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Role of the thymus in tolerance. I. Tolerance to bovine gamma globulin in thymectomized, irradiated rats grafted with thymus from tolerant donors.

Rats thymectomized and irradiated as adults were restored to immunologic reactivity by grafts of normal adult rat thymus and bone marrow. Reactivity of the delayed (cellular) type and formation of mercaptoethanol-sensitive (MES) and mercaptoethanol-resistant (MER) antibody returned within 3 weeks, while Arthus reactivity remained subnormal till 9 weeks after irradiation and grafting. When the thymus donor was tolerant to BGG, the recipient showed specific non-reactivity to this antigen 3 weeks and, to a much lesser extent, 6 weeks after grafting. This non-reactivity affected delayed responses and MER antibody. No effect was noted on Arthus reactivity and a slight effect on MES antibody. Controls showed that the non-reactivity was not due to transfer of free antigen at the time of grafting. It was concluded that different source organs are responsible for different immune functions and that specific immunologic tolerance may be induced within such an organ as the thymus.

Animals↗

Sustained recovery of hematopoiesis and immunity following transplantation of fetal liver cells in dogs.

We studied the ability of fetal liver cells to reconstitute hematopoiesis and immunity in lethally irradiated dogs. Engraftment and sustained lymphoid and hematopoietic recovery was achieved when the recipients received a preparative regime of high-dose total body irradiation (TBI) alone followed by transplantation of DLA-identical fetal liver. The combination of high-dose TBI and cyclosporine allowed engraftment in DLA-mismatched fetal liver transplants. Typical features of graft-versus-host disease (GvHD) did not occur although autoimmune-like syndromes (myasthenia gravis, immune thrombocytopenia) were observed in some recipients. Hematopoietic recovery was rapid and complete. Recovery of T- and B-lymphocyte function was comparatively delayed, but sufficient to prevent opportunistic infections after the initial 3 months post transplant. These data indicate that cells from a single fetal liver can reconstitute hematopoiesis and immunity in DLA-mismatched recipients and suggest that human fetal liver cell transplantation may be an effective source of stem cells for patients who lack an HLA-identical donor for bone marrow transplantation.

Animals↗

A new technique for delayed primary closure of fasciotomy wounds.

Fasciotomy for compartment syndrome in the lower limb is a surgical emergency to preserve future limb function. The advised standard procedure involves both medial and lateral dermotomy in addition to the fasciotomy. There is often concern before and after performing fasciotomy about the cosmetic appearance and prolonged hospital stay if split skin grafting is required to cover the resultant skin defect. This is the case in over 50% of lower limb fasciotomies. We have used a technique of subcuticular prolene suture, first described for the delayed primary closure of contaminated abdominal wounds, in six patients who had undergone lower limb fasciotomies. In all of these cases delayed primary closure was easily achieved without the need for skin grafting. Experiments using a synthetic skin model have shown a 60% reduction in suture tension when compared with interrupted vertical mattress suturing. The subcutaneous prolene suture has the advantage of being both the method of approximation and final closure whilst spreading tension evenly across the wound edges without causing skin edge necrosis. It appears to be simpler and more economical than any technique so far described for the successful delayed primary closure of fasciotomy wounds.

Compartment Syndromes↗

Patient recovery after infrainguinal bypass grafting for limb salvage.

