Cadherin-6 mediates the heterotypic interactions between the hemopoietic osteoclast cell lineage and stromal cells in a murine model of osteoclast differentiation

Osteoclasts are multinucleated cells of hemopoietic origin that are responsible for bone resorption during physiological bone remodeling and in a variety of bone diseases. Osteoclast development requires direct heterotypic cell-cell interactions of the hemopoietic osteoclast precursors with the neighboring osteoblast/stromal cells. However, the molecular mechanisms underlying these heterotypic interactions are poorly understood. We isolated cadherin-6 isoform, denoted cadherin-6/2 from a cDNA library of human osteoclast-like cells. The isolated cadherin-6/2 is 3,423 bp in size consisting of an open reading frame of 2,115 bp, which encodes 705 amino acids. This isoform lacks 85 amino acids between positions 333 and 418 and contains 9 different amino acids in the extracellular domain compared with the previously described cadherin-6. The human osteoclast-like cells also expressed another isoform denoted cadherin-6/1 together with the cadherin-6. Introduction of cadherin-6/2 into L-cells that showed no cell-cell contact caused evident morphological changes accompanied with tight cell-cell association, indicating the cadherin-6/2 we isolated here is functional. Moreover, expression of dominant-negative or antisense cadherin-6/2 construct in bone marrow-derived mouse stromal ST2 cells, which express only cadherin-6/2, markedly impaired their ability to support osteoclast formation in a mouse coculture model of osteoclastogenesis. Our results suggest that cadherin-6 may be a contributory molecule to the heterotypic interactions between the hemopoietic osteoclast cell lineage and osteoblast/bone marrow stromal cells required for the osteoclast differentiation. Since both osteoclasts and osteoblasts/bone marrow stromal cells are the primary cells controlling physiological bone remodeling, expression of cadherin-6 isoforms in these two cell types of different origin suggests a critical role of these molecules in the relationship of osteoclast precursors and cells of osteoblastic lineage within the bone microenvironment.     

Induction of tolerance to an experimental cardiac allograft through intrathymic inoculation of class II major histocompatibility complex disparate antigens

Indefinite donor-specific tolerance to a cardiac allograft can be induced through pretransplantation intrathymic injection of donor spleen cells and a single intraperitoneal injection of antilymphocyte serum. This study was designed to determine whether this phenomenon was reproducible with grafts differing in either class I major histocompatibility complex only or class II MHC only. Donors of cells and hearts in all experiments were RP rats. Class I MHC disparate grafts were performed by placing an RP heart into a Lewis recipient, and class II disparate grafts were performed with RP donors and Wistar Furth recipients. Lewis (n = 10) and Wistar Furth (n = 10) recipients underwent intraperitoneal injection of 1 ml antilympocyte serum and intrathymic injection of 5 x 10(7) RP spleen cells. Three weeks later, heterotopic cardiac transplantation was done with a heart from an RP rat. Control rats had no pretreatment or received antilympocyte serum alone. Without pretreatment, RP hearts survived 7 to 9 days (mean 8 days) in Lewis recipients (n = 5) and 9 to 14 days (mean 12 days) in Wistar Furth recipients (n = 5). Antilymphocyte serum alone produced slight prolongation of graft survival. Lewis rats pretreated with class I disparate RP splenocytes and antilympocyte serum had graft survivals of 8 to 27 days (mean 14 days), not significantly different from the results with antilympocyte serum alone. Class II disparate RP grafts placed in pretreated Wistar Furth rats had significant prolongation of graft survival, with four of five grafts surviving longer than 60 days (p < 0.01 vs antilympocyte serum alone). These results suggest that a disparity at the class II locus of the major histocompatibility complex is critical for the induction of cardiac allograft tolerance after intrathymic inoculation of allogeneic cells.     

Disruption of p53 function in immortalized human cells does not affect survival or apoptosis after taxol or vincristine treatment

OBJECTIVE: We assessed the feasibility of contrast-enhanced color Doppler, power Doppler, and spectral duplex sonography for visualization and quantification of flow through transjugular intrahepatic portosystemic shunts (TIPS) in patients in whom the baseline sonographic evaluation was unsatisfactory. SUBJECTS AND METHODS: Thirty-three patients underwent color Doppler, power Doppler, and spectral duplex sonography after TIPS insertion or before TIPS revision (mean time interval +/- SD, 1 +/- 1 day). All sonograms were obtained before and after patients received echo-enhancing contrast material. Sonography was evaluated with regard to presence or absence of flow in the mid portion, portal segment, and hepatic segment of the shunt. The maximal peak velocity was measured in the mid portion of the shunt. For identifying and quantifying stenoses, the percentage of luminal diameter reduction was calculated at the tightest part of the shunt. Shunt angiography and measurements of portosystemic pressure gradients were independently evaluated and compared with the sonographic findings. RESULTS: Flow visualization on unenhanced color Doppler sonography was significantly improved through the use of power Doppler sonography and contrast-enhanced color Doppler and power Doppler sonography (p < .01). Between contrast-enhanced power Doppler and contrast-enhanced color Doppler sonography, a significant difference was found in the portal and hepatic segments (p < .05). All shunt stenoses (n = 8) and occlusions (n = 3) were revealed by power Doppler sonography, whereas color Doppler sonography failed to reveal six of eight stenoses. Compared with unenhanced sonography, the quality of spectral duplex sonography was improved in eight patients after contrast enhancement (p < .05). Maximal peak velocity ranged from 54 to 252 cm/sec (mean +/- SD, 132.7 +/- 52.1 cm/sec) in normal shunts and from 24.5 to 70.0 cm/sec (mean +/- SD, 45.0 +/- 18.9 cm/sec) in stenosed shunts. No correlation was found between maximal peak velocity and portosystemic pressure gradients (r = .28). CONCLUSION: Unenhanced power Doppler and contrast-enhanced color and power Doppler sonography can be helpful in the assessment of TIPS status in patients who previously underwent unsatisfactory sonography. These techniques may allow anatomic evaluation and quantification of shunt stenosis in most patients. Contrast enhancement may also considerably improve the quality of spectral duplex sonography.     

Hospital-associated bacterial meningitis

Eighteen of 349 cases (5.2 per cent) of bacterial meningitis seen between 1949 and 1973 were hospital-associated (developed after admission to the hospital). The patients were adults, usually males, and developed symptoms and signs of meningitis from 2 to 23 days (mean, 10.1 days) after hospital admission. The diagnosis of bacterial meningitis was made from less than 1 day to 15 days (mean, 4.8 days) after the onset of symptoms. Fourteen of the 18 patients had received antibiotics during the week prior to developing meningitis. Nine (50 per cent) had a chronic, noninfection, underlying illness. Diagnostic or surgical procedures involving the neuraxis or adjacent structures preceded the development of meningitis in 10 of the 18 patients (56 per cent). Only 6 of the 18 patients survived their infection. Prompt recognition, diagnosis, and therapy of hospital-associated meningitis in high-risk patients may reduce the significant mortality.