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Biomedical subjects

David H Adams

Publications and source records attributed to David H Adams.

At least 55 records · Page 3Linked to original sources
PubMed2005

Lymphocyte traffic through sinusoidal endothelial cells is regulated by hepatocytes.

Crosstalk between hepatic sinusoidal ECs and closely juxtaposed hepatocytes via vascular endothelial growth factor is essential for the maintenance of sinusoidal endothelial growth and differentiation. We propose that paracrine interactions between endothelial cells and hepatocytes also may be responsible for the unique complement of adhesion receptors expressed on sinusoidal endothelium that regulate the recruitment of lymphocytes into the liver. To address this hypothesis, we developed an in vitro model of the hepatic sinusoid in which flowing lymphocytes could interact with hepatic endothelium conditioned by the presence of hepatocytes. Human hepatic sinusoidal endothelial cells cocultured with hepatocytes were activated so that they supported the adhesion of lymphocytes at levels equivalent to those seen on endothelium stimulated with the inflammatory cytokine tumour necrosis factor-beta. Lymphocyte adhesion was supported by intracellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin, with an additional contribution from the novel adhesion receptor VAP-1. In conclusion, we show that interactions between hepatocytes and endothelial cells amplify leukocyte recruitment through the sinusoids by regulating the expression and function of endothelial adhesion molecules. These paracrine interactions may be responsible for the induction of the adhesion molecules that support constitutive lymphocyte recruitment to the liver as well as contributing significantly to the patterns of leukocyte adhesion seen during episodes of hepatic inflammation.

Amine Oxidase (Copper-Containing)↗
PubMed2005

Long-term outcomes of tricuspid valve replacement in the current era.

BACKGROUND: Regardless of the indication, tricuspid valve replacement (TVR) has historically been associated with high mortality and morbidity. We report the results of our experience in a high-risk patient population with an emphasis on operative mortality, long-term survival, and valve related events according to the type of prosthesis. METHODS: Between 1985 and 1999 TVR was performed in 81 patients (isolated n = 25, combined with valve surgery n = 44, combined with CABG or other n = 12). The mean age was 61 years old (range 19-83 years old). Risk factors included New York Heart Association functional class III/IV (n = 73, 90%), reoperation (n = 58, 72%), urgent/emergent indication (n = 62, 76%), and hepatic dysfunction (n = 13, 16%). Mean pulmonary artery pressure was 34 mmHg. Etiology of tricuspid regurgitation was classified as functional (n = 18, 22%) or organic (n = 52, 64%), or failed previous tricuspid valve surgery (n = 11, 14%). RESULTS: Tricuspid valve replacement was performed with either a bioprosthetic (n = 34, 42%) or mechanical valve (n = 47, 58%). The overall operative mortality was 22% (n = 18). Risk factors for mortality included urgent/emergent status, age greater than 50 years old, functional etiology, and elevated pulmonary artery pressure. Of the 60 survivors, 26 (43%) died during follow up. After univariate analysis, organic etiology was the only predictor of late death (p = 0.01). Kaplan-Meier survival at 2.5, 5, and 10 years was 80%, 60%, and 45% for bioprosthetic, and 84%, 69%, and 59% for mechanical valves, respectively. CONCLUSIONS: Patients requiring TVR are typically high-risk with a high-percentage of reoperations, concomitant cardiac procedures, and end-stage functional class. Operative and overall mortality remains high. Heart failure was the predominant cause of early and late deaths, emphasizing importance of timely referral before the development of end-stage cardiac impairment.

Adult↗
PubMed2005

High-risk mitral valve surgery: perioperative hemodynamic optimization with nesiritide (BNP).

