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1.
Appl Clin Inform ; 6(2): 211-23, 2015.
Article in English | MEDLINE | ID: mdl-26171071

ABSTRACT

BACKGROUND: Health Information Management (HIM) and Health Informatics (HI) were very separate professions when they were first formed. However, with the increasing adoption of electronic health records, the interests of the two fields have become more aligned. OBJECTIVES: To describe the evolution of a joint master's program in health informatics(HI) and health information management (HIM). METHODS: After analyzing workforce needs, and reviewing both CAHIIM accreditation requirements and existing curricular offerings in separate programs in HIM and HI, a joint program was developed. RESULTS: An HI master's program with a core curriculum for all students and tracks in Data Analytics, User Experience and Advanced Practice HIM was developed. A model for a comprehensive examination, based on the CAHIIM competencies, to be administered prior to and after the core curriculum was also developed. CONCLUSIONS: A core and track curriculum that incorporates HIM education as part of the Master of Science of Health Informatics provides a feasible roadmap for the future as HIM and HI become more closely aligned.


Subject(s)
Cooperative Behavior , Health Information Management/education , Medical Informatics/education , Curriculum , Educational Measurement , Employment , Personnel Selection , Program Evaluation , Surveys and Questionnaires
2.
Appl Clin Inform ; 2(3): 270-83, 2011.
Article in English | MEDLINE | ID: mdl-23616876

ABSTRACT

BACKGROUND: Given relatively less favorable health outcomes in rural Alabama, electronic health records (EHRs) have an even greater potential to improve quality and alleviate disparities if meaningfully used. OBJECTIVES: We examined rural-urban differences as it pertained to perceived barriers, benefits, and motivating factors of EHR implementation. METHODS: We used multivariate logistic models to analyze data collected from a state-wide, self-completed survey of health information management directors in Alabama hospitals. RESULTS: Findings from our analyses indicate that fewer rural hospitals (8%) have implemented EHRs as compared with urban hospitals (18%). Rural hospitals were 71% less likely to consider reduction in costs as a benefit of EHRs (OR = 0.29), and were 75% less likely to consider lack of structured technology as a challenge factor of EHR implementation (OR = 0.25). CONCLUSION: Promotion of EHRs in rural areas is challenging but necessary. Understanding perceived barriers and motivating factors of EHR implementation among rural hospitals can inform policy decisions, especially in light of recent meaningful use initiatives.

3.
Am J Transplant ; 9(11): 2485-96, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19775318

ABSTRACT

The results of transplantation of human donor islets into the portal vein (PV) in patients with diabetes are encouraging. However, there are complications, for example, hemorrhage, thrombosis and an immediate loss of islets through the 'instant blood-mediated inflammatory reaction' (IBMIR). The gastric submucosal space (GSMS) offers potential advantages. Islets were isolated from adult pigs. Recipient pigs were made diabetic by streptozotocin. Donor islets were injected into the GSMS through a laparotomy (Group 1A, n = 4) or endoscopically (Group 1B, n = 8) or into the PV through a laparotomy (Group 2, n = 3). The pigs were followed for a maximum of 28 days. Monitoring of C-peptide in Group 1 indicated that there was minimal immediate loss of islets whereas in Group 2 there was considerable loss from IBMIR. In Group 1, there were significant reductions in mean blood glucose and mean exogenous insulin requirement between pretransplantation and 20 days posttransplantation. In Group 2, there was no significant reduction in either parameter. Insulin-positive cells were seen in the GSMS in Group 1, but not in the liver in Group 2. Endoscopic gastric submucosal transplantation of islets (ENDO-STI) offers a minimally invasive and quick approach to islet transplantation, avoids IBMIR and warrants further exploration.


Subject(s)
Diabetes Mellitus, Experimental/surgery , Endoscopy/methods , Gastric Mucosa/surgery , Islets of Langerhans Transplantation/methods , Animals , Blood Glucose/metabolism , C-Peptide/blood , Combined Modality Therapy , Diabetes Mellitus, Experimental/drug therapy , Female , Graft Rejection/drug therapy , Graft Rejection/immunology , Graft Rejection/pathology , Graft Survival , Hypoglycemic Agents/pharmacology , Immunosuppressive Agents/pharmacology , Insulin/pharmacology , Islets of Langerhans Transplantation/immunology , Mycophenolic Acid/analogs & derivatives , Mycophenolic Acid/pharmacology , Pancreatectomy , Sus scrofa , Tacrolimus/pharmacology , Transplantation, Homologous
4.
Am J Transplant ; 9(5): 1006-16, 2009 May.
Article in English | MEDLINE | ID: mdl-19422330

