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Biomedical subjects

I J Fox

Publications and source records attributed to I J Fox.

At least 55 records · Page 3Linked to original sources
PubMed1995

University of Nebraska Medical Center Liver Transplant Program.

The field of liver transplantation has evolved slowly over the past 5 years. The most important new additions to this field include new immunosuppressive agents and greatly broadened recipient selection criteria. The most compelling problem in transplantation today remains the lack of suitable donors. Innovative surgical techniques, such as auxiliary liver transplantation, extracorporeal support and living-related donation, represent new and important additions to the approach to patients with liver disease.

Academic Medical Centers↗
PubMed1994

Transfusion-induced graft-versus-host disease after liver transplantation. Documentation using polymerase chain reaction with HLA-DR sequence-specific primers.

Graft-versus-host disease (GVHD) occurring after liver transplantation can pose a difficult diagnostic dilemma. Similar clinical and pathologic skin and gastrointestinal manifestations can result from other causes (i.e., drugs, infections). Treatment for each of these entities differs, and the high mortality associated with GVHD makes this distinction critical. GVHD has been assumed to result from the cotransplantation of donor lymphoid tissue along with the allograft. In most instances, the patient also receives blood products during the operation, and occasionally during the postoperative period, and the lymphoid cells in these products are also a potential source of concern. In this report, we describe a patient who developed GVHD after liver transplantation. Using molecular diagnostic techniques, we determined that the source for this GVHD was not the organ donor, but was most likely nonirradiated blood products received during the hospital course. Our results suggest that transplant recipients with concomitant hematopoietic dysfunction would benefit from irradiated blood products to reduce the likelihood of this complication.

Biopsy↗
PubMed1994

Aplastic anemia after liver transplantation for fulminant liver failure.

We determined the incidence and outcome of aplastic anemia among 56 patients who underwent liver transplantation for fulminant liver failure at the University of Nebraska Medical Center between July 1985 and December 1993. Aplastic anemia developed in 6 of 18 (33%) children and 1 of 19 (5%) adults who had fulminant non-A, non-B hepatitis; no cases of aplastic anemia occurred among patients with other causes of fulminant liver failure. None of these patients had evidence of a preexisting hematological disorder or infection with hepatitis C virus (as determined with a second-generation ELISA). Aplastic anemia was diagnosed at a median of 4 wk after the onset of hepatitis, with five cases seen before transplantation. Six patients received antithymocyte globulin to promote remission of aplastic anemia. Three children died (fungal infection in two, intracranial hemorrhage in one)--one at 43, one at 108 and one at 119 days after transplantation--without remission of aplastic anemia. Among the four surviving patients, with median follow-up of 25 mo, complete and partial remission of aplastic anemia have occurred in three and one, respectively. Liver allograft function is stable in all surviving patients. The data demonstrate that aplastic anemia is a common complication among children who undergo liver transplantation for fulminant non-A, non-B hepatitis. It is associated with a high rate of mortality, although most survivors appear to have full hematological recovery.

Adolescent↗
PubMed1993

Extracorporeal support with a cadaver liver as a bridge to transplantation.

Extracorporeal liver perfusion (ECLP) has been used for detoxifying blood in patients in class IV hepatic encephalopathy. Palliation of the moribund patient utilizing extracorporeal devices with cross-circulation of a cadaver liver has been documented for over three decades. Common problems associated with this procedure which appear in the literature include cadaver liver distention, increased resistance to blood flow, and limited time of extracorporeal support due to cadaver liver failure. This report summarizes the experiences of the perfusion team in utilizing an extracorporeal circuit with an otherwise nontransplantable cadaveric liver, to support the decompensating hepatic patient as a bridge to transplantation. Between January and July 1992, three patients were supported for hepatic failure with ECLP. Two patients were placed on ECLP with a modified circuit containing two positive displacement pumps and one centrifugal pump. The third patient was placed on ECLP with a circuit that contained two centrifugal pumps and one positive displacement pump. Patient age ranged from 6 to 38 years and length of support ranged from 24 to 72 hours. In all three patients, a centrifugal pump was placed in the suprahepatic inferior vena cava line to facilitate cadaver liver drainage and decompression. Intensive monitoring of both patient and cadaver liver hemodynamics, hepatic function, and hematological status was performed. All three patients were successfully weaned from ECLP. Two patients received successful orthotopic liver transplantation. The third died of complications unrelated to ECLP after support was discontinued.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Successful application of extracorporeal liver perfusion: a technology whose time has come.

