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PubMed1987

The innervation of intraocular spinal cord transplants by cografts of locus ceruleus and substantia nigra neurons.

The nucleus locus ceruleus and the substantia nigra were sequentially cografted with spinal cord in the anterior chamber of the eye of adult rats. The double grafts were allowed to mature in oculo. After a survival time of 2 months, half of the number of rats were sacrificed, the grafts were dissected out and prepared for tyrosine hydroxylase immunohistochemistry and Falck-Hillarp monoamine histochemistry. The remaining animals were sacrificed after 12-14 months and processed according to the same protocol. No ingrowth from the sympathetic ground plexus in the host iris was seen in single spinal cord grafts at any of the survival times. At the shorter survival time there were no or very few catecholaminergic nerve fibers from the locus ceruleus or substantia nigra that were innervating the spinal cord cograft. In double grafts that were allowed to remain in oculo for 12-14 months, the entire spinal cord graft was innervated with varicose, catecholamine-containing nerve fibers. The locus grafts were able to innervate the spinal cord cografts much more densely than the substantia nigra grafts. In conclusion, the results demonstrate that isolated intraocular spinal cord grafts can be innervated by adjacent central catecholamine neurons. However, this is done in a delayed manner as compared to other models. The isolated replicas of descending adrenergic pathways to the spinal cord thus formed should provide useful information about the function of descending spinal catecholamine pathways.

Animals↗
PubMed2000

Hyperacute rejection of vascularized heart transplants in BALB/c Gal knockout mice.

Pig-to-primate vascularized xenografts undergo hyperacute rejection (HAR). This results from pre-formed xenoreactive antibodies directed against galactose-alpha1,3-galactose (alphaGal) in the donor organ and activation of the complement cascade. We describe an in vivo murine model of HAR using a BALB/c mice system devoid of histocompatibility or complement differences between donor and recipient to investigate in isolation, the effects of alphaGal epitope and anti-alphaGal antibody interactions in causing rejection of vascularized heart transplants. Gal KO mice were immunized with rabbit red blood cell membranes to induce high anti-alphaGal antibody titers that were predominantly IgM by ELISA (enzyme-linked immunosorbent assay). When alphaGal-expressing mice hearts were transplanted heterotopically into these recipients (n= 12), 67% of grafts rejected within 24 h, the majority within 16 h with histological features of HAR. In contrast, none of the grafts in the non-immunized Gal KO recipient control group (n=11) underwent HAR. Interestingly, approximately 50% of the remaining grafts in both the immunized and non-immunized Gal KO recipient group were rejected between 7 and 27 days by a rejection process characterized by a dense infiltrate of macrophage/monocytes, perivascular cuffing and tissue destruction similar to recent descriptions of delayed xenograft rejection (DXR). In addition, some grafts (21.5%) continued to survive in the immunized Gal KO recipients despite the presence of anti-alphaGal antibody and normal complement activity and these showed well-preserved myocardium when harvested whilst still functioning well at days 30 or 90. No rejection was seen when Gal KO donors were used in this system (n=4), nor when alphaGal-expressing BALB/c hearts were transplanted into alphaGal-expressing BALB/c recipients (n=5). This in vivo small animal model offers the opportunity to test a variety of strategies to overcome HAR prior to more resource intensive pig-to-primate studies, and may provide insights into the processes similar to DXR and accommodation.

Acute Disease↗
PubMed1989

Traumatic amputation of the upper limb: replantation of the arm.

From 1970 to 1985, 13 patients were treated as a result of an upper limb traumatic sub-amputation. Three of them were younger than 15 years and another one was only 3 years old at the time of the trauma. All the elements involved in the treatment of the lesions are described. When it was possible, an end-to-end anastomosis was used for the repair of arteries and veins. Otherwise, when the loss of tissue was marked, a saphenous vein graft was used. The fracture was treated, when possible, with an intramedullary fixation, surely less traumatizing for soft tissues than a plate. The repair of the nerve was at times simultaneous at other times delayed. The followup has shown a good functional restoration of the limb and of the joints affected by the trauma and a normal development of the patients in terms of age.

Adolescent↗
PubMed1992

Reduction mammaplasty following radiation therapy for breast cancer.

