Regulation of cadherin-mediated cell-cell adhesion by the Rho family GTPases.

Reports in the past two years have shown that Cdc42, Rac1, and Rho - belonging to the Rho small GTPase family - participate in the regulation of cadherin-mediated cell-cell adhesion. IQGAP1, an effector of Cdc42 and Rac1, interacts with cadherin and beta-catenin and induces the dissociation of alpha-catenin from the cadherin-catenins complex leading to disruption of cell-cell adhesion: activated Cdc42 and Rac1 counteract the effect of IQGAP1. Thus, Cdc42 and Rac1 appear to regulate cadherin-mediated cell-cell adhesion acting through IQGAP1.

Influence of common cardiac drugs on gastroesophageal reflux disease: multicenter questionnaire survey.

BACKGROUND: Although gastroesophageal reflux disease (GERD) causes noncardiac chest pain mimicking angina pectoris, systemic studies surveying the effects of common cardiac drugs on symptomatic GERD are rare. METHODS: To investigate the drugrelated GERD, this multicenter trial enrolled 201 consecutive cardiac outpatients (69.7 ± 10.5 y) after obtaining written informed consent. They were assessed using the Frequency Scale for Symptoms of GERD (F-scale) to screen for GERD with a cut-off value of 8.0. Clinical background was obtained from medical records. Gastric medicine was empirically administered at the discretion of the attending physician. F-scale score and incidence of GERD were analyzed individually in relation to background and prescription. RESULTS: The average F-scale score did not correlate with gender, age or underlying diseases. F-scale score was elevated significantly (p = 0.006) by administration of calcium channel blockers to the patients treated with gastric medicine, suggesting that calcium channel blockers exacerbate the possibly preexisting GERD. Incidence of GERD within 2 months after starting warfarin tended to be greater than that at other durations (p = 0.087). Patients showing a high score (≥ 8.0) suggestive of GERD showed a correlation with the combined administration of calcium channel blockers (OR = 3.19; 95% CI of 1.01 - 10.11; p = 0.049) and warfarin (OR = 3.05; 95% CI of 1.00 - 9.27; p = 0.049) in the best logistic model. CONCLUSION: Although larger cohort is required, this survey demonstrates that the combination of calcium channel blockers and warfarin is an independent risk factor for GERD.

Role of IQGAP1, a target of the small GTPases Cdc42 and Rac1, in regulation of E-cadherin- mediated cell-cell adhesion.

The small guanosine triphosphatases (GTPases) Cdc42 and Rac1 regulate E-cadherin-mediated cell-cell adhesion. IQGAP1, a target of Cdc42 and Rac1, was localized with E-cadherin and beta-catenin at sites of cell-cell contact in mouse L fibroblasts expressing E-cadherin (EL cells), and interacted with E-cadherin and beta-catenin both in vivo and in vitro. IQGAP1 induced the dissociation of alpha-catenin from a cadherin-catenin complex in vitro and in vivo. Overexpression of IQGAP1 in EL cells, but not in L cells expressing an E-cadherin-alpha-catenin chimeric protein, resulted in a decrease in E-cadherin-mediated cell-cell adhesive activity. Thus, IQGAP1, acting downstream of Cdc42 and Rac1, appears to regulate cell-cell adhesion through the cadherin-catenin pathway.

[A new technique of aortic occlusion in patient with severe aortic calcification].

A 63-year-old woman with severe aortic valve insufficiency and bilateral subclavian artery occlusion underwent ascending aorta-to-biaxillary artery bypass and aortic valve replacement, simultaneously. Because of severe aortic calcification, a hand-made aortic occluder was utilized to prevent embolic stroke. We believe that the new technique of aortic occllusion might be very useful for patients with severe aortic calcification.

Involvement of IQGAP1, an effector of Rac1 and Cdc42 GTPases, in cell-cell dissociation during cell scattering.

