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Biomedical subjects

R E Michler

Publications and source records attributed to R E Michler.

At least 91 records · Page 5Linked to original sources
PubMed1996

Recent advances and the potential for clinical use of xenotransplantation.

The success of allotransplantation has paradoxically led to a shortage in the supply of organs required to meet the increasing demand. Xenografts represent a potentially infinite supply of good quality organs. Recent advances in the understanding of the immunobiology of xenograft rejection has spurred experimental approaches aimed at abrogating or suppressing human xenospecific immune responses. The limited supply of colony-bred nonhuman primates (baboons) makes it highly unlikely that this species will be of widespread use as a donor source. Therefore, the pig has been proposed as a realistic alternative donor. Delineation of the major pig xenoantigens recognized by natural human xenoreactive antibodies has led to the development of strategies aimed at depletion of antibodies or the prevention of their binding to xenogeneic endothelium. Recognition that antibody binding leads to endothelial cell activation and complement-mediated injury has led to the development of genetically modified pigs whose organs are potentially resistant to damage by human complement by virtue of the fact that their endothelial cells express membranebound human complement regulatory proteins. Finally, dissection of the relative contributions of humoral and cellular immune responses directed against xenografts from closely or distantly related species has permitted rational recommendations for the administration of immunosuppressive regimens.

Animals↗
PubMed1996

Isolated cerebral hypothermia by single carotid artery perfusion of extracorporeally cooled blood in baboons.

OBJECTIVE: Hypothermia has been demonstrated to protect the brain from ischemic or traumatic injury. Previous efforts to induce cerebral hypothermia have relied on techniques requiring total body cooling that have resulted in serious cardiovascular derangements. A technique to selectively cool the brain, without systemic hypothermia, may have applications for the treatment of neurological disease. METHODS: After induction of general anesthesia in 12 baboons, the right common carotid artery and ipsilateral femoral artery were each occlusively cannulated and joined to a centrifugal pump. In a closed-circuit system, blood was continually withdrawn from the femoral artery, cooled by water bath, and infused through the common carotid artery with its external branches occluded. Pump flow was varied so that right carotid pressure approximated systemic blood pressure. In six animals, perfusate was cooled to decrease right cerebral temperature to < 19 degrees C for 30 minutes. In six animals, right cerebral temperature was decreased to < 25 degrees C for 3 hours. In those six animals, 133Xe was injected into the right carotid artery before, during, and after hypothermia. Peak radioactivity and washout curves were recorded from bilateral cranial detectors. Systemic warming was accomplished by convective air and warm water blankets. Esophageal, rectal, and bilateral cerebral temperatures were continuously recorded. RESULTS: In animals cooled to < 19 degrees C, right cerebral temperature decreased from 34 degrees C to 18.5 +/- 1.1 degrees C (mean +/- standard deviation), P < 0.01, in 26 +/- 13 minutes. Simultaneously, left cerebral temperature decreased to 20.7 +/- 1.6 degrees C. During 30 minutes of stable cerebral hypothermia, esophageal temperature decreased from 35.1 +/- 2.3 degrees C to 34.2 +/- 2.2 degrees C, P < 0.05. In animals cooled to < 25 degrees C, right cerebral temperature decreased from 34 degrees C to 24.5 +/- 0.6 degrees C in 12.0 +/- 6.0 minutes, P < 0.01. Simultaneously, left cerebral temperature decreased to 26.3 +/- 4.8 degrees C. After 3 hours of stable cerebral hypothermia, esophageal temperature was 34.4 +/- 0.5 degrees C, P < 0.05. Right hemispheric cerebral blood flow decreased during hypothermia (26 +/- 16 ml/min/100 g) compared to values before and after hypothermia (63 +/- 29 and 51 +/- 34 ml/min/100 g, respectively; P < 0.05). Furthermore, hypothermic perfusion resulted in a proportionally increased radioactivity peak detected in the left cerebral hemisphere after right carotid artery injection of 133Xe (0.8 +/- 0.2:1, left:right) compared to normothermia before and after hypothermia (0.3 +/- 2 and 0.3 +/- 1, respectively; P < 0.05). Normal heart rhythm, systemic arterial blood pressure, and arterial blood gas values were preserved during hypothermia in all animals. CONCLUSION: Bilateral cerebral deep or moderate hypothermia can be induced by selective perfusion of a single internal carotid artery, with minimal systemic cooling and without cardiovascular instability. This global brain hypothermia results from profoundly altered collateral cerebral circulation during artificial hypothermic perfusion. This technique may have clinical applications for neurosurgery, stroke, or traumatic brain injury.

