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PubMed2002

Regeneration of acutely and chronically injured descending respiratory pathways within post-traumatic nerve grafts.

Central respiratory neurons, which are acutely axotomized by peripheral nerve grafts implanted at the level of the descending respiratory pathways within the C2 spinal cord, can regenerate their axons within the grafts and still transmit normal physiological messages [Decherchi et al., 1996. Exp. Neurol. 137, 1-14]. The present work investigated the extent to which mature central neurons, acutely or chronically axotomized by a spinal lesion, still maintain the potential to regenerate an axon following post-traumatic nerve grafting within supra-lesional spinal structures and remained functional. This study is an extension of earlier work employing the more chronic lesions, that investigated whether respiratory neurons chronically axotomized by a spinal cord injury can retain the ability to regenerate their axonal process within a post-traumatic peripheral nerve graft. Here implantation was performed into the supra-lesional ventrolateral part of the ipsilateral C2 spinal cord (at the level of the descending respiratory pathways) previously hemisected at the C3 level. In the present study, these post-traumatic peripheral nerve grafts were performed either acutely (group I, n=15, 2.5 h post-injury: acute conditions) or chronically (group II, n=17, 3 weeks; group III, n=6, 3 months: chronic conditions) after the injury.Electrophysiological recording of teased filaments (n=2362) within the post-traumatic peripheral nerve grafts revealed the presence of regenerated nerve fibers with spontaneous unitary impulse traffic (graft units, n=954) in all animals. These graft units were respiratory (n=247) and non-respiratory (n=707). Respiratory discharges originated from central respiratory neurons which remained functional with preserved afferent connections. Except for the group III, post-traumatic C2 peripheral nerve grafts of the groups I and II contained a significantly higher occurrence rate (13.2+/-2% and 11.6+/-1.9%) of respiratory units than C2 spinal peripheral nerve grafts (5.9+/-1.6%) realized without previous CNS injury. The main conclusion of our study is that for a prolonged period of 3 weeks following a spinal cord injury, central respiratory neurons have the potential to remain functional and to regenerate their axonal process within post-traumatic peripheral nerve grafts inserted rostrally to the spinal damage. This indicates that supra-lesional post-traumatic nerve grafts may constitute an efficient delayed strategy for inducing axonal regrowth of chronically axotomized adult central neurons. This suggests that surgical intervention which is not always possible immediately after a spinal cord injury may be satisfactorily carried out after an appropriate delay.

Acute Disease↗
PubMed2003

Thumb metacarpal lengthening.

Over a period of 35 years, 92 patients have been treated: 70 adults and 22 children age 8 to 14. The metacarpal lengthening obtained varied from 2 to 4.5 cm with an average of 3.5 cm, or equal to the length of a thumb proximal phalanx. In one third of the adult patients, due to delayed spontaneous ossification, the interfragmental space was bridged by a bone graft taken from the iliac crest. Late follow-up of 21 patients made 10 to 14 years after the treatment showed good function of the thumb with a normal pattern of skin sensibility. The lack of trophic changes in the distal part of the reconstructed thumb is due to the interposition type of bone lengthening, that is, the new bone structure is placed into the bone middle and not superimposed on the bone stump end, as is done in other methods of thumb reconstruction. The metacarpal lengthening procedure has the following drawbacks: (1) the full treatment course lasts several months; (2) the reconstructed thumb has neither joint nor nail. Advantages of the method are: (1) reconstruction of the thumb is done by using the available stump tissue resources; (2) the reconstructed thumb is covered by its own, normally innervated skin.

Journal Article↗
PubMed2001

Effect of liver transplantation on islet allografts: up-regulation of Fas ligand and apoptosis of T lymphocytes are associated with islet graft tolerance.

