Rat heart-aorta cluster transplantation: a novel model to study transplant rejection

The purpose of this study was to develop a microsurgical cluster model of heart plus entire thoracic aorta transplantation and to compare it to the isolated model of heart transplantation as a tool to study transplant rejection. Thirty-six syngeneic (DA x DA and Lew x Lew) and allogeneic (DA x PVG and DA x Lew) cluster heart-aorta transplants were compared to 43 syngeneic and allogeneic isolated heart grafts. Graft survival, recipient survival and histological data on myocardial and aortic tissues were assessed. There was no statistically significant difference in graft survival between the two models studied (P > 0.05). In the cluster transplants, the aortic component was spared the severity of acute rejection noted for the myocardial counterpart. In conclusion, the results demonstrated that the cluster model was technically feasible and highly reproducible. Additionally, it was possible to apply this model to the study of experimental allograft rejection using novel immunosuppressants. The success of the cluster model in strongly mismatched transplant strain combinations underscores its potential for application in slower rejection combinations, making it particularly suited for chronic rejection studies. The inherent capacity for sampling a broader range of vessel sizes in one animal makes the cluster model more suitable than the isolated models of aorta or heart for application to experimental protocols.     

Immunological problems of transplantation into the subretinal space

The objective of retinal transplantation is to substitute destroyed or degenerated retina to improve visual function. Photoreceptors and retinal pigment epithelium cells of embryonic and nonembryonic origin have been transplanted into the subretinal space in different animal models. Recently, retinal cells have also been used for transplantation in untreated or immunosuppressed patients with retinitis pigmentosa and age-related macular degeneration. Transplants performed in animals such as the RCS rat have maintained retinal function at the transplantation site for long periods of time, although such transplantations in humans have not proved conclusively, to date, whether there is a real effect or not. One reason for this phenomenon seems to be an immune response to transplanted retinal cells at the transplantation site. The detectable rejection process shows that the posterior part of the eye is not absolutely immunologically privileged and that rejection is a serious problem in human retinal transplantation. Many questions concerning transplantation technique, graft treatment and postoperative treatment will be answered through more intensive experiments and clinical trials regarding the immunology. However, rejection of transplanted material is one of the main reasons why retinal transplantation has not yet proved successful.     

Two-dimensional ct-HC(C)H-COSY for resonance assignments of smaller 13C-labeled biomolecules

A new model for heterotopic aortic valve transplantation in the rat is described. A composite allograft with an intact aortic valve and partial mitral valve was harvested from 4-month-old (400-450 g) Long-Evans rats and grafted heterotopically into the abdominal aorta of 4-week-old (80-100 g) rats with an optimal size match. At the end of a 1-month observation period, all experimental animals were alive and all showed 100% patency of the aortic valve allografts on microscopic evaluation after death (n=40). Unlike previously used methods, the proposed model allows for the preservation of all three aortic valve cusps and a more remote placement of the anastomotic suture line from the aortic valve annulus. The use of younger recipient rats improves size match and amplifies allograft calcification. The purpose of this study was to provide an animal model to evaluate modalities of preservation and chemical treatment for aortic valves used as allografts or bioprosthesis.     

Cytomegalovirus infection enhances the neointima formation in rat aortic allografts: effect of major histocompatibility complex class I and class II antigen differences

BACKGROUND: The development of chronic rejection has emerged as a major cause of long-term graft failure. Previous studies have demonstrated that cytomegalovirus (CMV) infection is associated with an increased incidence of chronic allograft rejection in renal, cardiac, and aortic allografts. This study was designed to investigate the effects of the major histocompatibility complex (MHC) class I or class II mismatches on CMV-enhanced chronic rejection. METHODS: Aortic transplantation was performed between different inbred rat strain combinations; the Lewis to RP combination was class I-mismatched and Wag/Rij to RP class II-mismatched. At 7, 28, and 90 days after transplantation, the intensity of chronic rejection in mismatched grafts with or without CMV infection was evaluated using histological and immunohistological analysis. RESULTS: The results of this study demonstrated that CMV infection led to an increased influx of monocytes/ macrophages in class I-mismatched grafts at 1 week after transplantation and enhanced infiltration of T lymphocytes in class II-mismatched grafts at 4 weeks. Although more vascular lesions were observed in the class II-mismatched combinations, an intensified neointima formation by CMV infection was observed only in the MHC class I-mismatched allografts. CONCLUSIONS: CMV infection may increase neointima formation of allografts when an MHC class I disparity between donor and recipient is present. This may be associated with the increased perivascular influx of monocytes/macrophages observed in CMV-infected animals early after transplantation.     