ABSTRACT

Xenograft outcomes are dictated by xenoantigen expression, for example, Gal alpha1, 3Gal (Gal), but might also depend on differing vascular responses. We investigated whether differential vascular gene expression in kidney and cardiac xenografts correlate with development of thrombotic microangiopathy (TM) and consumptive coagulation (CC). Immunosuppressed baboons underwent miniswine or hDAF pig kidney (n = 6) or heart (n = 7), or Gal-transferase gene-knockout (GalT-KO) (thymo)kidney transplantation (n = 14). Porcine cDNA miniarrays determined donor proinflammatory, apoptosis-related and vascular coagulant/fibrinolytic gene expression at defined time points; validated by mRNA, protein levels and immunopathology. hDAF-transgenic and GalT-KO xenografts, (particularly thymokidneys) exhibited prolonged survival. CC was seen with Gal-expressing porcine kidneys (3 of 6), only 1 of 7 baboons postcardiac xenotransplantation and was infrequent following GalT-KO grafts (1 of 14). Protective-type genes (heme oxygenase-I, superoxide dismutases and CD39) together with von Willebrand factor and P-selectin were upregulated in all renal grafts. Transcriptional responses in Gal-expressing xenografts were comparable to those seen in the infrequent GalT-KO rejection. In cardiac xenografts, fibrin deposition was associated with increased plasminogen activator inhibitor-1 expression establishing that gene expression profiles in renal and cardiac xenografts differ in a quantitative manner. These findings suggest that therapeutic targets may differ for renal and cardiac xenotransplants.


Subject(s)
Graft Rejection/immunology , Heart Transplantation/immunology , Kidney Transplantation/immunology , Transplantation, Heterologous/immunology , ABO Blood-Group System/immunology , Acute Disease , Animals , DNA, Complementary/genetics , Graft Rejection/mortality , Graft Rejection/pathology , Graft Survival/immunology , Heart Transplantation/mortality , Kidney Transplantation/pathology , Oligonucleotide Array Sequence Analysis , Papio , Proteins/genetics , Swine/genetics , Thymus Gland/transplantation , Transplantation Conditioning/methods
5.
Transplant Proc ; 41(1): 429-30, 2009.
Article in English | MEDLINE | ID: mdl-19249572

ABSTRACT

BACKGROUND: We have previously reported the successful induction of renal allograft tolerance in non-human primates using a nonmyeloablative conditioning regimen to produce a mixed-chimeric state in the recipient. In the present study, we applied this same technique to lung allotransplantation in cynomolgus monkeys. METHODS: Nine pairs of fully major histocompatibility complex (MHC)-mismatched cynomolgus monkeys were used. The conditioning regimen consisted of total body irradiation, thymic irradiation, and antithymocyte globulin. The recipients underwent lung and bone marrow transplantation, followed by anti-CD154 monoclonal antibody (mAb), and a 1-month course of cyclosporine. The regimen included anti-CD8 mAb in the last 5 recipients and alpha 1-antitripsin in the last 3 recipients. The results were compared with 8 recipients that received kidney allografts using the same regimen. RESULTS: Transient chimerism developed in all lung recipients, as was previously seen in the kidney recipients. Nonetheless, the lung recipients rejected their allografts significant earlier than the kidney recipients (P < .01). CONCLUSIONS: Despite the successful induction of mixed chimerism in recipients of fully MHC-mismatched lung allografts, we have not observed long-term graft survival, as has been seen in an analogous kidney model. Strategies to overcome this problem include organ-specific modifications of the transplant regimen.


Subject(s)
Graft Survival/immunology , Immune Tolerance , Kidney Transplantation/immunology , Lung Transplantation/immunology , Transplantation Chimera , ABO Blood-Group System , Animals , Antilymphocyte Serum/therapeutic use , Bone Marrow Transplantation/immunology , Histocompatibility Testing , Macaca fascicularis , Major Histocompatibility Complex/immunology , Male , Whole-Body Irradiation
6.
Am J Transplant ; 9(1): 105-13, 2009 Jan.
Article in English | MEDLINE | ID: mdl-19145702

