444 days) after PEG placement. CONCLUSIONS: PEG for bowel decompression in patients with malignant obstruction can be carried out with an acceptable risk of minor complications. In combination with a trans-gastrostomy intestinal tube insertion, the elimination of nasal intubation can be achieved in most patients.

(Pro)renin receptor blocker improves survival of rats with sepsis.

BACKGROUND: The renin-angiotensin system (RAS) affects inflammatory responses during sepsis. Nonproteolytic activation of prorenin by the (pro)renin receptor has recently been shown to stimulate the tissue RAS. In the present study, the effect of (pro)renin receptor blocker (PRRB) pretreatment on sepsis in a rat cecal ligation and puncture (CLP) model was investigated. MATERIALS AND METHODS: Male Sprague-Dawley rats underwent CLP and were randomly divided into two groups: PRRB-treated group and control peptide-treated group. Survival was analyzed for 7 d after CLP. The serum concentrations of cytokines and high-mobility group box chromosomal protein 1 (HMGB1) were measured at three time points (0, 3, and 6 h after CLP). Hematoxylin-eosin staining and immunohistochemical staining for nonproteolytically activated prorenin and HMGB1 were performed on the cecum to assess pathologic changes found 6 h after CLP. RESULTS: Treatment with PRRB improved the survival rate of the post-CLP septic rats (P = 0.023). PRRB also significantly reduced serum tumor necrosis factor-α, interleukin-1ß, and HMGB1 levels 6 h after CLP. In CLP rats that were treated with control peptide, the expression of activated prorenin was elevated in peritoneal foam cells. Moreover, expression of HMGB1 was increased in peritoneal inflammatory cells. In contrast, both were markedly suppressed in CLP rats that were treated with PRRB. CONCLUSIONS: PRRB significantly improved the survival rate of rats with clinically relevant sepsis, possibly by attenuating a sepsis-induced systemic inflammatory response. We propose that overactivation of the RAS by activation of prorenin in foam cells may be a significant contributor to sepsis.

Early gastric cancer with spreading to heterotopic gastric glands in the submucosa: a case report and review of the literature.

We report two cases of early gastric cancer (EGC) with spreading to heterotopic gastric glands (HGG). The first case was a submucosal-tumor-like EGC and proximal gastrectomy was performed. The second case was a slightly elevated EGC and endoscopic submucosal dissection was performed. In both cases, pathological results showed adenocarcinoma spreading to the HGG in the submucosa. The depth of cancer was diagnosed as intramucosal carcinoma because cancer was limited to the epithelium of HGG without invasion to the submucosal stroma. There is no clear guideline concerning the management of early gastric cancers with spreading to heterotopic gastric glands.

Gastric obstruction after endoscopic submucosal dissection.

BACKGROUND: Bleeding and perforation are two major complications of gastric endoscopic submucosal dissection (ESD). There are only a few reports concerning gastric obstruction related to ESD in the stomach. OBJECTIVE: The aim of this study was to clarify the clinicopathological features of patients who experienced gastric obstruction after gastric ESD. METHODS: Clinicopathological data of 1878 patients who underwent gastric ESD from September 2002 to December 2010 were retrospectively reviewed. Data of lesion location, circumference, circumferential extent of ESD ulcer, specimen diameter, depth of cancer, ulcer findings within the lesion, curability of ESD, number of simultaneous lesions, and occurrence of post-operative bleeding and perforation were collected. The risk of gastric obstruction regarding lesion and procedure related factors were assessed, and treatment for these patients was studied. RESULTS: Gastric obstruction was observed in 2.5% of the patients (47/1878). Symptoms occurred in a median of 24 days after ESD. The incidence among patients with lesions in the upper part of the stomach was 4.7% (17/316), 0.36% (3/818) in the middle, and 3.8% (27/699) in the lower part. In relation to the circumferential extent, the incidence was 50% (33/66) among patients with a resection of >75% of the circumference. Stenosis was observed in 87% (41/47) of patients with gastric obstruction. Endoscopic balloon dilation was performed in 45 patients. Perforation due to EBD occurred in four patients; one was referred to surgery. CONCLUSIONS: Patients with a wide resection of >75% of the circumference should be considered for early repeat endoscopy after ESD, and dilation should be performed with caution if found to have stenosis.