We have previously proposed that IQGAP1, an effector of Rac1 and Cdc42, negatively regulates cadherin-mediated cell-cell adhesion by interacting with beta-catenin and by causing the dissociation of alpha-catenin from cadherin-beta-catenin-alpha-catenin complexes and that activated Rac1 and Cdc42 positively regulate cadherin-mediated cell-cell adhesion by inhibiting the interaction of IQGAP1 with beta-catenin. However, it remains to be clarified in which physiological processes the Rac1-Cdc42-IQGAP1 system is involved. We here examined whether the Rac1-IQGAP1 system is involved in the cell-cell dissociation of Madin-Darby canine kidney II cells during 12-O-tetradecanoylphorbol-13-acetate (TPA)- or hepatocyte growth factor (HGF)-induced cell scattering. By using enhanced green fluorescent protein (EGFP)-tagged alpha-catenin, we found that EGFP-alpha-catenin decreased prior to cell-cell dissociation during cell scattering. We also found that the Rac1-GTP level decreased after stimulation with TPA and that the Rac1-IQGAP1 complexes decreased, while the IQGAP1-beta-catenin complexes increased during action of TPA. Constitutively active Rac1 and IQGAP1 carboxyl terminus, a putative dominant-negative mutant of IQGAP1, inhibited the disappearance of alpha-catenin from sites of cell-cell contact induced by TPA. Taken together, these results indicate that alpha-catenin is delocalized from cell-cell contact sites prior to cell-cell dissociation induced by TPA or HGF and suggest that the Rac1-IQGAP1 system is involved in cell-cell dissociation through alpha-catenin relocalization.

TIR-domain-containing adapter-inducing interferon-ß (TRIF) regulates Th17-mediated intestinal immunopathology in colitis.

Gastrointestinal mucosa reserves abundant Th17 cells where host response to commensal bacteria maintains Th17-cell generation. Although functional heterogeneity and dynamic plasticity of Th17 cells appear to be involved in chronic inflammatory disorders, how their plasticity is regulated in intestinal mucosa is unknown. Here we show that innate TRIF signaling regulates intestinal Th17-cell generation and plasticity during colitis. Absence of TRIF in mice resulted in increased severity of experimental colitis, which was associated with aberrant generation of Th17 cells especially of interferon (IFN)-γ-expressing Th17 cells in the lamina propria. The abnormal generation and plasticity of Th17 cells involved impaired expression of interleukin (IL)-27p28 by lamina propria macrophages but not dendritic cells. Treatment of TRIF-deficient mice with IL-27p28 during colitis reduced the number and IFN-γ expression of Th17 cells in the intestine. In vitro, TRIF-deficient macrophages induced more Th17 cells than wild-type (WT) macrophages during co-culture with WT naive T cells in response to cecal bacterial antigen. Many of Th17 cells induced by TRIF-deficient macrophages expressed IFN-γ due to impaired expression of IL-27p28 by macrophages and defective activation of STAT1 in T cells. These results outline TRIF-dependent regulatory mechanism by which host response to intestinal bacteria maintains Th17-cell-mediated pathology during colitis.

Hybrid-type stabilizer for off-pump direct coronary artery bypass grafting.

We have developed a mechanical stabilizer for use in off-pump direct coronary artery bypass grafting. We consider it an improvement on the sucker-type stabilizer, although it uses the mechanisms of the compressor-type. Our hybrid stabilizer effectively immobilizes the local heart surface with light compression and low evacuation. We believe that its use will eliminate the need for further immobilization and thus reduce cardiac invasiveness.

Intraoperative map guided operation for atrial fibrillation due to mitral valve disease.

BACKGROUND: This study was designed to determine if intraoperative atrial activation mapping facilitates operations for chronic atrial fibrillation associated with mitral valve disease. METHODS: Surgical treatment guided by intraoperative electrophysiologic mapping was performed in 12 patients with chronic atrial fibrillation associated with isolated mitral valve disease. In 10 of 12 patients, regular and repetitive activation (cycle length ranged from 118 to 210 msec) originated in the left atrial appendage and/or orifice of the left pulmonary vein. In the remaining 2 patients, dominant repetitive activation and sporadic complex activation were alternately observed in the left atrium. However, the activation sequence of the right atrium was extremely complex and chaotic. RESULTS: On the basis of intraoperative mapping, surgical procedures, including resection of the left atrial appendage and/or cryoablation of the orifice of the left pulmonary vein, were applied on the breakthrough site of the repetitive activation. No surgical procedure was performed on the right atrium in 11 patients. Ten of 12 patients (83%) have maintained sinus rhythm for 6 to 40 months (average 24.8 months) after operation. CONCLUSIONS: In the majority of the patients with isolated mitral valve disease, the left atrium acts as an electrical driving chamber for chronic atrial fibrillation. Computerized intraoperative mapping should guide surgeons in determining the appropriate surgical procedure for chronic atrial fibrillation.