PURPOSE: The outcome of infrainguinal bypass surgery for limb salvage has traditionally been assessed by graft patency rates, limb salvage rates, and patient survival rates. Recently, functional outcome of limb salvage surgery has been assessed by patient ambulatory status and independent living status. These assessments fail to consider the adverse long-term patient effects of delayed wound healing, episodes of recurrent ischemia, and need for repeat operations. An ideal result of infrainguinal bypass surgery for limb salvage includes an uncomplicated operation, elimination of ischemia, prompt wound healing, and rapid return to premorbid functional status without recurrence or repeat surgery. The present study was performed to determine how often this ideal result is actually achieved. METHODS: The records of 112 consecutive patients who underwent initial infrainguinal bypass surgery for limb salvage 5 to 7 years before the study were reviewed for operative complications, graft patency, limb salvage, survival, patient functional status, time to achieve wound healing, need for repeat operations, and recurrence of ischemia. RESULTS: The mean patient age was 66 years. The mean postoperative follow-up was 42 months (range, 0 to 100.1 months). After operation 99 patients (88%) lived independently at home and 103 (92%) were ambulatory. There were seven perioperative deaths (6.3%), and wound complications occurred in 27 patients (24%). By life table, the assisted primary graft patency and limb salvage rates of the index extremity 5 years after operation were 77% and 87%, respectively, and the patient survival rate was 49%. At last follow-up or death, 73% of the patients (72 of 99) who lived independently at home before the operation were still living independently at home, and 70% (72 of 103) of those who were ambulatory before the operation remained ambulatory. Wound (operative and ischemic) healing required a mean of 4.2 months (range, 0.4 to 48 months), and 25 patients (22%) had not achieved complete wound healing at the time of last follow-up or death. Repeat operations to maintain graft patency, treat wound complications, or treat recurrent or contralateral ischemia were required in 61 patients (54%; mean, 1.6 reoperations/patient), and 26 patients (23.2%) ultimately required major limb amputation of the index or contralateral extremity. Only 16 of 112 patients (14.3%) achieved the ideal surgical result of an uncomplicated operation with long-term symptom relief, maintenance of functional status, and no recurrence or repeat operations. CONCLUSIONS: Most patients who undergo infrainguinal bypass surgery for limb salvage require ongoing treatment and have persistent or recurrent symptoms until their death. A significant minority have major tissue loss despite successful initial surgery. Clinically important palliation is frequently achieved by bypass surgery, but ideal results are distinctly infrequent.

Activities of Daily Living↗

Graft size assessment and analysis of donors for living donor liver transplantation using right lobe.

BACKGROUND: Modality of living donor liver transplantation (LDLT) has been expanded to adult cases. However, the safety of right lobectomy from living donors has not yet been proven. METHODS: A total of 62 cases of LDLT, using the right lobe, were reviewed. Study 1: Discrepancy between estimated graft volume and actual graft weight was evaluated. Study 2: Postoperative liver functions were analyzed in relation to residual liver volume (RLV) or age. Residual liver volume of donors was defined using two indices, (RLV = estimated whole liver volume - estimated graft volume and %RLV = RLV/estimated whole liver volumex100). Donors were divided into two groups on the basis of either %RLV (<40%; 40%< or =) or age (<50 years old; 50 years old < or =). Study 3: Right lobe donors were compared with left lobe donors (35 cases) in terms of their postoperative liver functions. RESULTS: Study 1: The relationship between estimated graft volume and actual graft weight was linear (y=159.136+0.735x, R2=0.571, P<0.001). Study 2: %RLV ranged from 23.5% to 55.8% (mean +/- SD: 43.2+/-6.0). Fifteen cases showed %RLV less than 40%. Postoperative bilirubin clearance was delayed in that group (%RLV<40%). Serum total bilirubin values on postoperative day 7 in the older group (age > or =50) were significantly higher than those in the younger group (age<50). Study 3: Postoperative liver functions of right lobe donors were significantly higher than those of left-lobe donors. Eleven donors (17.7%) had surgical complications, all of which were cured with proper treatment. CONCLUSIONS: Right lobectomy from living donors is a safe procedure with acceptable morbidity, but some care should be taken early after the operation for donors with small residual liver and aged donors.

Adult↗

PelviSoft BioMesh augmentation of rectocele repair: the initial clinical experience in 35 patients.

Graft materials have been utilized in the repair of posterior vaginal wall defects to enhance anatomical and functional results, and to improve long-term outcomes. We report on our initial series of 35 patients treated with porcine dermal acellular collagen matrix BioMesh (PelviSoft BioMesh, CR Bard, Cranston, R.I., USA), which has alleviated problems with early postoperative vaginal mucosal dehiscence and delayed healing experienced with the use of other graft materials in the posterior vaginal wall.