Endoscopic submucosal dissection for early gastric cancer in cases preoperatively contraindicated for endoscopic treatment.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is an optimal treatment for early gastric cancer (EGC) with negligible risk of lymph node metastasis; however, ESD is sometimes performed to treat lesions preoperatively contraindicated for the procedure due to various reasons. Here we aim to evaluate the treatment outcomes of ESD for lesions that were preoperatively contraindicated for ESD. PATIENTS AND METHODS: Clinicopathological data of 104 EGC lesions in 104 patients were reviewed retrospectively. The demographic characteristics of patients, reasons for ESD, treatment results, complications, and outcomes were assessed. RESULTS: The major reasons for undergoing ESD included advanced age, desire to undergo ESD, and the existence of comorbidities. En-bloc and complete resection rates were 97 and 71%, respectively. Perforation and postoperative bleeding rates were 13 and 9%, respectively. Resection was beyond the expanded Japanese criteria for endoscopic treatment of EGC in 87 patients (84%), 41 (47%) of whom underwent additional therapy, including subsequent gastrectomy (29 patients) and photodynamic therapy (12 patients). The median follow-up period was 47 months, during which seven patients died from recurrent disease. The 5-year overall and disease-specific survival rates were 70 and 91.5%, respectively. CONCLUSIONS: ESD is a technically demanding procedure for lesions preoperatively contraindicated for endoscopic resection. The curative resection rate was low, but the 5-year disease-specific survival rate of 91.5% was favourable. In experienced hands, ESD may be a treatment option for patients not suitable for radical surgery, and the relevant risk of complications must be considered before treatment.

Well-differentiated villoglandular adenocarcinoma of the uterine cervix: assessment of cytological features by histological subtypes.

OBJECTIVE: Well-differentiated villoglandular adenocarcinoma (VGA) of the cervix involves papillae lined by different types of epithelial cells that are histologically subclassified into endocervical, endometrioid, or intestinal subtypes. The objective of the current study was to evaluate the definite cytological features of VGA by histological subtype. STUDY DESIGN: We examined 8 cervical smears from patients confirmed to have pure VGA and classified them into the 3 histological subtypes. RESULTS: The cervical smears were highly cellular and had a relatively clean background. The nuclei had minimal anisonucleosis and fine granular chromatin with almost inconspicuous nucleoli. The characteristic findings of the endocervical type were a palisading arrangement consisting of columnar or spindle-shaped cells with apical or elongated nuclei. Small but clear nucleoli were identified only in the endocervical type. In the endometrioid type, tumor cells consisted of cohesive sheets with smooth edges and very round nuclei. Cytoplasmic vacuolation was never observed in the endometrioid type. The tumor cells in the intestinal type were prominent with abundant cytoplasmic mucin. CONCLUSIONS: We demonstrated that the cytological features of this tumor can vary depending on the histological subtype and one should be aware of these features in order to improve diagnostic accuracy.

Spherical sulfated cellulose adsorbs high-mobility-group box chromosomal protein 1 in vitro and in vivo.

High-mobility-group box chromosomal protein 1 (HMGB1) has recently been identified as a late mediator of various kinds of acute and chronic inflammation. A method for efficiently removing HMGB1 from systemic circulation could be a promising therapy for HMGB1-mediated inflammatory diseases. It is well known that the cationic portion of HMGB1 binds to heparin, which has abundant sulfates in its structure. In this study, we determined whether spherical sulfated cellulose (SC) efficiently adsorbed HMGB1, as well as other inflammatory mediators, in vitro. Then, we investigated the efficacy of hemoperfusion with the SC (SC group) or cellulose beads (control group) at adsorbing endogenous mediators, including HMGB1, in vivo. We have demonstrated that the SC adsorbed significantly larger amounts of HMGB1, interleukin (IL)-4, and IL-8 when compared with cellulose beads, in vitro. Hemoperfusion with the SC for 30 minute, starting 2 hour after an abdominal opening and closure operation, significantly reduced serum HMGB1 levels (p = 0.004) and consistently increased serum IL-10 levels, in vivo. These data suggest the potential benefits of hemoperfusion using the SC in treating HMGB1-mediated inflammatory diseases.

Identification and expression of a sialyltransferase responsible for the synthesis of disialylgalactosylgloboside in normal and malignant kidney cells: downregulation of ST6GalNAc VI in renal cancers.

Although disialyl glycosphingolipids such as GD3 and GD2 have been considered to be associated with malignant tumours, whether branched-type disialyl glycosphingolipids show such an association is not well understood. We investigated the sialyltransferases responsible for the biosynthesis of DSGG (disialylgalactosylgloboside) from MSGG (monosialylgalactosylgloboside). Among six GalNAc:alpha2,6-sialyltransferases cloned to date, we focused on ST6GalNAc III, V and VI, which utilize sialylglycolipids as substrates. In vitro enzyme analyses revealed that ST6GalNAc III and VI generated DSGG from MSGG with V(max)/K(m) values of 1.91 and 4.16 respectively. Transfection of the cDNA expression vectors for these enzymes resulted in DSGG expression in a renal cancer cell line. Although both ST6GalNAc III and VI genes were expressed in normal kidney cells, the expression profiles of ST6GalNAc VI among 20 renal cancer cell lines correlated clearly with those of DSGG, suggesting that the sialyltransferase involved in the synthesis of DSGG in the kidney is ST6GalNAc-VI. ST6GalNAc-VI and DSGG were found in proximal tubule epithelial cells in normal kidney tissues, while they were downregulated in renal cancer cell lines and cancer tissues. All these findings indicated that DSGG was suppressed during the malignant transformation of the proximal tubules as a maturation arrest of glycosylation.

