Barry H. J. Press

Efficacy of rapamycin and FK 506 in prolonging rat hind limb allograft survival.

ObjectiveGraft rejection and the toxicity of current immunosuppressive regimens preclude the application of microsurgical advances to transplantation of limbs or other nonessential parts. If limb transplantation is to become a clinical reality, newer, safer, more effective immunosuppressive agents are needed. Summary Background DataRapamycin (RPM) and FK 506 are fungal macrolide antibiotics with effective immunosuppressive properties demonstrated in several animal models. RPM is more potent and effective than is FK 506 in rat cardiac allografts and has demonstrated synergy with cyclosporine (CsA) in limb allograft models. MethodsAn orthotopic rat hind limb allograft model (Brown-Norway [RT-1n] to Lewis [RT-11] rats was used. RPM (doses, 3.0, 4.5, and 6.0 mg/kg/day) was administered intraperitoneally on postoperative days 1 to 14. FK 506 (6 mg/kg/day) was administered orally on postoperative 1 to 14 and 1 to 90 and at rejection onset (10 mg/kg/day for salvage). CsA with RPM (postoperative days 1 to 14) was used to assess synergy, with CsA alone serving as the control. Other controls included untreated and placebo-treated allografted animals. The permutation test and Mann-Whitney test were applied to the data. ResultsThe mean survival times were assessed as follows: (1) control (placebo, untreated), 5 days; (2) RPM groups, 9.5, 10.6, and 8.7 days; (3) 14-day FK 506, 28 days; (4) 90-day FK 506, > 90 days; (5) CsA, 17.3 days; and (6) CsA with RPM, 19.3 days. FK 506 significantly prolonged graft survival compared with RPM (Permutation Test, p < 0.001 and Mann-Whitney Test, p < 0.05). FK 506 salvage reversed early rejection. High-dose RPM produced significant toxicity. Synergy between CsA and RPM was not demonstrated. ConclusionsFK 506 prolongs allograft survival, reverses early rejection, and prevents rejection without clinical toxicity when given continually. RPM does not prevent rejection in this model and produces significant toxicity at high doses. FK 506 may be a first step in making limb transplantation a clinical reality in reconstructive surgery.

The Treatment of Earlobe Keloids by Surgical Excision and Postoperative Triamcinolone Injection

Thirty-one earlobe keloids in 20 patients were treated by complete surgical excision and three postoperative injections of .1 to .2 ml of 40 mg per milliliter of triamcinolone solution at four-week intervals beginning three weeks postoperation. Only 1 recurrence developed in a follow-up of twelve to sixty-two months.

Reduction mammaplasty for gigantomastia using inferiorly based pedicle and free nipple transplantation.

Patients with gigantomastia have severely distorted anatomical breast structures. Reduction mammaplasty in such cases using the inferiorly based pedicle containing the nipple-areola complex can be technically difficult, yield poor results, and cause postoperative complications such as nipple necrosis and loss. Alternative traditional methods such as amputation mammaplasty with free nipple-areola transplantation usually results in a flattened, nonaesthetic breast with poor projection. This unacceptable result is due to the lack of central breast tissue required for normal anatomical projection. Herein, we describe a method of reduction mammaplasty for gigantomastia combining free nipple transplantation and an inferiorly based pyramidal parenchymal flap for augmentation of breast fullness and nipple projection.

Limb Allotransplantation in the Rat: Extended Survival and Return of Nerve Function with Continuous Cyclosporin/Prednisone Immunosuppression

We report the variability of the rejection process among the several tissues of a limb allograft. We used a rat hind limb allograft model transplanting across a well-defined minor histocompatibility barrier (Fischer RT-11v1), donor animals, and Lewis (RT-11) recipient animals. Continuous cyclosporin and prednisone immunosuppression was used. Four immunosuppressive regimens all produced extended limb survival. The rejection process was most severe and difficult to control in the skin. Nonskin tissues reverted to a nearly normal appearance after a period of cellular infiltration 2 to 3 weeks posttransplantation. Clinical and electromyographic evidence of nerve regeneration and end-organ reinnervation was demonstrated in long-term surviving animals.

Association of down-regulation of cytokine activity with rat hind limb allograft survival

Cytokines are short-acting protein modulators of many physiologic processes including graft rejection. An understanding of the production, action, and interaction of cytokines may lead to better appreciation of the complex mechanism of graft rejection. The potential would then exist for more selective and less-toxic means of modulating the immune response. A rat hind limb allograft model with major immunohistoincompatibility was used to study the local mRNA expression of IL-1 alpha, IL-2, IL-6, gamma interferon (gamma INF), platelet-derived growth factor-alpha (PDGF-alpha), basic fibroblast growth factor (FGF), and transforming growth factor-beta (TGF-beta) during acute allograft rejection. A 14-day postoperative course of immunosuppressive therapy with FK506 or rapamycin was administered. In situ hybridization was performed on serial full-thickness skin punch biopsies of the untreated rejecting limb allograft and compared with tissue from treated allografts, isografts, and to normal limb tissue. A sequential pattern of cytokine mRNA expression was demonstrated which progressed in a time-dependent manner and paralleled observed clinical rejection. Maximal cytokine mRNA expression correlated with peak graft rejection. Cellular expression of IL-1 alpha, IL-2, IL-6, gamma-INF, FGF, and TGF-beta mRNA was suppressed with FK506 to below isograft levels, and clinical rejection was not observed with the doses, routes, and schedules used. Rapamycin was ineffective in suppressing cytokine expression, and allograft rejection was not prevented. Isografts demonstrated no evidence of rejection. The in situ hybridization technique demonstrates a time-dependent, selective expression of cytokines within rejecting allograft tissue, and the modification of this response with immunosuppressive therapy. Down-regulation of cytokine expression is associated with clinical allograft survival.