Adult↗

Mohs' surgery of periocular basal cell carcinoma using formalin-fixed sections and delayed closure.

Mohs' surgery of periocular basal cell carcinoma (BCC) ensures a high cure rate with maximal preservation of normal tissue. The formalin-fixed paraffin-embedded tissue technique allows Mohs' surgery to be performed using routine pathology facilities and permits the efficient use of operating room personnel and theatre time. The inevitable delay between excision and closure may potentially result in a poor functional and cosmetic outcome, particularly around the eye. We prospectively studied all patients with periocular BCC treated with this technique at our unit between 1985 and 1996. One hundred and twenty-three periocular BCCs in 120 patients were treated. Microscopic clearance was achieved in all cases. Closure was performed on average 5 days after the initial excisional stage. Closing procedures included direct closure, flaps and grafts. Significant complications affecting outcome were noted in only two patients. Eighty-eight per cent of patients assessed had a functional and cosmetic result regarded as excellent, good or adequate. Mohs' surgery of periocular BCC using formalin-fixed paraffin-embedded tissue and delayed closure results in a satisfactory functional and cosmetic outcome and offers a viable alternative to the frozen section fresh tissue technique.

Adult↗

Functional alveolar ridge reconstruction with prefabricated iliac crest free flap and osseointegrated implants after hemimaxillectomy.

We achieved functional alveolar ridge reconstruction after hemimaxillectomy using a prefabricated iliac crest flap. The iliac crest was vascularized secondarily by a long rectus abdominis muscle flap with its inferior epigastric vessels intact to obtain an ideal anatomic location between the maxillary defect and microvascular anastomosis site. The iliac crest was tightly resurfaced with a split-thickness skin graft as well. After a bony surgical delay, the prefabricated iliac crest flap was microsurgically transferred to the face. Three osseointegrated implants were placed in the prefabricated iliac crest, and a dental prosthesis was worn with immobilization and stability. Our procedure enabled recovery of a satisfactory facial appearance and excellent masticatory function.

Adult↗

The use of locked nails in the treatment of humeral shaft: delayed union and nonunion.

OBJECTIVES: To assess the results and clinical outcome of delayed union and nonunion humeral shaft treatment using locked medullary nails. SUBJECTS AND METHODS: The Russel and Taylor humeral locking nail was used to treat 21 patients with humeral shaft fractures at Al Razi hospital, Kuwait, from 1997 to 2001. Of these, 8 had delayed union and 13 nonunion. Also, 13 had previous operative treatment, while 8 had nonoperative treatment. Antegrade nailing was done in all cases, and all nails were fixed statically. Autogenous iliac bone grafts were used in 17 cases. RESULTS: Of the 21 cases of fractures, 19 were united. Only 2 cases had persistent nonunion. Eighteen cases had satisfactory shoulder function, and 3 lost shoulder abduction between 40 and 65 degrees. CONCLUSION: Our data showed that humeral locked nails can achieve satisfactory clinical results in treating humeral shaft delayed unions and nonunions.

Adult↗

Protection against ischemia/reperfusion injury by the cavitary two-layer method in canine small intestinal transplantation with reduction of reactive oxygen species.

