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PURPOSE: Intraosseous repair of nerves involves difficulty of access and there is concern that bone healing may interfere with repair outcomes. The present report describes the effect of 3 separate repair techniques on recovery from section of the rat intraosseous inferior alveolar nerve, with reference to the mental nerve distal and the trigeminal ganglion proximal to the nerve section. MATERIALS AND METHODS: Unilateral exposure of the inferior alveolar nerves of 28 rats was achieved through bone windows. Nerves were sectioned and rats were assigned to 1 of 4 groups (n = 7): untreated controls, microsuture repair, interpositional nerve grafts from the femoral nerve, or laser solder weld repair. Animals were sacrificed 1 year after surgery for histologic evaluation of the mental nerve, inferior alveolar nerve, and trigeminal ganglion compared with unoperated contralateral nerves. RESULTS: Compared with the unoperated contralateral nerves, nerve section substantially decreased mental nerve fiber number, mental nerve myelination, mental nerve fiber diameter, inferior alveolar nerve vascularity, trigeminal neuron number, and trigeminal neuron horseradish peroxidase tracer uptake and increased trigeminal ganglion degenerate neurons (P < .001). All 3 forms of repair substantially decreased these effects (P < .05). Interpositional nerve graft was least effective (P < .05). Nonetheless, mental nerve fiber diameter was significantly decreased compared with unsectioned nerves after microsuture and laser solder weld repair (P < .05). CONCLUSIONS: Intraosseous repair of the inferior alveolar nerve decreases peripheral and central signs of degeneration. Clinical hyperesthesia after repair may reflect a predominance of small fibers after recovery.

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Administration of donor bone marrow (BM) cells can improve the outcome of transplantation. The ability of donor vascularized bone marrow transplantation (VBM) to provide an ongoing source of donor cells and improve survival in a rigorous rat model of hind limb transplantation (HLTX) was investigated. HLTX were performed between Brown Norway (BN) donors and Lewis recipients in three groups: HLTX; HLTX plus intravenous donor BM cells and HLTX plus simultaneous VBM transplantation. Animals received 12 weeks triple immunosuppression. Survival was compared at 4 months and donor chimerism was evaluated. Simultaneous VBM transplantation led to slight but nonsignificant prolongation of survival (P=0.056). Donor cells in the VBM were eventually replaced by recipient and there was no long-term increase in chimerism. Few donor cells were observed in thymus. Simultaneous VBM transplantation showed a trend for improved survival of HLTX however the VBM failed to provide a sustained increase in chimerism.

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Prior to the advent of microsurgical equipment and techniques, it was rare for urologists or other surgeons to produce a full pregnancy as a result of reconstructing fine tubal blockages in the male reproductive tract. Perhaps 2% of vasectomized men, and a large percent of men born sterile, are desirous of being able to start a pregnancy, and so in 1970, I began a research project with new equipment to find a reliable way of joining fine body tubes. I found that our bodily tubes can be grouped as being three-layered and that their differences lay mainly in the kind of inner, individual mucosal cell structure and their type and thickness of the muscular layer. The latter was most important, because the pressure built up on peristaltic movement waves in extremely small diameter tubes can be very high indeed, forcing tubal contents out, and early escape of fluid from the anastomotic site will easily occur unless the joining technique is designed to specifically prevent this eventuality. Based on this anatomical and physiological information, new techniques for reconstruction of the vas deferens and the epididymis were perfected. Consecutive personal series of 5000 vaso-vasostomies and almost 500 epididymo-vasostomies have now been carried out since 1971 with extraordinary results in baby birth rates-far better than those that occurred before microsurgery.

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Despite the fact that gynecologists were very early users of the operating microscope to observe the possible pathology of the cervical mucosa by brilliant lighting and magnification, the advent of in vitro fertilization (IVF) seems to have stopped this specialty from using the benefits of microsurgery in female tubal reconstruction. Now having performed and followed up for at least 2 years nearly 1000 microsurgical tubal reconstructions after sterilizations, with an endpoint being the birth of a baby in the time following, it is obvious that there are real benefits in pursuing these techniques, because no single IVF Unit in the world gets even half as many live birth results from their best practices. Apart from a genuine 82.7% baby result from all comers, of any child-bearing age and "sterilization age," with an ectopic pregnancy rate of <1%, there are the benefits of (i) a single procedure, (ii) normal intercourse to become pregnant is the way to go, (iii) psychological trauma of the women involved is not a problem, and (iv) the next baby after the first is "free." In our opinion, it is sensible to scientifically attempt to reconstruct a deliberately blocked tube in the first instance because it is healthier (for mother and children), less expensive, more satisfying and psychologically acceptable, and is certainly far more reliable in its results than any other baby-promoting proceedure now available. It is regretted that gynecologists who flocked to workshops teaching microsurgical gynecological techniques before IVF was established now do not even seem to consider giving the operative reconstruction as a first alternative to their couples that come to them with sterilization as the cause of infertility.