Extended aortic replacement in acute dissection by the separated elephant trunk technique.

BACKGROUND: Extensive aortic replacement in acute dissection is currently not a widely accepted method of treatment. METHODS: We developed a safe method for extended aortic repair including the aortic arch in type A acute dissection, and describe here its application in 5 cases. This method was based on a modification of the elephant trunk method and several other strategies. Most of the procedures were carried out under simple hypothermic circulatory arrest. RESULTS: All patients recovered within 2 days without recurrent nerve injury. One patient suffered from unilateral upper arm palsy due to severe innominate dissection. Patients were all discharged and early postoperative computed tomography (CT) showed thrombotic obliteration around the elephant trunk. Follow-up CT after 4 to 18 months confirmed that thromboexclusion proceeded down to the distal end of the elephant graft in 1 patient and to the diaphragmatic level in 3 patients. Total obliteration was observed in the remaining 1 patient. CONCLUSIONS: This technique enables extended aortic repair in acute dissection with no increase in morbidity, and effectively promotes thromboexclusion of the dissected lumen to a wider extent than conventional methods.

Kinetics of Cd2+ in plasma, liver and kidneys after single intravenous injection of Cd-metallothionein-II.

To explore the kinetics of Cd2+ in the body, rats received a single intravenous injection of CdCl2 or Cd-saturated metallothionein-II at 0.3 mg Cd/kg body weight. Cd2+ in the two agents was biexponentially eliminated from plasma: rapidly in the first 5 min, and gradually later. Compared with CdCl2, Cd-saturated metallothionein-II showed lower Cd2+ concentrations in plasma during the first 30 min; larger values for parameters concerning distribution of Cd2+, its total body clearance and half-life time in the beta phase. Cd2+ uptake in the liver was higher with CdCl2, and, conversely, in the kidneys it was higher with Cd-saturated metallothionein-II. In Cd-saturated metallothionein-II, the renal content of Cd2+ reached a maximum (8 micrograms Cd2+/g tissue) on day 1, gradually decreasing thereafter; there was a higher area under the Cd2+ content-time curve, and a lower mean residence time of Cd2+; the kidneys showed severe necrosis and defluxion of proximal tubular cells at days 1 and 5, although there were regenerative and reversion signs on day 5. These findings suggested that, in the case of Cd-saturated metallothionein-II, Cd2+ being taken into the cells of proximal tubules was excluded predominantly due to cellular death and the resultant defluxion.

Partial sternotomy ("C" incision) as standard access for full range of adult cardiac operations.

OBJECTIVE: In our institute, partial sternotomy has been adopted for standard access in the full range of adult cardiac operations, including coronary artery bypass grafting. In this study, our clinical experience is reviewed. METHODS: Since April 1998, of 100 cardiac surgical patients, 64 underwent partial sternotomy, while 36 patients had the traditional full sternotomy because of high surgical risk factors or anatomical reasons. Most of the patients having minimal access had a "C" incision, that is, a left lower partial sternotomy. RESULTS: The procedures performed with the "C" incision were coronary artery bypass grafting, valve surgery, aortic root replacement, closure of atrial septal defect, and so on. There were two hospital deaths after partial sternotomy. Compared with full sternotomy patients, partial sternotomy patients had a shorter hospital stay, while their bypass times were longer. Their skin incisions were 11.7 cm on average. CONCLUSION: The "C" incision can provide satisfying results and can serve as the standard approach in the full range of cardiac operations.

Off-pump coronary artery bypass grafting via partial sternotomy. An alternative to left anterior small thoracotomy.

Four patients, who were considered to be inappropriate candidates for left anterior small thoracotomy, underwent off-pump coronary artery bypass grafting via partial sternotomy. Under a median skin incision over the lower half of the sternum, the sternum below the second rib was cut in an "inverted L" (or "C") shape. Without cardiopulmonary bypass, the left internal thoracic artery was anastomosed to the left anterior descending artery in all patients, and a saphenous vein graft was anastomosed to the right coronary artery in one of them. Partial sternotomy has some advantages as an alternative to left anterior small thoracotomy, in that it enables multiple-bypass grafting without cardiopulmonary bypass and conversion to cardiopulmonary bypass, should it be come necessary, would be relatively uncomplicated.