Facial fractures in trauma victims: the influence of treatment delay on ultimate outcome.

To obtain objective data on the consequences of delayed treatment of facial fractures we reviewed the records of 220 patients who had suffered facial fractures concomitantly with extrafacial trauma severe enough in its own right to warrant hospital admission. Fractures studied were those of the mandible, maxilla, zygoma, and frontal sinus. Seventy-three patients fit inclusion criteria. Most injuries occurred in motor vehicle accidents. Associated extrafacial injuries were common and frequently multiple, the more serious of which generally took priority over the facial injuries in the triage system. The two most common reasons for delay were instability of the patients neurological status, or initial non-recognition or poor definition of the facial fracture. Delays in treatment ranged from 0 to 24 days. In patients with mandible fracture only, delay of up to 24 days in definitive treatment led to no noticeable increase in morbidity due to malocclusion, infection, or nonunion. In no other facial fracture did treatment delay lead to an increased incidence of complications. Retrospective analysis of the patients who did suffer complications almost always revealed predisposing conditions that placed these patients at higher risk for poor results.

Parenchymal cytokine expression precedes clinically observed ischemia in dorsal flaps in the rat.

&NA; Cytokines have been implicated as pivotal mediators of the wound‐healing process. An understanding of the production and interaction of cytokines may lead to a better appreciation of the complex mechanisms of flap ischemia. The potential would then exist for novel diagnostic and therapeutic approaches to prevent and reverse damage to the endangered flap. The goal of this study was to determine the expression of parenchymal cytokines at various time points during flap ischemia. Punch biopsies were obtained from McFarlane dorsal flaps in the Sprague‐Dawley murine model. We examined cytokine mRNA profiles for interleukin 1&agr; (IL1&agr;), IL‐2, IL‐6, basic fibroblast growth factor (b‐FGF), &ggr;‐interferon (&ggr;IFN), transforming growth factor &bgr;(TGF&bgr;), and platelet‐derived growth factor A chain (PDGF‐&agr;) using in situ hybridization. Samples were taken from 0 to 48 hours postoperatively, with n = 3 for each time point. Eight hours postoperatively there was an abrupt peak of parenchymal cytokine expression at the bases of the flaps. Clinically at this time the flaps appeared completely viable without evidence of ischemic change. Leukocyte cytokine production peaked at 16 hours, when distal flap ischemia was evident clinically. These findings demonstrate an early peak of cytokine expression prior to clinical evidence of ischemia. (Plast, Reconstr. Surg. 98: 856, 1996.)

Outpatient or short-stay skin grafting with early ambulation for lower-extremity burns.

Lower-extremity burns and skin grafts to these wounds have traditionally required extended hospitalization. We have used early tangential excision of the burn wounds and application of an Unna boot to fresh skin grafts in an attempt to shorten the hospitalization for such patients. Over a six-month period, 9 patients were treated with Unna boots to fresh skin grafts on the lower extremity. The average hospital stay was 0.9 days (range, 0 to 3 days). Graft take was 85% to 100%; no regrafting was required. Ambulation was begun 24 hours postoperatively. The technique described is a safe, effective, and inexpensive alternative to prolonged immobilization and hospitalization in patients with lower-extremity skin grafts.

Light Microscopic and Immunohistochemical Features in Serial Biopsies of Epidermal Versus Dermal Allografts

The local immune response to allograft dermis and epidermis was studied in a rat skin-graft model. Biopsies taken at varying times after transplantation were analyzed using routine light microscopy and a panel of monoclonal antibodies. The dermis appeared to be spared by the rejection process, whereas the epithelium and adnexal elements of the dermis were destroyed. The persistence of dermis transplanted across major histoincompatibilities may allow it to be useful in reconstructing large skin losses.

Composite in situ vein bypass for upper extremity revascularization

Chronic upper extremity arterial insufficiency is rare. Consequently, major reports specifically limited to the topic are scarce, and the clinical experience is small. In addition, symptomatology, diagnostic criteria, and guidelines for surgical management remain ill-defined. In the lower extremities, however, in situ vein bypass has been attempted for nearly three decades. This technique offers many advantages over traditional revascularization methods. Although the procedure has become popular for the lower extremity, no report of its use in the upper extremity is found in the literature. We report what may be the first case in which in situ bypass was used in the upper extremity for a threatened limb secondary to diabetic occlusive vascular disease complicated by a previous shunt used for hemodialysis. Revascularization of the upper extremity using the in situ vein bypass technique may offer a new alternative to traditional methods of revascularization.