BACKGROUND:: This study investigated the influence of mechanical bowel preparation (MBP) on faecal microflora, using rRNA-targeted reverse transcription-quantitative polymerase chain reaction in patients undergoing colonic cancer resection. METHODS:: Forty-two patients undergoing elective colonic surgery were randomized into MBP or no-MBP groups (21 in each group). The main outcome was the bacterial microflora and faecal organic acid content of faecal material obtained at operation. RESULTS:: Clinical characteristics were similar in the two groups. Bowel content in the resected specimens did not differ significantly. The count of bacterial microflora, such as Bifidobacterium and total Lactobacillus, in both intraoperative faecal material and first material after surgery was significantly lower in the MBP group than the no-MBP group (P < 0.050). Levels of faecal organic acids, such as acetic acid, propionic acid and butyric acid, in intraoperative faecal material were significantly lower, and levels of lactic acid were significantly higher, in the MBP group than in the no-MBP group (P < 0.050). The succinic acid level was significantly higher after surgery than before operation in the MBP group (P = 0.008). CONCLUSION:: Preoperative MBP caused an imbalance in the bowel microflora, suggesting that it offers no advantages in terms of enterobacterial microflora for patients undergoing colonic cancer resection. Registration number: UMIN000003153 (http://www.umin.ac.jp/ctr/index.htm). Copyright (c) 2010 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Background: In this subanalysis of the CASE-J, which was conducted to compare the effects of candesartan and amlodipine in Japanese high-risk hypertensive patients, the association of left ventricular hypertrophy (LVH) with renal function is clarified. Methods and Results: Patients were divided into 2 groups: 1,082 patients with LVH and 2,119 patients without LVH. The primary endpoint was the change in the estimated glomerular filtration rate (eGFR). The eGFRs were increased from 63.6 to 65.1 ml . min(-1) . 1.73 m(-2) in patients with LVH and from 63.6 to 68.5 ml . min(-1) . 1.73 m(-2) in those without LVH. The improvement in the eGFR was greater in patients without LVH than in those with LVH (P=0.004). In patients with chronic kidney disease (CKD) patients, the eGFR increased from 52.7 to 60.5 ml . min(-1) . 1.73 m(-2) in patients without LVH, but from 53.1 to 57.2 ml . min(-1) . 1.73 m(-2) in those with LVH (P<0.001, patients without LVH vs patients with LVH). Furthermore, because the eGFR changed from 76.5 to 75.4 ml . min(-1) . 1.73 m(-2) in patients without CKD but with LVH, and from 76.5 to 77.5 ml . min(-1) . 1.73 m(-2) in those without either CKD or LVH, the final eGFR was higher in patients without LVH than in those with LVH (P=0.048). Conclusions: LVH related to the time-course of renal function in Japanese hypertensive patients.

The predominant risk factor of metabolic syndrome is intra-abdominal fat accumulation, which is determined by waist circumference and waist-hip ratio measurements and visceral fat area (VFA) that is measured by computed tomography (CT). There is evidence that waist circumference and waist-hip ratio in the Caucasian population are associated with variations in several genes, including neurexin 3 (NRXN3), transcription factor AP-2beta (TFAP2B), methionine sulfoxide reductase A (MSRA), lysophospholipase-like-1 (LYPLAL1), fat mass and obesity associated (FTO) and melanocortin 4 receptor (MC4R) genes. To investigate the relationship between VFA and subcutaneous fat area (SFA) and these genes in the recruited Japanese population, we genotyped 8 single-nucleotide polymorphisms (SNPs) in these 6 genes from 1228 subjects. Multiple regression analysis revealed that gender, age, and rs1558902 and rs1421085 genotypes (additive model) in FTO were significantly associated with body mass index (BMI; P=0.0039 and 0.0039, respectively), SFA (P=0.0027 and 0.0023, respectively) and VFA (P=0.045 and 0.040, respectively). However, SNPs in other genes, namely, NRXN3, TFAP2B, MSRA, LYPLAL1 and MC4R were not significantly associated with BMI, SFA or VFA. Our data suggest that some SNPs, which were identified in genome-wide studies in the Caucasians, also confer susceptibility to fat distribution in the Japanese subjects.Journal of Human Genetics advance online publication, 12 August 2010; doi:10.1038/jhg.2010.99.

