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Thomas M. Suszynski,
Kristen J. Gillingham,
Michael D. Rizzari,
Ty B. Dunn,
William D. Payne,
Srinath Chinnakotla, Erik B. Finger,
David E.R. Sutherland,
John S. Najarian,
Timothy L. Pruett,
Arthur J. Matas,
Raja Kandaswamy
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ABSTRACT: Rapid discontinuation of prednisone (RDP) has minimized steroid-related complications following kidney transplant (KT). This trial compares long-term (10-year) outcomes with three different maintenance immunosuppressive protocols following RDP in adult KT. Recipients (n = 440; 73% living donor) from March 2001 to April 2006 were randomized into one of three arms: cyclosporine (CSA) and mycophenolate mofetil (MMF) (CSA/MMF, n = 151); high-level tacrolimus (TAC, 8-12 μg/L) and low-level sirolimus (SIR, 3-7 μg/L) (TAC(H) /SIR(L) , n = 149) or low-level TAC (3-7 μg/L) and high-level SIR (8-12 μg/L) (TAC(L) /SIR(H) , n = 140). Median follow-up was ∼7 years. There were no differences between arms in 10-year actuarial patient, graft and death-censored graft survival or in allograft function. There were no differences in the 10-year actuarial rates of biopsy-proven acute rejection (30%, 26% and 20% in CSA/MMF, TAC(H) /SIR(L) and TAC(L) /SIR(H) ) and chronic rejection (38%, 35% and 31% in CSA/MMF, TAC(H) /SIR(L) and TAC(L) /SIR(H) ). Rates of new-onset diabetes mellitus were higher with TAC(H) /SIR(L) (p = 0.04), and rates of anemia were higher with TAC(H) /SIR(L) and TAC(L) /SIR(H) (p = 0.04). No differences were found in the overall rates of 16 other post-KT complications. These data indicate that RDP-based protocol yield acceptable 10-year outcomes, but side effects differ based on the maintenance regimen used and should be considered when optimizing immunosuppression following RDP.
American Journal of Transplantation 02/2013; · 6.39 Impact Factor
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ABSTRACT: The shortage of deceased donor organs for solid organ transplantation continues to be an ongoing dilemma. One approach to increase the number of pancreas transplants is to share organs between procurement regions. To assess for the effects of organ importation, we reviewed the outcomes of 1014 patients undergoing deceased donor pancreas transplant at a single center. We performed univariate and multivariate analyses of the association of donor, recipient and surgical characteristics with patient outcomes. Organ importation had no effect on graft or recipient survival for recipients of solitary pancreas transplants. Similarly, there was no effect on technical failure rate, graft survival or long-term patient survival for simultaneous kidney-pancreas (SPK) recipients. In contrast, there was a significant and independent increased risk of death in the first year in SPK recipients of imported organs. SPK recipients had longer hospitalizations and increased hospital costs. This increased medical complexity may make these patients more susceptible to short-term complications resulting from the longer preservation times of import transplants. These findings support the continued use of organ sharing to reduce transplant wait times but highlight the importance of strategies to reduce organ preservation times.
American Journal of Transplantation 11/2011; 12(2):447-57. · 6.39 Impact Factor
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ABSTRACT: To compare tris-acryl microspheres and polyvinyl alcohol (PVA) microspheres as embolic agents in uterine artery embolization (UAE) for uterine leiomyomas in terms of clinical outcome, inflammatory response, and adverse reactions.
A double-blinded randomized controlled trial was performed, with 27 patients in the tris-acryl microsphere group and 29 in the PVA microsphere group. The primary endpoint was clinical success, defined as a 2-year freedom from subsequent surgery as a result of persistent or deteriorated symptoms. Secondary endpoints included (i) posttreatment leiomyoma enlargement, (ii) leiomyoma volume reduction at 3 and 9 months, (iii) significant residual intratumoral perfusion, (iv) increase in inflammatory and stress markers, (v) incidence of complications, and (vi) duration of hospital stay.
There was no statistically significant difference between the two groups in patient demographics, clinical presentation, initial tumor findings, change in inflammatory and stress markers after treatment, incidence of complications, and duration of hospital stay. Tris-acryl microspheres were associated with a higher rate of clinical success than PVA microspheres (96.3% [26 of 27] vs 69% [20 of 29]; P = .012), a lower incidence of posttreatment leiomyoma enlargement (P = .030), and a lower incidence of significant residual intratumoral perfusion (P = .030).
In the treatment of uterine leiomyomas, UAE with tris-acryl microspheres was associated with a higher clinical success rate, a lower incidence of tumor enlargement, and no significant differences in adverse reactions and inflammatory response compared with the use of PVA microspheres. Tris-acryl microspheres therefore represent the preferred agent for UAE of uterine leiomyomas.
