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Biomedical subjects

R E Michler

Publications and source records attributed to R E Michler.

At least 127 records · Page 7Linked to original sources
PubMed1995

Post-transplantation lymphoproliferative disorders arising in solid organ transplant recipients are usually of recipient origin.

Recent clinical, pathological, and molecular studies have increased our understanding of posttransplantation lymphoproliferative disorders (PT-LPDs). Studies have shown that the majority of PT-LPDs arising in bone marrow transplant recipients are of donor origin; however, the source (host or donor) of the lymphoid cells that make up PT-LPDs arising in solid organ transplant recipients has not been systemically investigated. In this study, 18 PT-LPDs occurring in 16 organ transplant recipients (13 heart, 2 kidney, 1 lung), 9 donor tissues (for 10 recipients), and 14 uninvolved recipient tissues (from 12 patients) were examined employing restriction fragment length polymorphism analysis to determine their host or donor origin. The PstI-digested DNAs were analyzed by Southern blot hybridization using two highly informative polymorphic probes that map to chromosome 21 (CRI-PAT-pL427-4) and chromosome 7 (CRI-PAT-pS194). All solid organ PT-LPDs with corresponding uninvolved recipient DNA showed identical hybridization patterns; none of the PT-LPDs exhibited a hybridization pattern that matched donor DNA. These findings suggest that the vast majority of PT-LPDs arising in solid organ transplant recipients, in contrast to those arising in bone marrow transplant recipients, are of recipient origin.

Adolescent↗
PubMed1995

Cerebral blood flow is determined by arterial pressure and not cardiopulmonary bypass flow rate.

BACKGROUND: During cardiopulmonary bypass, global hypoperfusion of the brain has been shown to result in ischemic insult and subsequent neurologic injury. Furthermore, outcome after focal cerebral ischemia depends on collateral circulation, which is determined by the parameters of global perfusion. We therefore measured cerebral blood flow during independent manipulations of arterial blood pressure and pump flow rate to determine which of these hemodynamic parameters regulates cerebral perfusion during cardiopulmonary bypass. METHODS: Seven anesthesized baboons were placed on cardiopulmonary bypass and cooled to 28 degrees C. Pump flow rate and arterial blood pressure were altered in varied sequence to each of four conditions: (1) full flow (2.23 +/- 0.06 L.min-1.m-2, mean +/- standard deviation) at high pressure (61 +/- 2 mm Hg), (2) full flow (2.23 +/- 0.06 L.min-1.m-2) at low pressure (24 +/- 3 mm Hg), (3) low flow (0.75 L.min-1.m-2) at high pressure (62 +/- 2 mm Hg), and (4) low flow (0.75 L.min-1.m-2 at low pressure (23 +/- 3 mm Hg). During each of these hemodynamic conditions cerebral blood flow was measured by washout of intracarotid xenon. RESULTS: Cerebral blood flow was greater at high blood pressure than at low pressure during cardiopulmonary bypass both at low flow (34 +/- 8.3 versus 14.1 +/- 3.7 mL.min-1 x 100 g-1) and full flow (27.6 +/- 9.9 versus 16.8 +/- 3.7 mL.min-1 x 100 g-1) (p < 0.01). At comparable mean arterial blood pressures alteration of pump flow rate produced no changes in cerebral blood flow. CONCLUSIONS: These results indicate that cerebral blood flow during moderately hypothermic cardiopulmonary bypass is regulated by arterial blood pressure and not pump flow rate.

Animals↗
PubMed1995

Novel approach for orthotopic heart transplantation in visceroatrial situs inversus.

Orthotopic heart transplantation was performed successfully in a 7-year-old girl with visceroatrial situs inversus. Creation of two autologous left-sided atrial tissue baffles tunneled the left superior vena cava and inferior vena cava to the right of the pulmonary veins. The reconstructed caval tunnels remain widely patent more than 4 years after transplantation. The ability of autologous tissue to grow with the patient has distinct advantages in the pediatric transplant population.

Child↗
PubMed1994

Abrogation of baboon natural xenoantibody to pig splenocytes by DL-penicillamine.

Natural xenoantibodies are believed to be IgM in nature and are known to play a critical role in the hyperacute rejection of distantly related xenografts. The purpose of this study was to determine whether the reducing agent DL-penicillamine could inactivate baboon natural xenoantibodies to pig splenocytes. Pooled baboon serum was treated with varying concentrations of DL-penicillamine over different lengths of time and a complement-mediated cytotoxicity assay was used to determine the reactivity of baboon natural xenoantibodies to pig splenocytes. A whole-cell ELISA assay was used to assess the binding of both IgG and IgM xenoantibodies to pig splenocytes. In addition, DL-penicillamine-treated serum was dialyzed to assess its potential clinical application. These in vitro experiments indicate that both IgM and IgG baboon natural xenoantibodies bind to pig splenocytes, but only IgM xenoantibody is cytotoxic. The binding of baboon natural IgM xenoantibody can be eliminated, and the cytotoxicity of IgM xenoantibody markedly reduced by DL-penicillamine treatment despite continued binding of IgG xenoantibody to pig splenocytes. In addition, DL-penicillamine can be dialyzed, suggesting that it may be an efficacious clinical treatment, the toxicity of which can be regulated with hemodialysis.