ABSTRACT

We studied the effects of indirect allorecognition on the induction and maintenance phases of tolerance in miniature swine cotransplanted with heart and kidney allografts. MHC class I-mismatched heart and kidney grafts were cotransplanted in recipients receiving CyA for 12 days. Recipients were unimmunized or immunized with a set of donor-derived or control third-party MHC class I peptides either 21 days prior to transplantation or over 100 days after transplantation. T-cell proliferation, delayed type hypersensitivity reaction (DTH) and antibody production were assessed. All animals injected with donor MHC class I peptides developed potent indirect alloresponses specific to the immunizing peptides. While untreated recipients developed stable tolerance, all animals preimmunized with donor allopeptides rejected kidney-heart transplants acutely. In contrast, when peptide immunization was delayed until over 100 days after kidney-heart transplantation, no effects were observed on graft function or in vitro measures of alloimmunity. Donor peptide immunization prevented tolerance when administered to recipients pre transplantation but did not abrogate tolerance when administered to long-term survivors post transplantation. This suggests that the presence of T cells activated via indirect allorecognition represent a barrier to the induction but not the maintenance of tolerance.


Subject(s)
Heart Transplantation/immunology , Histocompatibility Antigens Class I/immunology , Immune Tolerance , Kidney Transplantation/immunology , Animals , Enzyme-Linked Immunosorbent Assay , Hypersensitivity, Delayed , Swine , Swine, Miniature , Transplantation, Homologous
7.
Am J Transplant ; 8(12): 2516-26, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19032222

ABSTRACT

The use of alpha1,3-galactosyltransferase gene-knockout (GalT-KO) swine donors in discordant xenotransplantation has extended the survival of cardiac xenografts in baboons following transplantation. Eight baboons received heterotopic cardiac xenografts from GalT-KO swine and were treated with a chronic immunosuppressive regimen. The pathologic features of acute humoral xenograft rejection (AHXR), acute cellular xenograft rejection (ACXR) and chronic rejection were assessed in the grafts. No hyperacute rejection developed and one graft survived up to 6 months after transplantation. However, all GalT-KO heart grafts underwent graft failure with AHXR, ACXR and/or chronic rejection. AHXR was characterized by interstitial hemorrhage and multiple thrombi in vessels of various sizes. ACXR was characterized by TUNEL(+) graft cell injury with the infiltration of T cells (including CD3 and TIA-1(+) cytotoxic T cells), CD4(+) cells, CD8(+) cells, macrophages and a small number of B and NK cells. Chronic xenograft vasculopathy, a manifestation of chronic rejection, was characterized by arterial intimal thickening with TUNEL(+) dead cells, antibody and complement deposition, and/or cytotoxic T-cell infiltration. In conclusion, despite the absence of the Gal epitope, acute and chronic antibody and cell-mediated rejection developed in grafts, maintained by chronic immunosupression, presumably due to de novo responses to non-Gal antigens.


Subject(s)
Galactosyltransferases/genetics , Galactosyltransferases/physiology , Graft Rejection/immunology , Heart Transplantation/immunology , Papio hamadryas/immunology , Swine, Miniature/immunology , Transplantation, Heterologous/immunology , Animals , Animals, Genetically Modified , Antibody Formation/physiology , CD4-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/pathology , Graft Rejection/pathology , Graft Rejection/physiopathology , Heart Transplantation/pathology , Heart Transplantation/physiology , Immunity, Cellular/physiology , Immunoglobulin G/blood , Immunoglobulin M/blood , Killer Cells, Natural/pathology , Swine , Swine, Miniature/genetics , Thrombosis/pathology , Transplantation, Heterologous/pathology , Transplantation, Heterologous/physiology , Troponin T/blood
8.
Transplant Proc ; 38(10): 3196-8, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17175220

ABSTRACT

It is well known that interferon-gamma (IFN-gamma) not only plays a critical role in antigen-dependent but also in antigen-independent tissue injury; however, it is not clear how tolerance induction affects the actions of IFN-gamma in the transplant setting. To address this question, we compared the effects of IFN-gamma on porcine recipients of near-syngeneic, rejecting, and tolerant heart transplants. IFN-gamma was infused continuously into the left anterior descending artery of hearts transplanted into 3 groups of major histocompatibility complex (MHC) inbred miniature swine, each treated with a 12-day course of cyclosporine A (CyA). Group 1 recipients received a MHC class I disparate heart, group 2 recipients received a near-syngeneic heart, and group 3 recipients were cotransplanted with a MHC class I disparate heart and kidney, which uniformly induces tolerance to both grafts. An additional group of animals was not transplanted but received intracoronary IFN-gamma infusion into their native hearts. IFN-gamma perfusion not only accelerated the acute rejection of MHC class I disparate hearts (mean survival time = 19 +/- 7.21 vs 38 +/- 8.19 days, P = .025), but caused near-syngeneic heart transplants, which otherwise survive indefinitely, to reject within 35 days (n = 3). In contrast, IFN-gamma perfusion had no demonstrable effects on interstitial rejection, the development of vascular lesions, or graft survival in tolerant heart plus kidney allograft recipients (n = 4) or in autologous hearts (n = 2). These results suggest that tolerance induction mitigates the damaging effects of IFN-gamma itself and that the beneficial effects of tolerance induction on acute and chronic rejection may extend to antigen-independent factors like ischemia/reperfusion injury.