This report describes an unusual case in which reduction mammaplasty was performed following radiation therapy for breast cancer. While healing was significantly prolonged (compared with the nonirradiated contralateral breast), the final result was satisfactory from both the functional and the aesthetic standpoint. Women with prior radiation therapy may be considered candidates for reduction mammaplasty. Patients should be warned of the increased risks of wound complications, the likelihood of delayed healing, and the possibility of pigmentation changes in the grafted nipple-areola complex. We elected to transpose the nipple as a full-thickness graft, but consideration also might be given to use of an inferiorly based pedicle flap.

Breast Neoplasms↗
PubMed1998

Fas-mediated cytotoxicity is not required for rejection of murine nonvascularized heterotopic cardiac allografts.

BACKGROUND: Using mice with loss-of-function mutations in the Fas and Fas ligand (FasL) genes (lpr and gld, respectively) in transplantation experiments has resulted in contradictory findings concerning the role of Fas/FasL-mediated cytotoxicity in allograft rejection. The observation that these mutant mice develop an abnormal lymphocyte phenotype with increasing age that is hyporesponsive in vitro led us to examine the possibility that this characteristic might explain seemingly discordant observations in the literature. Therefore, to distinguish between the effects of Fas/FasL pathway disruption and the effects of immune senescence on in vivo cytotoxicity and allograft rejection, we evaluated the survival of cardiac allografts in gld, lpr, and wild-type mice of varying ages. METHODS: Six- to 21-week-old C3H, C3H/HeJ-Fasl(gld), C57B1/6, and B6.MRL-Fas(lpr) recipients were transplanted with heterotopic, nonvascularized cardiac allografts from neonatal Balb/c, C3H, C57Bl/6, and B6.MRL-Fas(lpr) donors. Mixed lymphocyte reactions were performed in naive gld, lpr, and wild-type animals, 6 and 12 weeks of age. Rejected allografts in gld, lpr, and wild-type recipients and functioning syngeneic transplants were evaluated for intragraft apoptosis by a DNA fragmentation detection assay. RESULTS: Graft survival was not significantly different between 6-week-old gld and lpr recipients and their respective wild-type controls. However, allograft rejection was delayed significantly in older (13-week) gld mice compared with age-matched wild-type mice (P=0.02) or young (6-week) gld animals (P=0.04). Similarly, 21-week-old lpr mice exhibited prolonged graft survival compared with 6-week-old lpr animals (P=0.01). Reduced alloreactive proliferative responses in 12-week-old gld and lpr mice were observed when compared with age-matched wild-type strains. Rejecting allografts displayed a similar level of intragraft apoptotic cells regardless of mutant or wild-type phenotype or age of recipient. CONCLUSIONS: The findings of this study confirm that Fas/FasL-mediated cytotoxicity is not required for murine cardiac allograft rejection. Our findings also demonstrate that the observed delayed graft rejection in lpr and gld mice is a consequence of an age-related alteration of the immune system, specific to gld and lpr mice and associated with an in vivo and in vitro hyporeactivity to alloantigens.

Animals↗
PubMed1985

Management of lipomyelomeningoceles. Experience at the Hospital for Sick Children, Toronto.

Ninety-seven children with lipomyelomeningoceles were operated on at the Hospital for Sick Children between January, 1960, and December, 1982. The most common factor that caused these patients to seek help was the cosmetic effect of the mass on their back. However, 22 patients had urinary incontinence and 15 patients had a deformed or weak leg. Sixty of the 97 patients were female and 37 were male. The patients presented for treatment between 6 days and 18 1/2 years of age with a median age of 7 1/2 months. Fifty-six patients presented before the age of 6 months and 35 of these were perfectly normal at the time of presentation. On the other hand, of the 41 patients who were brought for treatment after the age of 6 months, only 12 were normal prior to surgery. When patients were appropriately treated at an early age, with their spinal cords untethered and their dura securely closed with a dural graft, then they remained unchanged neurologically or even improved. However, when treatment was delayed or not done appropriately then they were left with significant neurological sequelae. Lipomyelomeningoceles are serious lesions which without appropriate therapy can result in gross impairment of neurological function.

Adolescent↗
PubMed1990

Lengthening of the forearm by the Ilizarov technique.

