Ulcerative proctitis, rectal prolapse, and intestinal pseudo-obstruction in transgenic mice overexpressing hepatocyte growth factor/scatter factor

Hepatocyte growth factor/scatter factor (HGF/SF) can stimulate growth of gastrointestinal epithelial cells in vitro; however, the physiological role of HGF/SF in the digestive tract is poorly understood. To elucidate this in vivo function, mice were analyzed in which an HGF/SF transgene was overexpressed throughout the digestive tract. Nearly a third of all HGF/SF transgenic mice in this study (28 of 87) died by 6 months of age as a result of sporadic intestinal obstruction of unknown etiology. Enteric ganglia were not overtly affected, indicating that the pathogenesis of this intestinal lesion was different from that operating in Hirschsprung's disease. Transgenic mice also exhibited a rectal inflammatory bowel disease (IBD) with a high incidence of anorectal prolapse. Expression of interleukin-2 was decreased in the transgenic colon, indicating that HGF/SF may influence regulation of the local intestinal immune system within the colon. These results suggest that HGF/SF plays an important role in the development of gastrointestinal paresis and chronic intestinal inflammation. HGF/SF transgenic mice may represent a useful model for the study of molecular mechanisms associated with a subset of IBD and intestinal pseudo-obstruction. Moreover, our data identify previously unappreciated side effects that may be encountered when using HGF/SF as a therapeutic agent.     

Slight difference in primary amino acid sequence of p17 matrix protein of HIV-1 exerts profound influence on its antigenicity

Summary.  HIV-1 p17 antigen has been studied for its biological significance in vitro as well as its immunological roles in vivo. By immunological approach of antibody-binding to HIV-1 p17 antigens of several subtypes in combination with computerized analysis of those tertial structures, it became evident that, irrelevant of similarity of linear amino acid sequence of different HIV-1 subtypes, a few amino acid substitutions close to or distant from specified epitope(s) affected their tertial structure resulting in change in ability of its binding to selected antibody. ELISA employing two monoclonal antibodies, A144 and C415, could detect p17 of subtypes A and B, but not of subtypes C, D, and E. Since the epitope site corresponding to A144 has been reported to be important for biological activity of p17 of HIV-1, change in tertial structure around this epitope may explain some difference in biology of HIV-1, such as infectivity of subtypes B and E. Accepted January 9, 1998 Received October 24, 1997     

EBI1-ligand chemokine (ELC) attracts a broad spectrum of lymphocytes: activated T cells strongly up-regulate CCR7 and efficiently migrate toward ELC

EBI1-ligand chemokine (ELC) is a CC chemokine constitutively expressed in various lymphoid tissues and a high-affinity functional ligand for EBI1/CCR7, a seven transmembrane G-protein-coupled receptor originally identified as an Epstein-Barr virus (EBV)-inducible gene. Here we examined chemotactic activity of ELC on peripheral blood leukocytes. ELC attracted both CD4+ and CD8+ T cells, particularly efficiently after activation with IL-2 or with phytohemagglutinin (PHA) plus IL-2, as well as CD19+ B cells, but not CD16+ NK cells, CD14+ monocytes or neutrophils. Among CD3+ T cells, ELC attracted both CD45RO- naive and CD45RO+ memory subsets. ELC also induced vigorous calcium mobilization in T cells stimulated with IL-2 with an ED50 of 3 nM. ELC fused with the secreted form of alkaline phosphatase (ELC-SEAP) specifically bound to lymphocytes and this binding was blocked only by ELC among 10 CC chemokines so far tested. Notably, lymphocytes stimulated with IL-2 or T cells expanded by PHA plus IL-2 showed much higher levels of binding than fresh lymphocytes. Consistently, CCR7 mRNA was detected in CD4+ and CD8+ T cells as well as B cells, but not in NK cells, monocytes or neutrophils, and was dramatically increased in T cells upon treatment with IL-2 or with PHA plus IL-2. Like ELC mRNA, CCR7 mRNA was expressed in various lymphoid tissues. By in situ hybridization, ELC and CCR7 mRNA were detected in the parafollicular and inner cortical regions of a lymph node, and in the parafollicular regions of an appendix. Collectively, ELC and CCR7 may be involved in the trafficking of a broad spectrum of lymphocytes, especially activated T cells, into and within various lymphoid tissues.      

