Pharmacogenomics of metabotropic glutamate receptor subtype 1 and in vivo malignant melanoma formation

We have previously shown that ectopic expression of metabotropic glutamate receptor subtype 1 in melanocytes is essential for both development and in vivo growth of melanoma using newly developed transgenic mice which conditionally express metabotropic glutamate receptor subtype 1 (mGluR1). In this study, we developed conditional transgenic mice, which harbor melanocytes not only in the dermis and hair follicles but also in the epidermis using stem cell factor transgenic mice. Pigmented plaques on the backs, tails, ears or groins of the transgenic mice began to appear 13 weeks after activation of the mGluR1 transgene, and the transgenic mice produced melanomas at a frequency of 100% 36 weeks after transgene activation. Although this transgenic mouse harbors melanocytes in the epidermis, proliferation of melanoma cells took place in the dermis. To elucidate the signals involved in development and growth of melanoma, inhibitors to phospholipase C, protein kinase C and mitogen‐activated protein kinase kinase 1/2, and antagonists to Ca²⁺ and calmodulin were administrated to transgenic mice. Each signal inhibitor to phospholipase, protein kinase C, Ca²⁺ release, calmodulin and mitogen‐activated protein kinase kinase 1/2 inhibited melanoma development. However, once melanoma was developed, the growth of melanoma was dramatically inhibited only by the inhibitor to mitogen‐activated protein kinase kinase 1/2 with partial inhibition by inhibitors to protein kinase C and phospholipase C. This inhibition of melanoma growth was well correlated with the expression of phosphorylated extracellular signal‐regulated kinase 1/2 and Ki‐67. These results indicate that for development of melanoma, activation of every signaling pathway from mGluR1 is required. However, for growth of melanoma, the extracellular signal‐regulated kinase pathway plays a key role.     

Oral Tolerance Induced by Enterobacteria Altered the Process of Lymphocyte Recruitment to Intestinal Microvessels: Roles of Endothelial Cell Adhesion Molecules,TGF‐beta and Negative Regulators of TLR Signaling

Objective: Although enterobacteria are implicated in intestinal immune response, there has been no report on how intraluminal pathogens affect lymphocyte recruitment. The aim of this study was to determine how the presence of intestinal flora affects lymphocyte migration to intestine under physiological and lipopolysaccharide (LPS)‐induced inflammatory conditions. Methods: Interaction of T‐cells with ileal microvessels was monitored by using an intravital microscope in mice under germ‐free (GF) and specific pathogen‐free (SPF) conditions. LPS was administered into either the peritoneal cavity or duodenum before lymphocyte injection. Results: Adherence of T‐cells was greater in SPF than in GF mice, indicating that the presence of enterobacteria upregulated migration under physiological conditions. Intraperitoneally administered LPS significantly increased the adherence of T‐cells in both GF and SPF mice accompanied by the expression of adhesion molecules and proinflammatory cytokines. However, intraluminally administered LPS did not enhance the adherence of T‐cells in SPF mice. A significant induction of increase in mRNA expression of IRAK‐M, a negative regulator of TLR4 signaling, and transforming growth factor beta (TGF‐beta), a regulatory cytokine, was observed in SPF mice after luminal LPS treatment. Conclusions: Tolerance to intraluminally administered LPS in the lymphocyte recruitment process was induced by enterobacteria, possibly via the induction of IRAK‐M and TGF‐beta.     

VDD Pacing with a Previously Implanted Single Lead System

Three patients who had undergone implantation of a rate modulated, afrial sensitive RS4 pacemaker, with a single orthogonal lead underwent replacement of a depleted unit with a DDD pulse generator, reusing the original lead with an adapter that allowed conversion of the bipolar atrial electrode into unipolar configuration. The mean atrial electrogram amplitude was 1,8 mV and no significant atrial sensing defects were found during Holler monitoring. As the RS4 pulse generator is no longer available, continued VDD pacing is possible by replacing it with a DDD pulse generator using the previously implanted single lead system.     

Successful management of lower pole moiety ureteropelvic junction obstruction in a partially duplicated collecting system using retrograde endoureteropyelotomy with the Holmium:YAG laser

Abstract  A patient with lower pole moiety ureteropelvic junction obstruction in a partially duplicated collecting system was managed successfully by retrograde endoureteropyelotomy using a Holmium:YAG laser. To our knowledge, we report the first case of this entity managed successfully by retrograde endoureteropyelotomy without a percutaneous approach.