Role of metal-catalyzed oxidation reactions in the early pathogenesis of scleroderma

The value of the renal allograft biopsy has been significantly enhanced by several developments in 1997 including the following: the first convincing demonstration that molecular biology techniques can be applied to renal allograft tissue to obtain a diagnosis of acute rejection with high sensitivity and specificity; the development of an improved, internationally agreed classification of kidney transplantation pathology ('Banff 1997'); and significant new insights into the specific pathology of chronic rejection, involving splitting and lamination of peritubular capillary basement membranes and the presence of increased apoptotic cell death. Although it is predictable that long-term technology might eliminate the need for renal allograft biopsies altogether, in the short term these new breakthroughs will greatly increase the value of this procedure in the management of renal transplant patients.     

Drug induced contraction and relaxation in mouse isolated aorta

Possibility of using mouse isolated aorta to evaluate the effect of vasoactive agents was demonstrated. The results suggested that aortic contraction induced by the alpha adrenoceptor agonist norepinephrine was sensitive to prazosin, and the contraction induced by the membrane depolarization agent KCl was sensitive to verapamil. Clonidine acting as a partial agonist attenuated the norepinephrine or methoxamine induced contraction. Both IBMX and nitroprusside relaxed the aortic contraction. These vascular changes induced by the above vasoactive agents in mouse isolated aorta were similar to those of rat described elsewhere. The present findings suggested that mouse isolated aorta can be used as a tool to test the effect of vasoactive agents.     

Effect of cytomegalovirus on an experimental model of chronic renal allograft rejection under triple-drug treatment in the rat

BACKGROUND: Cytomegalovirus (CMV) infection is thought to be a risk factor of chronic rejection. In clinical studies and animal models, mainly concerning graft vasculopathy, CMV has been demonstrated to enhance allograft arteriosclerosis. In this study we have investigated the effect of CMV on the early inflammatory response and graft histology in an experimental model of renal transplantation in a rat strain combination that develops chronic rejection under triple-drug immunosuppression. METHODS: Renal transplantations were performed in a rat strain combination of DA-->BN receiving triple-drug treatment (2 mg/kg methylprednisolone, 2 mg/kg azathioprine, 5 mg/kg cyclosporine daily subcutaneously). One group of immunosuppressed animals was infected with rat CMV, the Maastricht strain (10(5) plaque-forming units intraperitoneally), and the other group was left uninfected. As a positive control for alloresponse, one group of recipients received neither immunosuppression nor virus. Syngenic transplantations with triple-drug treatment and CMV were used as negative controls. The grafts were monitored by frequent ultrasound-guided fine-needle aspiration biopsies, and the intragraft inflammation was quantified in detail by the increment method and expressed in corrected increment units (CIU). Graft histology was performed in parallel. RESULTS: Nonimmunosuppressed animals developed acute rejection with a high peak of inflammation (7.9+/-3.2 CIU), a typical blast response, and lymphocytosis followed by infiltration of macrophages and necrosis within 7 days. Triple drug-treated animals had a short, mild inflammatory response (3.3+/-1.4 CIU at the peak) in the graft 3-5 days after transplantation but ended up with histological changes characteristic of chronic rejection with vasculopathy and fibrosis 40-60 days later. Triple drug-treated animals with CMV demonstrated a significantly stronger inflammation (4.5+/-1.8 CIU, P<0.01) than those without, and lymphoid activation continued longer and was followed by infiltration of macrophages in the graft. CMV infection of the graft was demonstrated by viral culture and antigen detection. In histology, chronic rejection with intimal thickening of arteries and arterioles and medial necrosis of large arteries was seen at 14 days, ending up with remarkable graft fibrosis within 20 days after transplantation. CONCLUSION: CMV prolonged and increased graft inflammation and accelerated chronic rejection of renal allografts under triple-drug treatment.     

