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PubMed1989

Functions of vascular wall cells related to development of transplantation-associated coronary arteriosclerosis.

The accelerated form of arteriosclerosis that occurs in the coronary circulation of transplanted hearts currently presents a major limitation to the long-term success of this therapy. The pathogenesis of this lesion is unclear. Recent advances in vessel wall biology have disclosed interplay between mediators of the immune response and functions of vascular cells of potential significance in the formation of this accelerated form of arterial disease. We hypothesize that the development of accelerated arteriosclerosis in the arteries of transplanted hearts represents a form of chronic immunologic reaction resembling delayed-type hypersensitivity localized in the graft's arteries, a manifestation of cellular immunity mediated in large part by a regionally acting cytokine network. We emphasize the active responses of intrinsic vessel wall cells, including inappropriate expression of HLA and the likely participation of cytokines derived from vascular cells as well as from infiltrating leukocytes in amplification and propagation of this localized chronic immune reaction. This mechanism, which involves helper T cells interacting with class II HLA, may distinguish transplantation-associated arteriosclerosis from typical acute rejection, which may involve primarily cytolytic T cells interacting with class I HLA. Lesions of the common variety of atherosclerosis manifest certain features of immune activation. Therefore, we further hypothesize that the transplantation-associated form represents an extreme case of processes that also contribute to usual coronary atherosclerosis. For this reason, study of the accelerated disease may aid understanding of atherogenesis in general. Unraveling the basic pathobiology of these clinically important arterial diseases should lay the groundwork for rational design of selective therapeutic strategies to prevent or retard their development.

Animals↗
PubMed1988

Duchenne-Erb palsy. Experience with direct surgery.

Between 1973 and 1984, 31 direct explorations of traumatic Duchenne-Erb palsy (C5 and C6) were performed in two hospitals. Simple neurolysis was performed in 12 cases, in which C5 and C6 were found to be in continuity; the operation resulted in useful motor function in nine of the 12 cases. A cause-and-effect relationship of neurolysis to the recovery of function was difficult to prove. In five cases where only one root was completely damaged, four nerve graftings produced useful motor results but the function of one graft was not demonstrable when the other root was in continuity. In 14 cases of complete lesions of both C5 and C6 treated by nerve grafting, there were seven functional motor results that were attributable to the grafts. Both the overall results and the result of elbow flexion were statistically correlated with the number of grafts used to repair the corresponding nerve structure (p less than 0.01). Favorable results were not obtained when the graft had been delayed for more than nine months. All of the patients who had nerve grafts within five months had favorable results.

Adolescent↗
PubMed1987

Acquired immunity to Trichophyton mentagrophytes in thymus-grafted or peritoneal exudate cell-injected nude rats.

Congenitally athymic "nude" (RNU/RNU) rats were grafted with syngeneic neonatal thymus glands and 30 days later cutaneously inoculated with Trichophyton mentagrophytes. Nude rats and thymus-grafted nude rats were susceptible to infection with T. mentagrophytes but only thymus-grafted nude rats cleared the dermatophytosis. Clearance of the fungal infection took twice as long (approximately 60 days) in thymus-grafted nude rats when compared with heterozygous euthymic (+/RNU) controls (approximately 35 days). Following clearance of the primary dermatophytosis, peritoneal exudate cells (PEC) were adoptively transferred from either thymus-grafted or heterozygous rats to nude rats. Eight of 12 PEC-recipient nude rats acquired the capacity to resolve T. mentagrophytes-induced dermatophytosis (mean clearance time was approximately 40 days). All heterozygous (+/RNU) rats, thymus-grafted nude rats (4/4), and 8 of 12 PEC-recipient nude rats, which had cleared a primary dermatophytosis also expressed delayed-type hypersensitivity and elevated serum antibody titers to trichophytin antigen. These results demonstrate that immunity to T. mentagrophytes can be acquired in congenitally athymic nude rats following thymus grafting or injection of PEC from syngeneic +/RNU rats; however, injection of PEC from trichophytin-sensitized +/RNU donor rats to nude recipient rats did not result in transfer of specific adoptive immunity to T. mentagrophytes. Interestingly, PEC transfer from non-sensitized +/RNU rats was comparable to thymus grafting in effecting clearance of T. mentagrophytes dermatophytosis. These results suggest that acquired immunity to T. mentagrophytes in the rat is T cell-dependent, and that the absence of functional T lymphocytes and not an epithelial defect results in chronic dermatophytosis in the nude rat.