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The experience obtained from the human hand allografts (HHA) performed to date suggests that the skin is a priviledged target of allograft rejection in this setting. The aim of this study was to establish a pathological score for assessing the severity of HHA rejection. The pathological slides of 89 skin biopsies obtained from the allografted limbs of six HHA recipients from day 0 to 5 years post-graft were retrospectively examined. According to the severity of the pathological changes observed, the following grades of rejection are proposed: 0: no rejection, I: mild rejection, II: moderate rejection, III: severe rejection, IV: very severe rejection. This grading system can be used as a basis for monitoring allograft rejection and for assessing the effects of the immunosuppressive treatment aiming at reversing HHA rejection; it can also be used for monitoring rejection of other skin-containing CTA.

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BACKGROUND: The first human hand allograft, performed in Lyon, France, on September 23, 1998, was removed during month 29 posttransplantation as the result of rejection because the patient did not comply with the immunosuppressive treatment. METHODS: The patient was regularly examined from the day of transplantation to amputation. Biopsies were taken from the skin of the allograft and examined immunohistologically. After amputation, various tissue specimens obtained from the allograft (including skin, tendons, bone, muscles, and joints) were studied. RESULTS: From month 15 onward, the allografted skin presented lichenoid papules that progressively spread and coalesced into diffuse erythematous-scaly lesions over the allografted hand. Histologically, these showed an aspect of chronic lichenoid cutaneous graft-versus-host disease. At the time of amputation, erosive and necrotic areas over the skin were present. Pathologic examination of the allograft showed that the most severe changes were found in the skin. Mild inflammation was found in muscles and tendons. Bones (including bone marrow) and joints were spared. CONCLUSIONS: The skin is the main target of rejection in human hand allografts. Close clinicopathologic monitoring of the skin is the most reliable way to detect rejection in human composite tissue allografts.

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OBJECTIVE: Objective of this study was to analyze fifteen months after surgery the sensorimotor recovery of the first human double hand transplantation. SUMMARY BACKGROUND DATA: As for any organ transplantation the success of composite tissue allografts such as a double hand allograft depends on prevention of rejection and its functional recovery. METHODS: The recipient was a 33-year-old man with bilateral amputation. Surgery included procurement of the upper extremities from a multiorgan cadaveric donor, preparation of the graft and recipient's stumps; then, bone fixation, arterial and venous anastomoses, nerve sutures, joining of tendons and muscles and skin closure. Rehabilitation program included physiotherapy, electrostimulation and occupational therapy. Immunosuppressive protocol included tacrolimus, prednisone and mycophenolate mofetil and, for induction, antithymocyte globulins and then CD25 monoclonal antibody were added. Sensorimotor recovery tests and functional magnetic resonance imaging (fMRI) were performed to assess functional return and cortical reorganization. All the results were classified according to Ipsen's classification. RESULTS: No surgical complications occurred. Two episodes of skin acute rejection characterized by maculopapular lesions were completely reversed increasing steroid dose within 10 days. By fifteen months the sensorimotor recovery was encouraging and the life quality improved. fMRI showed that cortical hand representation progressively shifted from lateral to medial region in the motor cortex. CONCLUSION: Even though at present this double hand allograft, treated using a conventional immunosuppression, allowed to obtain results at least as good as those achieved in replanted upper extremities, longer follow-up will be necessary to demonstrate the final functional restoration.