Changes in characteristics of chronic pancreatitis during the course of disease

OBJECTIVES: This study was undertaken to investigate the incidence of posttransplant recoarctation of the aorta, delineate the mode of presentation, identify risk factors that predict recoarctation and examine the results of intervention for posttransplant recoarctation. BACKGROUND: Patients with aortic arch hypoplasia require extended arch reconstruction at transplant, with an inherent possibility of subsequent recoarctation of the aorta. METHODS: This was a retrospective review of all children (age <18 years) who underwent cardiac transplantation over a 10-year period. Collected data included pretransplant diagnosis, details of the transplant procedure and posttransplant data including development of recoarctation of the aorta, interventions for recoarctation and the most recent follow-up assessment of the aortic arch. RESULTS: Two hundred eighty-eight transplants were performed on 279 children (follow-up = 1,075 patient-years; range 0 to 133 months, median 43.7). Thirty-two of 152 patients (21%) who underwent extended aortic arch reconstruction subsequently developed recoarctation. All but one patient developed recoarctation within 2 years after transplant; 87% were hypertensive at presentation. Of 30 patients who underwent intervention for recoarctation (balloon angioplasty [n = 26] and surgical repair of recoarctation [n = 4]), 26 (87%) have remained recurrence-free (follow-up = 133 patient-years; range 8 to 106 months, median 47). CONCLUSIONS: The high frequency of recoarctation after cardiac transplantation with extended aortic arch reconstruction mandates serial echocardiographic evaluation of the aortic arch. Patients typically present with systemic hypertension within the first two years after transplantation. Balloon angioplasty is a safe, effective and durable method of treatment.     

Deposition and retention of radiolabeled serum constituents in hair after systemic administration

We investigated the relationship between the changes in the pulmonary blood flow and histology during acute rejection following single lung transplantation. In single lung transplantation using adult mongrel dogs, immunosuppression with cyclosporine and azathioprine was discontinued after postoperative day 14 to induce rejection. Doppler flow probes were placed adjacent to the ascending aorta and the left pulmonary artery to measure the blood flow on a daily basis. In addition, chest roentgenograms were also examined daily. The pulmonary pressure was measured using a Swan-Ganz catheter prior to and following the induction of rejection. Open lung biopsies were performed when the left pulmonary artery flow decreased to half of the prerejection value. The pulmonary artery flow decreased to 14.3% of the aortic flow 5 days after the discontinuation of immunosuppression. The graft pulmonary vascular resistance increased significantly compared to the prerejection values (P < 0.001). This was not accompanied by any abnormalities on chest roentgenography. The histology was consistent, with marked perivascular lymphocytic infiltration with little alveolar or interstitial changes. During rejection, the increased pulmonary vascular resistance in the graft was probably the result of perivascular inflammatory cell infiltration, which was seen prior to changes on chest roentgenography. Changes in the left pulmonary artery flow and histology thus appear to be closely correlated in the early stages of acute rejection.     

Allografting for chronic myeloid leukaemia

Marrow transplantation from human leukocyte antigen (HLA) matched related donors offers a high probability of prolonged treatment-free survival for patients with chronic myeloid leukaemia in chronic phase. Delay, patient and donor gender, patient age and previous palliation with busulphan predict outcome in this setting. Because of the median age at diagnosis and the genetics of the HLA system, transplants from HLA-matched related donors are available to less than 15% of newly diagnosed patients. Alternative donors include relatives with minor degrees of incompatibility and HLA-compatible unrelated volunteers. The probability of finding suitable unrelated donors has increased with the development of a network of registries now containing more than 3.6 million donors worldwide. Survival prospects will be improved by transplantation earlier in the course of the disease, better-matched donors and the discovery of new approaches for the prevention of graft-versus-host disease and opportunistic infections.     

