Biomedical subjects

M L Barr

Publications and source records attributed to M L Barr.

At least 55 records · Page 3Linked to original sources

PubMed1994

Living-related donor lobectomy for bilateral lobar transplantation in patients with cystic fibrosis.

Donor lobectomy has been performed in 14 patients enabling 7 recipients with cystic fibrosis to undergo bilateral living-related lobar pulmonary transplantation. Donors included 11 patients, 2 brothers, and 1 uncle. Donor mean age was 43 years (range 24 to 55 years). Their mean height and weight was 170 cm (range, 169 to 180 cm) and 72.4 kg (range, 55 to 90 kg), respectively, compared with 161 cm (range, 140 to 175 cm) and 42.4 kg (range, 27 to 55 kg), respectively, in the recipient group. Donor pulmonary evaluation consisted of a history and physical examination, chest roentgenogram and computed tomographic scan, spirometry with arterial blood gas measurement, echocardiography, and perfusion scanning. From each pair of donors, one was selected for right lower lobectomy and the other for left lower lobectomy. Standard lobectomy techniques were modified to facilitate implantation and optimize preservation of the donor lobes. On the right side, the middle lobe was removed and discarded in the first three donors to provide an adequate cuff of pulmonary artery and bronchus for implantation. With increased experience, this has proved not to be necessary. There have been no deaths and no long-term complications in the donor group. Prolonged postoperative air leaks occurred in the 3 patients who underwent right lower and middle lobectomies. All donors have been able to resume their previous lifestyles. Living-related donor lobectomy provides an alternative to cadaveric organs in select patients in need of pulmonary transplantation.

Adolescent↗

PubMed1994

Lobar transplantation. Indications, technique, and outcome.

Lobar transplantation represents a therapeutic option for children and some adults with severe end-stage pulmonary disease. Six patients including two neonates, three children, and one adult underwent lobar transplantation. Ages ranged from 17 days to 21 years. Transplant procedures were unilateral in the neonates and two of the children and bilateral in the child and adult who had cystic fibrosis. The donor lobes were from cadavers in the two neonates and living related donors in the children and the adult. Unilateral grafts involved use of the right upper lobe in the 12-year-old patient with bronchopulmonary dysplasia; right middle lobe with a ventricular septal defect repair in the 4-year-old patient with Eisenmenger's syndrome, left upper lobe in the 28-day-old patient with primary pulmonary hypertension, and the right upper and middle lobes in the 17-day-old patient with diaphragmatic hernia. Bilateral lobar transplantations were performed with the right lower and left lower lobes in the two patients with cystic fibrosis (aged 13 and 21 years). The two neonates underwent emergency transplantation with the use of extracorporeal membrane oxygenation as a bridge. Perioperative survival was 83%, with only the 4-year-old patient with ventricular septal defect/Eisenmenger's syndrome dying early. No airway complications were observed. The unilateral grafts received most of the blood flow as shown by perfusion scanning (range 74% to 99%). Living related donor complications included prolonged air leaks (> 6 days) in two patients. In urgent situations, such as an infant requiring extracorporeal membrane oxygenation, and in the existing milieu of donor shortage, lobar transplantation (living related or cadaveric) is a surgically feasible procedure and can provide a donor source in the limited time frame of these clinical situations. Bilateral lobe transplantation may be a viable option for patients with cystic fibrosis and life-threatening respiratory decompensation.

Adolescent↗

PubMed1993

Posttransplantation lymphoproliferative disorders treated with cyclophosphamide-doxorubicin-vincristine-prednisone chemotherapy.