Aldosterone

Aldosterone is one the representative cardiovascular hormones involved in the blood pressure and body-fluid homeostasis. Elevation of aldosterone leads to systemic hypertension through its action on the mineralocorticoid receptor (MR) in the kidney. More recent studies demonstrated that aldosterone may produce target organ damage through its direct actions on the non-epithelial MR of the heart in addition to its systemic effects. Clinical experience in primary aldosteronism supports the concept that aldosterone is a risk factor of cardiovascular complications, since concentric type of cardiac hypertrophy is most common in primary aldosteronism among various types of endocrine hypertension. Clinical mega-trial in congestive heart failure (RALES study, EPHESUS study) demonstrated blocking angiotensin II action is not sufficient for cardioprotection unless aldosterone action is equally blocked. An important phenomenon related to this issue is the aldosterone breakthrough which implies a reelevation of plasma aldosterone during chronic administration of ACE inhibitors and Angiotensin receptor antagonists. Normal level of aldosterone could still be a risk factor. Combination of ACE inhibitor or ARB with aldosterone antagonist could result in a better cardioprotection in cardiovascular diseases. Although spironolactone has been the only one aldosterone antagonist, a new antagonist eplerenone has been developed. Eplerenone is specific to MR and is practically devoid of the major side effect gynecomastia of spironolactone. Another topic of aldosterone is its very quick cardiovascular effect presumably via a non-genomic action. All these recent findings support that this adrenocortical steroid hormone is as important as angiotensin II. Determining aldosterone levels is therefore much morel important than before in the diagnosis and treatment of cardiovascular diseases.     

PROLIFERATIVE MYOSITIS AND FASCIITIS: Report of Five Cases with an Ultrastructural and Immunohistochemical Study

Cases of proliferative myositis and fasciitis were studied immunohisto-chemically and ultra structurally for further understanding of the nature of ganglion cell-like giant cells. Blood coagulation factor XIIIa, fibronectin, myoglobin, myosin, CPK MM, and alpha-1-antichymotrypsin were detected in three cases of proliferative myositis and two cases of proliferative fasciitis by the avid in-biotin-peroxidase complex method. Factor XIIIa (a fibrin-stabilizing factor) and flbronectin were strongly positive in the giant cells, but not in striated muscle fibers. A small quantity of myosin was demonstrated in the giant cells, but myoglobin and CPK MM were never demonstrated in these cells. No alpha-1-antichymotrypsin was demonstrated in the giant cells. One case of proliferative myositis showed ultrastructural features suggestive of fibroblast rather than muscle cell or histiocytic origin. Strongly positive factor XIIIa in the giant cells is suggestive of the fact that they are active fibroblasts.     

Projection of the retinal ganglion cells to the tectum differentiated from the prosencephalon.

The alar plate of the prosencephalon differentiates into a tectum-like structure when transplanted into the mesencephalon around the 10-somite stage. Here, we report on the projection pattern of the retinal ganglion cells to the transplants. Optic nerve fibers were labeled with horseradish peroxidase (HRP) and 3H-proline, and the innervation of the optic nerve fibers to the chimeric tectum was analyzed by HRP histochemistry on whole-mounted specimens, by autoradiography and by electron microscopy on embryonic day 16. In the chimeric tectum, the transplant was distinguished from the host by difference in nuclear structure between the quail and the chick cells. It was shown that the transplant had the laminar pattern of the optic tectum when the transplant was integrated into the host mesencephalon. The whole-mount HRP histochemistry showed that the optic nerve fibers extend to the transplants. Autoradiography showed that the distribution pattern of silver grains was similar in both the host and the transplant. These results may indicate that the optic nerve fibers turn to the transplant and terminate on the transplant. Electron microscopy further confirmed that optic nerve fibers ended by making synaptic contacts with the dendrites in the transplant region of the tectum. These results indicate that the transplant with the laminar pattern of the optic tectum is a true tectum receiving input from the eye.     

Vagal afferents interact with substance P-immunoreactive structures in the nucleus of the tractus solitarius: immunoelectron microscopy combined with an anterograde degeneration study

The morphological features of substance P-immunoreactive (SP-IR) structures in the nucleus of the tractus solitarius (NTS) were examined by immunoelectron microscopy combined with an anterograde degeneration study. Vagal afferents were allowed to degenerate by resecting the nodose ganglion two days prior to the examination. SP-IR axon terminals in the ipsilateral NTS were often found to make a synaptic contact with non-reactive dendrites in contact with degenerated terminals. SP-IR terminals also made contact with degenerated terminals, or SP-IR cells in contact with degenerated terminals. These findings suggest a close relationship between SP neuronal structures and vagal afferents in the NTS.