The Ilizarov technique was used for lengthening 13 forearms in 12 patients. The different types of treatment were: lengthening of the radius alone, lengthening of the ulna alone with or without radial head relocation, lengthening of one-bone forearms, lengthening of the radius and ulna to the same extent, and differential lengthening of the radius and ulna. The lengthenings ranged from 2 cm to 13 cm (10%-143%). Bone consolidation was achieved in three to 19 months without the need for bone grafting. Eleven of 12 patients were functionally and cosmetically improved. In nine patients, the cosmetic improvement made a significant psychologic difference to the patient. There were 11 complications, including three temporary deep radial nerve palsies, one sympathetic dystrophy, one malunion, one delayed malunion, two refractures, and three mild loss of motion. All of these dysfunctions were temporary, but mild stiffness persisted in three patients. The goals of treatment were achieved in all patients.

Activities of Daily Living↗
PubMed1988

Prevention of early postoperative renal dysfunction in cardiac transplantation.

Fifty six patients undergoing cardiac transplantation were immunosuppressed with a multi-drug induction regimen in which Cs administration was delayed postoperatively until satisfactory hemodynamics and renal function were achieved. The advantage of this approach is the absence of acute renal dysfunction in the early postoperative period. This immunosuppressive regimen was well tolerated and without significant detrimental effects on patient survival, graft rejection, or infection.

Antilymphocyte Serum↗
PubMed1983

Prospective study of burn wound excision of the hands.

To examine the role of early excision and grafting in the preservation of maximal function of hands with deep dermal burns, we prospectively evaluated 164 burned hands in consecutively admitted patients (mean age, 29 years; mean burn size, 37% of body surface). All hands with burn depths of second degree, deep second degree, or third degree above the level of the tendons and joint capsules were assessed preoperatively, intraoperatively, and at discharge from the hospital. Patients were treated by excision and grafting in the first or second postburn week, by delayed grafting alone, or by allowing primary healing. Total active range of motion measurements were made on the day of discharge (mean, 64th postoperative day). Mean operative blood loss per hand was 1,270 ml. When all (alive and dead) patients undergoing early excision and grafting were examined by a binomial probability model, early surgery was shown to produce no adverse affect on survival. Excision and grafting of hands with deep dermal burns, whether early or late, offered no advantage over physical therapy and primary healing in maintaining hand function. Likewise, hands with more superficial burns responded equally to operative and nonoperative treatment. While early excision and grafting of hands with third-degree burns tended to produce poorer results than did initial nonoperative care and late grafting, the differences are just outside the range of significance. Early excision and grafting of selected third-degree injuries of the hands may be indicated in patients with small total body surface burns in order to shorten hospital stay. However, early surgical intervention in patients with massive burns should be directed toward area coverage, not toward hand excision.

Adolescent↗
PubMed1987

Immunosuppressive activity of 15-deoxyspergualin and its effect on skin allografts in rats.

The immunosuppressive activity of spergualin analogues, 15-deoxyspergualin and N-30, is presented. These compounds suppressed antibody formation and establishment of delayed-type hypersensitivity to sheep red blood cells (SRBC) in mice. Among spergualin, 15-deoxyspergualin, and N-30, 15-deoxyspergualin was most effective in suppressing immune responses. It suppressed antibody formation against SRBC by spleen cell cultures in a dose-dependent fashion without reducing cell viability. The spergualins also suppressed the mixed lymphocyte culture reaction. Peritoneal exudate cells taken from mice given immunosuppressive doses of 15-deoxyspergualin were not reduced in their functions measured: Release of lysosomal enzymes and production of superoxide anions. 15-Deoxyspergualin and N-30 were markedly effective in prolonging skin graft in rats.

Animals↗
PubMed2003

The impact of residual renal function on graft and patient survival rates in recipients of preemptive renal transplants.

