Biomedical subjects

S L Houser

Publications and source records attributed to S L Houser.

At least 19 recordsLinked to original sources

PubMed2006

The role of indirect recognition of MHC class I and II allopeptides in a fully mismatched miniature swine model of lung transplantation.

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.

Animals↗

PubMed2006

Thymectomy does not abrogate long-term acceptance of MHC class I-disparate lung allografts in miniature Swine.

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.

Animals↗

PubMed2006

Effects of tolerance induction on the actions of interferon-gamma on porcine cardiac allografts.

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.

Animals↗

PubMed2006

An MHC class II disparity raises the threshold for tolerance induction in pulmonary allografts in miniature swine.

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.

Animals↗

PubMed2003

Spleen transplantation in miniature swine: surgical technique and results in major histocompatibility complex-matched donor and recipient pairs.

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.

Animals↗

PubMed2003

Histopathology of coronary in-stent restenosis following gamma brachytherapy.

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.

Aged↗

PubMed2003

Evaluation of intracoronary stenting by intravascular optical coherence tomography.

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.

Adult↗

PubMed2002

Significant atheromatous debris following uncomplicated vein graft direct stenting: evidence supporting routine use of distal protection devices.

We present the case of an angiographically uncomplicated direct stent vein graft intervention in which the Percusurge embolization containment device was used. We performed histological examination of the resulting debris and observed massive particulate atheromatous material. This case illustrates the severity of distal embolization that can go clinically unnoticed after direct stenting and also supports the routine use of distal protection devices for vein graft intervention.

Aged↗

PubMed2001

Indirect recognition of allopeptides promotes the development of cardiac allograft vasculopathy.

Graft loss from chronic rejection has become the major obstacle to the long-term success of whole organ transplantation. In cardiac allografts, chronic rejection is manifested as a diffuse and accelerated form of arteriosclerosis, termed cardiac allograft vasculopathy. It has been suggested that T-cell recognition of processed alloantigens (allopeptides) presented by recipient antigen-presenting cells through the indirect pathway of allorecognition plays a critical role in the development and progression of chronic rejection. However, definitive preclinical evidence to support this hypothesis is lacking. To examine the role of indirect allorecognition in a clinically relevant large animal model of cardiac allograft vasculopathy, we immunized MHC inbred miniature swine with synthetic polymorphic peptides spanning the alpha(1) domain of an allogeneic donor-derived swine leukocyte antigen class I gene. Pigs immunized with swine leukocyte antigen class I allopeptides showed in vitro proliferative responses and in vivo delayed-type hypersensitivity responses to the allogeneic peptides. Donor MHC class I disparate hearts transplanted into peptide-immunized cyclosporine-treated pigs not only rejected faster than unimmunized cyclosporine-treated controls (mean survival time = 5.5 +/-1.7 vs. 54.7 +/-3.8 days, P < 0.001), but they also developed obstructive fibroproliferative coronary artery lesions much earlier than unimmunized controls (<9 vs. >30 days). These results definitively link indirect allorecognition and cardiac allograft vasculopathy.

Animals↗

PubMed2000

The impact of cocaine on the donor heart: a case report.

With a limited supply of donor hearts in the United States and a prevalent history of cocaine abuse among potential heart donors, the question of transplanting the hearts of cocaine users presents a dilemma to the surgeon. We report a patient who died of the acute right ventricular failure of a heart from a donor with a history of binge drinking and cocaine abuse and who had sustained traumatic brain death. The donor's serum was positive for cocaine prior to transplantation, and autopsy findings were consistent with cocaine cardiomyopathy. This case illustrates the importance of accurate donor history and toxicologic screen prior to heart transplantation and suggests that hearts of cocaine users should not be transplanted, especially in a setting of traumatic brain death.

Adult↗

PubMed2000

Porcine coronary imaging in vivo by optical coherence tomography.

OBJECTIVE: A high-resolution coronary artery imaging modality has the potential to address important diagnostic and management problems in cardiology. Optical coherence tomography (OCT) is a promising new optical imaging technique with a resolution of approximately 10 microm. The purpose of this study was to use a new OCT catheter to demonstrate the feasibility of performing OCT imaging of normal coronary arteries, intimal dissections, and deployed stents in vivo. METHODS AND RESULTS: Normal coronary arteries, intimal dissections, and stents were imaged in five swine with OCT and compared with intravascular ultrasound (IVUS). In the normal coronary arteries, visualization of all of the layers of the vessel wall was achieved with a saline flush, including the intima which was not identified by IVUS. Following dissection, detailed layered structures including intimal flaps, intimal defects, and disruption of the medial wall were visualized by OCT. IVUS failed to show clear evidence of intimal and medial disruption. Finally, the microanatomic relationships between stents and the vessel walls were clearly identified only by OCT. CONCLUSIONS: In this preliminary experiment, we have demonstrated that in vivo OCT imaging of normal coronary arteries, intimal dissections, and deployed stents is feasible, and allows identification of clinically relevant coronary artery morphology with high-resolution and contrast.