Genetic polymorphisms of methylenetetrahydrofolate reductase and aldehyde dehydrogenase 2, alcohol use and risk of colorectal adenomas: Self-Defense Forces Health Study.

Methylenetetrahydrofolate reductase is a key enzyme in folate metabolism, which affects DNA synthesis and methylation and is possibly linked to colorectal carcinogenesis. Alcohol and acetaldehyde have an adverse effect on folate metabolism. This study investigated the relationship of functional MTHFR C677T and ALDH2 polymorphisms to colorectal adenomas with reference to alcohol consumption in a case-control study of male officials in the Self-Defense Forces (SDF) who received a preretirement health examination at two SDF hospitals. The study subjects were 452 cases of colorectal adenoma and 1050 controls with no polyp who underwent total colonoscopy. Genotypes were determined by the PCR-RFLP method using genomic DNA extracted from the buffy coat. Statistical adjustment was made for age, hospital, rank in the SDF, body mass index, cigarette-years and alcohol intake. Neither MTHFR C677T nor ALDH2 showed a measurable association with colorectal adenoma. While high alcohol consumption was associated with a moderately increased risk of colorectal adenoma, neither of the two polymorphisms showed a significant effect on the association between alcohol and colorectal adenoma. Individuals with the variant alleles ALDH2*2 and MTHFR 677T had a decreased risk of colorectal adenomas, showing adjusted odds ratios of 0.70 (95% confidence interval 0.49-1.00) for all adenomas and 0.57 (0.34-0.95) for large adenomas (> or = 5 mm), as compared to individuals with ALDH2*1/1 and MTHFR 677CC genotypes combined. The findings may be interpreted as suggesting that folate inhibits the growth of colorectal adenomas, but further confirmation is needed.

Genetic polymorphism in cytochrome P450 7A1 and risk of colorectal cancer: the Fukuoka Colorectal Cancer Study.

Bile acids have long been implicated in the etiology of colorectal cancer, but epidemiologic evidence remains elusive. Cholesterol 7alpha-hydroxylase (CYP7A1) is the rate-limiting enzyme in the synthesis of bile acids from cholesterol in the liver, and thus may be an important determinant of bile acid production. We examined the association between the CYP7A1 A-203C polymorphism and colorectal cancer. The CYP7A1 A-203C polymorphism was determined by the PCR-RFLP method in 685 incident cases of colorectal cancer and 778 controls randomly selected from a community in the Fukuoka area, Japan. The CC genotype was slightly less frequent in the case group, and the adjusted odds ratio for the CC versus AA genotype was 0.88 (95% confidence interval, 0.65-1.20). In the analysis by subsite of the colorectum, a decreased risk associated with the CYP7A1 CC genotype was observed for proximal colon cancer, but not for either distal colon or rectal cancer. The adjusted odds ratios (95% confidence intervals) of proximal colon cancer for the CC genotype were 0.63 (0.36-1.10) compared with the AA genotype, and 0.59 (0.37-0.96) compared with the AA and AC genotypes combined. A decreased risk of proximal colon cancer in relation to the CC genotype of CYP7A1 A-203C, which probably renders less activity of the enzyme converting cholesterol to bile acids, is new evidence for the role of bile acids in colorectal carcinogenesis.

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and colorectal cancer: the Fukuoka Colorectal Cancer Study.

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating folate metabolism, which affects DNA synthesis and methylation. This study investigated the relation of MTHFR C677T and A1298C polymorphisms to colorectal cancer in a case-control study in Fukuoka, Japan. The subjects comprised 685 incident cases of histologically confirmed colorectal adenocarcinomas and 778 community controls selected randomly in the study area. The genotype was determined by the PCR-RFLP method using genomic DNA extracted from buffy coat. Alcohol use was ascertained by in-person interview. Statistical adjustment was made for gender, age class, area, and alcohol use. The MTHFR 677TT genotype was associated with a statistically significant decrease in the risk with an adjusted odds ratio of 0.69 (95% confidence interval 0.51-0.93) compared with the 677CC and 677CT combined, and the decrease was most evident in individuals with no alcohol consumption. While the A1298C polymorphism showed no measurable association with the overall risk of colorectal cancer, the 1298CC genotype was associated with a statistically significant increase in the risk when alcohol consumption was high, and was also associated with an approximately 2-fold increase in the risk of each of proximal and distal colon cancer. The findings add to evidence that individuals with the MTHFR 677TT genotype have a decreased risk of colorectal cancer in the absence of folate depletion, suggesting a protective role of folate by ensuring a sufficient thymidylate pool for DNA synthesis. Because very few individuals had the 1298CC genotype, the findings regarding the A1298C polymorphism need careful interpretation and confirmation in larger studies.