BACKGROUND: Nesiritide is a recombinant brain-type natriuretic peptide (BNP), which decreases pulmonary arterial (PA) pressures and myocardial oxygen consumption while increasing coronary flow and urine output. Mitral valve (MV) surgery in patients with severe mitral regurgitation (MR), impaired left ventricular function, and pulmonary hypertension is associated with a high operative mortality. We hypothesized that the perioperative use of Nesiritide is safe, and may improve surgical outcomes. METHODS: From May 2003 to August 2004, 14 patients (11 male, 3 female; mean age, 64 years [23-87 years]; mean systolic PA, 63 mm Hg [48-94 mm Hg]; mean ejection fraction, 36% [10-50%]), undergoing MV surgery (10 repairs, 2 replacements, and 2 rereplacements) for severe MR, were treated for a median of 24 hours (13-55 hours) preoperatively with intravenous Nesiritide. Expected mortality by EuroSCORE was 26% (7.8-59%) (5 reoperations). Concomitant procedures included tricuspid valve repair (n = 7), coronary artery bypass grafting (n = 5), and left atrial maze procedure (n = 3). Eleven patients received Nesiritide postoperatively during a mean duration of 22 hours (2-80 hours). RESULTS: Operative mortality was 0%. Prior to surgery after BNP treatment, mean systolic PA pressure dropped to 39 mm Hg (p = 0.0003), pulmonary capillary wedge pressure to 15 mm Hg (p = 0.001), central venous pressure to 6 mm Hg (p = 0.002), and weight by 3.7 kg (p = 0.006). Postoperative median ventilation time was 14 hours (4-48 hours). All other major hemodynamic parameters (systemic blood pressure, heart rate, and cardiac output) remained constant. The treatment was well-tolerated in all patients. CONCLUSIONS: Perioperative use of Nesiritide is safe, and may contribute to improved early outcomes in high-risk patients undergoing MV surgery. This may be due to improved ventricular loading conditions (decreased PA pressures, more effective diuresis) and/or a direct myocardial effect of BNP. Further prospective evaluation of the role of BNP in cardiac surgery is warranted.

Adult↗
PubMed2005

CXCR 3 activation promotes lymphocyte transendothelial migration across human hepatic endothelium under fluid flow.

T cells infiltrating the inflamed liver express high levels of CXCR 3 and show enhanced migration to CXCR 3 ligands in chemotactic assays. Moreover, CXCR 3 ligands are up-regulated on hepatic endothelium at sites of T-cell infiltration in chronic hepatitis, and their presence correlates with outcome of inflammatory liver disease. We used a flow-based adhesion assay with human hepatic endothelium to investigate the function of CXCR 3 on lymphocyte adhesion to and transmigration through hepatic endothelium under physiological conditions of blood flow. To more accurately model the function of in vivo activated CXCR 3(high) lymphocytes, we isolated T cells from human liver tissue and studied their behavior in flow-based adhesion assays. We demonstrate that CXCR 3 not only promoted the adhesion of effector T cells to endothelium from flow but also drove transendothelial migration. Moreover, these responses could be stimulated either by endogenous CXCR 3 ligands secreted by the endothelium or by exogenous CXCR 3 ligands derived from other cell types and presented by the endothelium. This study thus demonstrates that activation of CXCR 3 promotes lymphocyte adhesion and transendothelial migration under flow and that human hepatic endothelium can present functionally active chemokines secreted by other cell types within the liver.

Biliary Tract↗
PubMed2005

Effector mechanisms of nonsuppurative destructive cholangitis in graft-versus-host disease and allograft rejection.

The biliary epithelium provides a physical barrier to ascending infection from the gastrointestinal tract and is also involved in actively regulating the immune response to invading pathogens. Cholangiocytes secrete chemokines and express adhesion molecules that attract effector leukocytes and promote the clearance of infected cells. However in the context of transplantation these properties make cholangiocytes targets for allogeneic cytotoxic T cells, and both graft-versus-host disease and liver allograft rejection are characterized by destruction of intrahepatic bile ducts by infiltrating lymphocytes. The mechanisms of cholangiocyte killing are complex but involve activation of apoptosis by the granzyme/perforin pathway and by activation of death receptors belonging to the tumor necrosis factor (TNF) receptor superfamily, most notably Fas. Fas-dependent apoptosis is carefully regulated by cooperative interactions with other TNF receptors, particularly CD40, that act to amplify autocrine and paracrine expression of Fas ligand and Fas-mediated killing. A better understanding of the molecular control of these processes may explain why bile duct loss continues despite conventional immunosuppression in the vanishing bile duct syndromes, and lead to novel therapies aimed at switching off the chronic inflammatory response and protecting cholangiocytes from apoptosis.

Apoptosis↗
PubMed2005

Coronary artery surgery: conventional coronary artery bypass grafting versus off-pump coronary artery bypass grafting.