Animals↗

PubMed2000

Bronchocentric granulomatosis with mucus impaction due to bronchogenic carcinoma. An association with clinical relevance.

OBJECTIVE: To describe an unexpected inflammatory process associated with malignancy in the lung and to postulate a new mode of pathogenesis. DESIGN: Retrospective review of surgical pathologic findings. SETTING: Academic hospital pathology department. PATIENTS: Four patients, 2 men and 2 women, ranging in age from 45 to 74 years, each of whom had a solitary mass on chest radiographs. INTERVENTIONS: Pulmonary lobectomy. MAIN OUTCOME MEASURE: Histopathologic identification of bronchocentric granulomatosis. RESULTS: Accompanying a bronchogenic carcinoma in each case was a necrotizing chronic granulomatous reaction centered around bronchioles that were plugged with mucus, necrotic detritus from the tumor, lipid, or a combination of these substances. Eosinophils were present in small numbers in one case. The pathologic findings characterize bronchocentric granulomatosis. CONCLUSIONS: The presence of bronchocentric granulomatosis in the biopsy of a mass does not exclude the presence of an accompanying bronchogenic carcinoma associated with obstruction of bronchioles. Bronchocentric granulomatosis in some cases may represent an immunologic response to tumor detritus or lipid, as well as to mucus impaction.

Adenocarcinoma↗

PubMed1995

Enhancement of cardiac function by cyclocreatine in models of cardiopulmonary bypass.

This study tests the hypothesis that the administration of cyclocreatine prior to global ischemia enhances recovery of cardiac function during reperfusion. Two models were used. First, in a Langendorff-working heart model of normothermic cardioplegic arrest, rats (n = 6 per group) were injected intravenously with saline or cyclocreatine (600, 300, or 150 mg/kg). After 30 min or 2 h, hearts were excised and perfused in the Langendorff mode for 5 min and then in the working heart mode for 20 min. Normothermic arrest was induced by infusing warm St. Thomas solution once; then hearts were kept at 37 degrees C for 40 min. Following arrest, hearts were reperfused in the Langendorff mode for 15 min and then in the working mode for 30 min. Cyclocreatine consistently produced significantly better recovery of aortic flow and cardiac output compared to that of saline hearts. Second, in an intact canine model of cold cardioplegic arrest, adult mongrel dogs (n = 3 to 6 per group) underwent aortic cross-clamping for 1 h, followed by reperfusion on bypass for 45 min and off bypass for 4 h. Dogs were injected intravenously with saline or cyclocreatine (500 mg/kg) for 1 h before experiment. Post-bypass segmental contractility and cardiac output were significantly better in cyclocreatine hearts compared to that of controls. In a limited study, after a 3 h aortic cross-clamp time, cyclocreatine hearts achieved 91% baseline function while control hearts failed after 2 h. Results of this study suggest that cyclocreatine, without inotropic or chronotropic effect, protects the heart from global ischemic injury.

Animals↗

PubMed1994

Enhancement of the recovery of rat hearts after prolonged cold storage by cyclocreatine phosphate.

The present study determined whether the administration of cyclocreatine phosphate (CCrP) prior to ischemia can enhance the recovery of rat hearts hypothermically preserved for a prolonged period. Rats (n = 6 per group) were injected intravenously with 1 ml saline or CCrP (500 mg/kg). After 2 hr, hearts were excised and arrested by an infusion of University of Wisconsin solution. Saline hearts were then incubated in 40 ml UW, while CCrP hearts were incubated in 40 ml UW containing 100 mg CCrP; a mixture that is now referred to as Hartford Hospital (HH) solution. After 6 hr of storage at 4 degrees C, hearts were reperfused in the Langendorff mode for 15 min and then in the working heart mode for 30 min. Results indicated that the recovery of cardiac function--measured as aortic flow, coronary flow, cardiac output, stroke volume, and stroke work--was significantly better in CCrP group (50-55% baseline) compared with that of saline hearts (20-25%). Although no difference in enzyme leakage (i.e., creatine kinase) or lactate was detected between the two groups, the increase in heart weight after the initial 6-hr storage was significantly higher in saline hearts compared with that of CCrP hearts. Results of this study support the conclusion that CCrP treatment provides improved functional recovery after prolonged hypothermic preservation.

Animals↗

PubMed1994

Evidence of cardiac inflammation after open heart operations.