BACKGROUND: Liver allografts in spontaneously tolerant strain combinations can protect other organs of the same donor origin from rejection and reverse ongoing rejection in previously placed grafts. The aims of this study were to examine whether liver allografts have the same protective effect on islet allografts and to investigate the underlying mechanisms. METHODS: PVG islets were transplanted beneath the kidney capsule of streptozotocin-induced diabetic DA rats with or without liver allografting. The cellular infiltrate, and the extent of apoptosis and of Fas ligand (FasL) expression in the islet grafts were evaluated on days 2, 4, and 7 after transplantation by means of immunostaining and the in situ terminal deoxynucleotide transferase-mediated dUTP nick end labeling assay. Donor and recipient mixed lymphocyte reactions (MLR) were determined at 7 days or 100 days after islet transplantation. RESULTS: Islet allografts transplanted alone were rapidly rejected within 5-8 days. Rejection was delayed, but not prevented, when islets were transplanted simultaneously with the liver. Liver transplantation 1 month before islet transplantation resulted in long-term survival (>100 days) of islet grafts in three of seven animals, whereas the other four died of liver rejection with functional islet grafts. Liver transplantation on day 4 after islet grafting reversed ongoing islet rejection and led to indefinite islet graft survival in three of seven cases. There was a progressive increase of cellular infiltration in all of the islet allografts, but the intensity of the infiltrate did not correlate with the outcome of the islet allografts. Islet rejection was characterized by an early dominance of monocytes/macrophages and CD25+ T cells in the infiltrates, a high incidence of apoptotic beta cells in grafts, and a sensitized status in the MLR. Tolerance of islet allografts was associated with increased numbers of dendritic cells in the graft infiltrates, up-regulation of FasL, and prominent apoptosis of alloreactive leukocytes in the islet grafts, as well as donor-specific MLR suppression in long-term survivors. CONCLUSIONS: These results demonstrate that the extent of the protective effect of liver transplantation on islet allografts varies with the time of liver grafting, ranging from delay in islet rejection to complete islet acceptance. Islet graft tolerance induced by liver transplantation is the result of an immune process that involves up-regulation of Fas ligand expression on, and apoptosis of, islet graft infiltrating lymphocytes.

Animals↗
PubMed1997

Lack of immune responses to immediate or delayed implanted allogeneic and xenogeneic Schwann cell suspensions.

Previous studies have shown that Schwann cell implantation offers a potential therapeutic approach to a variety of neurodegenerative disorders and traumatic injuries. In a clinically relevant paradigm, however, the implantation of autologous Schwann cells is problematic and the use of heterogenetic Schwann cells will be required. In the present study we addressed this important issue and analysed the immunogenicity and survival of allogeneic and xenogeneic Schwann cell suspension grafts in a prelesioned CNS fiber tract, the transected postcommissural fornix of the adult Wistar rat. Cultured Schwann cells from Wistar rat or human peripheral nerve were injected either immediately or after a delay into the transection site and the spatio-temporal pattern of leukocyte infiltration and of major histocompatibility antigen expression was characterized and semiquantified with immunocytochemical methods. Our main findings are that (1) invasive cerebral lesions induce the expression of MHC class I and II antigens, but only sparse infiltration of T-lymphocytes, (2) both allogeneic and xenogeneic discordant Schwann cell suspension grafts, from either neonatal or adult peripheral nerve, survive without any overt signs of rejection for up to 10 weeks after implantation; and (3) delayed implantation procedures have no effect on immune responses to allogeneic Schwann cell grafts. These results demonstrate that there is no marked ongoing immune reactions to heterogenetic Schwann cell suspension grafts and that long-term survival of cross-species Schwann cell grafts can be achieved in the absence of any immunsuppressive treatment. Thus the conditions for functional transplantation of Schwann cells across immunological barriers seem to be favourable and will have implications for future cross-species studies, and possibly also for clinical application.

Animals↗
PubMed2005

Oral rehabilitation after treatment for head and neck malignancy.

