On Benzofuroindole Analogues as Smooth Muscle Relaxants

At least two laboratories have independently reported the synthesis of benzofuroindole compounds having potential therapeutic implications in many disease states including those that involve smooth muscle hyperactivity. Through a series of in vitro screenings, they demonstrated the efficacy (and selectivity) of these compounds to potentiate large conductance calcium- (Ca2+-) activated K+ (BKCa) channels, by far, the most characterized of all Ca2+-dependent K+ channels. Interestingly, promising benzofuroindole derivatives such as compound 7 (10H-benzo[4,5]furo[3,2-b]indole) and compound 22 (4-chloro-7-trifluoromethyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid) both exhibited high bladder (versus aorta) selectivity, making them attractive alternative treatments for bladder overactivity. In recent reports, compound 22 (LDD175 or TBIC) also showed inhibition of ileum and uterine contractions, indicating multiple target tissues, which is not surprising as BKCa channels are ubiquitously expressed in the animal and human tissues. In this paper, the authors discuss the value of benzofuroindole compounds and the challenges that need to be overcome if they were considered as smooth muscle relaxants

Identification of antigen-presenting dendritic cells in mouse aorta and cardiac valves

Presumptive dendritic cells (DCs) bearing the CD11c integrin and other markers have previously been identified in normal mouse and human aorta. We used CD11c promoter-enhanced yellow fluorescent protein (EYFP) transgenic mice to visualize aortic DCs and study their antigen-presenting capacity. Stellate EYFP + cells were readily identified in the aorta and could be double labeled with antibodies to CD11c and antigen-presenting major histo-compatability complex (MHC) II products. The DCs proved to be particularly abundant in the cardiac valves and aortic sinus. In all aortic locations, the CD11c + cells localized to the subintimal space with occasional processes probing the vascular lumen. Aortic DCs expressed little CD40 but expressed low levels of CD1d, CD80, and CD86. In studies of antigen presentation, DCs selected on the basis of EYFP expression or binding of anti-CD11c antibody were as effective as DCs similarly elected from the spleen. In particular, the aortic DCs could cross-present two different protein antigens on MHC class I to CD8 + TCR transgenic T cells. In addition, after intravenous injection, aortic DCs could capture anti-CD11c antibody and cross-present ovalbumin to T cells. These results indicate that bona fide DCs are a constituent of the normal aorta and cardiac valves

Microbial stimulation fully differentiates monocytes to DC-SIGN/CD209 + dendritic cells for immune T cell areas

Dendritic cells (DCs), critical antigen-presenting cells for immune control, normally derive from bone marrow precursors distinct from monocytes. It is not yet established if the large reservoir of monocytes can develop into cells with critical features of DCs in vivo. We now show that fully differentiated monocyte-derived DCs (Mo-DCs) develop in mice and DC-SIGN/CD209a marks the cells. Mo-DCs are recruited from blood monocytes into lymph nodes by lipopolysaccharide and live or dead gram-negative bacteria. Mobilization requires TLR4 and its CD14 coreceptor and Trif. When tested for antigen-presenting function, Mo-DCs are as active as classical DCs, including cross-presentation of proteins and live gram-negative bacteria on MHC I in vivo. Fully differentiated Mo-DCs acquire DC morphology and localize to T cell areas via L-selectin and CCR7. Thus the blood monocyte reservoir becomes the dominant presenting cell in response to select microbes, yielding DC-SIGN + cells with critical functions of DCs

Flt3 signaling-dependent dendritic cells protect against atherosclerosis

Early events in atherosclerosis occur in the aortic intima and involve monocytes that become macrophages. We looked for these cells in the steady state adult mouse aorta, and surprisingly, we found a dominance of dendritic cells (DCs) in the intima. In contrast to aortic adventitial macrophages, CD11c +MHC II hi DCs were poorly phagocytic but were immune stimulatory. DCs were of two types primarily: classical Flt3-Flt3L signaling-dependent, CD103 +CD11b - DCs and macrophage-colony stimulating factor (M-CSF)-dependent, CD14 +CD11b +DC-SIGN + monocyte-derived DCs. Both types expanded during atherosclerosis. By crossing Flt3 -/- to Ldlr -/- atherosclerosis-prone mice, we developed a selective and marked deficiency of classical CD103 + aortic DCs, and they were associated with exacerbated atherosclerosis without alterations in blood lipids. Concomitantly, the Flt3 -/-Ldlr -/- mice had fewer Foxp3 + Treg cells and increased inflammatory cytokine mRNAs in the aorta. Therefore, functional DCs are dominant in normal aortic intima and, in contrast to macrophages, CD103 + classical DCs are associated with atherosclerosis protection