BACKGROUND: Ischemia and reperfusion (I/R) injury is a major determinant of early graft dysfunction and long-term graft survival in small intestinal transplantation. The cavitary two-layer method (TLM) has been reported to be superior to the University of Wisconsin cold storage method (UWM) in long-term preservation of canine small intestine. This study was designed to evaluate the protective effect of the cavitary TLM against I/R injury in canine small intestinal transplantation. METHODS: Intestinal grafts harvested from beagles were allotransplanted after 24-hour preservation by UWM (group 1) or the cavitary TLM (group 2). The graft in the controls (group 3) was immediately allotransplanted without preservation. I/R injury was assessed by functional success rates, biochemical assay, graft adenosine triphosphate (ATP) and lipid peroxidation (LPO) concentrations, and histopathologic examination including TUNEL staining for apoptosis. RESULTS: In group 1, ATP recovery was delayed after reperfusion, and most recipients died with hemorrhage of the grafts and lungs. In group 2, graft ATP concentrations recovered rapidly, and I/R injury was prevented with reduced LPO production, resulting in good outcome. CONCLUSIONS: The cavitary TLM protected intestinal grafts against I/R injury evidenced by maintenance of graft ATP levels and reduction of LPO production compared with UWM in canine small intestinal transplantation.

Adenosine Triphosphate↗

Effect of the stenosis location and severity on left ventricular function after single-vessel anterior wall myocardial infarction.

BACKGROUND: The purpose of the current study was to determine how the location of the infarct-related lesion (IRL) and the degree of stenosis during the acute and chronic phases of infarction might affect left ventricular (LV) function in patients with acute anterior wall myocardial infarction. METHODS: Ninety consecutive patients with a first single-vessel anterior wall myocardial infarction (male/female ratio 75:15, mean age 60+/-9 years) underwent coronary angiography (CAG) immediately and 1 month after infarction. Patients were grouped according to IRL location (proximal [Coronary Artery Surgery Study (CASS) No. 12] or distal [CASS No. 13] to the first diagonal branch of the left anterior descending artery) and according to the severity of stenosis at 1 month (severe stenosis [IRL >75%] and mild stenosis [IRL < or =75%]). At the time of infarction and 1 month and 1 year after infarction, total wall motion index (TWMI), left ventricular end-diastolic dimension (LVDd), left ventricular end-systolic dimension (LVDs), and fractional shortening (FS) were determined. RESULTS: TWMI was greater and FS was lower for CASS No. 12 lesions than for CASS No. 13 lesions. CASS No. 12 lesions were associated with a greater LVDd at 1 year and a greater LVDs throughout 1 year of observation. The patients with mild stenoses had significant improvements in TWMI and FS over time, whereas those with severe stenoses showed no improvement. Multivariate analysis showed that the independent factors predicting left ventricular function were IRL location at CASS No. 12, initial TIMI 0-1 flow in the IRL at emergency coronary artery graft, and the presence of a severe stenosis at 1 month. CONCLUSIONS: In patients with severe stenoses at 1 month at CASS No. 12, left ventricular functional recovery is delayed and the left ventricular chamber is enlarged. In patients with CASS No. 13 lesions, left ventricular function is preserved well, regardless of the severity of residual stenosis.

Coronary Disease↗

Prolonging organ allograft survival: potential role of nitric oxide scavengers.

A growing number of studies suggest a key role of nitric oxide (NO) derived from the inducible NO synthase (iNOS) isoform as a signalling molecule leading to acute organ transplant rejection. Current theory suggests that NO targets certain tissue proteins for nitrosylation or nitration leading to inhibition of enzyme/protein function and to cell death via apoptosis. Gene expression of iNOS and formation of nitrotyrosine residues have been confirmed in biopsies of rejecting grafts in humans. Experimental attempts to delay graft rejection by treatment with iNOS enzyme inhibitors have yielded conflicting results. An alternative strategy to alter rejection mediated by NO is to scavenge and/or neutralise the actions of excess NO, thereby by-passing the inhibition of iNOS enzyme activity. This review summarises recent laboratory evidence that new experimental NO scavengers/neutralisers have potential value to prolong graft survival. To date, various metal-based NO scavenging/neutralising compounds have been shown to enhance cardiac allograft survival in the absence of immunosuppression. When used in combination with low-dose cyclosporin, these agents produce a synergistic action to enhance graft survival or even to produce "permanent graft survival" under certain prolonged drug regimens. A portion of this benefit may be accounted for by the property of some of these compounds to display immunosuppressant and anti-inflammatory activity in vivo. These properties are based on findings including the following: (i) attenuating cell infiltration into the graft; (ii) attenuating activation of NFkappaB (a transcription factor important for upregulation of various inflammatory genes); (iii) attenuating cyclin D3 gene expression (a marker of cell proliferation; (iv) antagonising autoimmune activation (as determined by attenuated cytokine gene expression in splenocytes isolated from treated animals but stimulated for several days ex vivo in mixed lymphocyte cultures).