Reoperations after operation on the thoracic aorta: etiology, surgical techniques, and prevention

Recurrent aortic aneurysms, persistent or new dissection, new onset of valvular and coronary artery disease, graft infection, and prosthetic endocarditis are not rare after thoracic aortic operations; they can be difficult to diagnose and represent a formidable surgical challenge. Between 1977 and 1991, 876 operations were performed on the thoracic aorta in our institution: 340 in dissections, 299 in true aneurysms, 150 for aortic remodeling and external wall support during aortic valve replacement, and 87 for miscellaneous causes. During the same period, there were 193 additional reoperations. Vascular reoperations on abdominal aorta and peripheral arteries accounted for 73 cases and are not further discussed in this study. The reasons for reoperation (n = 130) in 120 patients were: failure of biologic valves (n = 23); aneurysm recurrence in a proximal or distal aortic segment (n = 21); pseudoaneurysm formation at suture lines (n = 13); new dissection or dilatation involving ascending aorta (n = 11), aortic arch (n = 13), and descending aorta (n = 10); aneurysm after aortic remodeling (n = 13); new onset of valvular disease (n = 5); and new onset of coronary disease (n = 5). Infected aortic graft and prosthetic endocarditis accounted for 10 reoperations, and a planned two-staged procedure was performed in 6 patients. Omitting the failed biologic valves, reoperations were performed on the aortic segment previously operated on in 69.3% of the cases and on other thoracic segments in 30.7%. Overall hospital mortality rate after reoperation was 5.8%. A significant decrease in operative mortality was observed in the most recent period (3.0% between 1989 and 1991). Reoperations are technically demanding, and some of them are preventable; therefore (1) graft inclusion technique should be abandoned in ascending aortic operation due to formation of false aneurysms; (2) in patients with Marfan syndrome, complete repair of the diseased aorta should be attempted during the initial operation; (3) aortic arch dissection should be repaired definitively during the first operation in low-risk patients; (4) biological valves should be avoided in aneurysm operations; and (5) homograft replacement is the treatment of choice in prosthetic endocarditis or in infected composite graft after an aortic valve or ascending aortic operation.     

Molecular biology of human melanoma development and progression

In the United States, Australia, Northern Europe, and Canada, malignant melanoma is increasing at a faster rate than any other cancer, with the exception of lung cancer in women. Major advances have been made in the molecular biology and immunology of melanoma. These advances in basic science have led to more rational approaches to specifically targeting melanoma cells, with promising results in the clinic. An increased understanding of how melanoma spreads has led to more selective, less invasive surgical procedures that do not compromise patient health. Combinations of chemotherapy and immunotherapy are now available for patients with advanced melanoma that affect both the length and quality of the patients' lives. This review of the molecular biology of melanoma development and progression discusses the disease's etiology, molecular genetics, cell-surface antigens, experimental models, biological markers, and new forms of treatment. As we continue to learn more about malignant melanoma, we will be able to devise more specific and effective treatments that will give patients with this potentially deadly disease longer and more productive lives.     

CsA levels in the early posttransplant period--predictive of chronic rejection in liver transplantation?