BACKGROUND: Advances in the management of oral malignancy have resulted in significant improvements in survival and functional outcome. Ablation of oral tissues and radiotherapy render many patients unable to wear conventional prostheses, and these patients are, thus, candidates for oral rehabilitation with osseointegrated implants. We aim to present outcomes and complications of such treatment over a 14-year period in a single unit. METHODS: Data were collected for 81 consecutive patients, most of whom had received microvascular free flap reconstruction after surgical ablation of oral squamous cell carcinoma. Three hundred eighty-six implants were placed after a delay of 12 months after surgery. Sixty-five percent of implants were placed in the anterior mandible. Radiotherapy was used in 47% of the patients, and hyperbaric oxygen treatment was routinely used in irradiated subjects during the latter half of the series. Retrospective analysis of implants and prostheses was made by use of case notes, radiographs, and a computerized database. RESULTS: Data are presented for 364 of the 386 implants in 77 of the 81 patients after a median follow-up of 4 years. Two hundred sixty-five (73%) of the implants were in function supporting prostheses, 56 (15%) had been lost, and 43 (12%) were present but not loaded (ie, "sleepers"). Implant loss seemed patient specific and was also correlated with host bone type. Thirteen percent of patients in whom implants were placed in the mandible lost at least one implant, and the equivalent values for the maxilla was 40%. Thirty-six percent of patients in whom implants were placed in bone graft or flap lost at least one implant. The effects of implant manufacture, dimensions, radiotherapy, and hyperbaric oxygen did not reach statistical significance in this series. Cases of a second primary malignancy were noteworthy; however, the impact of recurrence was minimized by the delay between resection and rehabilitation. Of the 42 fixed and 29 removable prostheses fitted, 12 (17%) failed. CONCLUSIONS: Implants placed in mandible were reliable, but failure rates in vascularized bone graft and maxilla were higher. Radiotherapy did not seem to prejudice implant survival, and hyperbaric oxygen had no demonstrable benefit in this series. Despite some persistent soft tissue problems and implant loss, most patients reached a successful prosthetic and functional outcome.

Adolescent↗
PubMed1996

The use of the lidocaine-monoethylglycinexylidide test in the liver transplant recipient.

The lidocaine-monoethylglycinexylidide (MEGX) test is used to monitor liver function in liver transplant recipients. Serial studies have been undertaken after 155 allografts. The initial MEGX concentration is significantly correlated with the donor MEGX concentration. It is also influenced by the recipient's pretransplant bilirubin concentration, being lowest among patients with very high bilirubin levels. Use of segmental grafts is also accompanied by low MEGX concentrations. The flow-dependent clearance of lidocaine makes it a sensitive indicator of disturbed liver blood flow, with decreased MEGX concentrations occurring in hepatic artery thrombosis and rejection and as a result of cardiac failure and pulmonary effusions. Significant hepatic ischemia resulting in delayed initial function or cholestasis also is associated with low MEGX concentrations. The initial median MEGX concentrations were lowest among patients who required retransplantation or who died within 2 months of allografting.

Adolescent↗
PubMed1995

Liver transplantation in patients with situs inversus.

Seven patients with situs inversus abdominis and one with situs inversus totalis underwent liver transplantation; all are alive at follow-up of between 7 months and 5 years. Two patients required retransplantation within the first 3 weeks (for primary non-function and thrombotic infarction). Seven had additional abnormalities associated with the polysplenia-biliary atresia syndrome. Liver transplantation in these patients involved selection of relatively small donor organs or use of reduced-size grafts. Delayed abdominal wall closure was necessary in two patients and all required a modification of the 'piggy-back' technique of suprahepatic vena caval anastomosis to overcome recipient venous anomalies. Biliary drainage by Roux-en-Y choledochojejunostomy was the preferred technique. Although technically challenging, situs inversus is not a contraindication to liver transplantation and patients should expect full recovery.

Anastomosis, Roux-en-Y↗
PubMed1994

Experimental rat pancreas transplant: surgical technique and immunological considerations.