Subject(s)
Heart Transplantation/immunology , Immune Tolerance , Interferon-gamma/pharmacology , Transplantation, Homologous/immunology , Animals , Graft Rejection/prevention & control , Swine
9.
Transplant Proc ; 38(10): 3253-5, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17175240

ABSTRACT

UNLABELLED: We have previously reported that tolerance to class I disparate lung allografts in miniature swine could be induced using an intensive 12-day course of tacrolimus and that pretransplant sensitization with immunogenic MHC class I allopeptides failed to block the induction of tolerance. We also have previously reported the importance of the presence of the thymus in the induction of tolerance to isolated heart, kidney, and combined heart-kidney transplants. In this study, we examined the impact of thymectomy on tolerance induction in lung transplantation. METHODS: Orthotopic left lung transplantation was performed using MHC class I-disparate donors. The recipients received a 12-day course of high-dose tacrolimus (n = 6). Total thymectomies were performed in three of the swine 21 days prior to transplantation. Lung grafts were monitored by chest radiography and serial open lung biopsy. RESULTS: All euthymic recipients maintained their grafts for over 1 year. None of the thymectomized recipients has experienced graft loss in the 6 to 10 months following transplantation. Although isolated lesions of obliterative bronchiolitis were occasionally seen in one thymectomized animal on biopsy, donor-specific unresponsiveness has been observed on assays of cell-mediated lymphocytotoxicity in all recipients. Moreover, co-culture assays have shown that recipient lymphocytes can strongly inhibit the normally robust response of naïve recipient-matched lymphocytes to donor antigen. This inhibition was not seen when using stimulators primed with third-party antigens against appropriate targets. CONCLUSIONS: These data suggest that thymus-independent peripheral regulatory mechanisms may be sufficient to induce and maintain long-term acceptance of the lung allografts.


Subject(s)
Histocompatibility Antigens Class I/immunology , Lung Transplantation/immunology , Thymectomy , Transplantation, Homologous/immunology , Animals , Genotype , Graft Rejection/immunology , Homozygote , Immunosuppressive Agents/therapeutic use , Lung Transplantation/pathology , Swine , Swine, Miniature , Tacrolimus/therapeutic use
10.
Transplant Proc ; 38(10): 3256-8, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17175241

ABSTRACT

UNLABELLED: Considerable evidence suggests that indirect recognition of MHC allopeptides plays an important role in solid-organ rejection. Here, we examine whether immunization with class I or class II allopeptides accelerates rejection in a fully MHC-mismatched lung transplant model in miniature swine. METHODS: Recipients were immunized with either donor-derived class I or class II peptides. Sensitization to the peptides was confirmed by DTH testing and in vitro proliferation assays. Nonimmunized control (n = 6), class I peptide-immunized (n = 3), and class II peptide-immunized (n = 3) swine were transplanted with fully mismatched lungs using only a 12-day course of tacrolimus. RESULTS: One control animal rejected its graft on postoperative day 103, while the others maintained their grafts for over 1 year. In the class I peptide-immunized group, two recipients rejected their grafts (days 14 and 52). The third animal has not rejected the graft (day 120, experiment is ongoing). In contrast, in the class II-peptide immunized group, only one animal rejected its graft on day 52, while the others maintained their grafts over 1 year. Both anti-donor IgM and IgG antibodies were detectable in all acute rejectors, although no alloantibody was detectable in long-term acceptors. Regardless of the fate of the graft, all animals have maintained their proliferative responses to the peptides. However, only acceptors maintained donor-specific hyporesponsiveness in cell-mediated lymphocytotoxity and mixed lymphocyte reaction assays. CONCLUSIONS: Pretransplant sensitization of lung allograft recipients to donor allopeptides accelerates graft rejection. This appears particularly true for class I-derived allopeptides, suggesting that class II molecules may be less antigenic when presented indirectly.