Journal of vascular and interventional radiology: JVIR 09/2011; 22(9):1229-35. · 1.81 Impact Factor
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ABSTRACT: Two mechanisms have been proposed for regulating rolling velocities on selectins. These are (a) the intrinsic kinetics of bond dissociation, and (b) the reactive compliance, i.e., the susceptibility of the bond dissociation reaction to applied force. To determine which of these mechanisms explains the 7.5-11.5-fold faster rolling of leukocytes on L-selectin than on E- and P-selectins, we have compared the three selectins by examining the dissociation of transient tethers. We find that the intrinsic kinetics for tether bond dissociation are 7-10-fold more rapid for L-selectin than for E- and P-selectins, and are proportional to the rolling velocities through these selectins. The durations of pauses during rolling correspond to the duration of transient tethers on low density substrates. Moreover, applied force increases dissociation kinetics less for L-selectin than for E- and P-selectins, demonstrating that reactive compliance is not responsible for the faster rolling through L-selectin. Further measurements provide a biochemical and biophysical framework for understanding the molecular basis of rolling. Displacements of tethered cells during flow reversal, and measurements of the distance between successive pauses during rolling provide estimates of the length of a tether and the length of the adhesive contact zone, and suggest that rolling occurs with as few as two tethers per contact zone. Tether bond lifetime is an exponential function of the force on the bond, and the upper limit for the tether bond spring constant is of the same order of magnitude as the estimated elastic spring constant of the lectin-EGF unit. Shear uniquely enhances the rate of L-selectin transient tether formation, and conversion of tethers to rolling adhesions, providing further understanding of the shear threshold requirement for rolling through L-selectin.
The Journal of Cell Biology 10/1997; 138(5):1169-80. · 10.26 Impact Factor
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ABSTRACT: Selectins are a family of lectins that mediate tethering and rolling of leukocytes on endothelium in vascular shear flow. To test the hypothesis that the kinetics and the strength of rolling interactions can be independently varied for different selectin:ligand pairs, we have directly compared all three selectins with regard to distinct measures of selectin-mediated interactions in shear flow: tethering, rolling velocity, and strength of rolling adhesions. At comparable site densities of E-selectin, P-selectin, and the L-selectin counter-receptor CD34, neutrophils tethered with similar efficiency and developed rolling adhesions of similar strength as measured by resistance to detachment. Under the same conditions, neutrophils rolled 7.5- to 10.5-fold faster on CD34 than on E-selectin and P-selectin. These findings suggest that the kinetics of bond dissociation and bond formation are faster for L-selectin than for E- and P-selectin. We also compared the behavior of neutrophils and lymphocytes on the same selectin. Both cell types showed comparable strength of binding to CD34; however, neutrophils rolled with faster velocities than lymphocytes.
The Journal of Immunology 02/1997; 158(1):405-13. · 5.79 Impact Factor
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ABSTRACT: We investigated the role of neutrophil microvilli in interactions with E-selectin and P-selectin in hydrodynamic shear flow by disruption with cytochalasin B, hypotonic swelling, and chilling. Cytochalasin B only marginally reduced microvilli numbers (from 30 +/- 6 to 16 +/- 6 per cell perimeter, p < 0.005) as shown by electron microscopy, completely disrupted tethering in shear flow to E-selectin and P-selectin, increased the strength of rolling adhesions on E-selectin and P-selectin, and increased cell deformability in shear flow with a likely increase in the area of cell:substrate contact. Hypoosmotic swelling markedly reduced microvilli number (to 6 +/- 5 per perimeter, p < 0.005), almost completely inhibited tethering on E- and P-selectin, and increased the strength of rolling adhesions on P-selectin but not on E-selectin. Chilling almost completely abolished microvilli (to 3 +/- 3 per perimeter, p < 0.005), but pseudopod-like structures were present, and had little effect on tethering in flow. Immunogold labeling of L-selectin, which is normally clustered on tips of microvilli, showed that in the absence of microvilli it remained in small clusters. Our studies show that alterations in cell morphology and viscoelasticity can have opposing effects on tethering and rolling, showing that they are independently regulatable. Furthermore, our results suggest that the association of molecules that mediate rolling with microvilli tips may be important not just to enhance presentation, but for other functions such as to promote resistance to extraction from the membrane or cooperative interactions among clustered receptors.
The Journal of Immunology 12/1996; 157(11):5085-96. · 5.79 Impact Factor
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ABSTRACT: We demonstrate an additional step and a positive feedback loop in leukocyte accumulation on inflamed endothelium. Leukocytes in shear flow bind to adherent leukocytes through L-selectin/ligand interactions and subsequently bind downstream and roll on inflamed endothelium, purified E-selectin, P-selectin, L-selectin, VCAM-1, or peripheral node addressin. Thus adherent leukocytes nucleate formation of strings of rolling cells and synergistically enhance leukocyte accumulation. Neutrophils, monocytes, and activated T cell lines, but not peripheral blood T lymphocytes, tether to each other through L-selectin. L-selectin is not involved in direct binding to either E- or P-selectin and is not a major counterreceptor of endothelial selectins. Leukocyte-leukocyte tethers are more tolerant to high shear than direct tethers to endothelial selectins and, like other L-selectin-mediated interactions, require a shear threshold. Synergism between leukocyte-leukocyte and leukocyte-endothelial interactions introduces novel regulatory mechanisms in recruitment of leukocytes in inflammation.