Animals↗
PubMed1996

Selective cerebral hypothermia by means of transfemoral internal carotid artery catheterization.

Global cerebral hypothermia of 24 degrees C was induced without systemic cooling by means of selective hypothermic perfusion of a single internal carotid artery in four baboons. With a closed-circuit pump system, blood was withdrawn from the femoral artery, cooled in a water bath, and infused through an internal carotid artery catheter, which was positioned with fluoroscopic guidance. This endovascular technique may have applications in the treatment of neurologic disease in humans.

Animals↗
PubMed1996

cAMP-mediated vascular protection in an orthotopic rat lung transplant model. Insights into the mechanism of action of prostaglandin E1 to improve lung preservation.

Prostaglandin E1 (PGE1) is often added to the donor pulmonary flush solution to enhance clinical lung preservation for transplantation. Although PGE1 is thought to act as a pulmonary vasodilator during the harvest period, the precise mechanism(s) of action whereby PGE1 enhances lung preservation is unknown. Because cAMP levels decline in endothelial and vascular smooth muscle cells exposed to hypoxia, we hypothesized that a PGE1-mediated increase in cAMP levels within the preserved lungs might improve pulmonary vascular homeostasis following lung transplantation. Rat lungs demonstrated a time-dependent decline in cAMP levels during hypothermic storage, with cAMP levels significantly increased by PGE1 supplementation (approximately 2-fold by 6 hours, P < .0005). To test whether augmenting cAMP levels may enhance lung preservation, experiments were performed using an orthotopic rat left lung transplant model. Compared with controls, supplementing the preservation solution with the membrane-permeable cAMP analogue dibutyryl-cAMP resulted in dose-dependent preservation enhancement, marked by reduced pulmonary vascular resistance (6.0-fold, P < .01), improved arterial oxygenation (3.0-fold, P < .01), reduced graft neutrophil infiltration (1.5-fold, P < .05), and improved recipient survival (7.0-fold, P < .005). Similar preservation enhancement was observed with another cAMP analogue (8-bromo-cAMP) or the phosphodiesterase inhibitor indolidan. Stimulating the cAMP second messenger system by PGE1 supplementation resulted in marked hemodynamic benefits and improved recipient survival, in parallel with reduced graft neutrophil infiltration, vascular permeability, and platelet deposition. These beneficial effects of PGE1 were abrogated by simultaneous administration of the cAMP-dependent protein kinase antagonist Rp-cAMPS. Although an arterial vasodilator (minoxidil) resulted in significant pulmonary vasodilation during harvest, it lacked other nonvasodilating effects of PGE1 and resulted in poor preservation. These data show that harvest vasodilation by itself is insufficient to enhance lung preservation and that PGE1 enhances lung preservation by stimulating the cAMP-dependent protein kinase and promoting non-vasodilatory mechanisms of pulmonary protection.

Alprostadil↗
PubMed1996

Fracture after cardiac transplantation: a prospective longitudinal study.