BACKGROUND: Posttransplantation lymphoproliferative disorders after solid organ transplantation are a serious complication occurring in 1-10% of patients. Different therapies have been used, but the optimal treatment is unknown. There is relatively little information in the literature on the experience with cytotoxic chemotherapy. METHODS: The disease stage of patients with biopsy-documented posttransplantation lymphoproliferative was determined with standard methods to establish the extent of the disease. Patients in whom the disease failed to regress after initial management, which included reduction in immunosuppression, were treated with a combination chemotherapy regimen consisting of six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Response to therapy was determined by following previously defined sites of disease with appropriate tests. Patients were maintained on a reduced dose of immunosuppressants. RESULTS: In the four patients studied, lymphoproliferative disorders developed after heart (three cases) or lung (one case) transplantation, which did not regress after immunosuppression was reduced. All four experienced a complete remission with CHOP chemotherapy, which continued at 3, 13+, 20 and 30+ months after completion of treatment. One patient died of sepsis after completing therapy at a point when his leukocyte count was normal, and no evidence of posttransplantation lymphoproliferative disorder was found at autopsy. A second patient died of liver failure with no clinical evidence of lymphoproliferative disorder. CONCLUSION: Although this is a small series, it demonstrates that patients with posttransplantation lymphoproliferative disorders may respond to cytotoxic chemotherapy. The duration of response is undetermined.

Adult↗

PubMed1993

Management of lymphoproliferative disorders after cardiac transplantation.

We conducted a retrospective study of 516 cardiac recipients who underwent transplantation between April 1983 and April 1992, 19 of whom had development of post-transplantation lymphoproliferative disorders (PTLDs). These 19 patients presented with involvement of lung (5), gastrointestinal tract (5), disseminated disease (6), and adenoids and lymph nodes (3). B-cell proliferations ranging from an atypical hyperplasia to malignant lymphoma developed in 18 patients, and mixed cellularity Hodgkin's disease developed in 1 patient. The 19 patients with PTLD displayed a predominance of both women and cardiomyopathy as the indication for transplantation when compared with two separate control populations. No correlation was found between demographic criteria analyzed and (1) early versus late diagnosis of PTLD after transplantation, (2) the site of PTLD involvement, or (3) the histopathologic category of the PTLD lesion. Patients with gastrointestinal tract and lung PTLD involvement enjoyed an improved survival after both transplantation and PTLD diagnosis when compared with patients with PTLD involvement of all other extranodal sites. We report a high incidence of PTLD involving the lung and gastrointestinal tract in our cohort study. These sites of involvement responded better to a reduction in immunosuppression than did the other extranodal sites of involvement.

Adult↗

PubMed1993

Pediatric lung transplantation.

As the first decade of successful clinical lung transplantation draws to a close, the number of patients who are able to benefit from it continues to increase. Pulmonary transplantation in the pediatric age group is possible for an expanding range of diagnoses currently known to cause end-stage lung disease. However, more experience will be required before the answers to a number of clinical problems are found. The following issues are particularly pertinent to the pediatric age group: (1) Controversy still exists as to the most appropriate operation for certain clinical situations (eg, single- or double-lung transplants for primary pulmonary hypertension, or secondary pulmonary hypertension after cardiac repair). These decisions are made based on physiological considerations as well as donor availability and the need to use the donor pool as efficiently as possible. (2) Technical controversies in pediatric lung transplantation include the optimal technique for performing the bronchial anastomosis in a manner that will permit healing without stenosis of the airway. Cardiopulmonary bypass is required for most lung transplants in children. (3) OB continues to plague the long-term results of lung transplantation and may be more common in the pediatric age group. OB may respond to increased immunosuppression. (4) Lobar transplantation in children may be an effective method of increasing the availability of donors. More experience will be necessary to further refine this technique.

Adolescent↗

PubMed1993

Clinical experience with cardiac retransplantation.