In this study, 6 anesthetized dogs underwent global cardiac arrest for 1 hour, followed by reperfusion on bypass for 45 minutes. The hearts were then weaned off cardiopulmonary bypass and monitored for an additional 2 hours. Using modified Boyden chambers, high levels of neutrophil chemotactic activity were detected (using a checkerboard analysis) in the coronary sinus effluents obtained during cardiac arrest. The activity tended to decline during reperfusion. Assay of myeloperoxidase (a marker for neutrophils) revealed an accumulation of large numbers of neutrophils in the right (14 +/- 1.1 x 10(4) cells/g wet weight) and left (16 +/- 1 x 10(4) cells/g wet weight) ventricles after 2 hours of reperfusion. Light microscopy evaluation confirmed the presence of neutrophils, not only in the ventricles, but also in a greater number in the right and left atria. Electron microscopy study of these hearts revealed the presence of mild reversible changes, indicating good preservation of the hearts during arrest. Results of this study provide evidence for an acute inflammatory reaction that takes place after cardiac operations and suggest a role for myocardial tissues in the initiation of such a response through their release of neutrophil chemotactic factors.

Animals↗

PubMed1992

Cardiac-derived neutrophil chemotactic factors: detection in coronary sinus effluents of patients undergoing myocardial revascularization.

Recent studies from our laboratory have demonstrated the release of neutrophil chemotactic factors from isolated rabbit hearts perfused with cardioplegic solutions and from ischemic dog hearts after coronary artery occlusion for 1 hour. On the basis of these animal studies, a test is now made of the hypothesis that neutrophil chemotactic factors are released by myocardial tissues of patients who undergo surgical myocardial revascularization. By means of modified Boyden chambers, the levels of neutrophil chemotactic factors were measured in effluent collected from the coronary sinuses of six patients undergoing cardiopulmonary bypass during periods of cold cardioplegia. Plain cardioplegic solutions were also analyzed. The standard formyl-methionyl-leucyl-phenylalanine, a stimulant of neutrophil recruitment, was used as a positive control solution. Results indicated the recovery of significantly high levels of neutrophil chemotactic factors in patient samples (i.e., 128% +/- 19% of formyl-methionyl-leucyl-phenylalanine) compared with control plain cardioplegic solution (less than 5% of formyl-methionyl-leucyl-phenylalanine) (p less than 0.0001). A standard checkerboard analysis indicated that the observed activity is chemotactic (i.e., directed migration) and not chemokinetic (i.e., random migration). This study also showed that these factors are proteins of a molecular weight in excess of 300 kd and exhibit in vivo activity by recruiting neutrophils into rabbit skin. The absence of immune cell-derived chemoattractants such as interleukin-1 and leukotriene B4 in these coronary sinus effluents suggests that the observed chemotactic activity is cardiac derived. Results of this investigation therefore demonstrate the release of neutrophil chemotactic factors by ischemic human hearts during cardiopulmonary bypass.

Cardioplegic Solutions↗

PubMed1992

Repeat coronary artery bypass: a seven-year experience.

Repeat coronary artery bypass (RCAB) procedures were performed on 323 patients from March 1984 through December 1990. The mean interval between bypass operations was 7.8 years. The operative mortality rate was 4.6%; six of the 15 deaths (40%) occurred in the operating room. Fourteen of the 15 operative deaths (93.3%) were cardiac, all but one of which were due to ventricular failure. Follow-up data for 83 of 91 (91.2%) patients at least five years following RCAB show that 64 (77.1%) are still alive, 39 (60.9%) of whom remain free of cardiac symptoms. Findings in this report, which are notably consistent with those of previous reports, are a significantly higher operative mortality rate and higher risk of death in the operating room in patients undergoing repeat bypass compared with those having initial coronary artery bypass. The challenge of reducing the mortality risk following coronary reoperation is discussed in this report.

Adult↗

PubMed1990

Coronary artery bypass plus mitral valve replacement. A five-year study.

Fifty-two patients with a mean age of 67.6 years underwent coronary artery bypass plus mitral valve replacement from 2 April 1984, through 6 February 1989. All but four of these 25 males and 27 females were in the New York Heart Association Functional Classes III and IV, with presenting symptoms of angina and/or dyspnea. Twenty-four patients (44.2%) presented with acute myocardial infarctions, and eleven patients (21.2%) had a past history of rheumatic fever or rheumatic heart disease. Forty-five patients (86.5%) had a diagnosis of coronary artery disease plus mitral regurgitation. Treatment included a mean of 2.3 bypass grafts per patient plus mitral valve replacement with Carpentier-Edwards (41), St. Jude (10), and Bjork-Shiley (1) prostheses. The four operative deaths (7.7%) were attributed to congestive heart failure (1), mediastinal bleeding (1), mediastinitis (1), and stroke (1). There were eight late cardiac deaths (16.7%) and six late noncardiac deaths (12.5%), a mean of 16.6 and 18.9 months postoperatively, respectively. Thirty-four patients have survived from 10 to 65 (mean 33.7) months postoperatively with a mean New York Heart Association Functional Class 1.6. Follow-up determination of patients' attitudes toward their surgery was ascertained in 28 of the 34 survivors, and 26 (92.8%) patients indicated that they were pleased with their surgery. These results compare favorably with data reported in the recent literature. In addition, the study shows that patients requiring supportive treatment in a critical care unit preoperatively had the same operative mortality but more postoperative complications and a longer mean hospital stay than the equal number of patients who were not in a critical care unit preoperatively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