We have used extracorporeal liver perfusion (ECLP) to aid in the management of three patients with fulminant hepatic failure (FHF). Organs were used for ECLP only if they would have gone otherwise unused through United Network for Organ Sharing. In all three patients treated, serial serum bilirubin and arterial ammonia values trended toward the normal range. The neurologic examinations improved dramatically in two patients, and metabolic function of the extracorporeally perfused livers was unequivocally demonstrated by the clearance of theophylline in the last two patients. Two patients ultimately had successful liver transplants, whereas the third patient failed to improve neurologically despite evidence of metabolic function by the extracorporeally perfused liver, and died 7 days after ECLP was discontinued, from pulmonary and renal failure. These studies suggest that, 30 yr after initial clinical trials, ECLP can be applied safely without the need for arterial access 1) as a bridge to transplantation, 2) to assess whether patients in FHF will benefit from improved hepatic function and therefore transplantation, and 3) potentially, to evaluate the "usability" of questionable donor organs.

Adolescent↗
PubMed1993

Use of gene therapy to induce human-mouse xenogeneic chimerism.

BACKGROUND: Bone marrow transplantation (BMT) has been used in the laboratory to overcome the immunologic barriers to xenotransplantation and results in chimerism and specific tolerance to donor antigens in lethally irradiated mice. Clinically, BMT carries the considerable risks of graft-versus-host disease and graft failure. Retrovirus-mediated gene transfer could provide a means of introducing foreign major histocompatibility (MHC) genes into host bone marrow cells (BMC) and thus accomplish the immunologic goals of BMT, without the associated risks. METHODS: Using a Moloney virus-based vector, a replication defective retrovirus was constructed that contained a complementary DNA encoding the human MHC antigen HLA-A2. Three million C57BL/6 mouse BMC were cocultured for 48 hours with 1 x 10(6) HLA-A2 virus "producer" cells in the presence of 15% WEHI supernatant (interleukin-3) and 200 units/ml interleukin-6. Putatively infected BMC were then used at 2 to 3 x 10(6) BMC/animal to reconstitute lethally irradiated syngeneic mice. RESULTS: Twelve days after reconstitution, spleen colonies were found to have integrated the full-length retroviral sequences. Thirty days after BMT, the introduced DNA could be found in the bone marrow, thymus, and spleen, and approximately 5% of T cells in the spleen expressed the HLA-A2 surface antigen. CONCLUSIONS: These data show that xenogeneic MHC genes can be introduced and expressed in mouse hematopoietic cells in vivo and indicate that gene therapy potentially may be used in the future to manipulate the immune system to induce transplantation tolerance.

Animals↗
PubMed1993

Soluble factors modulate changes in collagen gene expression in abdominal aortic aneurysms.

BACKGROUND: Although increased procollagen gene expression and synthesis have been implicated in the progression of abdominal aortic aneurysms (AAA), factors modulating this change have not been identified. Furthermore, it is not known whether the increase in AAA procollagen expression is specific to this disease or also occurs in tissue affected by atherosclerotic occlusive disease (AOD). If paracrine rather than autocrine factors are responsible for increased gene expression in AAA, this effect should be transferable to target smooth muscle cells through conditioned media. Our objectives were to determine 1 alpha (I) procollagen messenger RNA levels in AOD tissue compared with normal and AAA and to determine whether differences noted in tissue procollagen gene expression could be transferred through conditioned media from normal, AOD, and AAA tissues to target smooth muscle cells in primary culture. METHODS: Normal, AOD, and AAA tissue was used for tissue RNA extraction or was minced and washed with serum-free media (4 degrees C) x 30 minutes and the media applied to human aortic smooth muscle cells (SMC) in primary culture for 36 hours. Total RNA from tissue and SMC exposed to conditioned media was analyzed by Northern and dot blot analysis for 1 alpha (I) procollagen. RESULTS: Relative tissue 1 alpha (I) procollagen levels were not increased in AOD (0.23 +/- 0.05) as compared with normal (0.17 +/- 0.03); both were decreased compared with AAA (0.53 +/- 0.07; p < 0.01). The 1 alpha (I) procollagen levels in SMC exposed to conditioned media from AAA (1.73 +/- 0.15) were increased (p < 0.05) compared with AOD (1.10 +/- 0.12) and normal (1.16 +/- 0.16). CONCLUSIONS: There is no increase in tissue AOD procollagen gene expression. The ability to transfer the same relative patterns of gene expression from tissue to target SMC with conditioned media suggests that paracrine, rather than autocrine, factors modulate procollagen expression in AAA tissues.