Although more than 560 patients worldwide have undergone cardiac retransplantation, few studies of this population have been reported. To evaluate the risk of cardiac retransplantation and to better establish selection criteria, we reviewed the records of all patients who underwent retransplantation at the Columbia-Presbyterian Medical Center. Of 431 patients who underwent transplantation between February 1977 and March 1991, 408 underwent the procedure in the era of cyclosporine-based immunosuppression. Thirteen of these 408 patients underwent retransplantation (including one patient who received a third graft). Indications for the 14 retransplantations included transplant coronary artery disease (n = 8), rejection (n = 5), and intraoperative graft failure (n = 1). Immunosuppression and follow-up protocols used in this cohort were similar to those in the primary transplantation population. No significant differences were found in either actuarial survival between primary transplant recipients (75.1% +/- 2.2% at 1 year and 71.3% +/- 2.4% at 2 years) and patients who underwent retransplantation (71.4% +/- 12.1% at 1 year and 59.5% +/- 14.8% at 2 years) or in linearized rates of rejection and actuarial freedom from rejection between the two groups. No differences between these groups were found with regard to age, sex, race, origin of end-stage heart disease, or early (< 30 day) mortality. The origin of primary graft failure did not correlate with survival outcome in the retransplantation cohort. Follow-up time for patients having primary transplantation ranged from 0 to 8 years (mean 24 months) with a cumulative patient follow-up of 830 patient-years; follow-up time for patients who underwent retransplantation ranged from 0 to 3 years (mean 8.1 months) with a cumulative patient follow-up of 9.5 patient-years. Approximately 50% of patients in both groups had at least one rejection episode by 3 months. Within the limited time period studied after retransplantation, only one patient had transplant coronary artery disease, approximately 27 months after her first retransplantation procedure for acute rejection. These results indicate that the prognosis for patients undergoing cardiac retransplantation is good for patients for whom the indication for retransplantation is identified more than 30 days after initial transplantation.

Adolescent↗

PubMed1993

Effect of anti-HLA antibodies on the long-term survival of heart and kidney allografts.

Study of anti-HLA antibodies in a population of 238 primary renal and 199 primary heart allograft recipients showed significant association between development of anti-HLA antibodies and that of chronic allograft rejection. The 5-year renal allograft survival was 70% in recipients without antibodies and 53% in recipients who developed anti-HLA alloantibodies during the first year following transplantation. Heart allograft survival at 5 years was 91% in patients without and 78% in patients with antibodies during the first 12 months posttransplantation. Development of antibodies is associated with acute rejection episodes and probably with the release of soluble HLA antigens.

Antibodies, Anti-Idiotypic↗

PubMed1992

Alternative splicing of the mRNA encoding the human cholesteryl ester transfer protein.

The plasma cholesteryl ester transfer protein (CETP) is known to facilitate the transfer of lipids between plasma lipoproteins. The human CETP gene is a complex locus encompassing 16 exons. The CETP mRNA is found in liver and small intestine as well as in a variety of peripheral tissues. While the CETP cDNA from human adipose tissue was being cloned, a variant CETP cDNA was discovered which excluded the complete sequence encoded by exon 9, but which was otherwise identical to the full-length CETP cDNA, suggesting modification of the CETP gene transcript by an alternative RNA splicing mechanism. RNase protection analysis of tissue RNA confirmed the presence of exon 9 deleted transcripts and showed that they represented a variable proportion of the total CETP mRNA in various human tissues including adipose tissue (25%), liver (33%), and spleen (46%). Transient expression of the exon 9 deleted cDNA in COS cells or stable expression in CHO cells showed that the protein encoded by the alternatively spliced transcript was inactive in neutral lipid transfer, smaller, and poorly secreted compared to the protein derived from the full-length cDNA. Endo H digestion suggested that the inactive, cell-associated protein was present within the endoplasmic reticulum. The experiments show that the expression of the human CETP gene is modified by alternative splicing of the ninth exon, in a tissue-specific fashion. The function of alternative splicing is unknown but could serve to produce a protein with a function other than plasma neutral lipid transfer, or as an on-off switch to regulate the local concentration of biologically active protein.

Adipose Tissue↗

PubMed1992

Effect of complete cardiac denervation on atrial natriuretic factor release in baboons.

We investigated the influence of cardiac innervation on atrial natriuretic factor (ANF) release in baboons. For this purpose, plasma ANF levels were measured in control conditions and in response to head-down (-45 degrees) and head-up tilt (+45 degrees) in six anesthetized baboons before and after complete cardiac denervation obtained by orthotopic autotransplantation of the heart. Cardiac denervation did not modify baseline plasma ANF levels (60.4 +/- 17 pg/ml before and 63.1 +/- 16 pg/ml after heart autotransplantation). In contrast the significant ANF responses to changes in central venous pressure (CVP) induced by postural maneuvers (-45 degrees, + 16.2 +/- 4 pg/ml; +45 degrees, -18.5 +/- 4 pg/ml) were markedly altered after cardiac denervation (-45 degrees, +5.8 +/- 2 pg/ml; +45 degrees, -7.6 +/- 1 pg/ml). The changes in CVP and systemic blood pressure evoked by the postural challenges were comparable before and after cardiac denervation. These results demonstrate that cardiac nerves play a role in the control of ANF release.