Vascularized whole pancreas transplantation in the rat was performed on the abdomen using a cuff technique for vascular anastomoses. Two different exocrine drainage procedures, either intestinal or ureter drainage, were used. In the isograft transplant models, hyperglycemia was ameliorated immediately after transplantation and all of the grafts functioned during the observation period. In the allograft transplant models without immunosuppression, graft rejection, as defined by recurrence of hyperglycemia (blood glucose > 200 mg/dl) occurred 6-9 days post-transplant. Allograft rejection could be delayed approximately 1 month after transplant with short-term use of FK506. These different models, using either intestinal or ureter exocrine drainage, are similar to dominant clinical pancreas transplantation with enteric exocrine drainage or urinary tract drainage, respectively. It is thus concluded that whole pancreas transplant with either intestinal or ureter exocrine drainage is an ideal model for physiological and immunological experimental studies in pancreas transplantation.

Animals↗
PubMed2006

Surgical treatment of Peyronie's disease: a critical analysis.

OBJECTIVE: The present paper reviews surgical treatment alternatives for patients with Peyronie's disease using knowledge obtained from the contemporary literature. METHODS: : All aspects of surgical treatment for Peyronie's disease were examined on the basis of MEDLINE database researches. RESULTS: Surgical treatment should be delayed until the acute inflammatory phase has resolved and should be considered in patients with deformity that impairs sexual function. Currently, surgical treatment alternatives are reconstructive surgery by either lengthening the concave side (incision and grafting) or shortening the convex side (Nesbit procedure or plication) of the penis, and implantation of penile prosthesis with or without incision of the plaque. PD patients with good erectile capacity are candidates for reconstructive surgery. Meanwhile, implantation of penile prosthesis with or without remodeling should be considered for patients without adequate erectile capacity. CONCLUSIONS: The aim of the surgical treatment in Peyronie's disease is to correct the deformity while preserving or improving erectile capacity of the penis. Appropriate treatment options should be individualized according to the patients' expectations and erectile capacity.

Humans↗
PubMed1987

A new surgical approach to closure of large lumbosacral meningomyelocele defects.

A new method for the reconstruction of large thoracolumbar and lumbosacral meningomyelocele defects is described in which latissimus dorsi and gluteus maximus myocutaneous units are advanced medially and reapproximated in the midline, permitting primary closure of the defect in three layers. The flaps are based on the thoracodorsal and superior gluteal vessels and the intervening thoracolumbar fascia, providing tension-free, durable, and viable soft-tissue coverage over the dural repair. No lateral relaxing incisions, delays, or skin grafts are necessary. This technique has been used successfully in the repair of nine large meningomyelocele defects, and uncomplicated wound closure was achieved in all cases. The anatomic basis, technique, advantages, and functional implications of our approach are described. The flaps described do not alter the nerve supply of the muscles and merely redefine the muscle origins; therefore, no functional deficit from the reconstructive surgery is anticipated.

Follow-Up Studies↗
PubMed1997

[Long-term survival of fetal substantia nigra grafts in striatum of PD rats: an observation of tyrosine hydroxylase immunohistochemistry and western blot].

By using immunohistochemistry and Western blot, we observed the varied patterns of survival, development and growth of dopaminergic neurons after intrastriatal transplantation of fetal substantia nigra. There was a phenomenon of "developmental delay" of grafts in the host. As the time of transplantation went on, the grafted dopaminergic neurons could reinnervate the host neurons. The observation reveals that the reinnervation between graft and host is more beneficial to the functioning of the grafts.

Animals↗
PubMed1981

Effectiveness of the adriamycin-DNA complex in kidney allograft immunosuppression.

The chemotherapeutic effectiveness of the lysosomotropic Adriamycin-DNA complex has been demonstrated experimentally. This study evaluated the immunosuppressive activity of the complex on renal allografts in rats of the Buffalo-Lewis strain. Six rats receiving no treatment served as a control. Five rats received DNA along (at a dose equivalent to that in the complex), seven received the Adriamycin-DNA complex (molar ratio of DNA mononucleotide to Adriamycin, 20:1) and five were given free Adriamycin. Adriamycin, free or linked to DNA, was injected as follows: 2 mg/kg on days 2, 6 and 9 and 1 mg/kg on day 13 after transplantation. The Adriamycin-DNA complex prevented renal allograft rejection in the early postoperative period, by delaying for more than a week, the increase in serum creatinine levels in animals receiving transplants. Histologic examination of renal grafts in these rats confirmed the reduced severity of acute cellular rejection. There was also functional and morphologic evidence of reduced toxicity of Adriamycin when linked to DNA. The beneficial effect of such a drug should be attributed to its lysosomotropic mechanism of activity.