Animals↗
PubMed2007

Pasteurized intercalary autogenous bone graft combined with vascularized fibula.

The optimal reconstruction procedure after wide resection of bone tumors is debatable. We reviewed pasteurized intercalary autogenous bone graft combined with a vascularized fibula graft in 15 patients with malignant bone tumors, and assessed whether this procedure would improve bone union and function. The mean duration until bone union of the pasteurized autogenous bone was 13.5 months and duration until union of the vascularized fibula was 7.7 months. Complete bone union between the pasteurized autogenous bone and the vascularized fibula eventually was achieved in 13 patients (86.7%). In the remaining two patients, fibula union was achieved but union of the pasteurized autogenous bone was not attributable to infection. Postoperative complications included two fractures and two infections. Three patients with delayed union eventually achieved bone union using an autogenous cancellous bone graft. The mean Musculoskeletal Tumor Society score was 80.6% and it was comparable to scores from other procedures. Our results suggest a pasteurized autogenous bone graft combined with a vascularized fibula graft can be a useful reconstruction method in selected patients with large bone defects after wide resection of malignant bone tumors.

Adolescent↗
PubMed1998

Predominant role of the Fab fragment in delaying hyperacute rejection in guinea pig-to-rat xenotransplantation.

BACKGROUND: Human intravenous immunoglobulin G delayed xenogeneic hyperacute rejection (HAR) in the guinea pig-to-rat combination. We investigated the respective roles of the Fc and Fab fragments of the IgG molecule in this inhibitory effect. METHODS: By using a guinea pig-to-rat heart transplantation model, the efficiency of IgG, Fab, and Fc in prolonging the grafted heart's survival time (ST) was compared. RESULTS: A dose-dependent increase in the ST was observed with Fab (r=0.74, P < 0.0001), IgG (r=0.57, P < 0.001), and Fc (r=0.51, P < 0.01). The linear regression slopes with Fab and with IgG were, respectively, sevenfold and fourfold steeper than with Fc. The ST was significantly longer than controls (23+/-7 min) after infusion of 2 g/kg IgG (147+/-42 min) or 1 g/kg Fab (176+/-38 min), whereas the highest dose of Fc (1.5 g/kg) did not induce significant prolongation of ST. In terms of equivalent functional doses, 1 g/kg Fab was significantly more potent in prolonging the ST than 1.5 g/kg IgG (87+/-25 min) or 0.5 g/kg Fc (33+/-14 min). Analysis of the rejected hearts evidenced edema, necrosis, and rat C3 deposits characteristic of HAR. CONCLUSION: These results indicated that the delaying action of intravenous immunoglobulin G on HAR in the guinea pig-to-rat combination is mostly mediated through the Fab fragment.

Animals↗
PubMed2006

Suprascapular nerve reconstruction in 118 cases of adult posttraumatic brachial plexus.