Animals↗

PubMed1992

Effect of anti-HLA and anti-idiotypic antibodies on the long-term survival of heart and kidney allografts.

Long-term survival of heart and kidney allografts is threatened by the development of chronic rejection. Analysis of the relationship between reversible acute rejection episodes and actuarial survival at 5 years showed an inverse correlation suggesting that early cellular events may trigger antibody-mediated chronic rejection. In both heart and kidney allograft recipients producing anti-HLA antibodies we found a significant decrease in the 5-year graft survival rate. However, there was heterogeneity among anti-HLA antibody producers with respect to the development of anti-idiotypic antibodies. The actuarial 5-year graft survival was significantly higher in patients with Ab2 compared to patients without.

Actuarial Analysis↗

PubMed1992

Effect of recipient gender and race on heart and kidney allograft survival.

Study of long-term survival of heart allografts shows that AA males and females have lower graft survival rates than those observed in NAC recipients. Primary kidney allografts in AA males, but not females, also display lower 5-year survival rates compared to those observed in the corresponding populations of NAC. Comparison of graft survival in the overall population of male and female recipients of kidney allografts shows that females have higher graft survival rates, probably as a result of better HLA matching. The level of alloantibody activity in posttransplantation sera is similar in the two populations, suggesting that factors other than HLA mismatching may contribute to the higher degree of graft failure in AA recipients.

Actuarial Analysis↗

PubMed1992

University of Wisconsin solution versus crystalloid cardioplegia for human donor heart preservation. A randomized blinded prospective clinical trial.

We have previously shown the safety and efficacy of University of Wisconsin solution for hypothermic preservation of the human donor heart in a pilot group of 16 transplant recipients. The present study is a randomized clinical trial comparing University of Wisconsin solution to conventional preservation using crystalloid cardioplegia and saline storage within a 4-hour limit of ischemia. Heart transplant recipients (n = 42) were randomized into two groups: those receiving hearts preserved by University of Wisconsin solution, the UWS group (n = 22), and those receiving hearts preserved in the conventional manner, the CCS group (n = 20). Recipient age, gender, heart disease, and preoperative inotropic support and donor age, gender, and mean ischemic time in hours (UWS 2 hours 36 minutes, range 1 hour 36 minutes to 2 hours 53 minutes; CCS 2 hours 20 minutes, range 1 hour 20 minutes to 2 hours 44 minutes; p = not significant) were similar. Significant differences observed between the two groups included (1) mean time (minutes) from reperfusion to achieve a stable rhythm, (2) need for intraoperative defibrillations, (3) need for transient cardiac pacing, and (4) integrated postoperative creatinine kinase and aspartate aminotransferase release over 48 hours. There was no difference in postoperative electrocardiogram, endomyocardial biopsy, or hemodynamics. One UWS patient died of sepsis and another of a ruptured cerebral aneurysm. UWS is safe for donor organ arrest and preservation despite high viscosity and potassium concentration. When compared with CCS hearts, hearts preserved in UWS regained electrical activity more rapidly and had better myocardial protection as demonstrated by enzymatic analysis. Further investigation is required to determine the effects of UWS preservation on long-term survival, to determine the prevalence of rejection and graft atherosclerosis, and to test the ability of UWS to extend donor ischemic time in human cardiac transplantation.

Adenosine↗

PubMed1991

University of Wisconsin solution for human donor heart preservation: initial clinical experience.