The increasing success of clinical liver transplantation has brought rejection to the forefront as a cause of morbidity and graft loss. The relationship of immunosuppressive drug doses and levels to acute and chronic rejection remains a matter of debate. The effect of blood CsA levels and drug doses on the incidence of acute and chronic rejection and the impact of acute rejection episodes on the occurrence of chronic rejection were studied in 146 grafts in 132 patients. These patients were transplanted in the 4-year period from June 1989 using CsA-based immunosuppression (CsA, azathioprine, prednisolone). Liver grafts in patients maintained on median CsA levels (whole blood, trough level) of > or = 175 micrograms/L in the first 28 days posttransplant had a significantly lower incidence of chronic rejection (2 out of 49 vs. 22 out of 97; P = 0.002). There was no significant difference in incidence of graft loss due to fatal sepsis (6% vs. 5%) or nephrotoxicity between the high and low CsA level groups. The overall graft loss rate was lower in the higher CsA level group (22% vs. 37%). The total doses of the individual drugs did not correlate with the incidence of acute or chronic rejection. Although the occurrence of acute rejection itself did not determine later chronic rejection, late occurrence (P < 0.00001) and multiple episodes (two or more; P = 0.0002) of acute rejection were significant risk factors for the occurrence of chronic rejection. We conclude that to minimize graft loss to rejection, CsA levels should be maintained at greater than 175 micrograms/L in the early posttransplant period, and late and recurrent episodes of acute rejection should be prevented.     

Induction of allograft nonresponsiveness after intrathymic inoculation with donor class I allopeptides. I. Correlation of graft survival with antidonor IgG antibody subclasses

We have recently demonstrated that cardiac allograft rejection in the PVG.R8-to-PVG.1U rat strain combination involves the recognition of a isolated class I (RT1.Aa) molecules as peptides in the context of the recipient MHC molecules. Three synthetic peptides (P1, P2, and P3) corresponding to the alpha-helices of the RT1.Aa molecule served as T-cell epitopes for graft rejection. In this study, we demonstrate that two of these peptides (P2 and P3) are sufficient to induce immune nonresponsiveness (median survival time >237 days) to cardiac allografts when presented to the recipient immune system in the thymus 7 days before transplantation. This effect was time dependent, as intrathymic inoculation 60 days before transplantation did not prolong graft survival (median survival time=12 days). Previous studies have demonstrated a critical role for alloantibody responses in mediating graft rejection in this rat strain combination. We, therefore, studied the role alloantibody responses may play in the observed immune nonresponsiveness. The titers of alloantibody in serum samples harvested from graft recipients at different times after transplantation were measured. We used recipient primary aortic endothelial cells genetically manipulated to express the donor RT1.Aa molecule as targets in an enzyme-linked immunosorbent assay. High titers of anti-RT1.Aa IgM antibody were detected in unmanipulated controls at the time of graft rejection. The IgM antibody switched to high IgG titers in intrathymically inoculated rats with accelerated or delayed rejection. Graft rejection in intrathymically manipulated recipients that had achieved a transient state of immunological nonresponsiveness correlated with higher titers of the IgG2b alloantibody. In marked contrast, the long-term graft survivors expressed undetectable or low levels of the IgG2b antibody and moderate to high levels of the IgG1 and IgG2a subclasses. These data suggest that the IgG2b alloantibody may contribute to the rejection reaction, whereas IgG1 and IgG2a may be involved in active enhancement of graft survival.     

Expression of interleukin-6 in association with rat lung reimplantation and allograft rejection

Organ transplantation has become a therapeutic option for the replacement of malfunctioning tissues and organs. Since the advent of the first combined heart-lung transplant in 1981, there has been a rapid growth in the popularity of lung transplantation for a number of end-stage pulmonary disorders. Interestingly, these lung transplant patients experience more complications of acute and chronic allograft rejection compared with recipients of other solid organs. These episodes of rejection are related to a complex series of events that depend on the interaction of many cells and soluble mediators leading to cellular and tissue injury. The histopathology of lung allograft rejection has been actively studied and is associated with the sequestration of activated mononuclear phagocytes, T and B lymphocytes. These cells secrete a number of soluble mediators, that is, cytokines, that participate in the evolution of the immune response via autocrine, paracrine, or endocrine mechanisms. The interaction of cytokines with their targets leads to cellular activation, proliferation, and differentiation. In this study, we postulated that interleukin-6 (IL-6) may have a central role in the pathogenesis of acute lung allograft rejection. To test this hypothesis, we employed an unmodified RT1-incompatible rat lung allograft model and assessed the time course and major tissue compartment(s) of IL-6 production during the evolution of lung allograft rejection. The expression and production of IL-6 during the pathogenesis of lung allograft rejection was measured at the whole-animal, organ, cellular, and molecular levels. The expression of IL-6 was found to be bimodal in character, initially related to the reimplantation response and finally to the maximal allograft rejection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ethnic variations in patient and graft survival after liver transplantation. Identification of a new risk factor for chronic allograft rejection