BACKGROUND/AIMS: Cancer death in the early period after hepatectomy remains problematic in patients with hepatocellular carcinoma (HCC). We examined the relationship between clinicopathological parameters' and survival periods in 234 HCC patients who underwent hepatectomy. METHODOLOGY: Patients were divided into four groups: Group 1, survival > 5 years; Group 2, survival for 2-5 years; Group 3, cancer death at 2-5 years; and Group 4, cancer death in < 2 years. RESULTS: Numbers of patients in each subgroup were: Group 1, n = 87 (37%); Group 2, n = 44 (19%); Group 3, n = 46 (20%); and Group 4, n = 57 (24%). Child-Pugh B status, blood loss > 1500 ml, multiple tumors, tumor size > 5 cm, not meeting Milan criteria, irregular macroscopic findings, invasion of Glissonian pedicle, invasion of hepatic vein, higher modified Japan Integrated Staging score (3-5), long-term ascites after hepatectomy and postoperative tumor recurrence within 12 months were frequent in Group 4 ( p < 0.05). Multivariate analysis revealed AFP level > or = 1000 ng/ml (hazard ratio (HR), 2.6) and early tumor relapse (HR, 8.1) as independently related parameters ( p < 0.05). CONCLUSIONS: Careful follow-up for early tumor relapse may be important for improving postoperative outcomes in HCC patients with high preoperative AFP levels.

We synthesized pyrrolomorphinan derivatives 6, 7, and 9 to examine whether the pyrrole ring would be an accessory site in the kappa opioid receptor selective antagonist, nor-binaltorphimine. Derivative 6 had an alpha,beta-unsaturated ketone substituent that strongly bound to the kappa receptor. The compound with the highest kappa receptor selectivity, 6e, produced a dose-dependent antinociceptive effect in the mouse acetic acid writhing test. However, derivatives 7 and 9, which did not have alpha,beta-unsaturated ketone substituents, showed less kappa receptor selectivity than compound 6. Based on structure-activity relationships, we proposed that these compounds adopted active structures for kappa selective agonist activity. The pyrrole ring would not function as an accessory site, but the ability of the side chain on the pyrrole ring to localize above the C-ring appeared to confer kappa selective agonist activity. These results will promote the design of novel kappa agonists.

By using transgenic and knockout mice, we have elucidated that C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth. Furthermore, loss-of-function mutations in the gene coding for guanylyl cyclase-B (GC-B) , the specific receptor for CNP, have been proved to cause impaired skeletal growth in humans. Following these results, we have started to translate the stimulatory effect of CNP on endochondral bone growth into the therapy for patients with achondroplasia, and have shown that targeted overexpression of CNP in cartilage or systemic administration of CNP reverses the impaired skeletal growth of mice model of achondroplasia.

Adrenal neuroblastoma and pheochromocytoma have the same embryonic origin from neural crest cells and mainly arise from the adrenal medulla. Recently, transgenic mice exhibiting tumors in the bilateral adrenal medulla by the expression of SV40 T-antigen were developed. In this study, we investigated mRNA expression in adrenal tumors of transgenic mice and compared them with human pheochromocytoma by DNA microarray analysis. To compare mouse adrenal tumors and human pheochromacytoma, we found that the expressions of noradrenergic neuron-related genes, including dopa decarboxylase, phenylethanolamine-N-methyltransferase and chromogranin B, were up-regulated in humans but not in mice; however, the expression of neuroblastoma-related genes, including Mycn, paired-like homeobox 2b, gamma-aminobutyric acid A receptor beta3 subunit, islet 1 and kinesin family member 1A, was up-regulated in both species. From the gene expression profiles, the characterization of mouse adrenal tumor, may be similar to that of human adrenal neuroblastoma rather than pheochromacytomas. This mouse model would be a useful tool for the development of anti-cancer drugs and for understanding the etiology of adrenal neuroblastoma.

In this review, isolation and characterization of several kidney-derived molecules are described, namely carbonic anhydrase XIV, cysteine-rich protein 61, and kidney-liver-specific immunoglobulin-like protein. Features of neutrophil gelatinase-associated lipocalin (LCN2 or human neutrophil lipocalin) as a kidney differentiation inducer and renal injury biomarker and also as an iron-carrier protein are also summarized. Furthermore, the concepts of forest fire theory and the biology of siderophore-binding proteins are discussed.