Animals↗
PubMed1994

The nitric oxide/cyclic GMP pathway in organ transplantation: critical role in successful lung preservation.

Reestablishment of vascular homeostasis following ex vivo preservation is a critical determinant of successful organ transplantation. Because the nitric oxide (NO) pathway modulates pulmonary vascular tone and leukocyte/endothelial interactions, we hypothesized that reactive oxygen intermediates would lead to decreased NO (and hence cGMP) levels following pulmonary reperfusion, leading to increased pulmonary vascular resistance and leukostasis. Using an orthotopic rat model of lung transplantation, a porphyrinic microsensor was used to make direct in vivo measurements of pulmonary NO. NO levels measured at the surface of the transplanted lung plummeted immediately upon reperfusion, with levels moderately increased by topical application of superoxide dismutase. Because cGMP levels declined in preserved lungs after reperfusion, this led us to buttress the NO pathway by adding a membrane-permeant cGMP analog to the preservation solution. Compared with grafts stored in its absence, grafts stored with supplemental 8-Br-cGMP and evaluated 30 min after reperfusion demonstrated lower pulmonary vascular resistances with increased graft blood flow, improved arterial oxygenation, decreased neutrophil infiltration, and improved recipient survival. These beneficial effects were dose dependent, mimicked by the type V phosphodiesterase inhibitor 2-o-propoxyphenyl-8-azapurin-6-one, and inhibited by a cGMP-dependent protein kinase antagonist, the R isomer of 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate. Augmenting the NO pathway at the level of cGMP improves graft function and recipient survival following lung transplantation.

Amino Acid Oxidoreductases↗
PubMed1994

Novel technique for extending the use of allografts in cardiac operations.

Small cryopreserved allografts for use in neonates and infants are increasingly difficult to find. We describe a technique for surgically reducing the size of the more readily available large-diameter allografts to make them conform to size requirements appropriate for neonates and infants. This technique involves a longitudinal incision of the allograft from its muscular annulus to its distal orifice with the excision of a single valve leaflet. The two commissural posts of the excised leaflet and the wall of the allograft are then reapproximated with fine suture. Four patients ranging in age from 14 days to 11 months (mean age, 5.2 months) and ranging in weight from 3 to 8.4 kg (mean weight, 5.2 kg) underwent reconstruction of the right ventricular outflow tract using this surgical technique. Two patients underwent repair of truncus arteriosus (age, 14 days and 16 days) and two patients underwent Rastelli operations (age, 9 months and 11 months). The mean follow-up time was 22.5 months (range, 14 to 28 months). All 4 patients are alive and well. One patient requires digoxin and furosemide for moderate quadricuspid truncal valve insufficiency. Serial echocardiography documents mild allograft stenosis in 2 patients and trivial to mild allograft insufficiency in 2 patients. Because handling characteristics and lower bleeding risks render allograft conduits preferable to synthetic conduits and, furthermore, because conduit insertion of any type in the neonate will eventually be outgrown and require replacement, we find this technique to be justifiable as a therapeutic option. In the short term, the technique results in excellent functional results and provides an alternative to synthetic conduits when an appropriate sized allograft is unavailable.

Female↗
PubMed1994

Incidence of pulmonary vein complications after lung transplantation: a prospective transesophageal echocardiographic study.

OBJECTIVES: This study attempted to document the incidence of pulmonary vein complications and their potential relation to clinical outcome in patients after lung transplantation. BACKGROUND: Several case reports have documented the presence of pulmonary venous thrombosis causing graft failure in patients after lung transplantation. Because the presentation of these complications mimics that of other postoperative problems, the true incidence of pulmonary vein abnormalities remains unclear. Transesophageal echocardiography is ideally suited to examine the pulmonary veins in the postoperative setting. METHODS: Twenty-one consecutive patients undergoing lung transplantation at our institution underwent transesophageal echocardiography within 32 days of transplantation (mean [+/- SD] 6.5 +/- 7.8 days). Special attention was placed on visualizing the pulmonary veins. RESULTS: Six (29%) of the 21 patients were noted to have abnormalities of the pulmonary veins in the vicinity of the anastomotic site. After follow-up of 30 days, 4 of these patients (67%) had significant cardiovascular morbidity, and 2 died, compared with 1 (7%) of 15 patients with normal pulmonary veins (p = 0.03). The degree of obstruction of the pulmonary vein appeared to correlate with short-term outcome. CONCLUSIONS: Abnormalities of the pulmonary veins are common after lung transplantation and are easily identified by transesophageal echocardiography. Occlusive thrombi appear to be detrimental to short-term outcome.