Although in vitro and primate orthotopic transplant experiments have suggested the superiority of University of Wisconsin solution (UWS) compared with crystalloid cardioplegia and saline solution storage for hypothermic heart preservation, concerns about the viscosity and the high potassium concentration of UWS have precluded its use in human cardiac transplantation. To test the safety and efficacy of UWS, 16 patients received hearts arrested with, flushed with, and stored in UWS at 4 degrees C for a mean ischemic time of 153.3 +/- 30.7 minutes. After reperfusion, the hearts contracted vigorously and attained a stable sinus rhythm within 4.0 +/- 2.4 minutes, and the patients were weaned from bypass in 24.5 +/- 8.0 minutes. There was no evidence of acute or chronic ischemic myocardial injury by enzymatic analysis, electrocardiography, or biopsy specimen histology. The results suggest UWS can be safely used, within currently accepted limits of donor ischemic time, to arrest and preserve human hearts for transplantation. Further studies of preservation are required to compare UWS with crystalloid cardioplegia and saline solution storage and to test the ability of UWS to prolong the period of safe donor hypothermic ischemia in clinical heart transplantation.

Adenosine↗

PubMed1991

Beta-adrenergic receptor sensitivity and guanine nucleotide regulatory proteins in transplanted human hearts and autotransplanted baboons.

This study was conducted in human subjects and in baboons to assess elements of the beta-adrenergic receptor complex in vivo and in vitro following cardiac transplantation. In human subjects, the concentration at which administered isoproterenol increased heart rate by 25 beats per min was within the normal range (mean, 3.2 +/- 0.4 micrograms). Myocardial biopsies and lymphocytes were obtained from 14 transplant recipients undergoing routine right heart catheterization. The stimulatory guanine nucleotide regulatory protein, Gs, was significantly greater in the lymphocyte than in right ventricular myocardium (5.8 +/- 1.7 vs. 2.0 +/- 0.5 relative to standard rat heart membrane preparation, P less than 0.05). In contrast, Gi was significantly greater in the myocardium than in the lymphocyte (4.2 +/- 1.3 vs. 1.1 +/- 0.3, P less than 0.025). There was no correlation between lymphocyte and cardiac G protein determinations. In the autotransplanted baboon heart, beta-receptors were increased (73 +/- 4 vs. 36 +/- 10 fmol/mg, P less than 0.05). Gs was not significantly different in denervated myocardial tissue vs. control cardiac tissue (1.1 +/- 0.2 vs. 0.8 +/- 0.2, P greater than 0.05). However, the inhibitory G protein, Gi, was significantly greater in transplanted animals (0.4 +/- 0.1 vs. 0.2 +/- 0.04, P less than 0.05). Relative enrichment of a Gi-like protein in the autotransplanted baboon heart was associated with a non-statistically significant trend towards a uniform reduction in basal and Gs-mediated adrenergic effects on adenylate cyclase activity. Despite the lack of biochemical evidence of enhanced beta-adrenergic receptor-mediated adenylate cyclase coupling, denervation in the autotransplanted baboon was associated with in vitro evidence of chronotropic and inotropic supersensitivity to isoproterenol. The results call into question the notion of adrenergic hypersensitivity in human subjects following cardiac transplantation, indicate the potential role for guanine nucleotide regulatory proteins in mediating responses of the denervated heart, and distinguish between several characteristics of the chronically denervated, transplanted human heart compared with the acutely auto-denervated of the baboon heart.

Adenylyl Cyclases↗

PubMed1991

Improved heart preservation with University of Wisconsin solution: experimental and preliminary human experience.

We tested the ability of University of Wisconsin solution (UWS) to extend hypothermic nonperfused heart preservation in baboons and then proceeded to human transplantation. Orthotopic transplantation was performed in five baboons (UWS cardioplegia and storage [4 degrees C]; preservation time 10.3 +/- 0.6 hours). Four survivors were immunosuppressed for 45 days and killed. One animal died from disruption of the aortic anastomosis due to technical error. Preservation did not alter histology under light and electron microscopy or heart weight (at harvest, 51.4 +/- 11.6 g; before implant, 52.5 +/- 11.1 g). Animals were weaned from bypass (mean, 23 +/- 12 minutes) and returned to their cages without intravenous support within 3.6 +/- 0.6 hours. Weekly biopsy, electrocardiogram, enzyme analysis, echocardiogram, and right heart catheterization demonstrated excellent cardiac function. Following success in baboons, UWS was applied to human transplantation (n = 2, UWS cardioplegia and storage [4 degrees C]; preservation time 4.2 and 2.1 hours). The hearts returned to sinus rhythm within 4 minutes of reperfusion without defibrillation, and enzymatic and hemodynamic data reveal excellent heart preservation. Preliminary data suggest the ability of UWS to prolong heart preservation in baboons and be used safely in humans. Further studies are required to compare UWS with crystalloid cardioplegia and saline storage and to prolong donor heart preservation in humans.