The ethnic origin of renal graft recipients is recognized as an important determinant of graft survival. In liver transplantation, the effect of racial origin has been studied in black American recipients and has suggested a trend toward inferior graft survival in this group. In this study, we have analyzed outcome of transplantation in a large multiethnic liver transplant program. Non-Caucasoid recipients had an inferior patient survival compared with Caucasoids and, in particular, European Caucasoids at 1, 3, and 5 years after transplantation (46.7% vs. 60.2% at 3 years, P = 0.05). Non-European recipients had an inferior graft survival compared with European recipients at 1, 2, and 3 years after transplantation (e.g., north Europeans 53.5%, south Europeans 48.5%, Middle Eastern 40%, and non-Caucasoids 27% at 3 years, P < 0.01). Different frequencies of chronic allograft rejection in the ethnic groups contributed to the rates of graft survival, with the non-European recipients developing chronic rejection at over twice the rate of European recipients (12.6% vs. 5.9%, respectively, P = 0.002). The findings in this study support the evidence from renal transplant programs that the ethnic origin of recipients is an important determinant of outcome after transplantation, with increasing frequency of chronic rejection in recipients nonindigenous to the donor population contributing to the variations in patient and graft survival rates.     

Right ventricular function in orthotopic total atrioventricular heart transplantation

BACKGROUND: Total orthotopic heart transplantation was recently introduced into clinical practice as an alternative technique of orthotopic heart transplantation, adding bicaval and left and right pulmonary vein anastomoses to pulmonary artery and ascending aorta connection (total technique). The conventional technique (ventricular transplantation with atrioplasty) is compared with the total technique with particular emphasis on right ventricular performance. METHODS: Forty-eight mongrel dogs (23 to 31 kg) were used for 12 total and 12 standard orthotopic heart transplantations. Right ventricular (RV) function and atrial systole were analyzed with the use of micromanometry, sonomicrometry, and ultrasonic flow probes (preload-independent RV recruitable stroke work, RVPRSW). Fourier analysis was used to calculate RV power and pulmonary vascular impedance. RESULTS: There was no significant difference in cardiac ischemic and bypass times between the two groups. After transplantation, sinus rhythm was preserved after all total transplantations and after only one standard transplantation; no significant hemodynamic differences were observed. RVPRSW in the total group was conserved after transplantation; however, RVPRSW decreased by 39% (+/-8, p < .05) in the standard group. There was also a significant decrease in the rate of RV filling in the standard group after transplantation, suggesting decreased right atrial function. Pulmonary vascular impedance and RV power output were not significantly different after transplantation between the two groups. CONCLUSIONS: Total atrioventricular transplantation is a feasible alternative and conserves normal sinus rhythm. Ischemic and bypass times were not significantly different when the superior vena cava anastomosis is performed last after the release of the aortic cross-clamp. The insignificant decrease in the rate of RV filling with the use of the total technique suggests conserved RV diastolic function after transplantation with less decreased RV function in the total group.     

Early and late results of replacement of the ascending aorta and/or aortic arch using selective cerebral perfusion