BACKGROUND: Transplantation before the initiation of dialysis is associated with prolonged allograft survival. It is unclear if this benefit is attributable to greater residual renal function or to avoidance of dialysis exposure. The authors performed an analysis to determine whether higher renal function at transplant was associated with increased patient and graft survival rates. METHODS: The authors identified individuals who between 1994 and June 2000 were >or= 18 years and had undergone a living donor renal transplant (Tx) as initial form of renal replacement therapy. Pre-Tx and 6-month estimated glomerular filtration rates (eGFR) were calculated using the 4-variable Modification of Diet in Renal Disease formula. Survival was compared in those with a pre-Tx eGFR >or=15mL/min to those with an eGFR less than 15 mL/min, after adjusting for demographic variables, co-morbidities, and transplant characteristics. Survival rate then was adjusted for calculated propensity scores. RESULTS: A total of 4,046 patients were included. Mean pre-Tx eGFR was 9.9 mL/min (0.9 to 57.1 mL/min). There was no difference in graft survival rates by strata of eGFR in any of the tested models, even after correcting for propensity score (hazard ratio, 0.95; 95% confidence interval, 0.69 to 1.30). There was no correlation between pre-Tx eGFR and 6-month post-Tx eGFR (r(2) =-0.005). CONCLUSION: Recipients of preemptive transplants fare equally, regardless of the eGFR at which they receive their transplant. There was no relationship between pre-Tx eGFR and 6-month eGFR, suggesting that post-Tx renal function is independent of the level of pre-Tx renal function. These data suggest that preemptive kidney transplantation should be delayed as long as possible, provided the patient does not have uremic symptoms, and dialysis can be safely avoided.

Adult↗
PubMed2003

Alloreactive CD4 T cell activation in vivo: an autonomous function of the indirect pathway of alloantigen presentation.

Activation of alloreactive CD4 T cells occurs via the direct and indirect pathways of alloantigen presentation. A novel TCR/alloantigen transgenic system was designed that permitted in vivo visualization of CD4 T cell priming through these pathways. When both pathways of alloantigen presentation were intact, CD4 T cell activation in response to cardiac allografts was rapid and systemic by day 4 after transplantation, in contrast to that seen in response to skin allografts, which was delayed until 10-12 days after transplantation. Despite this systemic CD4 T cell activation in response to cardiac allografts, there was a paucity of activated graft-infiltrating CD4 T cells at 4 days posttransplantation. This finding suggests that the initial priming of alloimmune CD4 T cell responses occurs within draining lymphoid organs. Furthermore, alloantigens derived from cardiac allografts failed to promote thymic negative selection of developing thymocytes expressing the alloreactive TCR clonotype. In the absence of a functional direct pathway, the kinetics of activation, anatomic localization, and effector function of alloreactive CD4 T cells remained unchanged. Overall, the present study defines the anatomic and temporal characteristics of CD4 T cell alloimmune responses and demonstrates that CD4 T cell priming via the indirect pathway proceeds optimally in the absence of the direct pathway of alloantigen presentation.

Adoptive Transfer↗
PubMed1986

Allograft rejection and immune responses against allogeneic antigens in neonatally thymectomized mice.

Skin allograft survival and immune responses against allogeneic antigens homologous to skin grafts were observed in BALB/c Cr Slc (BALB) mice (H-2d) thymectomized at 1 day after birth and grafted with skin from major histocompatibility complex (MHC)-incompatible, fully allogeneic C3H/HeN (C3H) (H-2k) or MHC-compatible allogeneic DBA/2 Cr Slc (DBA) mice (H-2d), at 14 weeks of age. In neonatally thymectomized (NTx) BALB mice, survival of C3H skin grafts was not prolonged at all, but survival of DBA skin grafts was prolonged significantly, although the survival periods of DBA skin grafts were very different among individual recipients. In NTx recipients grafted with C3H skin, delayed foot-pad reaction (DFR) was not reduced, but cytotoxic lymphocyte (CTL) activity and cytotoxic antibody (CTAb) production were appreciably depressed. CTL and CTAb were reduced profoundly and consistently in all NTx mice grafted with DBA skin, while DFR was reduced to various degrees in each. The degrees of depression of DFR in these NTx mice correlated well with the prolongation of DBA skin survival, although the sample number was small. The rejection of skin allografts appears to be attributable largely to a T cell subset, the function of which can be expressed as DFR. Thymus dependency in the ontogenic development is low as compared with other T cell subsets.

Animals↗
PubMed1997

Immune reconstitution following transplantation of selected hematopoietic stem cells.