BACKGROUND: Shoulder stabilization is of utmost importance in upper extremity reanimation following paralysis from devastating brachial plexus injuries. The purpose of this report is to present the authors' experience with suprascapular nerve reconstruction in 118 cases of adult brachial plexus lesions. Outcomes were analyzed in relation to various factors, including patient age, denervation time, donor nerve used, and functional restoration achieved in the supraspinatus versus the infraspinatus muscles. METHODS: The medical records of 118 adult patients operated on by a single surgeon between 1978 and 2002 who had suprascapular nerve reconstruction were reviewed; 102 patients had adequate follow-up. Direct neurotization of the suprascapular nerve was carried out in 78 patients, while in 40 patients, interposition nerve grafts were used. In 80 patients, the distal spinal accessory was used as the motor donor nerve for suprascapular nerve neurotization, while in 10 patients, other extraplexus motor donors were used. In 28 patients, intraplexus motor donors were used to reinnervate the suprascapular nerve. RESULTS: Results were good or excellent in 79 percent of the patients for the supraspinatus muscle and in 55 percent for the infraspinatus. There was a statistically significant difference between direct spinal accessory to suprascapular nerve neurotization and accessory to suprascapular via a nerve graft. Early surgery and less than 6 months of denervation time yielded significantly better results than late surgery and more than 6 months of delay in the treatment. CONCLUSIONS: Suprascapular nerve neurotization is a high priority in upper limb reanimation for restoration of glenohumeral joint stability, shoulder abduction, and external rotation. Concomitant neurotization of the axillary nerve yields improved outcomes in shoulder abduction function. The best results are seen when direct neurotization of the suprascapular nerve is performed within 6 months from the injury.

Accessory Nerve↗
PubMed1994

Experimental immunological screening tests on pidotimod.

Pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6), a new biological response modifier, was administered to immunodepressed (by prednisolone, cyclophosphamide or methotrexate) mice by oral and intraperitoneal route (respectively up to 400 and 200 mg/kg) during several days (up to 9 days). The stimulatory action of the drug on cell-mediated immunity is investigated by measuring the rosette formation by the murine splenic lymphocytes ex vivo, by T- and B-lymphocytes ex vivo proliferative response to mitogens, by dinitrochlorobenzene delayed hypersensitivity induced on the ear, by the graft-versus-host reaction with immunodepressed mice as donors. In all tests pidotimod reveals a potent action in restoring the depressed reactivity. The action of pidotimod on humoral immunity is showed in two tests where the antibody response is induced by a thymus dependent (sheep erythrocytes) or a thymus independent (lipopolysaccharide) antigen. Pidotimod was active in both tests. Macrophage functions, anion superoxide production and the non-stimulated ex vivo chemotaxis reveal that pidotimod significantly reduces the immunodepressant action of prednisolone; particularly in i.p. treated mice the chemotaxis is likely to be restored to the levels of the non-immunodepressed controls. The colloidal china ink blood clearance in vivo in immunodepressed mice, after pidotimod treatment, results similar to that found in the control mice.

Adjuvants, Immunologic↗
PubMed2004

Spanish experience with cyclosporine.

Our experience with cyclosporine (CsA) in de novo renal transplantation (RT) may be systematized in four consecutive periods. From February 1986 to December 1989, patient survival was higher among 128 consecutive CsA-prednisone-treated cadaver allograft recipients than in previous patients on azathioprine. One-year graft survival was significantly higher in CsA patients, a difference that was thereafter progressively reduced: at 10 years graft survivals were 50% versus 45%, and at 15 years 37% versus 35%, respectively. The most frequent cause of graft loss was death with a functioning graft. Acute rejection caused more graft losses among Aza-treated patients than CsA-treated ones. However, chronic allograft nephropathy produced more graft losses in CsA patients. After this initial experience with CsA-based immunosuppression we developed a second phase in which better results were obtained in 209 first cadaveric RT recipients. The use of lower initial CsA doses, more rapid steroid tapering, and a better approach to CsA nephrotoxicity or chronic nephropathy by substantial reductions in CsA exposure and delayed azathioprine addition, lead to these improvements. From March 1995 through 2000, we used the new microemulsion CsA formulation (Neoral) with steroids or azathioprine in 110 first de novo RT recipients. Mean donor and recipient ages were significantly higher in this phase than in previous ones; consequently, survival and function results were slightly worse. Blood CsA concentrations measured 2 hours after administration represent a more precise predictor of exposure than trough concentrations. The last step in optimizing Neoral use in RT on our service was application of reduced-dosage with C2 monitoring instead of classical C0 testing. Acute rejection and treatment failure rates were low and renal allograft function improved with respect to previous full-dose C0 experiences. CsA use has evolved in these two decades in four consecutive phases. Short-term results have improved or been maintained from phase to phase, even with expanded-criteria donors until excellent features during last years with C2 monitoring and combination with potent drugs such as MMF or everolimus. During the coming years, new drugs and protocols will allow even more optimized use.