Subject(s)
Histocompatibility Antigens Class II/immunology , Histocompatibility Antigens Class I/immunology , Lung Transplantation/immunology , Animals , Graft Rejection/immunology , Graft Survival/immunology , HLA Antigens/immunology , Histocompatibility Testing , Immunoglobulin G/blood , Immunoglobulin M/blood , Major Histocompatibility Complex , Models, Animal , Swine , Swine, Miniature
11.
Transplant Proc ; 38(10): 3268-70, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17175245

ABSTRACT

OBJECTIVES: The mechanisms and treatment of chronic rejection in pulmonary allotransplantation remain elusive. We have induced robust tolerance to class I-disparate lung allografts in miniature swine using an intensive 12-day course of tacrolimus. Here, we tested whether a tolerant state can be induced in swine receiving fully mismatched lung allografts. METHODS: Orthotopic left lung allografts were performed using MHC class I-disparate (group 1: n = 3) or fully disparate (group 2: n = 6) donors. The recipients received a 12-day postoperative course of tacrolimus (continuous intravenous infusion; target level = 35-50 ng/mL) as their only immunosuppression. RESULTS: All swine in group 1 maintained their grafts long term without developing any lesions of chronic rejection (>497, >432, >451 days). These recipients exhibited donor-specific hyporesponsiveness in cell-mediated lymphocytotoxity (CML) and mixed lymphocyte reaction (MLR) assays. In group 2, five of the six recipients maintained their grafts long term (sacrificed on postoperative days 515, 389, 429, 481, and 438 with viable grafts). Isolated lesions of obliterative bronchiolitis were occasionally seen on biopsy, and donor-specific hyporesponsiveness on assays was consistently observed. The remaining recipient rejected its graft on day 103 with histologic findings of obliterative bronchiolitis. CONCLUSIONS: We report long-term graft acceptance without chronic immunosuppression in five of six recipients across a full MHC disparity, albeit with some evidence of obliterative bronchiolitis. These data suggest that the class II disparity inherent in a fully mismatched transplant increases the requirement for tolerance induction.


Subject(s)
Histocompatibility Antigens Class II/immunology , Immune Tolerance , Lung Transplantation/immunology , Animals , Graft Rejection/pathology , Lung Transplantation/pathology , Major Histocompatibility Complex , Models, Animal , Swine , Swine, Miniature , Transplantation, Homologous/immunology
12.
Gene Ther ; 13(18): 1320-7, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16708077

ABSTRACT

Gelatin hydrogel microspheres (GHMs) have been reported as novel non-viral vectors for gene or protein delivery (GHM therapy). However, the components of an effective catheter-based delivery strategy for GHM therapy are unknown. We evaluated the effectiveness of three catheter-based strategies for cardiac GHM therapy: (1) antegrade injection (AI) via coronary arteries; (2) retrograde injection (RI) via coronary veins; and (3) direct myocardial injection (DI) via the coronary sinus. AI distributed microspheres homogeneously throughout the target area with 73+/-11% retention. RI scattered microspheres non-homogenously with 22+/-8% retention. DI distributed microspheres in the needle-advanced area with 47+/-14% retention. However, despite high efficiency, AI did not show biological effects of inducing angiogenesis from basic fibroblast growth factor bound to GHMs. Furthermore, focal micro-infarctions, owing to micro-embolism of aggregated GHMs into small coronary arterioles, were detected in the AI group. Conversely, only RI and DI groups displayed increased coronary flow reserve. DI groups also demonstrated increased capillary density. These results suggest that RI and DI are effective for cardiac GHM therapy, while AI appears inappropriate owing to the risk of focal infarctions.


Subject(s)
Fibroblast Growth Factor 2/administration & dosage , Myocardium/metabolism , Animals , Catheterization , Coronary Circulation , Coronary Vessels , Fibroblast Growth Factor 2/metabolism , Gelatin , Genetic Therapy/methods , Hydrogel, Polyethylene Glycol Dimethacrylate , Injections/adverse effects , Injections/methods , Microspheres , Models, Animal , Myocardial Infarction/etiology , Neovascularization, Physiologic , Recombinant Proteins/administration & dosage , Regional Blood Flow , Stem Cell Transplantation/methods , Swine
13.
Transplant Proc ; 37(1): 72-4, 2005.
Article in English | MEDLINE | ID: mdl-15808551