Animals↗
PubMed1995

[Coronary endothelial dysfunction and graft atheromatosis following heart transplantation].

Graft atheromatosis is the most important limiting factor on long-term survival after heart transplantation. Histologically it involves so-called myointimal proliferation occurring in either circumscribed or diffuse form. Endothelial dysfunction with impaired release of nitric oxide represents an early stage of graft atheromatosis. Progression of the disease typically leads to a diffuse narrowing of the coronary tree; however, focal stenoses may also occur. Endothelial dysfunction results in a decrease in physiological coronary flow reserve during exercise, whereas pharmacological flow reserve after papaverine or adenosine administration is maintained. This functional disturbance can be enhanced by transplantation-related (e.g., vascular graft rejections, cytomegalovirus infections, etc.) as well as by cardiovascular risk factors (e.g., hypercholesterolemia, hypertension). The occurrence of endothelial dysfunction and graft atheromatosis may be delayed, although probably not prevented, by elimination of risk factors and optimization of immunosuppressive treatment. Preliminary data suggest that long-term administration of the calcium-antagonist diltiazem may have a protective effect.

Coronary Artery Disease↗
PubMed1991

Evidence that addition of azathioprine improves renal function in cyclosporine-treated patients with allograft dysfunction.

Several approaches have been attempted to manage renal allograft dysfunction in cyclosporine-prednisone (CsA-Pred)-treated patients. Conversion to conventional therapy and perioperative triple drug have been associated with high rates of acute rejection episodes, infections, or neoplasms. We report our experience in delayed addition of azathioprine (1-2 mg/kg/day) to CsA/Pred protocol in three groups of patients. Group I (n = 9) had chronic renal function deterioration due to chronic rejection; group II (n = 10) had repeated or severe acute rejection episodes despite adequate CsA levels; and group III (n = 8) had CsA toxicity despite drug tapering. In group I, serum creatinine (SCr) had risen from 2.2 +/- 0.9 to 2.9 +/- 0.7 mg/dl over the 6 months prior to Aza addition (P less than 0.05), renal function declining at a rate of -0.14 +/- 0.12 Cr-1/year. In the 6-month post-Aza, renal function improved at a rate of 0.06 +/- 0.06 Cr-1/year and during the entire follow-up at a rate of 0.04 +/- 0.12 Cr-1/year (P less than 0.05) with stable CsA levels (288 +/- 167 vs. 251 +/- 172 ng/dl, NS). In group II response was worse, though the rate of declining renal function prior to Aza (-0.10 +/- 0.10 Cr-1/year) was almost stopped after Aza. In group III there was very good response to Aza addition, as 7 out of 8 patients improved graft function (baseline SCr 2.5 +/- 0.7 mg/dl vs. 1.9 +/- 0.6 mg/dl at last follow-up, P less than 0.05), with significantly decreased CsA levels (480 +/- 97 vs. 268 +/- 120, P less than 0.05). One patient from group II died from pneumonia, and 6 patients (1 from group I and 5 from group II) lost their grafts. Fifteen patients improved graft function, and 9 worsened after addition of Aza. The bad-responders had significantly higher SCr at baseline compared with the good-responders (3.8 +/- 1.8 vs. 2.7 +/- 0.6 mg/dl, P less than 0.01). Amelioration of chronic graft dysfunction can be achieved by delayed addition of Aza to CsA-Pred in patients with chronic rejection or CsA toxicity. This is accompanied by low rate of acute rejection, good patient and graft survival, and low rate of infections. A worse outcome can be seen in patients with high-baseline SCr levels, suggesting the need for addition of Aza in the initial chronic graft dysfunction.