The use of selected stem cell grafts has recently entered the era of clinical application. Its potential interest lies in the decreased contamination of the graft by tumor cells in the autologous graft setting and in the depletion of T-lymphocytes from the graft in the allogeneic situation. Very few and only phenotypic studies of immunologic recovery post selected stem cell transplant have been performed. Most studies conclude an absence of influence of stem cell selection on quantitative neutrophil, NK, B-lymphocyte and CD8+ T-lymphocyte recovery. CD4+ T-lymphocyte recovery seems delayed in half of the studies, particularly in the context of allogeneic unrelated donor or HLA-mismatched transplants and this could explain viral infections frequently noted in this situation. Additional follow-up and comparative studies with non selected grafts including functional tests of immunity will be required to better assess the relationship of immune recovery post graft to the age of the patient, the type of donor and HLA compatibility between donor and recipient, the underlying pathology and the number of reinfused stem cells and accessory cells.

Adaptation, Physiological↗
PubMed2005

Combined treatment of glatiramer acetate and low doses of immunosuppressive drugs is effective in the prevention of graft rejection.

The immunomodulator glatiramer acetate (GA, copolymer 1, Copaxone, GLAT), currently used for the treatment of multiple sclerosis, is a well-tolerated drug with a high safety profile. We have previously demonstrated that GA suppresses the immune rejection manifested in graft versus host disease, as well as in graft rejection. In an attempt to reduce the dosage and toxicity of the current immunosuppressive regimens, we have now tested the ability of GA, combined with low doses of cyclosporin (CyA) or tacrolimus (FK506), to suppress the rejection of mismatched allografts across major histocompatibility barriers. We report herewith that such combination therapy was effective in several animal models: (1) it led to a significant delay of the vigorous process of skin rejection in mice, manifested by evidential prolongation in skin graft survival (higher than that obtained with at least double dose of the immunosuppressive drug alone). (2) The combined treatment led to efficient inhibition of the functional deterioration of thyroid grafts in mice, manifested by 2.2- to 20.1-fold increase in iodine absorbance of the transplanted thyroids, as compared to each drug alone. (3) Combination therapy inhibited significantly the rejection of vascularized heart transplants in rats. Thus, cardiac allograft survival following the combined treatment with GA and low dose of CyA was longer than the survival obtained by fourfold higher dose of CyA alone. In all transplantation systems, combination therapy of GA with either CyA or FK506 significantly suppressed graft rejection and was more effective than treatment with either GA or the immunosuppressive drug alone, suggesting that such treatment may be beneficial for human transplantation.

Animals↗
PubMed2003

Pressure-flow loops and instantaneous input impedance in the thoracic aorta: another way to assess the effect of aortic bypass graft implantation on myocardial, brain, and subdiaphragmatic perfusion.

BACKGROUND: The serious disturbances in ventriculoarterial coupling after thoracic aorta bypass grafting are addressed through aortic entry impedance in the frequency domain from flow-pressure waves. We designed a method for synthesizing pressure and flow waves to evaluate opposal to aortic flow along the cardiac cycle, addressing myocardial, brain, and visceral tissue perfusions from pressure-flow hysteresis loops and forward-backward aortic entry impedance in the ascending aorta, transverse aortic arch, and distal descending aorta, respectively, before and after extra-anatomic grafting of the descending aorta in the swine. METHODS: Twelve pigs underwent extra-anatomic grafting (woven double-velour prosthesis, 18-mm diameter), bypassing the descending aorta. Periarterial flow and endovascular pressure signals were mathematically synthesized (error minimization) to yield continuous functions of flow, pressure along the cardiac cycle before treatment for mean hemodynamics, pressure-flow hysteresis loops, and aortic entry impedance. RESULTS: Grafting of the descending aorta overshadowed pressure-flow hysteresis loops in the ascending aorta by shortening maximum pressure delay on maximum flow and diastolic flow reversal. Clamping of the descending aorta substantially restored hemodynamics in the ascending aorta, although the diastolic flow decrease was accelerated. Identical processes developed in the transverse aorta. Subdiaphragmatic descending aortic flow was flattened after grafting and restored, although thickened, after clamping of the descending aorta. Flow wave peak was framed by a diastolic aortic entry impedance peak, which was damped along the transverse aortic arch (aortic entry impedance peak in the ascending aorta, 1700 +/- 102 kN x s x m(-5); aortic entry impedance peak in the descending aorta, 292 +/- 45 kN x s x m(-5); P <.05). After grafting, the aortic entry impedance peak was transferred to early systole (aortic entry impedance peak in the transverse aortic arch, 2104 +/- 94 kN x s x m(-5); aortic entry impedance peak in the descending aorta, 450 +/- 75 kN x s x m(-5); P <.05). Clamping of the descending aorta attenuated the early systolic aortic entry impedance peak (aortic entry impedance peak in the transverse aortic arch, 1269 +/- 104 kN x s x m(-5); aortic entry impedance peak in the descending aorta, 491 +/- 75 kN x s x m(-5); P <.05), although aortic entry impedance in the descending aorta remained higher than before grafting (P <.05). Specifically, the backward flow ascending aorta to coronary trunks generated a backward aortic entry impedance peak (2234 +/- 350 kN x s x m(-5)) superimposed onto the forward aortic entry impedance peak with asymptotic boundaries that diminished after grafting and further enlarged after clamping of the descending aorta. CONCLUSIONS: Hemodynamic opposition of grafting of the descending aorta are specific to the aortic site and cardiac cycle and are dependent on clamping of the descending aorta. Our approach to thoracic aorta hemodynamics could enable optimization of bypass grafting.