ABSTRACT

OBJECTIVES: The mechanisms and treatment of chronic rejection in pulmonary allotransplantation remain elusive. Using a strategy to induce tolerance across strong allogeneic barriers, we have employed a brief, intensive course of immunosuppression to determine whether the induction of donor-specific hyporesponsiveness would prevent allograft rejection in a preclinical model of lung transplantation using MHC-inbred miniature swine. METHODS: Orthotopic left lung allografts were performed using MHC class I-disparate donors. The recipients received a 12-day postoperative course of cyclosporine (n = 6) or a 12-day postoperative course of high-dose tacrolimus (n = 3) as their only immunosuppression. Control animals received no immunosuppression (n = 3). RESULTS: Cyclosporine-treated recipients exhibited graft survival ranging from 67 to >605 days. All six animals developed acute cellular rejection between postoperative days (PODs) 27 and 108. Two animals lost their grafts on PODs 67 and 69, before developing obliterative bronchiolitis (OB). The other four recipients developed OB between PODs 119 and 238. In contrast, all tacrolimus-treated recipients maintained their grafts long term, without developing chronic rejection (>339, >308, and >231). These recipients also exhibited donor-specific hyporesponsiveness in assays of cell-mediated lymphocytotoxity. All untreated control animals lost their grafts to acute rejection by POD 11. CONCLUSIONS: This study demonstrates the ability of a brief course of high-dose tacrolimus to induce long-term graft acceptance with donor-specific hyporesponsiveness in a class I-disparate preclinical lung transplant model.


Subject(s)
Graft Survival/immunology , Lung Transplantation/immunology , Animals , Graft Rejection/prevention & control , Graft Survival/drug effects , Immunosuppressive Agents/therapeutic use , Lung Transplantation/pathology , Swine , Swine, Miniature , Tacrolimus/therapeutic use , Transplantation, Homologous/immunology , Transplantation, Homologous/pathology
14.
Transplant Proc ; 37(1): 489-90, 2005.
Article in English | MEDLINE | ID: mdl-15808685

ABSTRACT

Hearts from alpha1,3-Galactosyltransferase gene-knockout (GaIT-KO) pigs were transplanted heterotopically into 8 baboons that received an anti-CD154 monoclonal antibody (mAb)-based immunosuppressive regimen and heparin. Three baboons died or were euthanized with beating grafts on 16, 23, and 56 days, respectively, and the remaining 5 grafts functioned for 59-179 days. Hyperacute rejection did not occur, and classical features of acute humoral xenograft or acute cellular rejection were rare. However, thrombotic microangiopathy (TM) developed in all cases; its onset was delayed in 2 baboons that received aspirin. Function of a pig organ in a baboon for a period approaching 6 months has not been reported previously and lends encouragement that the barriers to xenotransplantation will be overcome, but TM requires investigation.


Subject(s)
Aspirin/therapeutic use , Fibrinolytic Agents/therapeutic use , Galactosyltransferases/deficiency , Galactosyltransferases/genetics , Gene Deletion , Graft Rejection/prevention & control , Heart Transplantation/methods , Thrombosis/prevention & control , Transplantation, Heterologous/methods , Animals , Graft Survival , Papio , Swine
15.
J Heart Lung Transplant ; 24(1): 92-4, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15653386

ABSTRACT

Troponin T levels have been monitored in baboons (n = 8) undergoing pig heterotopic heart transplantation, and correlated with a decrease in graft contractions and graft survival. Pig heart graft survival was from 12 to 139 days (mean 45, median 33), and graft failure was associated with predominant thrombotic microangiopathy and ischemia, with focal hemorrhage, and edema. An increase in troponin T levels 5 to 6 days before graft failure correlated closely with diminished graft contractions. An increase in troponin T was a reliable indicator that graft dysfunction was occurring.


