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Biomedical subjects

David H Adams

Publications and source records attributed to David H Adams.

At least 19 recordsLinked to original sources
PubMed2007

C4b binding protein binds to CD154 preventing CD40 mediated cholangiocyte apoptosis: a novel link between complement and epithelial cell survival.

Activation of CD40 on hepatocytes and cholangiocytes is critical for amplifying Fas-mediated apoptosis in the human liver. C4b-Binding Protein (C4BP) has been reported to act as a potential surrogate ligand for CD40, suggesting that it could be involved in modulating liver epithelial cell survival. Using surface plasmon resonance (BiaCore) analysis supported by gel filtration we have shown that C4BP does not bind CD40, but it forms stable high molecular weight complexes with soluble CD40 ligand (sCD154). These C4BP/sCD154 complexes bound efficiently to immobilised CD40, but when applied to cholangiocytes they failed to induce apoptosis or proliferation or to activate NFkB, AP-1 or STAT 3, which are activated by sCD154 alone. Thus C4BP can modulate CD40/sCD154 interactions by presenting a high molecular weight multimeric sCD154/C4BP complex that suppresses critical intracellular signalling pathways, permitting cell survival without inducing proliferation. Immunohistochemistry demonstrated co-localisation and enhanced expression of C4BP and CD40 in human liver cancers. These findings suggest a novel pathway whereby components of the complement system and TNF ligands and receptors might be involved in modulating epithelial cell survival in chronic inflammation and malignant disease.

Animals↗
PubMed2006

Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells.

Normal intestinal mucosa contains abundant immunoglobulin A (IgA)-secreting cells, which are generated from B cells in gut-associated lymphoid tissues (GALT). We show that dendritic cells (DC) from GALT induce T cell-independent expression of IgA and gut-homing receptors on B cells. GALT-DC-derived retinoic acid (RA) alone conferred gut tropism but could not promote IgA secretion. However, RA potently synergized with GALT-DC-derived interleukin-6 (IL-6) or IL-5 to induce IgA secretion. Consequently, mice deficient in the RA precursor vitamin A lacked IgA-secreting cells in the small intestine. Thus, GALT-DC shape mucosal immunity by modulating B cell migration and effector activity through synergistically acting mediators.

Animals↗
PubMed2006

Interstitial lactic acidosis in the graft during organ harvest, cold storage, and reperfusion of human liver allografts predicts subsequent ischemia reperfusion injury.

BACKGROUND: The impact of the process of liver transplantation on glucose metabolism in the graft was studied using microdialysis. METHODS: Microdialysis catheters were inserted into 15 human livers to monitor metabolic changes that took place during organ harvest, the process of backtable preparation of the graft, and following implantation in the recipient where it remained in situ for 48 hours. The cannula was perfused with isotonic solution and hourly samples of perfusate were collected and analyzed. RESULTS: Six livers showed serum biochemical evidence of ischemia/reperfusion (IR) injury with 24 hours aspartate transaminase (AST) levels >2000 IU/L (Group A) whereas the remaining patients showed little evidence of IR injury (Group B). In Group A, lactate levels in the donor microdialysate rose to >6 mM (P < 0.05), were significantly higher during backtable preparation of the liver (>15 mM; P < 0.03), and took longer to normalize in the recipient following implantation (18 vs. 8 hours, P < 0.03) than lactate levels of the livers of patients in Group B who did not develop ischemia reperfusion injury. No significant differences were observed in glucose, pyruvate, or glycerol concentrations between the two groups. CONCLUSIONS: Interstitial lactic acidosis in the donor allograft is associated with significant reperfusion injury on implantation.

Acidosis, Lactic↗
PubMed2006

Increased neointimal formation after surgical vein grafting in a murine model of type 2 diabetes.

BACKGROUND: Diabetes is an independent risk factor for the development of neointimal hyperplasia and subsequent vein graft failure after coronary or peripheral artery bypass grafting. We evaluate a new mouse model of surgical vein grafting to investigate the mechanisms of neointimal formation in the setting of type 2 diabetes. METHODS AND RESULTS: Surgical vein grafts were created by inserting vein segments from age-matched C57BL/KsJ wild-type mice into the infra-renal aorta of lepr(db/db) diabetic and C57BL/KsJ wild-type mice. Mice were euthanized &4 weeks later, and vein grafts were analyzed using morphometric and immunohistochemical techniques. A significant increase in neointimal formation was noted in lepr(db/db) mice (139+/-64 versus 109+/-62 mm2; P=0.008) after 4 weeks. This difference was mainly secondary to an increase in collagen formation within the lesion in the vein grafts from lepr(db/db) mice (0.53+/-0.4 versus 0.44+/-0.05; P<0.001), whereas only slight increases (P=not significant) in alpha actin-stained smooth muscle cells were noted in the lepr(db/db) mice. CONCLUSIONS: We established a new physiologically relevant model of surgical vein grafting in mice. In this report, type 2 diabetes was associated with significant increase in extracellular matrix deposition in addition to increased smooth muscle cell deposition. This new model may allow mechanistic studies of cellular and molecular pathways of increased neointimal formation in the setting of diabetes.