Analysis of Variance↗
PubMed2006

Responses of IL-18- and IL-18 receptor-deficient pancreatic islets with convergence of positive and negative signals for the IL-18 receptor.

Pancreatic islets contain cells that produce IL-18 and cells that express IL-18 receptors. In experimentally induced diabetes, islet failure correlates with IL-18 levels and diabetes is delayed with blockade of endogenous IL-18. We studied islet-derived IL-18 and responses to IL-18 in a mouse model of islet allograft transplantation. In vitro, IL-18-stimulated islets produced nitric oxide, which closely matched islet apoptosis. By neutralizing IL-18 activity with IL-18 binding protein (IL-18BP), we observed that islets produce bioactive IL-18. In vivo, transgenic mice overproducing IL-18BP (IL-18BP-Tg) exhibited delayed hyperglycemia induced by beta cell toxic streptozotocin. Similarly, cultured IL-18BP-Tg islets were protected from streptozotocin-induced apoptosis. In the transplant model, islets grafted from WT to IL-18BP-Tg mice achieved prolonged normoglycemia (P = 0.031). Improved graft function was also observed by using IL-18-deficient islets transplanted into WT recipients, demonstrating that endogenous, islet-derived IL-18 mediates IL-18-driven graft damage. Unexpectedly, islets from mice deficient in IL-18 receptor alpha chain (IL-18R) exhibited rapid graft failure (P = 0.024; IL-18- versus IL-18R-deficient grafts in WT recipients). In related studies, IL-18R-deficient splenocytes and macrophages produced 2- to 3-fold greater amounts of IL-18, TNFalpha, macrophage inflammatory protein 1, macrophage inflammatory protein 2, and IFNgamma upon stimulation with Con A, Toll-like receptor 2 agonist, or anti-CD3 antibodies. These data reveal a role for islet-derived IL-18 activity during inflammation-mediated islet injury. Importantly, discrepancies between IL-18- and IL-18R-deficient cells suggest that IL-18Ralpha chain is used by an inflammation-suppressing signal.

Animals↗
PubMed1987

Prognostic value of eustachian tube function in pediatric tympanoplasty.

Poor eustachian tube function and prevalence of infectious ear disease are thought to be the reasons for less successful outcome associated with tympanoplasty in children. Since both of these factors are related to age, identification of those patients who may benefit by delaying the surgery has been a concern to otolaryngologists. In an effort to investigate the role of eustachian tube function on the outcome, we tested the tubal function in 63 ears (56 children) undergoing tympanoplasty for central perforations. In 49 ears (78%), the graft took; of these, 33 had good middle-ear function, 8 developed persistent or recurrent otitis media, and 8 had severe retraction or atelectasis. There was a significant association (p less than 0.01) between outcome and preoperative tubal function as determined by combining the active and passive function parameters. However, the prognostic value of tubal function testing was low; predictive values for success and lack of success being 68% and 56%, respectively. Other factors, such as graft placement (medial or lateral) contralateral ear status, and child's age, were not associated with outcome. Consistent with other studies, good eustachian tube function was shown to predict good outcome, but poor tubal function was not helpful in predicting poor outcome.

Adolescent↗