Animals↗

Malacoplakia in a renal transplant. Report of a case studied by light and electron microscopy.

A case of malacoplakia in a transplanted patient is reported. Several months after the operation typical lesions with numerous Michaelis-Gutmann bodies were found by biopsies from the urinary bladder and the renal transplant, the latter being ultimately destroyed by the process. Recurrent urinary infections with Escherichia coli might have contributed to the development of the process in combination with an altered macrophage function owing to the immunosuppressive regimen, which was considered mainly responsible for the progressive course of an otherwise benign inflammatory reaction. If malacoplakia occurs in a renal transplant and the renal function deteriorates despite adequate antibiotic therapy, transplantectomy should not be delayed.

Adult↗

FK 506 therapy for refractory renal allograft rejection: lessons from liver transplantation.

FK 506 has proven to be an effective immunosuppressive agent in liver transplantation, but its role in renal transplantation remains to be defined. Since the initial availability of FK 506 for treatment of refractory renal allograft rejection, we have applied an aggressive approach consisting of institution of rescue therapy at an early point in the rejection process combined with assiduous monitoring of FK 506 blood levels and the histologic response to therapy. A total of 17 adult patients were treated for refractory renal allograft rejection with this approach. Median follow-up was 9 months post-initiation of FK 506 therapy. Median time to first rejection was 26 d post-transplant, and median time to FK 506 rescue therapy was 113 d post-transplant. Sixteen of 17 patients received either ATGAM or OKT3 induction therapy. Prior to FK 506 rescue therapy, patients received the following antirejection therapy: corticosteroids 40 + 21 mg/kg (prednisone or Solumedrol), OKT3 (median 14 d), ATGAM (3 patients, 14 d each). FK 506 rescue therapy was successful in reversing the rejection process in all 17 patients. Fifteen patients (88%) demonstrated rapid reversal of rejection (i.e. reversal within 14 d), whereas three patients demonstrated delayed reversal. Nine month actuarial patient and graft survivals were 92% and 84%. When censored for documented noncompliance, nine month actuarial graft survival was 92%. Good long-term renal function was observed (pre-FK 506 baseline creatinine 2.1 +/- 0.5 mg/dl, current serum creatinine 2.1 +/- 0.6 mg/dl. Six recurrent rejection episodes occurred in 5 patients (29%) with a median time to recurrent rejection of 59 d post-initiation of FK 506 rescue therapy. Each recurrent rejection episode was successfully treated by corticosteroids and/or increased FK 506 dose. CMV disease and lymphoma were not observed. Histologic evidence of FK 506 nephrotoxicity (hyaline necrosis in preglomerular arterioles) was observed in 6 patients 30% (median time to diagnosis 49 d). FK 506 blood levels (whole blood TDX) between 10 and 20 ng/ml provided effective reversal in most patients. Current FK 506 dose and blood levels are 0.18 +/- 0.09 mg/kg/d and 7 +/- 2 ng/dl). FK 506 rescue therapy also allowed aggressive reductions in prednisone dose: (mean current prednisone dose 0.08 +/- 0.05 mg/kg/d). In conclusion, an aggressive approach toward FK 506 rescue: 1) provides prompt, effective reversal of refractory renal allograft rejection, 2) good long-term renal allograft function, 3) balanced immunosuppression with respect to recurrent rejection, opportunistic infection and PTLD, 4) acceptable toxicity, and 5) aggressive reduction in corticosteroid dosing. Based on these findings, FK 506 rescue therapy is now the treatment of choice in our program for renal allograft rejection episodes that occur following antilymphocyte antibody therapy.