Actins↗
PubMed2006

Mitral valve repair with Carpentier-McCarthy-Adams IMR ETlogix annuloplasty ring for ischemic mitral regurgitation: early echocardiographic results from a multi-center study.

BACKGROUND: Ischemic mitral regurgitation (IMR) is associated with asymmetric changes in annular and ventricular geometry. Surgical repair with standard symmetric annuloplasty rings results in a high incidence of residual or recurrent mitral regurgitation (MR). The Carpentier-McCarthy-Adams (CMA) IMR ETlogix annuloplasty ring is the first remodeling ring specifically designed to treat asymmetric leaflet tethering and annular dilatation. We used quantitative 2-dimensional echo to examine early results of mitral valve (MV) repair with the CMA IMR ETlogix annuloplasty ring in patients with IMR. METHODS AND RESULTS: Fifty-nine patients (aged 68+/-12 years) with grade > or = 2+ IMR (graded on a scale of 0 to 4+) underwent MV repair with the CMA IMR ETlogix annuloplasty ring. We assessed the mitral annular diameter (MAD), tethering area (TA), and tenting height (TH) of the MV in 4-chamber, 2-chamber, and long axis views at mid-systole before and 3 to 10 days after surgery. After surgery, 57 of 59 (97%) patients had grade 0 or 1+ MR, whereas 2 patients had 2+ MR. MV repair with the CMA IMR ETlogix ring significantly reduced MAD, TA, and TH (P<0.001, for all 3 echo views), particularly in the long axis and 4-chamber views. CONCLUSIONS: Surgical repair of IMR with the novel asymmetric CMA IMR ETlogix annuloplasty ring provided excellent early results with effective reduction of MR, MAD, and leaflet tethering. This novel etiology-specific strategy may result in improved outcomes in IMR patients.

Aged↗
PubMed2006

Epithelial inflammation is associated with CCL28 production and the recruitment of regulatory T cells expressing CCR10.

Mucosal tissues require constant immune surveillance to clear harmful pathogens while maintaining tolerance to self Ags. Regulatory T cells (Tregs) play a central role in this process and expression of alpha(E)beta(7) has been reported to define a subset of Tregs with tropism for inflamed tissues. However, the signals responsible for recruiting Tregs to epithelial surfaces are poorly understood. We have isolated a subset of CCR10-expressing CD25+CD4+Foxp3+ Tregs with potent anti-inflammatory properties from chronically inflamed human liver. The CCR10+ Tregs were detected around bile ducts that expressed increased levels of the CCR10 ligand CCL28. CCL28 was secreted by primary human cholangiocytes in vitro in response to LPS, IL-1beta, or bile acids. Exposure of CCR10+ Tregs to CCL28 in vitro stimulated migration and adhesion to mucosal addressin cell adhesion molecule-1 and VCAM-1. Liver-derived CCR10+ Tregs expressed low levels of CCR7 but high levels of CXCR3, a chemokine receptor associated with infiltration into inflamed tissue and contained a subset of alpha(E)beta7(+) cells. We propose that CXCR3 promotes the recruitment of Tregs to inflamed tissues and CCR10 allows them to respond to CCL28 secreted by epithelial cells resulting in the accumulation of CCR10+ Tregs at mucosal surfaces.

Bile Ducts↗
PubMed2006

Detailed analysis of intrahepatic CD8 T cells in the normal and hepatitis C-infected liver reveals differences in specific populations of memory cells with distinct homing phenotypes.

In hepatitis C virus (HCV) infection the immune response is ineffective, leading to chronic hepatitis and liver damage. Primed CD8 T cells are critical for antiviral immunity and subsets of circulating CD8 T cells have been defined in blood but these do not necessarily reflect the clonality or differentiation of cells within tissue. Current models divide primed CD8 T cells into effector and memory cells, further subdivided into central memory (CCR7+, L-selectin+), recirculating through lymphoid tissues and effector memory (CCR7-, L-selectin-) mediating immune response in peripheral organs. We characterized CD8 T cells derived from organ donors and patients with end-stage HCV infection to show that: 1) all liver-infiltrating CD8 T cells express high levels of CD11a, indicating the effective absence of naive CD8 T cells in the liver. 2) The liver contains distinct subsets of primed CD8+ T cells including a population of CCR7+ L-selectin- cells, which does not reflect current paradigms. The expression of CCR7 by these cells may be induced by the hepatic microenvironment to facilitate recirculation. 3) The CCR7 ligands CCL19 and CCL21 are present on lymphatic, vascular, and sinusoidal endothelium in normal liver and in patients with HCV infection. We suggest that the recirculation of CCR7+/L-selectin- intrahepatic CD8 T cells to regional lymphoid tissue will be facilitated by CCL19 and CCL21 on hepatic sinusoids and lymphatics. This centripetal pathway of migration would allow restimulation in lymph nodes, thereby promoting immune surveillance in normal liver and renewal of effector responses in chronic viral infection.