PURPOSE OF REVIEW: Coronary revascularization has become the principal treatment modality in patients with severe coronary artery disease. The broader application of percutaneous coronary interventions in patients with multivessel disease and the recent introduction of drug-eluting stents have both lead to a decline in the number of patients referred for surgical revascularization. Conventional coronary artery bypass grafting using cardiopulmonary bypass is an excellent treatment, however less invasive surgical approaches such as off-pump coronary artery bypass grafting have appeared in the past few years. The exact role of off-pump coronary artery bypass grafting is still vaguely defined and being critically evaluated. Our aim is to provide an objective review of the recent literature in regard to surgical outcomes. RECENT FINDINGS: A critical review of all relevant clinical series from May 2003 to May 2005 was conducted. Current prospective data suggests that both techniques have similar rates of mortality, in regard to morbidity, multiple prospective studies suggest a decrease in stroke rates for off-pump coronary artery bypass grafting. The incidence of postoperative myocardial infarction does not appear to differ between techniques. When analyzed carefully, the results presented herein seem to indicate that both techniques provide similar rates for long-term patency and freedom from surgical reintervention. SUMMARY: Coronary artery bypass grafting and off-pump coronary artery bypass grafting are both safe and beneficial in patients with multivessel coronary artery disease. It appears that elderly patients with additional co-morbid risk factors may benefit most from off-pump coronary artery bypass grafting. It has become increasingly apparent that off-pump coronary artery bypass grafting can be performed safely in reference centers.

Coronary Artery Bypass↗
PubMed2005

Current management of ischemic mitral regurgitation.

Severe coronary artery disease and myocardial infarction can be complicated by ischemic mitral regurgitation (IMR). IMR results from left ventricular remodeling after myocardial infarction and in rare instances can accompany acute ischemia. A better understanding of the pathophysiology of IMR and increased awareness of its negative impact on long-term survival explain the recent rise in the number of patients referred for surgical correction of IMR at the time of coronary revascularization. The most common mechanism of IMR is Carpentier's type IIIb dysfunction, for which an undersized remodeling annuloplasty is the treatment of choice. In this article we define ischemic mitral regurgitation and review its pathophysiology, clinical presentations, diagnosis, indication for surgery, and management.

Coronary Artery Bypass↗
PubMed2004

Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC), a chronic inflammatory liver disease characterized by progressive bile duct destruction, develops as an extra-intestinal complication of inflammatory bowel disease (IBD) (Chapman, R.W. 1991. Gut. 32:1433-1435). However, the liver and bowel inflammation are rarely concomitant, and PSC can develop in patients whose colons have been removed previously. We hypothesized that PSC is mediated by long-lived memory T cells originally activated in the gut, but able to mediate extra-intestinal inflammation in the absence of active IBD (Grant, A.J., P.F. Lalor, M. Salmi, S. Jalkanen, and D.H. Adams. 2002. Lancet. 359:150-157). In support of this, we show that liver-infiltrating lymphocytes in PSC include mucosal T cells recruited to the liver by aberrant expression of the gut-specific chemokine CCL25 that activates alpha4beta7 binding to mucosal addressin cell adhesion molecule 1 on the hepatic endothelium. This is the first demonstration in humans that T cells activated in the gut can be recruited to an extra-intestinal site of disease and provides a paradigm to explain the pathogenesis of extra-intestinal complications of IBD.

Cell Movement↗
PubMed2004

Demonstration that donor-specific nonresponsiveness in human liver allograft recipients is both rare and transient.

BACKGROUND: The side effects of lifetime immunosuppression are a major cause of morbidity and mortality; however, in the absence of prospective monitoring, immunosuppression withdrawal may lead to graft loss from rejection. To detect and monitor suitable recipients for immunosuppression withdrawal, the authors used an in vitro assay of T-cell function to study 71 long-term liver allograft recipients. METHODS: Interleukin-2 secretion by blood mononuclear cells was measured in response to recall antigens, alloantigen (donor and third-party), and phytohemagglutinin. RESULTS: Forty-four recipients were studied at a single time point at least 1 month after transplantation. The majority reacted to all antigens (n=33), whereas four showed globally reduced or absent responses (n=4) and six had markedly reduced or absent responses to donor alloantigen in the presence of preserved responses to third-party alloantigen and recall antigens. Four of these donor-nonresponsive recipients were retested 6 to 12 months later, by which time all had redeveloped responses to donor alloantigen. Serial measurements for up to 2 years in a prospective cohort of 27 liver allograft recipients showed only two patients to be consistently donor-nonresponsive posttransplant. CONCLUSIONS: Most patients rapidly reacquire vigorous immune responses after liver transplantation, and only a minority are hyporesponsive to donor alloantigen. Donor-specific nonresponsiveness is transient in most patients, and serial monitoring is required to define sustained periods of donor-specific nonresponsiveness. Whether such patients are suitable for immunosuppressive withdrawal is unclear.