Cyclosporins↗
PubMed2005

Balloon flexor sheathplasty: one-stage grafting at 19 years.

The technique of dilatation of a flexor sheath to allow one-stage grafting was recently described and named balloon flexor sheathplasty [J. Hand Surg. 27B (2001) 487-488]. The scope of this procedure is not yet known and the application after significant delay has not been described. We report a case where balloon flexor sheathplasty allowed return of useful function after an interval of 19 years.

Adult↗
PubMed1993

Epidermal culture and grafting. A brief review.

In summary, technological advances in culturing epidermis for the purpose of grafting allow this approach in the treatment of cutaneous wounds. Certainly, full- and split-thickness autografts offer immediate availability and permanent wound coverage, but they also involve a large, painful donor site. Cultured epidermal autografts can provide permanent wound coverage, but the delay required for cultivation of confluent sheets of keratinocytes makes them somewhat less desirable. Both allografts and cultured allografts, on the other hand, are available for immediate use, but the possibility of infectious disease transmission may be a concern. In any case, all types of skin grafts function as biological dressings that promote the proliferation of the host's epidermis and, thus, facilitate the ability of the patient's skin to repair itself.

Cells, Cultured↗
PubMed1981

[Immediate renal function after kidney transplantation (author's transl)].

The postoperative course management of kidney transplant patients appears to be easier when a large efficient diuresis resumes without delay. A decreased hemodialysis rate is observed and diagnosis of rejection is easier. Immediate diuresis resumed in 180 out of 186 (97%) recipients who received a large fluid load, given under mean pulmonary arterial pressure (PAP) monitoring. The purpose of fluid load is to provide the graft with an optimal blood flow immediately after vascular clamp release. The optimal filling pressure required varies according to initial PAP value. Fluid load aims to raise PAP to reach 25 mm Hg when the initial value is below this figure whereas it merely maintains the initial value when PAP is at 25 mm Hg or above. Mean peroperative fluid load reaches 3860 ml of water with 33 g of sodium chloride, 600 ml of 20% albumin and 3 units of packed red blood cells. During the immediate postoperative course a minimal 400 ml/h urine output is aimed at. Good hemodynamic tolerance is maintained through deliberate controlled ventilation during the first six postoperative hours. Application of this protocol was associated with general improvement of kidney transplantation outcome.

Adolescent↗
PubMed2006

A one-stage shoulder arthrodesis and Brooks Seddon pectoralis major to biceps tendon transfer for upper brachial plexus injuries.

Reconstructive procedures to optimise the function of patients with upper brachial plexus injuries are well described. From 1999 to 2005, nine patients underwent a single stage Brooks Seddon pectoralis major to biceps tendon transfer with a glenohumeral arthrodesis for restoration of elbow flexion and shoulder stability. All of these patients had sustained traumatic upper trunk brachial plexus injuries which had not responded to nerve repair, grafting or neurotisation or had a delayed presentation. Results were assessed using a goniometer and the Medical Research Council strength grading. At follow-up of 28.5 months, the average arc of elbow flexion was 103 degrees and eight had good elbow flexion power. There was one failure. We had two complications, both related to humerus fractures below the arthrodesis plate. Both united with conservative treatment. Our experience has given encouraging results with a high level of patient satisfaction. Our indications, operative technique and results are presented.

Adult↗
PubMed2000

Clinical applications of the posterior rectus sheath-peritoneal free flap.