The role of pattern recognition receptors in intestinal inflammation.

Recognition of microorganisms by pattern-recognition receptors (PRRs) is the primary component of innate immunity that is responsible for the maintenance of host-microbial interactions in intestinal mucosa. Dysregulation in host-commensal interactions has been implicated as the central pathogenesis of inflammatory bowel disease (IBD), which predisposes to developing colorectal cancer. Recent animal studies have begun to outline some unique physiology and pathology involving each PRR signaling in the intestine. The major roles played by PRRs in the gut appear to be the regulation of the number and the composition of commensal bacteria, epithelial proliferation, and mucosal permeability in response to epithelial injury. In addition, PRR signaling in lamina propria immune cells may be involved in induction of inflammation in response to invasion of pathogens. Because some PRR-deficient mice have shown variable susceptibility to colitis, the outcome of intestinal inflammation may be modified depending on PRR signaling in epithelial cells, immune cells, and the composition of commensal flora. Through recent findings in animal models of IBD, this review will discuss how abnormal PRR signaling may contribute to the pathogenesis of inflammation and inflammation-associated tumorigenesis in the intestine.

NSAID-induced antral ulcers are associated with distinct changes in mucosal gene expression.

BACKGROUND: The basis for individual variation in gastroduodenal vulnerability to NSAIDs is not well understood. AIM: To assess whether a gene expression signature is associated with susceptibility to gastroduodenal ulcerations. METHODS: Twenty-five Helicobacter pylori negative adults were treated for 7 days with naproxen 500 mg b.d. Subjects underwent baseline and post-treatment endoscopy, during which biopsies were taken from antrum and duodenum. RNA extraction and cDNA synthesis were performed, followed by PCR of 23 genes relevant to mucosal injury and repair. Fold changes in gene expression were compared between subjects who developed ulcers and those who did not. RESULTS: Compared with subjects who did not develop ulcers (n = 18), subjects who developed antral ulcers (n = 7) had significantly greater mucosal up-regulation of interleukin-8 [Fold change = 33.5 (S.E.M. = 18.5) vs. -7.7 (3.2)] and of cyclo-oxygenase-2 [2.3 (1.7) vs. -10.8 (2.2)]. Conversely, non-ulcer subjects had significantly greater up-regulation of toll-like receptor-4, cyclo-oxygenase-1 and hepatocyte growth factor [14.0 (2.2) vs. -0.8 (1.0), 9.8 (2.4) vs. 0.0 (0.7) and 8.2 (2.6) vs. -2.2 (0.3) respectively]. CONCLUSIONS: NSAID-induced antral ulcers are associated with a specific pattern of gastroduodenal mucosal gene expression. These patterns may provide an insight into the molecular basis of individual susceptibility to mucosal injury.

Role of Toll-like receptors in gastrointestinal malignancies.

Mounting evidence supports the tenet that innate immune responses to luminal microbes participate in the development of gastrointestinal malignancies. The gastrointestinal tract is relatively unique in that it has evolved in the presence of diverse enteric microflora. Intestinal flora is required to develop a normal adaptive immune response in the periphery. With the characterization of the innate immune system, we have begun to understand the adaptations the intestine has made to the microbiota. The interaction between the microbiota and the intestinal mucosa through Toll-like receptors (TLRs) is required to maintain intestinal homeostasis. In particular, intestinal epithelial cells and lamina propria mononuclear cells such as antigen-presenting cells and T cells must respond to breaches in the mucosal barrier by activating TLR-dependent pathways that result in increased epithelial proliferation, wound healing and recruitment of acute inflammatory cells. In the setting of chronic inflammation such as Helicobacter pylori (H. pylori) infection in the stomach or idiopathic inflammatory bowel disease, the process of repair may eventually result in carcinogenesis. The following review highlights human and animal data that support a role for innate immune responses and TLRs specifically in promoting gastrointestinal malignancies. Candidate pathways linking TLRs to gastrointestinal malignancies include activation of nuclear factor-kappaB and cyclooxygenase-2. Studying the link between innate immune signaling and gastrointestinal malignancies offers the possibility to identify novel ways to both prevent and treat gastrointestinal cancer.