Totally laparoscopic colectomy with intracorporeal anastomosis achieved using a laparoscopic linear stapler: experience of a single institute

Purpose  

Laparoscopic colonic surgery is now widely accepted. We assessed the safety and effectiveness of using a total intracorporeal surgical strategy to perform intracorporeal functional end-to-end anastomosis with an endoscopic linear stapler to treat colon cancer.     

Rho-Associated Kinase Inhibitor Reduces Tumor Recurrence After Liver Transplantation in a Rat Hepatoma Model

Tumor recurrence after liver transplantation still remains a significant problem in patients with hepatocellular carcinoma. The small GTPase Rho/Rho-associated kinase (ROCK) pathway is involved in the motility and invasiveness of cancer cells. We investigated whether tacrolimus activated the Rho/ROCK signal pathway to promote the invasiveness of rat hepatocellular carcinoma cells. We also investigated whether the ROCK inhibitor Y-27632 suppressed tumor recurrence after experimental liver transplantation in a rat hepatocellular carcinoma model. Orthotopic liver transplantation was performed in hepatocellular carcinoma cell line McA-RH7777-bearing rats. Tacrolimus was administered to liver transplant rats and these rats were divided into two groups: the Y-27632-treated (10 mg/kg, for 28 days) group and the Y-27632-untreated group. Tacrolimus enhanced the cancer cell migration and stimulated phosphorylation of the myosin light chain (MLC), a downstream effector of Rho/ROCK signaling. Y-27632 suppressed the cancer cell migration and tacrolimus-induced MLC phosphorylation. Suppression of tumor recurrence after liver transplantation and significant prolongation of survival were observed in the Y-27632-treated rats in comparison with theY-27632-untreated rats. Tacrolimus stimulates the Rho/ROCK signal pathway to enhance the invasiveness of hepatocellular carcinoma, and the ROCK inhibitor Y-27632 can be used as a new antimetastatic agent for the prevention of tumor recurrence after liver transplantation.     

Glucose intolerance caused by a defect in the entero-insular axis: a study in gastric inhibitory polypeptide receptor knockout mice

Mice with a targeted mutation of the gastric inhibitory polypeptide (GIP) receptor gene (GIPR) were generated to determine the role of GIP as a mediator of signals from the gut to pancreatic beta cells. GIPR-/- mice have higher blood glucose levels with impaired initial insulin response after oral glucose load. Although blood glucose levels after meal ingestion are not increased by high-fat diet in GIPR+/+ mice because of compensatory higher insulin secretion, they are significantly increased in GIPR-/- mice because of the lack of such enhancement. Accordingly, early insulin secretion mediated by GIP determines glucose tolerance after oral glucose load in vivo, and because GIP plays an important role in the compensatory enhancement of insulin secretion produced by a high insulin demand, a defect in this entero-insular axis may contribute to the pathogenesis of diabetes.     

Three susceptible loci associated with primary open-angle glaucoma identified by genome-wide association study in a Japanese population

Primary open-angle glaucoma (POAG) is the major type of glaucoma. To discover genetic markers associated with POAG, we examined a total of 1,575 Japanese subjects in a genome-wide association study (stage 1) and a subsequent study (stage 2). Both studies were carried out at a single institution. In the stage 1 association study, we compared SNPs between 418 POAG patients and 300 control subjects. First, low-quality data were eliminated by a stringent filter, and 331,838 autosomal SNPs were selected for analysis. Poorly clustered SNPs were eliminated by a visual assessment, leaving 255 that showed a significant deviation (P < 0.001) in the allele frequency comparison. In the stage 2 analysis, we tested these 255 SNPs for association in DNA samples from a separate group of 409 POAG and 448 control subjects. High-quality genotype data were selected and used to calculate the combined P values of stages 1 and 2 by the Mantel–Haenszel test. These analyses yielded 6 SNPs with P < 0.0001. All 6 SNPs showed a significant association (P < 0.05) in stage 2, demonstrating a confirmed association with POAG. Although we could not link the SNPs to the annotated gene(s), it turned out that we have identified 3 genetic loci probably associated with POAG. These findings would provide the foundation for future studies to build on, such as for the metaanalysis, to reveal the molecular mechanism of the POAG pathogenesis.     

No influence of OPG and its ligands, RANKL and TRAIL, on proliferation and regulation of the calcification process in primary human vascular smooth muscle cells

The aim of this study was to examine the effects of the OPG-RANKL-TRAIL system on proliferation, regulation of calcification-associated genes and calcification of human vascular smooth muscle cells (HVSMCs). Small interfering (si)RNA-mediated knockdown of OPG was followed by treatment of HVSMCs with recombinant RANKL or TRAIL. Regulation of a calcification-associated gene set was assayed by pathway analysis of microarray results. The lack of OPG in HVSMCs or treatment with RANKL or TRAIL did not affect proliferation of HVSMCs. In addition, OPG, RANKL or TRAIL did not modify the regulation of a calcification-associated gene set. Finally, in the long term calcification assay, we found that cells isolated from seven different human donors showed a great variability in the response to RANKL and insulin. However, overall RANKL and/or insulin did not affect the development of calcification of HVSMCs. These studies indicate that OPG knockdown does not alter the calcification process in HVSMCs.     