Soft-tissue injuries involving the dorsum of the hand and foot continue to pose complex reconstructive challenges in terms of function and contour. Requirements for coverage include thin, vascularized tissue that supports skin grafts and at the same time provides a gliding surface for tendon excursion. This article reports the authors' clinical experience with the free posterior rectus sheath-peritoneal flap foil dorsal coverage in three patients. Two patients required dorsal hand coverage; one following acute trauma and another for delayed reconstruction 1 year after near hand replantation. A third patient required dorsal foot coverage for exposed tendons resulting from skin loss secondary to vasculitis. In all three patients, the flap was harvested through a paramedian incision at the lateral border of the anterior rectus sheath. After opening the anterior rectus sheath, the rectus muscle was elevated off of the posterior rectus sheath and peritoneum. When elevating the muscle, the attachments of the inferior epigastric vessels to the posterior rectus sheath and peritoneum were preserved while ligating any branches of these vessels to the muscle. Segmental intercostal innervation to the muscle was preserved. The deep inferior epigastric vessels were then dissected to their origin to maximize pedicle length and diameter. The maximum dimension of the flaps harvested for the selected cases was 16 X 8 cm. The anterior rectus sheath was closed primarily with non-absorbable suture. Mean follow-up was 1 year, and all flaps survived with excellent contour and good function in all three patients. Complications included a postoperative ileus in one patient, which resolved after 5 days with nasogastric tube decompression.

Adult↗
PubMed1990

Direct evidence of a functional separation of alloreactive T lymphocytes from bystander cells infiltrating rat allografts. Interleukin 2 receptor-positive cells reacting with the monoclonal antibody ART 18 mediating second-set rejection.

In this study we examined the functional capacity of unseparated, IL-2R positive and IL-2R negative leukocytes infiltrating BN rat hearts or kidneys grafted into allogeneic LEW rats. Upon adoptive transfer into syngeneic LEW recipients, splenocytes or day-3 graft infiltrate cells of either cardiac or renal transplants were ineffective to alter BN cardiac test graft survival (controls 7.8 +/- 0.8 day). However, adoptive transfer of day-5 heart infiltrate cells resulted in a delay of test graft rejection (9.4 +/- 0.7 day, P less than 0.001), while day-5 kidney-graft-infiltrating cells produced second set rejection (6.2 +/- 0.5, P less than 0.001). Specificity controls of day-5 cells infiltrating DA heart or kidney grafts rejected at 7.8 +/- 0.8 or 7.7 +/- 0.5 days. Following separation into IL-2R positive and negative subpopulations by use of the mAB ART 18, IL-2R positive but not IL-2R negative cells caused second set rejection in both the renal and the cardiac model (6.2 +/- 0.4, respectively, 6.3 +/- 0.5 days, P less than 0.001 or P less than 0.005). Furthermore, in the kidney model IL-2R positive nylon-wool nonadherent cells also caused second set rejection (6.2 +/- 0.4, P less than 0.005) suggesting that IL-2R positive T cells present in the graft at maximal infiltration are the mediators of rejection. Thus, it appears that these cells can be phenotypically and functionally separated from bystander cells.

Animals↗
PubMed1997

Delayed xenograft rejection of pig-to-baboon cardiac transplants after cobra venom factor therapy.