BACKGROUND AND PURPOSE Hypertriglyceridaemia is associated with an increased risk of cardiovascular disease. Irbesartan, a well-established angiotensin II type 1 receptor (AT(1)) blocker, improves hypertriglyceridaemia in rodents and humans but the underlying mechanism of action is unclear. EXPERIMENTAL APPROACH Male obese Koletsky (fa(k)/fa(k)) rats, which exhibit spontaneous hypertension and metabolic abnormalities, received irbesartan (40 mg.kg(-1).day(-1)) or vehicle by oral gavage over 7 weeks. Adipocyte-derived hormones in plasma were measured by ELISA. Gene expression in liver and other tissues was assessed by real-time PCR and Western immunoblotting. KEY RESULTS In Koletsky (fa(k)/fa(k)) rats irbesartan lowered plasma concentrations of triglycerides and non-esterified fatty acids, and decreased plasma insulin concentrations and the homeostasis model assessment of insulin resistance index. However, this treatment did not affect food intake, body weight, epididymal white adipose tissue weight, adipocyte size and plasma leptin concentrations, although plasma adiponectin was decreased. Irbesartan up-regulated hepatic expression of mRNAs corresponding to peroxisome proliferator-activated receptor (PPAR)alpha and its target genes (carnitine palmitoyltransferase-1a, acyl-CoA oxidase and fatty acid translocase/CD36) that mediate hepatic fatty acid uptake and oxidation; the increase in hepatic PPARalpha expression was confirmed at the protein level. In contrast, irbesartan did not affect expression of adipose PPARgamma and its downstream genes or hepatic genes that mediate fatty acid synthesis. CONCLUSIONS AND IMPLICATIONS These findings demonstrate that irbesartan treatment up-regulates PPARalpha and several target genes in liver of obese spontaneously hypertensive Koletsky (fa(k)/fa(k)) rats and offers a novel insight into the lipid-lowering mechanism of irbesartan.

A 62-year-old female was admitted for examination of an abnormal liver function. Plain CT and MRI of the abdomen showed marked hepatomegaly but no visible nodular lesion in the liver. On the 3rd hospital day she had hepatic encephalopathy and was treated with a course of high-dose steroids, but ultimately died of disease progression on the 7th hospital day. An autopsy revealed a small pulmonary nodule with the histological findings showing small cell carcinoma. There was almost complete parenchymal replacement with metastatic tumor in the liver. Neoplastic involvement of the liver should be considered in the differential diagnosis of fulminant hepatic failure of unknown etiology.

BACKGROUND: To assess the predictive value of polymorphism in nine genes, primarily thymidylate synthase (TS) and orotate phosphoribosyltransferase (OPRT), which relates to 5-fluorouracil (5-FU) metabolism, for toxicity in patients treated with oral uracil/tegafur (UFT) plus leucovorin (LV). PATIENTS AND METHODS: We treated 99 patients with stage II or III colorectal carcinoma with oral UFT + LV. Germline DNA from patients was genotyped for 5-FU and folate metabolism-relating genes. CYP2A6, tegafur-activating enzyme, and uridine diphosphate-glucuronosyltransferase 1A1 genetic variation were also assessed. Toxicity was graded by the National Cancer Institute Common Toxicity Criteria, version 2.0. RESULTS: The multivariate logistic regression revealed that OPRT 638G>C polymorphism was associated with grade 3 diarrhea [odds ratio (OR) 19.84 for patients with the C/C homozygous type compared with patients with wild type, P = 0.014] and polymorphisms of UGT1A1 were associated with hyperbilirubinemia (OR 38.76 for homozygotes and double heterozygotes of *6 or *28 compared with wild type, P = 0.0008). No relationships were observed between TS polymorphisms and any toxicity. CONCLUSIONS: OPRT polymorphism predicts toxicity, especially grade 3 or greater diarrhea to oral UFT + LV adjuvant chemotherapy, whereas TS does not, in our study cohort. UGT1A1 polymorphism seems to be a risk factor for hyperbilirubinemia due to UFT+LV.

BACKGROUND: Although sleep apnea has recently become a concern in patients with congestive heart failure (CHF), some patients with CHF exhibit characteristic oscillatory ventilation (OV) even when they are awake. We investigated the clinical significance of OV in patients with CHF, and effects of open-heart surgery on the OV. HYPOTHESIS: OV is an indicator of the severity of CHF, and this abnormal respiratory pattern improves with hemodynamic changes after open-heart surgery. METHODS: According to respiratory pattern in the cardiopulmonary exercise testing (CPX) before cardiac surgery, 50 patients with CHF were divided into 14 patients of OV-positive (OV+) and 36 patients of OV-negative (OV-). Then, the several indices of CPX before surgey, 1 week and 6 months after surgery were compared between the 2 groups. RESULTS: The peak VO2 before surgery was lower in OV+ patients than those in OV- patients (15.3 vs 18.8 m1/min/kg, p < 0.05). One week after surgery, anaerobic threshold (AT) and end-tidal C02 (ETC02) were lower in OV+ patients than those in OV- patients (AT: 9.5 vs 10,7 ml/min/kg, p < 0.05, ETCO2: 5.3 vs 5.6%, p < 0.05). However, 6 months after surgery, the statistical differences of these CPX parameters between the 2 groups were not found, and OV disappeared in 79% of OV+ patients. CONCLUSIONS: These data suggest that OV is an indicator of the severity of CHF, and gradually improved with the open-heart surgery. Copyright (c) 2010 Wiley Periodicals, Inc.