Subject(s)
Heart Transplantation , Transplantation, Heterotopic , Troponin T/metabolism , Animals , Biomarkers/blood , Cold Ischemia , Graft Survival/physiology , Models, Cardiovascular , Myocardial Ischemia/etiology , Myocardial Ischemia/metabolism , Myocardial Ischemia/physiopathology , Papio , Swine
16.
Circulation ; 109(1): 97-102, 2004 Jan 06.
Article in English | MEDLINE | ID: mdl-14676147

ABSTRACT

BACKGROUND: Although hypercholesterolemia is a well-established risk factor for coronary artery disease, little is known regarding its direct effects on cardiac function. METHODS AND RESULTS: We examined the effects of cholesterol feeding (0.5%) on cardiac function in rabbits. After 10 weeks, both systolic shortening and diastolic relaxation rates were impaired without any change in aortic pressure or ventricular hypertrophy. However, sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA)-2 mRNA levels were reduced within 4 days after initiation of cholesterol feeding. After this effect, SERCA-2 protein and SERCA-mediated Ca uptake into sarcoplasmic reticulum vesicles were impaired, and the ratio of MHC-beta to MHC-alpha mRNA increased 5-fold. Suppression of the SERCA-2 message correlated temporally with enrichment of the cardiac sarcolemma with cholesterol. CONCLUSIONS: These data demonstrate that dietary hypercholesterolemia induces a "cholesterol cardiomyopathy" characterized by systolic and diastolic dysfunction. These alterations were independent of vascular disease and demonstrate a dietary link to cardiac dysfunction.


Subject(s)
Cholesterol, Dietary/adverse effects , Diastole , Hypercholesterolemia/physiopathology , Systole , Ventricular Dysfunction, Left/etiology , Animals , Calcium-Transporting ATPases/metabolism , Cholesterol/metabolism , Hypercholesterolemia/complications , Hypercholesterolemia/metabolism , Hypercholesterolemia/pathology , Myocardium/metabolism , Myocardium/pathology , Myosin Heavy Chains/metabolism , Organ Size , RNA, Messenger/metabolism , Rabbits , Sarcolemma/metabolism , Sarcoplasmic Reticulum Calcium-Transporting ATPases , Ventricular Dysfunction, Left/metabolism , Ventricular Dysfunction, Left/pathology
17.
J Heart Lung Transplant ; 22(11): 1234-44, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14585385

ABSTRACT

BACKGROUND: Hearts from non-heart-beating organ donors are not transplanted because of risk of ischemia-reperfusion injury. We tested whether pharmacologic pre-conditioning with adenosine and the Na(+)/H(+) exchanger inhibitor, cariporide, combined with controlled reperfusion, would prevent injury in porcine hearts that had sustained 30 minutes of hypoxia/ischemia in closed-chest animals. METHODS: Hearts from Yorkshire pigs (100 kg) were studied in 3 groups. Group 1 (control) hearts were surgically removed while beating. Group 2 hearts were harvested from animals made hypoxic by discontinuing mechanical ventilation for 30 minutes. Group 3 hearts were hypoxic as in Group 2, but these animals received adenosine (40 mg) and cariporide (400 mg) 10 minutes before stopping ventilation. Cardiac function in all groups was assessed ex vivo in a working heart apparatus in which pressure and flow measurements were made over 3 hours. Controlled reperfusion in Group 3 hearts used leukocyte-depleted blood perfusate containing free radical scavengers. Myocardial injury was assessed on the basis of perfusate creatine phosphokinase activity and histopathologically determined injury score. RESULTS: Groups 1 and 3 hearts could be resuscitated to perform work equivalently during the entire reperfusion period and showed positive responses to increases in pre-load and norepinephrine. Group 2 hearts could not perform work. After 3 hours, Group 2 hearts showed significantly higher creatine phosphokinase and histopathologic injury scores compared to with Groups 1 and 3, which were not significantly different from each other. CONCLUSIONS: Pharmacologic pre-conditioning and controlled reperfusion effectively protect non-beating porcine hearts from injury after 30 minutes of hypoxia/ischemia in situ.


Subject(s)
Adenosine/therapeutic use , Anti-Arrhythmia Agents/therapeutic use , Guanidines/therapeutic use , Ischemic Preconditioning, Myocardial/methods , Myocardial Reperfusion Injury/prevention & control , Sulfones/therapeutic use , Vasodilator Agents/therapeutic use , Animals , Creatine Kinase/metabolism , Heart/drug effects , Heart/physiopathology , Hypoxia/metabolism , Myocardial Reperfusion Injury/enzymology , Myocardial Reperfusion Injury/pathology , Myocardium/enzymology , Myocardium/pathology , Swine
18.
Transplantation ; 75(11): 1799-806, 2003 Jun 15.
Article in English | MEDLINE | ID: mdl-12811237