Adult↗
PubMed1992

Liver transplantation at the University of Nebraska Medical Center from 1985 to 1992.

Based on our 7 and one-half-year experience with liver transplantation at the University of Nebraska Medical Center: 1. Success and growth of the program has been, in part, the result of close interaction and support of the various specialists involved. 2. We have demonstrated that outstanding patient and graft survival rates can be obtained with cyclosporine/prednisone immunosuppression. 3. Few, if any, technical contraindications exist to liver transplantation. 4. Surgical advances have allowed allografts to be salvaged which would otherwise require replacement. 5. Routine donor-liver biopsy prior to implantation has reduced the rate of primary nonfunction. 6. New strategies to improve survival for patients with hepatitis-B-related liver disease and hepatic malignancies undergoing liver transplantation need to be developed. 7. The management of patients with fulminant hepatic failure is evolving and now includes innovative approaches such as the use of ECLS and auxiliary transplants.

Academic Medical Centers↗
PubMed1990

Clonal deletion: a mechanism of tolerance in mixed bone marrow chimeras.

The mechanism of antigen-specific immunologic unresponsiveness which results from lethal irradiation and mixed (syngeneic-allogeneic) bone marrow cell (BMC) reconstitution is unknown. To determine whether clonal deletion is the mechanism of tolerance in this model, monoclonal antibody (Mab) RR-4-4, specific for a T-cell receptor (V beta 6) reactive against the minor alloantigen MLsa, was employed. Six-week-old B10 mice (H-2b, Mlsb, Thyl.2) were tolerized to AKR antigens (H-2k, Mlsa, Thyl.1) by whole body irradiation (950 R) and iv infusion of T-cell-depleted (TCD) B10 BMC + non-TCD AKR BMC. Chimerism and antigen-specific tolerance were documented by flow microfluorometry (FMF), skin grafting, mixed lymphocyte reaction, and cell-mediated lympholysis. When tolerant B10 mice (n = 15) had accepted AKR skin grafts for greater than 100 days, these animals were studied for the presence of host V beta 6+ T cells using Mab RR-4-4. FMF revealed that 0-5% of host (B10) lymph node and spleen cells from chimeras were V beta 6+ while 15-20% of lymph node and spleen cells from control B10 mice expressed V beta 6. These data demonstrate that clonal deletion occurs in the lethal irradiation-mixed reconstitution model as evidenced by the near total elimination of Mlsa-reactive V beta 6+ T cells and suggest that it maybe a mechanism responsible for tolerance in adult mice.

Animals↗
PubMed1989

Modulation of the major histocompatibility complex antigen and the immunogenicity of islet allografts.

Modulation of major histocompatibility complex (MHC) antigen by parenchymal cells and "passenger leukocytes" is a common feature of allograft rejection. To assess its significance we have examined the fate of antigen-presenting cell (APC)-depleted pancreatic islet allografts subsequent to increasing their expression of MHC antigens by in vitro exposure to the lymphokine interferon-gamma (gIFN). While most untreated grafts survived indefinitely, gIFN-exposed grafts were acutely rejected. Using in vitro islet cell-lymphocyte coculture assays, we attempted to dissect the underlying mechanism of enhanced islet cell immunogenicity resulting from gIFN treatment. We determined that gIFN exposure did not affect the capacity of islet cells to serve as APC for T lymphocytes, however islet cell exposure to gIFN was associated with enhanced vulnerability to allogeneic cytotoxic T lymphocyte (CTL) lysis in vitro by an CD5+ (OX-19+), CD8+ (OX-8+), CD4- (W3/25-), class I-restricted CTL. On the basis of these findings, we conclude that antigenic modulation can be a decisive factor in the survival of engrafted tissues by augmenting the interaction of the graft antigens with cytolytic effector T lymphocytes.

Animals↗
PubMed1989

Frog ventricle: participation of SR in excitation-contraction coupling.