Cardiac transplantation is associated with increased prevalence of vertebral fractures, but the natural history of and risk factors for fracture after this life-saving procedure are unclear. We evaluated 47 patients (34 men and 13 postmenopausal women) before transplantation with spinal radiographs, determination of bone density by dual energy x-ray absorptiometry, and measurement of biochemical indexes of mineral metabolism. During the first year after transplantation, incident fractures were documented radiographically. Associations among demographic characteristics, bone density, biochemistries, and fracture risk were evaluated with logistic regression analysis. Despite supplementation with elemental calcium (1000 mg/day) and vitamin D (400 IU/day), 17 patients (7 women and 10 men) sustained a total of 34 fractures. Most fractures involved the spine, and 85% of the patients who experienced fracture did so within 6 months of transplantation. Fifty-four percent of the women and 29% of the men experienced fracture. Femoral neck bone mineral density was significantly lower in women who experienced fracture than in those who did not (0.604 +/- 0.11 vs. 0.760 +/- 0.12 g/cm2; P < 0.04), but did not differ in men according to fracture outcome. The amount of bone loss at the femoral neck by 6 months after transplantation was significantly greater in men with fracture than in men without fracture (12.0 +/- 6.4% vs. 6.8 +/- 5.3%; P < 0.04), but did not differ in women according to fracture outcome. Pretransplant 1,25-dihydroxyvitamin D levels were significantly lower (25 +/- 9 vs. 39 +/- 17 pg/mL; P < 0.007) and intact PTH levels tended to be higher in men who did not experience fracture (37 +/- 15 vs. 69 +/- 46 pg/mL; P < 0.06). Individual pretransplant bone density measurements demonstrated substantial overlap between patients who did and did not experience fracture, and normal bone density did not necessarily protect against fracture after transplantation. We conclude that fractures are a common and early complication of cardiac transplantation. No pretransplant measurement has yet been identified that reliably predicts fracture after transplantation in the individual patient.

Bone Density↗
PubMed1996

Two decades of cardiac transplantation at the Columbia-Presbyterian Medical Center: 1977-1997.

Since its inception in 1977, the Cardiac Transplantation Service at Columbia-Presbyterian Medical Center has performed more than 900 heart transplant procedures, with a one-year survival rate of approximately 80%, and a 5-year survival rate of approximately 60%. Throughout our 20-year experience, the criteria for eligibility both donors and recipients has widened to include older and "reanimated" donors for selected recipients, as well as an extensive experience with recipients bridged to transplantation with mechanical assist devices. Of particular interest in recent years has been the need for additional therapy for the highly sensitized transplant candidate and ultimate transplant recipient, whose immunosuppressive regimen must be continuously monitored and modified to ensure graft survival. In light of the persistent donor organ crisis, continued efforts are being developed to more accurately characterize the transplant candidate waiting list in order to identify those patients who may be better served by either medical management or an alternative surgical procedure to transplantation, including high-risk coronary revascularization and mechanical or biological assistance. Current research interests at CPMC include left ventricular assist devices, xenotransplantation, and management of both transplant coronary artery disease and immunologic sensitization. Ongoing investigations in these and other areas of transplantation have been established to encourage continued growth both within the field and at CPMC through the 21st century.

Adult↗
PubMed1995

Discriminating between preservation and reperfusion injury in human cardiac allografts using heart weight and left ventricular mass.

BACKGROUND: Myocardial edema caused by injury during preservation or reperfusion can affect cardiac function after heart transplantation. This study was designed to distinguish these forms of injury in human allografts. METHODS AND RESULTS: In 15 donor hearts preserved in University of Wisconsin solution, heart weight (HW) was obtained immediately after explantation and after transport before implantation. Left ventricular mass (LVM) was calculated separately in 18 patients with the use of epicardial two-dimensional echocardiograms obtained both before explantation from the donor and after transplantation and weaning from cardiopulmonary bypass. While changes in LVM could be due to preservation or reperfusion injury, changes in HW can only be due to edema occurring during transport. HW averaged 339 +/- 24 g (mean +/- SE) before and 340 +/- 24 g after transport (P = NS); however, LVM increased 14 g, from 164 +/- 8 to 178 +/- 11 g (P < .05, paired t test). LVM increased in 10 of 18 patients (56%). No correlation was demonstrated between duration of ischemia (mean, 172 +/- 13 minutes) and changes in HW or LVM. Two patients died as a result of primary graft failure. In the first, HW increased 54 g, 2 SD above the mean. In the second, LVM increased 66 g, 2 SD above the mean, but HW changed minimally. CONCLUSIONS: While current preservation methods result in minimal change in HW during transport, reperfusion injury frequently increases LVM. LVM determination by two-dimensional echocardiography may prove valuable in detecting allograft injury.

Diagnosis, Differential↗
PubMed1995

Ischemia-induced interleukin-8 release after human heart transplantation. A potential role for endothelial cells.