ABSTRACT

BACKGROUND: Spleen transplantation (Tx) between some strains of rodents can lead to donor-specific tolerance either spontaneously or after a short course of immunosuppression. This study developed a surgical technique for spleen Tx in miniature swine to investigate its immunologic impact in a large animal model. METHODS: The preferred surgical technique of spleen Tx (n=8) involved excision of the donor spleen with its vascular pedicle to the aorta and portal vein. Carrel patches of donor aorta and portal vein were anastomosed to the abdominal aorta and inferior vena cava, respectively, of the (splenectomized) recipient. The results in four major histocompatibility complex-matched pairs that were mismatched for the porcine allelic antigen are reported. Two recipients were untreated, one received a 12-day course of cyclosporine A (CsA) alone, and one received thymic irradiation (700 cGy) and CsA. Hematopoietic cell chimerism was followed by fluorescence-activated cell sorter, and graft survival was assessed by histology. RESULTS: Spleen Tx was technically successful. In two untreated pigs, chimerism was detected in the blood (maximum 5% for 17 and 25 days) and lymph nodes (maximum 6% for 28 and 56 days), but both grafts showed histologic rejection by day 28. In two treated pigs, chimerism was present in the blood for 47 and 57 days, and rejection was prevented, with follow-up for 57 and 217 days, respectively. CONCLUSION: Spleen Tx in major histocompatibility complex-matched pairs treated with CsA+/-thymic irradiation results in prolonged chimerism and is associated with the development of in vivo unresponsiveness to the transplanted spleen.


Subject(s)
Major Histocompatibility Complex/immunology , Spleen/transplantation , Splenectomy/methods , Animals , Biopsy , Cyclosporine/pharmacology , Flow Cytometry , Graft Rejection/mortality , Graft Rejection/pathology , Hematopoietic Stem Cells/cytology , Histocompatibility Testing , Immunosuppressive Agents/pharmacology , Postoperative Complications , Skin Transplantation/immunology , Spleen/pathology , Swine, Miniature , Tissue Donors , Transplantation Chimera
19.
Heart ; 89(3): 317-20, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12591841

ABSTRACT

BACKGROUND: Conventional contrast cineangiography and intravascular ultrasound (IVUS) provide a limited definition of vessel microstructure and are unable to evaluate dissection, tissue prolapse, and stent apposition on a size scale less than 100 micro m. OBJECTIVE: To evaluate the use of intravascular optical coherence tomography (OCT) to assess the coronary arteries in patients undergoing coronary stenting. METHODS: OCT was employed in patients having percutaneous coronary interventions. Images were obtained before initial balloon dilatation and following stent deployment, and were evaluated for vessel dissection, tissue prolapse, stent apposition, and stent asymmetry. IVUS images were obtained before OCT, using an automatic pull back device. RESULTS: 42 stents were imaged in 39 patients without complications. Dissection, prolapse, and incomplete stent apposition were observed more often with OCT than with IVUS. Vessel dissection was identified in eight stents by OCT and two by IVUS. Tissue prolapse was identified in 29 stents by OCT and 12 by IVUS; the extent of the prolapse (mean (SD)) was 242 (156) microm by OCT and 400 (100) microm by IVUS. Incomplete stent apposition was observed in seven stents by OCT and three by IVUS. Irregular strut separation was identified in 18 stents by both OCT and IVUS. CONCLUSIONS: Intracoronary OCT for monitoring stent deployment is feasible and provides superior contrast and resolution of arterial pathology than IVUS.


Subject(s)
Coronary Disease/diagnostic imaging , Endosonography/methods , Stents , Adult , Aged , Coronary Restenosis/diagnostic imaging , Female , Humans , Male , Middle Aged , Ultrasonography, Interventional
20.
Heart ; 89(1): 11-3, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12482781

ABSTRACT

The histopathology of in-stent restenosis (ISR) following gamma brachytherapy is described. Such histology has not been reported previously. An 82 year old man presented with recurrent ISR three months after gamma brachytherapy to an area of ISR within a native circumflex vessel. The recurrent ISR was treated with directional coronary atherectomy; the histopathology of this directional coronary atherectomy specimen is discussed. These histopathological examinations showed abundant extracellular matrix material. Surprisingly, there was a relatively small cellular (myofibroblastic) component, with an absence of endothelial cells and little evidence of active proliferation. ISR after gamma brachytherapy may be a pathologically distinct entity.


Subject(s)
Brachytherapy/methods , Coronary Restenosis/pathology , Prosthesis Failure , Stents , Aged , Aged, 80 and over , Atherectomy, Coronary , Coronary Angiography/methods , Coronary Restenosis/radiotherapy , Coronary Restenosis/surgery , Humans , Immunohistochemistry/methods , Male
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