CD11a Antigen↗
PubMed2006

Optimal surgical management of severe tricuspid regurgitation in cardiac transplant patients.

BACKGROUND: Severe tricuspid regurgitation (TR) with signs of right-sided heart failure is rare after orthotopic heart transplantation (OHT). In some instances, this condition will require surgical correction using reconstructive surgery or prosthetic valve replacement. Repair techniques of atrioventricular valves are now well described. However, the results of the different surgical procedures in this setting have not been widely reported and may depend on the type of valvular dysfunction and lesions present. Herein we report our experience in a group of patients requiring surgical correction of symptomatic severe TR after OHT. METHODS: We reviewed our transplant experience during the period from July 1992 to July 1999 (n = 138 cardiac transplants). Eight patients (5.8%) developed symptomatic severe TR requiring surgical correction after a mean duration of 21 months after OHT. Patients were divided into 2 groups based on the mechanism of regurgitation using Carpentier's functional classification. In Group 1 (n = 4), the mechanism of tricuspid regurgitation was Carpentier's Type I, secondary to annular dilation. In Group 2 (n = 4) the mechanism of TR was leaflet prolapse (Type II), due to chordal rupture after biopsy injury. Initially, tricuspid valve integrity was surgically restored in all 8 patients with either valve repair (n = 6) or replacement (n = 2). In Group 1, 2 patients underwent valve repair using a ring annuloplasty and 2 patients underwent valve replacement with a bioprosthetic valve (n = 1) or pulmonary allograft (n = 1). In Group 2, all patients underwent valve repair using a variety of techniques in combination with tricuspid annuloplasty. RESULTS: During the follow-up period, 3 of the 6 (50%) primary repairs (1 patient in Group 1 and 2 in Group 2) failed and required replacement with a bioprosthesis at 8 days, 14 days and 4 years, respectively. The pulmonary allograft failed secondary to valvular stenosis and was replaced with a bioprosthesis after 10 months. Overall, no failures occurred in any of the 5 bioprosthetic valves placed at the primary operation (n = 1) or after failed tricuspid repair/pulmonary allograft (n = 4), after a mean follow-up of 55 months. CONCLUSIONS: TR requiring surgical correction after OHT is a rare condition and requires a tailored surgical strategy. This strategy should take into account the mechanism of valve dysfunction and specific valvular lesions. In patients with Type I dysfunction secondary to annular dilation, valve repair with a remodeling annuloplasty should be performed; however, in the presence of any residual TR on transesophageal echocardiography (TEE) at the completion of cardiopulmonary bypass (CPB), a valve replacement with a bioprosthesis is warranted during the same procedure. In patients with Type II dysfunction with leaflet prolapse and biopsy-induced chordal injury, a bioprosthetic valve replacement seems a reliable surgical option.

Adult↗
PubMed2006

A three-dimensional ring annuloplasty for the treatment of tricuspid regurgitation.

PURPOSE: Significant functional tricuspid regurgitation should be corrected in patients undergoing surgery for left-sided valvular diseases. Several clinical studies have shown the superiority of the remodeling annuloplasty over other repair techniques. Herein we report our early experience with a new three-dimensional remodeling prosthetic ring (Edwards MC3 annuloplasty system [Edwards LifeSciences, Irvine, CA]). DESCRIPTION: From June 2002 to November 2004, 75 patients with functional tricuspid regurgitation (mean, 3.1 +/- 0.9) underwent tricuspid valve repair with this new prosthesis. Concomitant procedures were mitral valve repair (70%), replacement (26%), aortic valve replacement (10%), coronary artery bypass grafting (13%), and left atrial maze (34%). Median predicted EuroScore mortality was 21% (r = 3 to 62). EVALUATION: Operative mortality was 5.3% (n = 4). Pre-discharge echocardiography showed significant decrease in tricuspid regurgitation to 0.3 +/- 0.4 (p < 0.001). Forty-five patients had follow-up transthoracic echocardiography after a median of 16 months (range, 4 to 34) demonstrating a stable result (mean tricuspid regurgitation, 0.3 +/- 0.5). There were no cases of ring dehiscence, prosthetic ring endocarditis, or thromboembolic events. CONCLUSIONS: This new three-dimensional ring is easy to implant, corrects tricuspid regurgitation effectively, and provides good short-term clinical and echocardiographic results. Long-term evaluation, however, is necessary to determine the stability of tricuspid valve repair using the MC3 annuloplasty system.