Activation of the first beat (B1) following a 60-s pause is diminished in isometrically contracting frog ventricular strips, in contrast to the augmentation documented for sarcoplasmic reticulum (SR)-dependent mammalian myocardium. However, treatment of frog ventricular strips with ouabain, an indirect inhibitor of the sarcolemmal Na+-Ca2+ exchanger, selectively enhanced postpause beats suggesting that in the absence of ouabain significant extrusion of cellular Ca2+ occurred during the pause. Because resting tension did not increase during the pause in ouabain-treated strips, the nonextruded Ca2+ must have been sequestered into a compartment such as SR. Steady-state beats were not affected by ouabain; its actions appeared to be separate from its known positive inotropism. Caffeine, a direct SR stimulus, initially enhanced B1 and subsequently decreased activation of all beats, which was consistent with initial augmentation of SR Ca2+ release and subsequent depletion of SR Ca2+ stores. Ouabain both potentiated the stimulatory effects and blocked the inhibitory effects of caffeine, suggesting that ouabain increased Ca2+ stores in the same intracellular Ca2+ pool as that acted on by caffeine, the SR. Ryanodine, an inhibitor of SR in mammalian myocardium, did not affect activation of frog myocardium. SR may be an important site for activator Ca2+ cycling in frog myocardium under control conditions as well as after long diastolic intervals in the presence of ouabain.

Animals↗
PubMed1988

Prophylaxis of serious cytomegalovirus infection in renal transplant candidates using live human cytomegalovirus vaccine. Interim results of a randomized controlled trial.

We report the interim results of a randomized, double-blind, placebo-controlled, clinical trial of prophylactic, live, attenuated cytomegalovirus (CMV) vaccination (Towne strain of CMV) of renal transplant candidates (RTCs). One hundred seventy-two RTCs were treated and subsequently underwent transplantation and followed up for at least one year and up to five years after transplantation. Eighty-eight RTCs received vaccine, and 84 received placebo. Results were analyzed according to the prevaccination serologic status (anti-CMV antibody titer) of the recipient (R- or R+) and the donor (D- or D+). The overall incidence of CMV disease was highest in the R-D+ group and almost absent in the R-D- group. There was no difference in the incidence of CMV infection or disease between vaccinated and respective placebo control recipients in either the R-D+, R+D+, R+D-, or R-D- groups. In contrast, the severity of CMV disease was significantly decreased in R-D+ vaccinees vs R-D+ placebo-treated recipients. Moreover, in the R-D+ group, one- and five-year cadaver renal allograft actuarial survival rates were 73% and 62%, respectively, for CMV vaccinees vs 40% and 25%, respectively, for control placebo patients. We conclude that seronegative cadaver RTCs may benefit from vaccination with live, attenuated, Towne strain CMV vaccine before transplantation.

Adult↗
PubMed1986

Reflex hypotension due to regional activation of left ventricular mechanoreceptors to explain the hypotension noted in clinical myocardial ischaemia or reperfusion.

To determine if regional increases in myocardial contractility, as may occur clinically in angina pectoris, myocardial infarction, or coronary thrombolysis, can initiate the reflex hypotension that sometimes accompanies these conditions, regional injections of positive inotropic agents were made into 32(3)% of the left ventricular myocardium in seven pneumonectomised dogs on total cardiac bypass. The coronary and systemic circulations were isolated and perfused separately. The systemic circulation was perfused at a constant rate so that changes in systemic pressure reflected changes in resistance. Regional injections of doses from 0.001 to 1.0 micrograms noradrenaline in a 0.1 ml volume appreciably increased regional contractility, detected visually and by strain gauge arches, whereas global contractility (left ventricular peak dP/dt) was increased much less. This caused a fall in the systemic pressure (resistance) of 14(2)% below the control value of 78(5)mm Hg, at the largest dose. The decreases in resistance were abolished by bilateral vagotomy, proving their reflex nature. The smaller (0.0001-0.01 micrograms) doses of noradrenaline and the smallest (0.25 micrograms) dose of veratridine increased regional contractility almost without increasing global contractility, indicating that the increase in regional contractility was the major cause of the reflex decrease in systemic resistance. In one animal a decrease in contractility in a control myocardial region occurred simultaneously with the experimentally produced increase in regional left ventricular contractility. This decrease may be analogous to the increase in contractility in the non-ischaemic left ventricular myocardium that occurs simultaneously with the decrease in contractility in the ischaemic region in clinical or experimental myocardial infarction. Left ventricular mechanoreceptors in the region with increased contractility probably initiate the reflex hypotension that sometimes occurs in both circumstances. Thus in angina pectoris or acute myocardial infarction the reflex hypotension probably originates in the hyperactive non-ischaemic myocardial region, whereas in coronary arterial thrombolysis it probably originates in the newly reperfused, formerly ischaemic, region.

Animals↗