Azathioprine↗
PubMed1983

A controlled serial ultrastructural tracer study of first-set cardiac allograft rejection in the rat. Evidence that the microvascular endothelium is the primary target of graft destruction.

In order to define the serial morphologic correlates of unmodified first-set cardiac allograft rejection in an inbred rat strain combination, a series of Wistar-Furth cardiac allografts transplanted to normal nonsensitized Lewis recipients were studied as a function of time with the use of well-documented ultrastructural tracer techniques. Colloidial carbon was employed as a vascular label for detection of microvascular endothelial structural alterations, and horseradish peroxidase was used as a tracer probe for localization of cell-membrane permeability dysfunction of allograft endothelium and cardiocytes as well as of elements of the cellular infiltrate. Wistar-Furth to Wistar-Furth syngeneic heart grafts and Wistar-Furth recipients' own hearts provided appropriate control data. This study was demonstrated that severe diffuse loss of functional and structural integrity of the microvascular endothelium precedes the development of extensive damage to cardiac muscle cells and thus provides strong evidence that the allograft microcirculation is the primary target of immunologic injury. In addition, the sequential pattern of injurious changes present in the rejecting allografts was similar to that observed in certain models of delayed-type hypersensitivity and of skin graft rejection, raising the possibility that lymphokine-mediated mechanisms may be of major pathogenetic significance in this setting.

Animals↗
PubMed2000

The pineal gland and cancer. I. Pinealectomy corrects congenital hormonal dysfunctions and prolongs life of cancer-prone C3H/He mice.

Hormonal derangements almost invariably anticipate and signal the onset of tumors. Chronic, nocturnal melatonin administration delays aging in normal strains of mice. On the contrary it promotes and accelerates the onset of tumors in the cancer-prone strain of C3H/He mice. Grafting of a young pineal gland into aging mice prolongs their longevity and maintains juvenile circadian hormonal functions while pinealectomy (Px) does the opposite. We investigated if Px in C3H/He mice would modify their congenitally deranged pituitary function and affect their longevity. It was found that contrarily to Px in normal mice, Px in C3H/He mice remarkably maintains juvenile night levels of thyroid hormones and lipids, preserves a cell-mediated immune response and significantly prolongs their life. The pineal gland and its pathology may be the key for understanding, not only the causes of metabolic aging, but also the origin of those congenital or progressive aging-related hormonal alterations preceding onset of all tumors and thus allow preventive corrective interventions with pineal-derived agents.

Aging↗
PubMedDate not supplied

Xenotransplantation of retinal pigment epithelial cells into RCS rats.

PURPOSE: Successful engraftment of retinal pigment epithelial cells (RPE) to treat RPE-related retinopathy will depend, at least in part, on controlling the immune response. In order to understand this process we evaluated the fate of RPE xenografts in the subretinal space, anterior chamber, and subcutis of nonimmunosuppressed Royal College of Surgeons rats. METHODS: Freshly isolated adult porcine RPE cells were used as xenografts and implanted when recipients were 17 to 21 days old. The extent of photoreceptor rescue by subretinal transplants was determined by counting the maximum layers of surviving photoreceptor nuclei in histologic sections. Cellular immune response was evaluated by immunohistochemistry. RESULTS: Compared to non- or sham-injected eyes, subretinal xenografts in RPE-transplanted eyes were able to induce a dramatic rescue effect (P <.01). However, the effect was not absolute and photoreceptor cell degeneration was only delayed. Xenografts both in the anterior chamber and in the subcutaneous tissue led to an inflammatory cellular infiltration. CONCLUSION: RPE xenografts in subcutaneous space and in the anterior chamber are rejected by a delayed but vigorous inflammatory cell infiltration. Subretinal RPE xenografts are protected from a strong cellular rejection, but seem to undergo a slow functional deterioration, reflected by a decline in their capability to rescue adjacent photoreceptors.

Animals↗