Case-Control Studies↗
PubMed2004

Simplified test of universality in lattice QCD.

A simplified test of universality in lattice QCD is performed by analytically evaluating the continuous Euclidean time limits of various lattice fermion determinants, both with and without a Wilson term to lift the fermion doubling on the Euclidean time axis, and comparing them with each other and with the zeta-regularized fermion determinant in the continuous time-lattice space setting. The determinant relations expected from universality considerations are found to be violated by a certain gauge field-dependent factor; i.e., we uncover a "universality anomaly." The physical significance, or lack thereof, of this factor is a delicate question that remains to be settled.

Journal Article↗
PubMed2004

The composition of intrahepatic lymphocytes: shaped by selective recruitment?

Intrahepatic lymphocytes have a distinct subset composition and phenotype. Compared with lymphoid tissues, the frequency of natural killer (NK) cells, NKT cells and gammadelta T cells among total lymphocytes is increased within the liver, and alphabeta T cells are predominantly effector/memory cells. Divergent hypotheses on the origin of intrahepatic T cells have emerged to explain this; in these hypotheses, either local development or selective recruitment of cells into the liver dominates. This Opinion highlights findings showing that the migratory preferences of lymphocyte subsets reflect their representation within the liver surprisingly well, suggesting that the composition of intrahepatic lymphocytes, in the absence of inflammation, is largely shaped by the dynamics of cell entry and exit into and from the liver.

Animals↗
PubMed2004

Interleukin-10 secretion differentiates dendritic cells from human liver and skin.

Liver dendritic cells (DCs), which may orchestrate the liver's unique immunoregulatory functions, remain poorly characterized. We used a technique of overnight migration from pieces of normal human liver and skin to obtain tissue-derived DCs with minimal culture and no additional cytokine treatment. Liver and skin DCs had a monocyte-like morphology and a partially mature phenotype, expressing myeloid markers, MHCII, and co-stimulatory molecules; but only the skin DCs contained a population of CD1a+ cells. Overnight-migrated liver DCs activated naïve cord blood T cells efficiently. Liver DCs produced interleukin (IL)-10 whereas skin DCs failed to secrete IL-10 even after stimulation and neither skin nor liver-derived DCs secreted significant amounts of IL-12p70. Compared with skin DCs, liver DCs were less effective at stimulating T-cell proliferation and stimulated T cells to produce IL-10 and IL-4 whereas skin DCs were more potent stimulators of interferon-gamma and IL-4. Monocyte-derived DCs were down-regulated after culture with liver-conditioned media, suggesting that local microenvironmental factors may be important. Thus we show for the first time clear tissue-specific differences in nonlymphoid DCs. Although it is not possible to conclude from our data whether liver DCs are more regulatory, or skin DCs more proimmunogenic, the ability of liver DCs to secrete IL-10 may be important for regulating local immune responses within the liver in the face of constant exposure to gut antigens.

Antigens, CD↗
PubMed2004

Downregulation of the CCAAT-enhancer binding protein beta in deltaFosB transgenic mice and by electroconvulsive seizures.

Previous studies demonstrate that chronic, but not acute electroconvulsive seizures (ECS), increases levels of deltaFosB, a long-lasting transcription factor, in the hippocampus, and this effect correlates with the slow onset and long-lasting clinical effects of antidepressant treatment. To understand how deltaFosB mediates long-term plasticity in the hippocampus, we analyzed the gene expression profile of inducible transgenic mice expressing deltaFosB with a highly sensitive microarray assay and a customized computer analysis program. The CCAAT-enhancing binding protein-beta (C/EBPbeta) was identified as one of the genes downregulated by deltaFosB in the hippocampus. The downregulation of C/EBPbeta in the inducible deltaFosB transgenic mice was confirmed by other quantitative assays including real-time RT-PCR and low density dot blotting. Analysis of the C/EBPbeta expression in the hippocampus of rats treated with ECS revealed that the C/EBPbeta mRNA was also downregulated by chronic, but not acute ECS administration, the most effective treatment for depression. Given the reported role of C/EBPbeta in behavioral conditioning models, it is possible that the deltaFosB-mediated downregulation of C/EBPbeta in the hippocampus may be a molecular mechanism by which antidepressants alleviate some of the symptoms of depressed patients.

Animals↗