BACKGROUND: Interleukin-8 (IL-8) secreted from endothelial cells is a powerful neutrophil chemoattractant and activator. We hypothesized that human endothelial cells deprived of oxygen would secrete IL-8, which might translate into elevated IL-8 production after cardiac ischemia. Furthermore, we hypothesized that coronary sinus (CS) IL-8 levels would be particularly high after cardiac preservation for transplantation, due to extended ischemic times. METHODS AND RESULTS: Human saphenous vein endothelial cells exposed to a hypoxic environment (PO2 < 20 mm Hg) demonstrated a time-dependent release of IL-8 (measured by ELISA) into the culture supernatant as early as 4 hours after exposure. To determine whether cardiac preservation in humans was associated with IL-8 production, we obtained CS blood samples 5 minutes after reperfusion in a consecutive series of patients after they underwent cardiac transplantation (CTX, n = 20) or elective cardiac surgery (non-CTX, n = 21). CTX patients demonstrated significantly higher CS IL-8 levels than non-CTX patients (325 +/- 123 versus 50 +/- 17 ng/mL, respectively, P < .05). Further analysis of the CS samples revealed that a biochemical marker of myocyte injury (myoglobin) was similarly elevated in the CTX patients compared with the non-CTX patients (3340 +/- 625 versus 1151 +/- 525 ng/mL, respectively, P < .05). CONCLUSIONS: These differences may reflect the longer ischemic times of CTX compared with non-CTX hearts (161 +/- 10 versus 80 +/- 6 minutes, P < .0001) and suggest that the neutrophil chemoattractant/activator IL-8 may contribute to myocyte injury after prolonged hypothermic cardiac ischemia, as occurs during human cardiac transplantation.

Aged↗
PubMed1995

Molecular genetic analysis demonstrates that multiple posttransplantation lymphoproliferative disorders occurring in one anatomic site in a single patient represent distinct primary lymphoid neoplasms.

BACKGROUND: Posttransplantation lymphoproliferative disorders (PT-LPDs) are a clinicopathologically heterogeneous group of lymphoid proliferations of varied clonal composition, the majority of which are associated with Epstein-Barr virus (EBV) infection. The clonal content and clonal relatedness of 24 separate PT-LPD lesions occurring synchronously in one organ in a single patient were investigated. METHODS: Twenty-four separate PT-LPD lesions from the colon and mesentery of a 15-year-old male, developing 4 months after cardiac transplantation, were studied for clonality based on immunoglobulin heavy chain (IgH) gene rearrangements for the presence, clonality, and type of EBV infection and for the presence of c-myc, ras, and p53 gene alterations. Southern blot hybridization, polymerase chain reaction, and single strand conformation polymorphism assays were employed. RESULTS: All 24 lesions were histologically similar (polymorphic B-cell lymphomas) but exhibited varied clonality and were clonally distinct with respect to both IgH gene rearrangements and EBV infection. All lesions were infected with EBV type A. Structural alterations of oncogenes or tumor suppressor genes were not identified. CONCLUSIONS: Separate PT-LPD lesions occurring synchronously in a single organ or patient may be clonally distinct, suggesting that they represent multiple distinct primary lymphoid proliferations rather than metastatic disease as in conventional malignant lymphomas. This may explain partially the rapid development in some patients of a large PT-LPD tumor burden that may regress rapidly after reduction of immunosuppression.

Adolescent↗
PubMed1995

Newborn baboon serum lacks natural anti-pig xenoantibody.

Discordant xenotransplantation represents an attractive alternative to allotransplantation in light of the shortage of donor organs currently available for cardiac allotransplantation. Unfortunately, discordant xenotransplantation is still limited by hyper-acute rejection, a process thought to be mediated by natural anti-xenodonor antibody. Based on data that cytotoxic natural xenoantibodies are IgM in nature, we postulated that natural xenoantibodies may be absent from newborn serum. Baboon sera were collected from infant baboons. Pooled adult baboon sera were used as controls. A whole cell ELISA was performed to determine the binding of xenoantibodies to pig aortic endothelial cells and pig lymphocytes. The cytotoxicity of both adult and newborn baboon sera to pig aortic endothelial cells was measured by a MTT (3-(4,5-dimethyl-thiazoyl-2-y) 2,5 diphenyl-tetrazolium bromide) assay. Newborn baboon sera demonstrated very low levels of binding of natural IgM xenoantibodies to pig endothelial cells and lymphocytes, whereas natural IgM xenoantibodies from adult baboon sera bound significantly to both pig aortic endothelial cells and lymphocytes. IgG natural antibodies in both adult and newborn sera bound to pig endothelial cells and pig lymphocytes. The MTT assay demonstrated high levels of cytotoxicity to pig endothelial cells from adult baboon sera and very low levels of cytotoxicity from newborn baboon sera. In this study, newborn baboon sera were demonstrated to be free of natural IgM xenoantibodies to pig endothelial cells and lymphocytes. Although natural anti-pig IgG antibodies were present in newborn sera, newborn baboon sera lack cytotoxicity to pig target cells. These findings suggest that IgM is the more important xenoantibody and that hyperacute rejection of discordant cardiac xenografts may be avoidable in the newborn.