C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth through a subtype of membranous guanylyl cyclase receptor, GC-B. Although its two cognate natriuretic peptides, ANP and BNP, are cardiac hormones produced from heart, CNP is thought to act as an autocrine/paracrine regulator. To elucidate whether systemic administration of CNP would be a novel medical treatment for chondrodysplasias, for which no drug therapy has yet been developed, we investigated the effect of circulating CNP by using the CNP transgenic mice with an increased circulating CNP under the control of human serum amyloid P component promoter (SAP-Nppc-Tg mice). SAP-Nppc-Tg mice developed prominent overgrowth of bones formed through endochondral ossification. In organ culture experiments, the growth of tibial explants of SAP-Nppc-Tg mice was not changed from that of their wild-type littermates, exhibiting that the stimulatory effect on endochondral bone growth observed in SAP-Nppc-Tg mice is humoral. Then we crossed chondrodysplastic CNP-depleted mice with SAP-Nppc-Tg mice. Impaired endochondral bone growth in CNP knockout mice were considerably and significantly recovered by increased circulating CNP, followed by the improvement in not only their longitudinal growth but also their body weight. In addition, the mortality of CNP knockout mice was greatly decreased by circulating CNP. Systemic administration of CNP might have therapeutic potential against not only impaired skeletal growth but also other aspects of impaired growth including impaired body weight gain in patients suffering from chondrodysplasias and might resultantly protect them from their early death.

Subjecting cardiomyocytes to mechanical stress or neurohumoral stimulation causes cardiac hypertrophy characterized in part by reactivation of the fetal cardiac gene program. Here we demonstrate a new common mechanism by which these stimuli are transduced to a signal activating the hypertrophic gene program. Mechanically stretching cardiomyocytes induced nuclear accumulation of myocardin-related transcription factor (MRTF)-A, a co-activator of serum response factor (SRF), in a Rho- and actin dynamics-dependent manner. Expression of brain natriuretic peptide (BNP) and other SRF-dependent fetal cardiac genes in response to acute mechanical stress was blunted in mice lacking MRTF-A. Hypertrophic responses to chronic pressure overload were also significantly attenuated in mice lacking MRTF-A. Mutation of a newly identified, conserved and functional SRF-binding site within the BNP promoter, or knockdown of MRTF-A, reduced the responsiveness of the BNP promoter to mechanical stretch. Nuclear translocation of MRTF-A was also involved in endothelin-1- and angiotensin II-induced activation of the BNP promoter. Moreover, mice lacking MRTF-A showed significantly weaker hypertrophic responses to chronic angiotensin II infusion than wild-type mice. Collectively, these findings point to nuclear translocation of MRTF-A as a novel signaling mechanism mediating both mechanical stretch- and neurohumoral stimulation-induced BNP gene expression and hypertrophic responses in cardiac myocytes.

Limb-girdle muscular dystrophy type 2A (LGMD2A) is a genetic disease that is caused by mutations in the calpain 3 gene (CAPN3), which encodes the skeletal muscle-specific calpain, calpain 3 (also known as p94). However, the precise mechanism by which p94 functions in the pathogenesis of this disease remains unclear. Here, using p94 knockin mice (termed herein p94KI mice) in which endogenous p94 was replaced with a proteolytically inactive but structurally intact p94:C129S mutant protein, we have demonstrated that stretch-dependent p94 distribution in sarcomeres plays a crucial role in the pathogenesis of LGMD2A. The p94KI mice developed a progressive muscular dystrophy, which was exacerbated by exercise. The exercise-induced muscle degeneration in p94KI mice was associated with an inefficient redistribution of p94:C129S in stretched sarcomeres. Furthermore, the p94KI mice showed impaired adaptation to physical stress, which was accompanied by compromised upregulation of muscle ankyrin-repeat protein-2 and hsp upon exercise. These findings indicate that the stretch-induced dynamic redistribution of p94 is dependent on its protease activity and essential to protect muscle from degeneration, particularly under conditions of physical stress. Furthermore, our data provide direct evidence that loss of p94 protease activity can result in LGMD2A and molecular insight into how this could occur.