Adult↗
PubMed1994

Cerebral blood flow during low-flow hypothermic cardiopulmonary bypass in baboons.

BACKGROUND: Neurologic injury after cardiopulmonary bypass (CPB) is a frequent and devastating complication of cardiothoracic surgery. Disordered cerebral hemodynamics during CPB has been implicated as an important factor in the etiology of these injuries. Evidence of disordered cerebral hemodynamics includes reports of a progressive time-dependent decrease in cerebral blood flow (CBF) during stable full-flow CPB. Low-flow hypothermic CPB has become a preferred technique for the management of pediatric patients undergoing surgical repair of complex cardiac lesions. Because CBF is already substantially reduced with the onset of low-flow CPB, we determined if a similar progressive decline in CBF occurs during the low-flow state. METHODS: After induction of general anesthesia in seven baboons, CPB was instituted. alpha-Stat management of arterial blood gases was used. Animals were cooled at a pump flow rate of 2.5 l.min-1.m-2 until tympanic membrane temperature decreased to 18 degrees C. CPB flow was then reduced to 0.5 l.min-1.m-2 and maintained constant for at least 77 min. Thereafter, CPB flow was increased to 2.5 l.min-1.m-2 and baboons rewarmed to normal temperature. CPB was discontinued after return of cardiac function. CBF was measured before, during and after CPB by washout of intraarterial xenon 133. RESULTS: Low-flow CPB resulted in a decrease in CBF to about 50% of the prebypass rate and about 30% of the value measured during full-flow CPB. Sequential measurements of CBF at 30-min intervals during low-flow CPB showed no time-dependent change in cerebral perfusion. CONCLUSIONS: Although systemic flow is reduced to 20% of full-flow during low-flow CPB, CBF reduced by half is disproportionately preserved relative to systemic flow. Furthermore, there is no time-dependent change in CBF under these low-flow conditions.

Animals↗
PubMed1994

Induction of myocardial nitric oxide synthase by cardiac allograft rejection.

Cardiac transplantation, effective therapy for end-stage heart failure, is frequently complicated by allograft rejection, the mechanisms of which remain incompletely understood. Nitric oxide (NO), a vasodilator which is cytotoxic and negatively inotropic, can be produced in large amounts by an inducible NO synthase (iNOS) in response to cytokines. To investigate whether iNOS is induced during cardiac allograft rejection, hearts from Lewis or Wistar-Furth rats were transplanted into Lewis recipients. At day 5, allogeneic grafts manifested reduced contractility and histologic evidence of rejection (inflammatory infiltrate, edema, necrosis of myocytes). The mRNA for iNOS and iNOS protein were detected in ventricular homogenates and in isolated cardiac myocytes from rejecting allogeneic grafts but not in tissue and myocytes from syngeneic control grafts. Immunocytochemistry showed increased iNOS staining in infiltrating macrophages and in microvascular endothelial cells and cardiac muscle fibers and also in isolated purified cardiac myocytes from the rejecting allografts. Using a myocardial cytosolic iNOS preparation, nitrite formation from L-arginine and [3H] citrulline formation from [3H]L-arginine were increased significantly in the rejecting allogeneic grafts (P < 0.01). Myocardial cyclic GMP was also increased significantly (P < 0.05). The data indicate myocardial iNOS mRNA, protein and enzyme activity are induced in infiltrating macrophages and cardiac myocytes of the rejecting allogeneic grafts. Synthesis of NO by iNOS may contribute to myocyte necrosis and ventricular failure during cardiac allograft rejection.

Amino Acid Oxidoreductases↗
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

Laboratory evaluation of a low prime closed-circuit cardiopulmonary bypass system.

We have explored the potential advantages of a low prime closed-circuit cardiopulmonary bypass (CPB) system using a non-human primate model. Although manufacturers have reduced priming volumes in individual CPB components, the standard circuit volume remains high because of the tubing diameter and length necessary for gravity drainage. By replacing gravity drainage with the negative pressure generated by a centrifugal pump, we can realize significant tubing volume reduction. Closed-circuit bypass was conducted on 13 baboons ranging from 5-15 kg. The circuit consisted of a centrifugal pump, a hollow fiber oxygenator, and 1/4" arterial and venous tubing. The design of the circuit included the capacity to remove a limited amount of venous air. Circulatory arrest during deep hypothermia with volume displacement into a reservoir was also accomplished with this circuit. The potential benefits of this low prime closed-circuit bypass system include blood conservation and reduction in blood surface area contact. The future safe clinical use of this type of closed-circuit bypass for routine open heart surgery will depend upon the incorporation of a device in the venous line to remove air. This is the greatest threat to patient safety in a closed circuit system and its use for open chest surgery must wait until an efficient venous air elimination device is available.

Blood Transfusion, Autologous↗