From 1987 to 1994, 116 patients received replacement of the ascending and/or aortic arch using selective cerebral perfusion. They were 82 male and 34 female, with average age of 64 years. There were 63 dissecting and 53 true aneurysms. Extent of replacement was: ascending aorta in 13, aortic root in 2, aortic arch in 93, and aortic root and complete arch in 8. Aortic arch replacements were composed of: 29 partial proximal aortic arch replacements, 44 complete aortic arch replacements, and 20 partial distal aortic arch replacements. Nineteen (16.4%) hospital deaths occurred. Univariate testing of pre-, intra-, and post-operative variables followed by stepwise logistic regression analyses identified elderly, ischemic heart disease, postoperative neurologic complication, cardiac dysfunction, renal failure, and massive bleeding as factors having independent association with hospital mortality. Neurologic complication was found in 10 patients (8.6%), and risk factor for this complication was preoperative peripheral vascular disease. Follow-up of hospital survivors documented an overall cumulative 5-year survive rate of 69%. There was no significant difference between dissection and true aneurysms in 5-year survive ratios, which were 63% and 82%, respectively. During follow-up periods, 18 patients died. Half of these cases were vascular deaths, caused by rupture, sudden death and secondary operation. Univariate analyses followed by stepwise Cox testing indicated that chronic obstructive pulmonary disease and a history of postoperative massive bleeding were associated with decreased later survival. Our experience suggests that selective cerebral perfusion is a safe technique for the repair of ascending aorta and/or aortic arch problems. High-risk subgroups of patients with these aortic problems can be identified by risk factors. Aggressive and careful management is necessary for such subgroups to improve early and late survival rates.     

A murine skeletal muscle ischemia-reperfusion injury model: differential pathology in BALB/c and DBA/2N mice

Ischemia-reperfusion injuries can occur with diseases such as myocardial infarction and stroke and during surgical procedures such as organ transplantation and correction of aortic aneurysms. We developed a murine model to mimic abdominal aortic aneurysm repair with cross-clamping of the aorta distal to the renal artery. After model development, we compared the normal complement BALB/c mouse with the C5-deficient DBA/2N mouse. To assess quantitative differences, we measured neuromuscular function up to 72 h after ischemia with a subjective clinical scoring system, as well as plasma chemistries, hematology, and histopathology. There were significant increases in clinical scores and creatine phosphokinase, lactate dehydrogenase, and muscle histopathology scores in BALB/c mice compared with those in DBA/2N mice and sham-surgery mice. Muscle histopathology scores of the cranial tibialis and quadriceps correlated well with clinical signs, creatine phosphokinase, and lactate dehydrogenase, and indicated the greatest pathology in these muscle groups. We developed a murine model of skeletal muscle ischemia-reperfusion injury that can utilize the benefits of murine genetic and transgenic models to assess therapeutic principles of this model. Additionally, we have shown a significant reduction in clinical signs, plasma muscle enzyme concentrations, and muscle pathology in the C5-deficient DBA/2N mouse in this model.     

Study of the beta -delayed neutron decay of 18N

The shortage of suitable liver donors for children has motivated the use of ABO-incompatible (ABO-I) grafts for transplantation in urgent situations. However, survival after ABO-I liver grafts has been reported at about 30% as compared with 80% in cases of ABO-identical or -compatible liver grafts. This difference has been attributed to antibody-mediated, hyperacute or chronic liver rejection, due to preformed ABO antibodies (alloantibodies). In this study, we report our results with ABO-I livers in children without alloantibodies at the time of transplantation. From January 1988 to June 1993, 143 OLT were performed in 122 children. Eight children received 8 ABO-I liver grafts. Of these, 7 patients were included in the study. All 7 were alloantibody free before OLT. Five children were spontaneously alloantibody free, while in 2 children, the plasma alloantibodies were eliminated before and after transplantation using intravenous infusion of specific blood group antigens of the donor blood group (soluble antigens). Immunosuppression consisted of a triple-drug treatment combining CsA, AZA, and steroids. The follow-up period was between 10 and 48 months. One child died from a surgical complication. Six children survived, but 1 died 10 months later from intestinal obstruction. There were no graft losses and no episodes of hyperacute or chronic rejection. The graft and patient survival rate was 71%. There was a 28% incidence of rejection, but all were mild (requiring steroid boluses only). Our results suggest that the absence of ABO alloantibodies at the time of and after transplantation can protect ABO-I liver grafts against antibody-mediated rejection, whether hyperacute or chronic, and that soluble antigens are effective in eliminating alloantibodies in children.