Esophageal cancer is a common cause of cancer death worldwide. Esophageal squamous cell carcinoma (ESCC) is the most predominant type. Certain microRNAs (miRNAs) function in tumorgenesis involved in important biological and pathologic processes. To reveal miRNAs' signatures of ESCC, we analyzed miRNAs extracted from ESCC cell lines with the microRNA microarray. The significant alterations were confirmed by quantitative real-time PCR using miRNAs extracted from cell lines or patients' esophageal biopsy tissues. We found that miR-205 and miR-10a were significantly altered in cellular expression, and might be specific for ESCC with potential roles in the pathogenesis. As a result of function studies in miR-205, alterations in miR-205 expression could modulate the phenotype of epithelial cells towards epithelial-mesenchymal transition characterized by reduced abundance of E-cadherin, that is the ESCC-specific miRNA target and inhibit translationally a representative E-cadherin repressor, ZEB1 and ZEB2. Similarly, miR-10a is reported as a tumor suppressor by controlling cell migration/invasion, as it can target homeobox genes. These results provide insight into the potential mechanisms of ESCC in the pathogenesis. This review also includes a comprehensive overview of the relationship between miRNAs and ESCC.

Background: Extension of the inflammatory process into the terminal ileum in ulcerative colitis is termed backwash ileitis. Ulcerative colitis patients with pancolitis and backwash ileitis may be at increased risk of colorectal carcinoma. A case of ulcerative colitis-associated cancer with backwash ileitis, which extended proximally over time, is described.<br /> Case Report: A 67-year-old man was diagnosed with pancolitis; despite prednisolone and mesalazine treatment, he showed no improvement. Although initial endoscopic examination showed no abnormalities in the terminal ileum, a repeat colonoscopy 4 months later revealed erythema, absence of the vascular pattern, mucosal friability, and erosions within 30 cm of the terminal ileum in a continuous fashion from the cecum, and a flat, elevated lesion was found in the transverse colon. On histopathologic examination, the patient had nonspecific, active, chronic inflammation of the ileal mucosa, consistent with backwash ileitis, and colonic adenocarcinoma. Despite additional treatment with leukocytapheresis, the backwash ileitis progressed, with increased severity of mucosal inflammation and extensive erosions, 20 cm proximal to the primarily affected site of the ileum on repeat colonoscopy 2 months later. The patient underwent a proctocolectomy and excision of the terminal ileum with an ileostomy.<br /> Conclusions: Histopathology of the surgical specimen revealed marked backwash ileitis and submucosal, well-differentiated adenocarcinoma. The patient has remained well for 5 years after surgery.<br />

Atrial and brain natriuretic peptides (ANP and BNP, respectively) are cardiac hormones. During cardiac development, their expression is a maker of cardiomyocyte differentiation and is under tight spatiotemporal regulation. After birth, however, their ventricular expression is only up-regulated in response to various cardiovascular diseases. As a result, analysis of ANP and BNP gene expression has led to discoveries of transcriptional regulators and signaling pathways involved in both cardiac differentiation and cardiac disease. Studies using genetically engineered mice have shed light on the molecular mechanisms regulating ANP and BNP gene expression, as well as the physiological and pathophysiological relevance of the cardiac natriuretic peptide system. In this review we will summarize what is currently known about their regulation and the significance of ANP and BNP as hormones derived from the heart.

NSABP C-06 study showed that an oralUFT /Leucovorin(LV)regimen proved to be equivalent to an infusional 5-fluorouracil/LV regimen in an adjuvant setting for colorectalcancer. Thus, the oralregimen has been approved as the treatment of choice in Japan, but compliance of the regimen for Japanese patients has scarcely been reported. We assessed the compliance of oralUFT /LV adjuvant chemotherapy(5 cycles, 25weeks)in 99 consecutive colorectal cancer patients undergoing curative resection. Eighty-two percent(81 of 99)received all scheduled doses of UFT plus LV for five cycles. The mean relative dose intensity was 0. 87. Mean treatment courses given were 4. 5. The treatment was discontinued because of toxicity in 18 of the 99 patients. Nine of 18 received UFT only after the toxicities resolved. The remaining nine patients had no chemotherapy. The toxicity was generally mild. Six patients each had grade 3 diarrhea or anorexia, despite inclusion of overlapping cases. Fifteen of the 99 patients(15%)developed grade 3 toxicities. These results suggest that the compliance of oral UFT/LV treatment was equivalent to that of oral UFT adjuvant treatment for various cancers(80-90%).