The Journal of Cell Biology 12/1996; 135(3):849-65. · 10.26 Impact Factor
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ABSTRACT: Selectins are cell adhesion molecules that bind carbohydrate ligands and promote interaction between leukocytes and the vessel wall in vascular shear flow. Selectin-ligand bonds have high mechanical strength, allowing initial tethering to the vessel wall through one or few bonds, and have fast on and off rates, permitting rolling in response to hydrodynamic drag. The L-selectin molecule on leukocytes binds to peripheral node addressin on high endothelial venules of lymph nodes to mediate leukocyte rolling and binds to a ligand on neutrophils to mediate rolling of leukocytes over one another. Here we describe a surprising mechanism for regulation of these interactions, both in vitro and in vivo. Shear above a critical threshold is required to promote and maintain rolling interactions through L-selectin, but not through E-selectin, P-selectin or VCAM-1. The shear threshold requirement for L-selectin may be physiologically important in low shear to prevent inappropriate aggregation of leukocytes and interaction with the vessel wall.
Nature 02/1996; 379(6562):266-9. · 36.28 Impact Factor
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ABSTRACT: Peripheral node addressin (PNAd) is a complex mixture of glycoproteins with L-selectin ligand activity that functions in lymphocyte homing. We have investigated the contribution of the sialomucin CD34 relative to other components of PNAd in lymphocyte tethering and rolling in in vitro laminar flow assays. PNAd was isolated with MECA-79 mAb-Sepharose from tonsillar stroma, and the CD34 component (PNAd,CD34+) and CD34-negative component (PNAd,CD34-) separated on CD34 mAb-Sepharose. Lymphocytes on the PNAd,CD34- fraction tether less efficiently, roll faster and are less resistant to shear detachment than on PNAd. The PNAd,CD34+ fraction constitutes about half the total functional activity. These studies show that CD34 is a major functional component of PNAd. Ligand activity in both the PNAd,CD34+ and PNAd,CD34- fractions is expressed on mucin-like domains, as shown with O-sialoglycoprotease. The CD34 component of PNAd has about four times higher tethering efficiency than total tonsillar CD34. CD34 from spleen shows no lymphocyte tethering. Although less efficient than the PNAd,CD34+ fraction from tonsil, CD34 from the KG1a hematopoietic cell line is functionally active as an L-selectin ligand despite lack of reactivity with MECA-79 mAb, which binds to a sulfation-dependent epitope. All four forms of CD34 are active in binding to E-selectin. KG1a CD34 but not spleen CD34 are active as L-selectin ligands, yet both lack MECA-79 reactivity and possess E-selectin ligand activity. This suggests that L-selectin ligands and E-selectin ligands differ in more respects than presence of the MECA-79 epitope.
The Journal of Cell Biology 11/1995; 131(1):261-70. · 10.26 Impact Factor
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ABSTRACT: Selectins have previously been shown to tether a flowing leukocyte to a vessel wall and mediate rolling. Here, we report that an intergrin, VLA-4, can also support tethering and rolling. Blood T lymphocytes and alpha 4 integrin-transfected cells can tether in shear flow, and then roll, through binding of the intergrin VLA-4 to purified VCAM-1 on the wall of a flow chamber. VLA-4 transfectants showed similar tethering and rolling on TNF-stimulated endothelium. Tethering efficiency, rolling velocity, and resistance to detachment are related to VCAM-1 density. Tethering and rolling did not occur on ICAM-1, fibronectin, or fibronectin fragments, and tethering did not require integrin activation or the presence of an alpha 4 cytoplasmic domain. Arrest of rolling cells on VCAM-1 occurred spontaneously, and/or was triggered by integrin activating agents Mn2+, phorbol ester, and mAb TS2/16. These agents, and the alpha 4 cytoplasmic domain, promoted increased resistance to detachment. Together the results show that VLA-4 is a versatile integrin that can mediate tethering, rolling, and firm arrest on VCAM-1.
The Journal of Cell Biology 04/1995; 128(6):1243-53. · 10.26 Impact Factor
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ABSTRACT: Calcineurin inhibitors (CNI) are the basis of contemporary immunosuppression in clinical pancreas transplantation (PT). Nevertheless, CNI toxicities, especially nephrotoxicity, have stimulated the search for CNI-sparing protocols. We performed a retrospective analysis of 25 PT patients with progressive CNI toxicities that were switched to a daclizumab (DAC)-based maintenance regimen.
From 2003 to 2007, 25 PT patients with progressive CNI toxicity (predominantly nephrotoxicity) were identified and switched from CNI to monthly DAC maintenance therapy. The DAC group was compared with matched control subjects (1:1) by transplant type and number, age, year of transplant, and duct management.
Results showed improved graft survival rates and decreased immunologic loss rates at 1, 3, and 5 years in the DAC group compared with the control group. There was no difference in patient survival rate between the 2 groups. Analysis demonstrates that DAC maintenance therapy is safe and effective for PT patients experiencing CNI toxicities. A randomized trial to compare DAC- and CNI-based regimens is needed in CNI-intolerant patients, with particular attention to the impact on renal function and patient morbidity (eg, infection rates).
Transplantation Proceedings 42(6):2003-5. · 1.00 Impact Factor