Current Management and Future Strategies of Gastric Cancer

The overall prognosis of gastric cancer has gradually improved over the past decades with growing awareness of potential carcinogens, surveillance programs and early diagnosis, as well as advances in surgical techniques and multimodality treatments. Nevertheless, the outcome of advanced stage disease still remains poor with currently available treatments, and a worldwide consensus on the standard management thereof has not been established. To improve prognosis and quality of life in gastric cancer patients, both standardization and individualization of managements are imperative. Diagnostic tests and surgical procedures need to be further sophisticated and standardized based on more recent evidences from ongoing and future randomized controlled trials, while comprehensive management should be individualized to each patient. Future challenges lie with how to optimize personalized therapies by deciphering biological complexity of gastric cancer and incorporating molecular biomarkers in clinical practice to forecast prognosis and to guide targeted therapeutics in adjunct to current standards of care

Reinforcing effects of methamphetamine in an animal model of Attention-Deficit/Hyperactivity Disorder-the Spontaneously Hypertensive Rat

Substrains of the Spontaneously Hypertensive rat (SHR), a putative animal model of Attention-Deficit/Hyperactivity Disorder (ADHD), have demonstrated increased sensitivity to many drugs of abuse, including psychostimulants. Therefore, it was suggested that studies in SHR may help elucidate ADHD and comorbidity with substance use disorder (SUD). However, the drug intake profile of the SHR in the most relevant animal model of drug addiction, the self-administration (SA) test, and its response on the conditioned place preference (CPP) paradigm are not yet determined. In the present study, we employed SA and CPP tests to investigate the reinforcing effects of the psychostimulant methamphetamine in an SHR substrain obtained from Charles River, Japan (SHR/NCrlCrlj). Concurrent tests were also performed in Wistar rats, the strain representing "normal" heterogeneous population. To address if the presence of ADHD behaviors further increases sensitivity to the rewarding effect of methamphetamine during adolescence, a critical period for the onset of drug abuse, CPP tests were especially conducted in adolescent Wistar and SHR/NCrlCrlj. We found that the SHR/NCrlCrlj also acquired methamphetamine SA and CPP, indicating reinforcing effects of methamphetamine in this ADHD animal model. However, we did not observe increased responsiveness of the SHR/NCrlCrlj to methamphetamine in both SA and CPP assays. This indicates that the reinforcing effects of methamphetamine may be similar in strains and that the SHR/NCrlCrlj may not adequately model ADHD and increased sensitivity to methamphetamine

Dimerization-Induced Fermi-Surface Reconstruction in IrTe2

We report a de Haas-van Alphen (dHvA) oscillation study on IrTe2 single crystals showing complex dimer formations. By comparing the angle dependence of dHvA oscillations with band structure calculations, we show distinct Fermi surface reconstruction induced by a 1/5-type and a 1/8-type dimerizations. This verifies that an intriguing quasi-two-dimensional conducting plane across the layers is induced by dimerization in both cases. A phase transition to the 1/8 phase with higher dimer density reveals that local instabilities associated with intra-and interdimer couplings are the main driving force for complex dimer formations in IrTe2.X11149sciescopu

Intracorporeal Anastomosis Using Linear Stapler in Laparoscopic Distal Gastrectomy: Comparison between Gastroduodenostomy and Gastrojejunostomy

Purpose: Intracorporeal anastomosis during laparoscopic gastrectomy is becoming increasingly prevalent. However, selection of the anastomosis method after laparoscopic distal gastrectomy is equivocal because of a lack of technical feasibility and safety. We compared intracorporeal gastroduodenostomy with gastrojejunostomy using linear staplers to evaluate the technical feasibility and safety of intracorporeal anastomoses as well as its' minimally invasiveness. Materials and Methods: Retrospective analyses of a prospectively collected database for gastric cancer revealed 47 gastric cancer patients who underwent laparoscopic distal gastrectomy with either intracorporeal gastroduodenostomy or gastrojejunostomy from March 2011 to June 2011. Perioperative outcomes such as operation time, postoperative complication, and hospital stay were compared according to the type of anastomosis. Postoperative inflammatory response was also compared between the two groups using white blood cell count and high sensitivity C-reactive protein. Results: Among the 47 patients, 26 patients received gastroduodenostomy, whereas 21 patients received gastrojejunostomy without open conversion or additional mini-laparotomy incision. There was no difference in mean operation time, blood loss, and length of postoperative hospital stays. There was no statistically significant difference in postoperative complication or mortality between two groups. However, significantly more staplers were used for gastroduodenostomy than for gastrojejunostomy (n=6) than for gastroduodenostomy and (n=5). Conclusions: Intracorporeal anastomosis during laparoscopic gastrectomy using linear stapler, either gastroduodenostomy or gastrojejunostomy, shows comparable and acceptable early postoperative outcomes and are safe and feasible. Therefore, surgeons may choose either anastomosis method as long as oncological safety is guaranteedope