Unique mode of binding between angiotensin II type 1 receptor and its blockers

ABSTRACT

BACKGROUND: We hypothesized that the 5-oxo-1,2,4-oxadiazole moiety of azilsartan (AZL), which represents a small difference in the molecular structures of AZL and candesartan (CAN) [angiotensin II type 1 receptor (AT₁R) blockers], may be responsible for the molecular effects of AZL. METHODS: We examined the binding affinities of AZL and CAN to AT₁R, along with their ability to block receptor activity. A competition binding study, inositol phosphate (IP) production assay and extracellular signal-regulated kinase (ERK) assay were performed using wild-type (WT) and mutants AT₁R-transfected cells. RESULTS: The binding affinities of CAN and AZL were reduced by > 5-fold for Y35F, W84F, R167K, K199Q and I288A compared with WT. In addition, AZL showed a > 5-fold reduction in its binding affinity to V108A. CAN and AZL exhibited > 20-fold and > 100-fold reductions in binding affinity to R167K, respectively. The loss of binding affinity of AZL to R167K was greater than that of CAN. CAN-7H exhibited a > 10-fold reduction in binding affinity to R167K compared with CAN. On the other hand, the binding affinity of AZL-7H to R167K was comparable to that of AZL. While 10^-6M CAN and CAN-7H partly blocked Ang II-induced IP production in R167K, 10^-6M AZL and AZL-7H did not. In addition, 10^-6M CAN, but not 10^-6M AZL, partly blocked Ang II-induced ERK activation in R167K. CONCLUSIONS: The interaction between 5-oxo-1,2,4-oxadiazole in AZL and Arg¹⁶⁷ in the AT1R appears to be more important than the interaction between the tetrazole ring in CAN and Arg¹⁶⁷.     

Pharmacokinetics of ivermectin applied topically by whole‐body bathing method in healthy volunteers

As a novel administration method of ivermectin (IVM) for scabies treatment, we proposed a “whole‐body bathing method (WBBM)”. In this method, the patients would bathe themselves in a bathing fluid containing IVM at an effective concentration. Previously, we demonstrated that WBBM could deliver IVM to the skin but not to the plasma in rats. In the present study, to assess the clinical validity of the method an arm bathing examination (first trial) and a whole‐body bathing examination (second trial) were conducted in healthy volunteers. In both the first and second trials, after bathing in fluid containing IVM, the exposure in the stratum corneum was higher compared with that after taking IVM p.o. as reported previously. IVM was not detected in plasma at any sampling point after the whole‐body bathing in the second trial. Furthermore no serious adverse events were found. These results in both trials suggest that WBBM can deliver IVM to the human stratum corneum without systemic exposure or serious adverse effects in healthy volunteers, and at concentrations that would be adequate for scabies treatment.     

Age‐dependent decreases in serum soluble interleukin‐1 receptor type I (sIL‐1RI) in healthy individuals: a population study of serum sIL‐1RI levels in Japanese subjects

The levels of several soluble cytokine receptors in body fluids of healthy individuals change with age. Clinical application of the measurement of the serum soluble interleukin‐1 receptor type I (sIL‐1RI) level depends critically on the samples used as the controls. At present, there is no information regarding the levels of serum sIL‐1RI in healthy subjects. The purpose of this study is to reveal the age‐related changes that occur in the serum sIL‐1RIlevels of healthy individuals. We determined the serum sIL‐1RI levels of healthy Japanese children using ELISA. The serum sIL‐1RI level of children (0–14 years) was significantly higher than that of adults (more than 15 years) (P=0.0138, n=90). Thus, it is recommended that when the serum sIL‐1RI level of patients is evaluated, it should be compared against age‐matched controls. J. Clin. Lab. Anal. 23:175–178, 2009. © 2009 Wiley‐Liss, Inc.     

Silymarin enhanced cytotoxic effect of anti-Fas agonistic antibody CH11 on A375-S2 cells

Silymarin is a polyphenolic flavonoid from milk thistle (Silybum marianum), which has anti-inflammatory, cytoprotective as well as antioxidant effects. Our previous study demonstrated that silymarin has anti-apoptotic effect against UV irradiation. In this study, we assessed the effect of silymarin on anti-Fas agonistic antibody CH11-treated human malignant melanoma, A375-S2 cells. Pretreatment with silymarin (3 × 10^- 4 mol/L) significantly induced cell apoptosis in CH11-treated A375-S2 cells. Mitochondrial transmembrane potential (ΔΨ_m) was also down-regulated by silymarin pretreatment. Caspase-8, -9, -3 and pan-caspase inhibitors partially reversed silymarin-induced apoptosis of CH11-treated cells. The expression of Fas-associated proteins with death domain (FADD), a downstream molecule of the death receptor pathway, was increased by silymarin pretreatment, followed by cleavage of procaspase-8, whose activation induced cell apoptosis. Moreover, cleavage of procaspase-3 and digestion of its substrate, the inhibitor of caspase-activated DNase (ICAD), were also increased by silymarin pretreatment. These results suggested that silymarin could also exaggerate the apoptotic effect of anti-Fas agonistic antibody CH11 on A375-S2 cells.     

Cervical myelopathy due to a "tight dural canal in flexion" with a posterior epidural cavity

A 41-year-old man noticed weakness and atrophy in his right hand and forearm resembling the non-progressive juvenile muscular atrophy of unilateral upper extremity (Hirayama's disease). MRI showed an abnormal cavity in the posterior epidural space which appeared on neck flexion communicating with the subarachnoid space in addition to the flattening of the lower cervical spinal cord on neck flexion. When evaluating atypical cases of Hirayama's disease, the pathomechanism demonstrated in the present case should be taken into consideration.