Adult↗

The protective effect of methyl prednisolone on the machine-preserved kidney.

Fifty cadaveric transplants were reviewed to determine whether graft failure was related to the method of preservation. Twenty-eight transplants were preserved by a combination of cold storage and perfusion with cryoprecipitated plasma. Twenty-two transplants were preserved by continuous perfusion with Plasmanate. The perfusate of 14 plasma-perfused kidneys contained 1.0 g of methyl prednisolone, whereas the Plasmanate contained only 100 mg hydrocortisone. Fourteen plasma-perfused kidneys functioned immediately (Group I), and 14 showed delayed function. Seventeen of 22 Plasmanate kidneys (Group III) functioned immediately. Of the Group I kidneys, 13 of 14 functioned for three to eight months, and eight (57%) are still functioning after two years vs. only three of 14 (21%) in Group II. Eleven of the 14 long-term surviving grafts were pretreated with methyl prednisolone. Only nine of the Plasmanate kidneys (39%) lasted more than three months; five (22%) survived more than 12 months. None of the Plasmanate-perfused kidneys that failed to function immediately lasted three months. It is concluded that immediate restoration of renal function after transplantation is a favorable sign for long-term graft survival. The addition of methyl prednisolone to the perfusate may enhance the survival of kidney allografts.

Graft Survival↗

Segmental duct-obstructed pancreas grafts versus pancreaticoduodenal grafts with enteric diversion.

Between January 1985 and September 1987, we performed a prospective comparative study between segmental-pancreas transplantation with duct obstruction by neoprene (n = 17) and pancreaticoduodenal transplantation with enteric diversion to a Roux-en-Y intestinal loop (n = 14). All recipients had insulin-dependent diabetes. The immunosuppressive protocol consisted of low doses of the steroids cyclosporin A and azathioprine. Mean follow-up was 16.5 mo for the enteric-diversion group and 13.5 mo for duct-obstructed groups. Two-year patient and pancreas- and kidney-graft actuarial survival rates were 92.9, 75.5, and 74.2%, respectively, in the former group and 92.3, 58.4, and 63.7%, respectively, in the latter group (NS). Five whole-organ grafts were lost (3 vascular thromboses, 1 pancreatitis, 1 rejection), and four segmental grafts were lost (2 vascular thromboses, 1 bleeding, 1 patient's death with functional graft). More surgical complications occurred in the recipients of whole-organ grafts and were often related to the intestinal anastomosis. A satisfactory blood glucose control was observed at 3 mo and 1 yr in both groups. Provocative tests showed higher and prompter insulin secretion in patients with whole-organ grafts. In patients with segmental grafts, the response was lower and delayed with a general tendency to impaired glucose tolerance. A marked hyperinsulinemia after meals was observed in whole-organ graft recipients. Slight nocturnal hyperinsulinemia was observed in both groups. At 1 yr, glycosylated hemoglobin was normal in both groups. The absence of a significant difference between the two groups, in terms of survival and graft function, and the lower surgical complication rate seen with segmental grafts have made us return to neoprene-injected segmental grafts.

Circadian Rhythm↗

Secondary microvascular tongue reconstruction: functional results.

Between 1978 and 1991, 56 microvascular composite flaps were used for oromandibular reconstructions: 15 for primary total and subtotal tongue reconstruction and five for secondary major tongue reconstruction. The delayed reconstructions were performed to improve the oral and pharyngeal phases of swallowing. Using a floor of the mouth composite bone grafting technique to reposition the tongue and obliterate the oral dead space intraoral food transport was improved (three of five patients), but aspiration persisted (three of four patients). When compared with 10 patients evaluated for primary total and subtotal tongue reconstruction the primary reconstruction group showed superior swallowing (eight dynamic oral transport, no aspiration) and speech results. The poor results of secondary reconstruction are attributed to scarring and irreversible damage to remaining functional muscles involved in protecting the laryngeal aditus.

Aged↗