Adult↗
PubMed2006

Effective management of refractory postcardiotomy bleeding with the use of recombinant activated factor VII.

BACKGROUND: Severe coagulopathy after cardiovascular surgery may lead to intractable bleeding and is associated with increased mortality and morbidity. Recent studies have suggested that recombinant activated factor VII (rFVIIa) may play a role in decreasing postoperative bleeding. Herein we report our experience with the off-label use of rFVIIa in patients with refractory postcardiotomy bleeding. METHODS: From June 2003 to December 2005, 17 patients (mean age, 65 +/- 18 years) received rFVIIa for refractory bleeding after cardiac surgery. Preoperative risk factors for bleeding included reoperation (n = 7), emergency surgery (n = 7), and renal or hepatic failure (n = 3). Surgical procedures were aortic surgery (n = 7), complex valve operations (n = 7), coronary artery bypass grafting (n = 2), and cardiac tumor resection (n = 1). RESULTS: The average dose of rFVIIa was 103.1 +/- 30.2 microg/kg. After the administration of rFVIIa the blood loss was reduced and chest tube output decreased from an average of 300 mL/h to 60 mL/h (p = 0.024). Coagulation variables normalized (mean prothrombin time, 18 +/- 7 versus 14 +/- 3 seconds; p = 0.03; mean partial thromboplastin time, 94 +/- 50 versus 49 +/- 14 seconds; p = 0.02), and the need for blood products was significantly reduced. Only 1 patient required mediastinal reexploration. No thromboembolic complications occurred during hospitalization. CONCLUSIONS: This study suggests that rFVIIa is safe and efficacious in the management of refractory postcardiotomy bleeding. The use of rFVIIa is associated with reduced blood loss, rapid improvement of coagulation variables, and decreased need for blood products. Further studies are necessary to determine the safety and efficacy of this new hemostatic agent and its precise role in the treatment of severe postoperative coagulopathy.

Adult↗
PubMed2006

Large annuloplasty rings facilitate mitral valve repair in Barlow's disease.

BACKGROUND: Excess leaflet tissue in Barlow's disease predisposes patients to left ventricular outflow tract obstruction and residual mitral regurgitation after mitral valve repair as a result of systolic anterior motion of the anterior mitral leaflet. In addition to conventional repair techniques such as sliding plasty and leaflet shortening, our approach in Barlow's disease has included the use of large remodeling annuloplasty rings (up to size 40 mm). We report our experience with the use of large rings in Barlow's disease. METHODS: From January 2002 to December 2005, 67 patients with Barlow's disease (46 men and 21 women; median age, 55 years; range, 22 to 85 years), mean ejection fraction 0.55 +/- 0.08, and grade 3+ or greater mitral regurgitation underwent mitral valve repair. All had Carpentier type II leaflet dysfunction, with anterior (n = 2), posterior (n = 41), or bileaflet (n = 24) prolapse. Predominant reconstructive techniques were posterior leaflet sliding plasty/plication (n = 65), anterior leaflet triangular resection (n = 16), and chordal transfer (n = 25). Concomitant procedures included coronary artery bypass grafting surgery (n = 8), tricuspid valve repair (n = 20), aortic valve replacement (n = 3), and CryoMaze (n = 22). RESULTS: Mitral valve repair was successfully completed in all patients. Annuloplasty ring size was 36 mm (n = 17), 38 mm (n = 22), and 40 mm (n = 28). Predischarge transthoracic echocardiography showed absence of systolic anterior motion (n = 67), no or trace mitral regurgitation (n = 62), and mild mitral regurgitation (n = 5). There was no operative mortality. CONCLUSIONS: Mitral valve repair can be predictably performed in Barlow's disease with excellent early outcomes. Large annuloplasty rings help minimize the risk of systolic anterior motion and are an important adjunct to established repair techniques in this patient cohort with large annular size and excess leaflet tissue.

Adult↗
PubMed2006

Aberrant homing of mucosal T cells and extra-intestinal manifestations of inflammatory bowel disease.

Active inflammatory bowel disease (IBD) is often associated with simultaneous inflammation in the skin, eyes and joints. Inflammatory disease in the liver can also occur in patients with IBD but seems to be independent of inflammation in the bowel. In this Opinion article, we propose that the hepatic complications of IBD are mediated by long-lived mucosal T cells that are recruited to the liver in response to aberrantly expressed endothelial-cell adhesion molecules and chemokines that are normally restricted to the gut. Similar mechanisms might explain why certain diseases are associated with site-specific tissue distributions and might point to new therapeutic strategies that are based on modulating tissue-specific lymphocyte homing.

Cell Adhesion Molecules↗