Aging↗
PubMed1995

Posttransplantation lymphoproliferative disorders frequently contain type A and not type B Epstein-Barr virus.

Two families of Epstein-Barr virus (EBV), type A and type B, have been defined on the basis of sequence divergence in the EBNA-2 gene. Type A EBV immortalizes B cells more efficiently in vitro and infects immunocompetent individuals more commonly than type B EBV. However, increased rates of infection by type B EBV are seen in immunocompromised hosts and in many lymphoid neoplasms associated with immunocompromise. The posttransplantation lymphoproliferative disorders (PT-LPDs) are a heterogeneous group of B-cell neoplasms that arise in the setting of immunosuppressive therapy, and are associated with EBV infection. Whether type A and/or type B EBV are associated with PT-LPDs is unknown. Therefore, we investigated 27 PT-LPD lesions from 22 solid-organ transplant recipients by polymerase chain reaction (PCR) at the EBNA-2 and EBNA-3c loci to detect sequence deletions that distinguish the two EBV families. Another locus, EBER, was examined by single-strand conformation polymorphism analysis (SSCP), in conjunction with direct sequencing in selected cases. Type A EBV was found in 24 of 27 cases (89%) as seen by amplification of the EBNA-2 and EBNA-3c regions. Four different EBER polymorphisms were detected, confirming the presence of different type A EBV isolates among these cases. Three cases were negative for infection by EBV. Surprisingly, despite the immunocompromised state of the hosts, none of the 27 PT-LPD lesions harbored type B EBV. Thus, although type B EBV may commonly infect peripheral blood lymphocytes in immunocompromised individuals, they do not appear to induce readily PT-LPD formation.

Antigens, Viral↗
PubMed1995

Absence of hyperacute rejection in pig-to-primate orthotopic pulmonary xenografts.

The shortage of organ donors for transplantation is more pronounced for the lung than for any other solid organ. To address this problem, we evaluated the feasibility of pulmonary xenotransplantation. Preliminary investigations demonstrated that orthotopically placed pig lungs in cynomologous monkey recipients could be engrafted up to 9 hr after reperfusion without evidence of hyperacute rejection. In this study, the rejection reaction of pig lungs transplanted orthotopically into baboons (n = 6) was further investigated by ELISA and immunohistochemistry. Four baboon recipients were killed at 24 hr and 2 recipients were killed at 72 hr after transplantation. Pulmonary arterial flow measurements demonstrated flow to the grafts, and systemic arterial and xenograft pulmonary venous blood gas analysis suggested function of the donor lungs during the course of engraftment. Serum levels of baboon anti-pig endothelial cell xenoantibody were normal and decreased minimally over time. Immunohistochemical staining of biopsies demonstrated trace IgG and IgM along graft endothelium 2 hr after reperfusion. At 8 hr, biopsy samples showed no immunoglobulin bound to endothelial cells. Staining for complement was negative. Fibrin and platelets were detected along xenograft endothelium. Despite these findings, the lung xenografts appeared injured and clinically rejected. During the first 8 hr after reperfusion, the grafts were hyperemic and subsequently became focally ecchymotic. Chest x-rays showed progressive pulmonary congestion. These findings suggest that the lung may be relatively resistant to antibody-mediated hyperacute rejection and efforts are being directed toward identifying the mechanism of the observed xenograft lung injury.

Animals↗