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Peripheral nerve repair can be accomplished by using a polytetrafluoroethylene tubular chamber to guide nerve healing and regeneration. In this study, we delivered basic fibroblast growth factor (bFGF) into the chamber for sciatic nerve repair in rats. In addition, the animals were given systemically 1 mg/kg/day FK506 (tacrolimus), a potent immunosuppressant with neurotrophic properties. Nerve regeneration was evaluated by means of a nociceptive test and a grasping test starting 2 weeks postoperatively. Animals that received bFGF and FK506 showed a significantly faster recovery from injury than did the control group. Morphometric analysis at 3 months showed no difference between the two groups in total number of axonal fibers, fiber diameter, fiber density, and myelin:axon ratio. We conclude that the combination of bFGF and low dose FK506 enhances nerve healing in this animal model by accelerating early regrowth but has no effect on the final outcome.

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OBJECTIVE: To evaluate the long-term outcome of Polytetrafluoroethylene (PTFE) conduit in nerve repair and to provide more evidence in view of its potential application to achieve a satisfactory functional recovery in clinical settings. METHODS: Thirty-six Wistar rats had their right sciatic nerve transected and were repaired with either conventional microsuture technique (Control group, n=18) or a PTFE conduit with a gap of 5 mm left between the nerve stumps (PTFE group, n=18). At 6 and 9 months after the operation, electrophysiological assessment and measurement of gastrocnemius muscle weight were conducted and morphology of the regenerated nerves were studied with image analysis. RESULTS: At 6 months postoperatively, the nerve conduction velocity recovered to 60.86% and 54.36% (P<0.05), and the gastrocnemius muscle weight recovered to 50.89% and 46.11% (P>0.05) in the Control group and the PTFE group respectively. At 9 months postoperatively, the recovery rate was 65.99% and 58.79% for NCV (P>0.05), and 52.56% and 47.89% for gastrocnemius muscle weight (P>0.05) in the Control group and the PTFE group respectively. Regenerated nerve fibers in the PTFE group had a regular round shape with no fragmentation, wrinkling or splitting of the myelin sheath. Image analysis revealed that the ratio of the myelin area to the total fiber area was larger at 9 months than at 6 months in both groups (P<0.01). CONCLUSIONS: Microporous PTFE conduit may be an alternative for nerve repair allowing of guided nerve regeneration and functional recovery with no obvious adverse effect at long-term.

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Based on the results achieved in single human hand transplantations, we decided to perform the first double hand transplantation with a conventional immunosuppressive protocol in a patient with a high potential for functional recovery. Two years after transplantation the efficacy and the safety of this immunosuppressive protocol are evaluated. The recipient was a 33-yr-old man suffering from a traumatic amputation of both hands in 1996. Five HLA-A, -B, and -DR mismatches were present with the donor; T and B cell cross-match was negative. Immunosuppressive protocol included tacrolimus, prednisone, mycophenolate mofetil and, for induction, antithymocyte globulins and then anti CD25 monoclonal antibody. Reconstitution of lymphocyte populations proceeded normally. Neither anti-HLA antibodies nor chimerism in peripheral blood were detected. Two episodes of acute rejection characterized by maculopapular lesions occurred on days 53 and 82 after transplantation. Skin biopsies revealed a dermal lymphocytic infiltrate. Both episodes were completely and rapidly reversed by topical clobetasol and increased systemic corticosteroid therapy. The only side-effects related to treatment were reversible serum sickness and hyperglycemia. No infectious complications and malignancies occurred. No signs of graft-versus-host disease have been detected. This case of double hand transplantation shows that conventional immunosuppression is effective and safe to ensure survival and functional recovery of the grafted limb.

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FK506 has been reported to enhance nerve regeneration in various rodent models. However, both the immunosuppressive properties and potential side effects may preclude the broad clinical use of FK506 to speed nerve regeneration. In this study, we examined the nerve regenerative property of a low, nonimmunosuppressive dose (0.5 mg/kg/day) of FK506. Two treatment schedules (continuous versus discontinuous) were compared. Evaluations were perforrmed at 1, 2, and 3 months. The gastrocnemius muscle mass was significantly higher in treated groups compared with the untreated group at 3 months, and the total number of fibers, percentage of neural tissue, fiber density, and fiber diameter were greater in treated groups than in the untreated group. However, at 3 months there was no difference in these parameters between groups in which FK506 was administered continuously and those in which the drug was stopped at 2 months. This study confirms that daily administration of low dose FK506 enhances peripheral nerve recovery after transection injury.

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