Adenosine↗

PubMed1990

Myocardial amiodarone and desethylamiodarone concentrations in patients undergoing cardiac transplantation.

Myocardial amiodarone and desethylamiodarone concentrations were measured at multiple sites in the explanted heart in four patients who underwent cardiac transplantation. Patients were taking amiodarone, 200 to 400 mg/day (mean 300 +/- 115), for 88 to 428 days (mean 229 +/- 148). The mean cumulative dose was 58 +/- 21.3 g. Plasma amiodarone concentration in three subjects was 204, 312 and 419 ng/ml and desethylamiodarone concentration was 268, 513 and 880 ng/ml, respectively. Significant interindividual variability in myocardial concentrations of amiodarone and desethylamiodarone was observed (p less than 0.05). Mean myocardial amiodarone concentration ranged from 4 +/- 1.0 to 29 +/- 17.2 micrograms/g (p less than 0.05); mean desethylamiodarone concentration ranged from 22 +/- 8.8 to 141 +/- 102.5 micrograms/g (p less than 0.05). At each site, save for fat, myocardial desethylamiodarone concentration was higher than amiodarone concentration. Greater intraindividual variability was observed in myocardial desethylamiodarone compared with amiodarone concentration particularly in septal and scar tissue (p = NS). No significant relation was found between myocardial concentration and duration of treatment. In patients with significant ventricular disease, usefulness of plasma amiodarone and desethylamiodarone concentration to estimate myocardial concentration is limited by intra- and interindividual variability.

Amiodarone↗

PubMed1990

Embolic stroke after smoking "crack" cocaine.

A 39-year-old woman had an embolic upper division middle cerebral artery branch occlusion 3 hours after smoking the free base of cocaine ("crack"). Radionuclide ventriculography demonstrated cardiomyopathy, and echocardiography documented a left atrial thrombus. This case demonstrates that embolism is one mechanism of ischemic stroke after cocaine use, and that cardiomyopathy, possibly cocaine induced, may be the source of embolus. A cardiac source of embolus should be sought in patients with cocaine-associated cerebral infarction.

Adult↗

PubMed1990

Anti-CD3 monoclonal antibody induction therapy. Immunological equivalency with triple-drug therapy in heart transplantation.

This study examines the hypothesis that induction immunosuppressive therapy with murine anti-CD3 monoclonal antibodies (OKT3) reduces the frequency of rejection episodes in heart transplant recipients receiving 3-drug maintenance therapy with cyclosporine, azathioprine, and steroids. A group of 26 adult heart transplant recipients requiring preoperative intravenous inotropic drugs or with elevated serum creatinine received OKT3 induction as well as long-term triple drug therapy. Cyclosporine was withheld for the first 4 postoperative days allowing for resolution of cardiogenic renal dysfunction. A corresponding group of 26 heart transplant recipients received triple drug therapy alone started immediately before transplantation. Both groups were comparable in age, sex distribution, and follow-up period. The frequency of rejection episodes was identical for the two groups (0.003 episodes per patient month). Time to first rejection episode in the induction group, however, was delayed twofold as compared with the noninduction group (42 versus 21 days, p less than 0.01). Actuarial survival at 6, 12, and 18 months was 88%, 81%, and 81% for the induction group and 92%, 92%, and 87% for the noninduction group (p = NS). Treatment for rejection was not required in 35% of the induction group and 38% of the noninduction group (p = NS). OKT3 provides satisfactory immunosuppression in heart transplant recipients with hemodynamic or renal compromise, yet it does not reduce the frequency of rejection episodes compared with patients receiving triple drug therapy alone. Although the time to first rejection may be delayed, routine adjuvant use of OKT3 for induction in all heart transplant recipients may incur needless expense without providing an important immunological advantage as compared with triple drug immunosuppression alone.

Antibodies, Monoclonal↗