BACKGROUND: This study sought to (i) investigate the efficacy of cobra venom factor (CVF) in preventing hyperacute rejection (HAR) after pig-to-baboon heart transplantation, (ii) examine the effect of additional splenectomy (Spx) and pharmacologic immunosuppression (IS), and (iii) study delayed graft rejection when HAR is avoided by complement depletion. METHODS: Eleven recipient baboons received heterotopic pig heart transplants. Three received either no therapy or IS (cyclosporine + methylprednisolone +/- cyclophosphamide +/- methotrexate) at clinically well-tolerated doses, with graft survival for only 40, 32, and 15 min, respectively. Two received CVF+/-Spx, which extended survival to 5 and 6 days, respectively. Six underwent Spx + CVF therapy + IS; graft survival was 3 hr (technical complication), 6 days (death from sepsis), 10, 12, and 22 days (vascular rejection), and <25 days (euthanized for viral pneumonia with a functioning graft that showed histopathologic features of vascular rejection). RESULTS: Dense deposition of IgM and, to a lesser extent, IgG and IgA were seen on the endothelial cells within 1 hr of transplantation, but only trace levels of complement deposition were present in CVF-treated recipients. Within approximately 5-12 days, cardiac xenografts showed progressive infiltration by mononuclear cells, consisting primarily of activated macrophages producing tumor necrosis factor-alpha and small numbers of natural killer cells; T and B cells were absent. CONCLUSIONS: We conclude that (i) CVF prevents HAR, (ii) the addition of Spx + IS delays rejection, but (iii) the early deposition of antibody leads to progressive graft injury, resulting in (iv) delayed vascular rejection. Our findings indicate that the features of delayed xenograft rejection described in small animal models also occur in the pig-to-baboon model, and that rejection may occur in a complement-independent manner from the effects of antibody and/or host macrophages.

Acute Disease↗
PubMed1986

Immunomodulating agents of plant origin. I: Preliminary screening.

The immunobiological activity was investigated of certain medicinal plants widely used in the Ayurvedic and Unani systems of medicine for treatment of chronic infections and immunological disorders. The effect of an ethanolic extract of each drug was studied on delayed type hypersensitivity, humoral responses to sheep red blood cells, skin allograft rejection, and phagocytic activity of the reticuloendothelial system in mice. Picrorhiza kurroa was found to be a potent immunostimulant, stimulating both cell-mediated and humoral immunity. Tylophora indica, Aconitum heterophyllum and Holarrhena antidysenterica appeared to stimulate phagocytic function while inhibiting the humoral component of the immune system. Tinospora cordifolia and Ocimum gratissimum appeared to improve the phagocytic function without affecting the humoral or cell-mediated immune system. Hemidesmus indicus suppressed both the cell-mediated and humoral components of the immune system.

Adjuvants, Immunologic↗
PubMed1985

Phenotype, activation status, and suppressor activity of host lymphocytes during acute rejection and after cyclosporine-induced unresponsiveness of rat cardiac allografts.

Serial changes in phenotype, cell cycle, and functional behavior of lymphocyte subpopulations occurring both during acute rejection in unmodified hosts and in long-surviving heterotopic cardiac allografts in rats treated with cyclosporine (CsA) were studied. Using flow cytometry, RNA and DNA content of cells was examined during various phases of cell activation. In animals acutely rejecting their grafts, numbers of cells infiltrating the grafts and in host spleen in G1 phase (higher RNA content) increased, starting from day 3, and peaked by 5-6 days posttransplantation, and numbers of cells in S/G2/M phase (higher DNA content) remained stable. Similar, although slightly delayed changes were noted in CsA-treated recipients. The ratio of T helper (Th) to T suppressor/cytotoxic (Ts/c) phenotype cells infiltrating acutely rejecting grafts by day 3, was 1.6; it inverted abruptly to 0.7 by days 5-6, suggesting a preponderance of Ts/c during the later stages of allograft rejection. Ratio inversion occurred slightly later in host spleen and later in peripheral blood. Similarly, treatment with CsA produced a transient depression of Th, with recovery of the Th: Ts/c ratio during weeks 3-4 following transplantation. Adoptive transfer studies were then performed to investigate the functional significance of the T cell subsets. Survival of test grafts was prolonged significantly (ca. 14 days, P less than 0.001) when cells infiltrating grafts and spleen were transferred during inversion of Th:Ts/c; before that period, test graft survival was shortened in a second-set manner. These experiments suggest that suppressor cells may be responsible for resolution of acute rejection, as well as for host unresponsiveness seen after CsA treatment, and they represent an important homeostatic host mechanism following immunological stimulation.

Animals↗