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Assessment of the method and timing of repair of a brachial plexus traction injury in an animal model for obstetric brachial plexus palsy.

A Sunderland type IV traction injury to the C6 root of adult sheep or newborn lamb brachial plexus was used as a model for obstetric traction injury to the C5 root in humans. In one experimental cohort the injury was created and repaired using interfascicular nerve autografts or coaxially aligned freeze-thawed skeletal muscle autografts in a group of adult sheep and in a group of newborn lambs. In a second cohort a similar injury was created and repaired either immediately or after a delay of 30 days, using either interfascicular nerve autografts or coaxially aligned freeze-thawed skeletal muscle autografts in four groups of six newborn lambs. In all cases both functional and morphometric indices of nerve regeneration were poorer in the injured and repaired nerves than in normal nerves. In lambs the method of repair made no difference and no significant differences were found for any of the indices of nerve function or morphology. In sheep the use of muscle grafts was associated with a poorer outcome than the use of nerve autografts. Where a delay of 30 days had elapsed between injury and repair, the results using nerve autografts were not significantly different. Where freeze-thawed muscle autografts had been used, the maturation of the regenerated nerve fibres after delay was significantly poorer than after immediate repair. The electrophysiological variables CV(max) and jitter, which may be applied clinically, were found to be good discriminators of recovery in all of the animals and in respect of all procedures.

Analysis of Variance↗

Arterial trauma in children: diagnosis and management.

Ninety-two children with arterial injuries were studied over a 14 year period, 66 boys and 26 girls, whose ages ranged from 14 months to 18 years. Thirty-eight children had associated nerve injuries and 21 had orthopedic injuries as well. Interval between initial evaluation and diagnosis of arterial injury ranged from immediate to six months--76% were treated within six hours of injury and 24% had a delay of greater than six hours before diagnosis. Arteriograms were performed on 20 (21%) of the children, and 13 of these were done late. Surgical treatment consisted of local debridement and end-to-end anastomosis, ligation, exploration with thrombectomy of distal branches, or bypass grafting with vein. Three children died in the immediate postoperative period, 83 had good functional results, and six had poor functional results. Four of these six had a delayed diagnosis of arterial injury, and had injuries in arteries adjacent to the elbow or knee. We conclude that early diagnosis of arterial injury and a more liberal use of arteriography is warranted in young trauma victims, especially in cases of fractures about the knee or elbow.

Adolescent↗

Immunosuppressive effects of 2-acetyl-4-tetrahydroxybutyl imidazole (THI) in the rat.

THI is a component of ammonia caramel, a widely used food colouring. The effect of THI on the immune system has been determined in the male F344 rat. THI was given in the drinking water at doses of 1, 10 and 50 mg/l (equivalent to 0.1, 1 and 5 mg/kg per day) to animals on a vitamin B6-deficient diet. After 1 week, the immune competence of the animals was assessed under continued THI treatment. No marked changes in thymus or spleen weight were observed after THI treatment, although there was an increased number of pyknotic cells in the thymic cortex, mainly engulfed by macrophages and there appeared to be a slight thinning of the cortex area. THI produced a significant loss in T and B lymphocytes in peripheral blood but not in the spleen. No change in natural killer (NK) cell activity against YAC-1 target cells was observed in the spleen. The observed increase in NK cell activity in peripheral blood was due to an increase in circulating large granular lymphocytes (LGL). Although the serum antibody titre against keyhole limpet haemocyanin (KLH) was not affected by THI treatment, B cells showed less proliferation when cultured with lipopolysaccharide. T cell function was impeded as measured in mitogen-induced proliferation assay, delayed-type hypersensitivity assay and host versus graft (popliteal lymph node) assay. The results indicate that THI is an immunosuppressor in the rat, in whom it can produce profound lymphopenia and suppression of cell-mediated immunity.

Animals↗

Monoclonal antibody specific for TIRC7 induces donor-specific anergy and prevents rejection of cardiac allografts in mice.

T cell immune response c-DNA (TIRC7) is up-regulated during the early stages of T-cell activation in response to alloantigens. In this study, we analyzed the effects of newly developed monoclonal antibodies (mAb) against TIRC7 in acute cardiac allograft rejection. Fully vascularized heterotopic allogeneic heart transplantation was performed in mice across a full-mismatch barrier (C57Bl/10 into CBA). Recipients received seven injections (day 0-7) of a novel anti-TIRC7 mAb or remained untreated. Graft survival, histology and ex vivo lymphocyte functions were tested. Targeting of TIRC7 with an anti-TIRC7 mAb diminishes lymphocyte infiltration into grafts resulting in delay of morphological graft damage and prolongation of allograft survival. The lymphocytes from anti-TIRC7 mAb-treated animals exhibit hypo-responsiveness without evidence of lymphocyte depletion against the donor allo-antigens. Proliferation and expression of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) were down-regulated while interleukin-4 (IL-4) and IL-10 expression were spared. Moreover, anti-TIRC7 mAb enhanced up-regulation of CTLA-4 expression but suppressed up-regulation of CD25 on stimulated lymphocytes in vitro and in vivo. Ligation of TIRC7 has important effects on the regulation of co-stimulatory signaling pathways associated with suppressing of T-cell activation. Targeting of TIRC7 may therefore provide a novel therapeutic approach for modulating T cell immune responses during organ transplantation.

Animals↗

Outcome of cadaver kidney transplantation in small children.

Small children have often been reported to have poor outcome after kidney transplantation (KT). Recent reports from North America have shown that the use of living-related donors improves patient and graft survival. We report the experience in one centre of primary cadaveric KT using sequential immunosuppression in nine children aged 8-30 months and weighing 5.4-9.8 kg; donors were 0.7-12.3 years old. Four patients had pre-emptive KT and the other five were on peritoneal dialysis; the mean +/- SD waiting time was 2.0 +/- 2.4 months. Perioperative care has been published previously. The surgical approach was intraperitoneal if the aorta and vena cava were used (n = 7) and extraperitoneal for common iliac vessels anastomosis (n = 2); the duration of surgery was 3.5 +/- 0.9 h and the time for vascular anastomosis was 32 +/- 6 min. The recipients received ATG, azathioprine, prednisone and delayed administration of cyclosporin A. The patients were followed for 12-98 (median 41) months and showed good graft function (inulin clearance 63-100 ml/min/1.73 m2); only one child with recurrent haemolytic uraemic syndrome lost his graft three months post-transplantation and died after he had received a second graft. None of the recipients required post-transplant dialysis; arterial hypertension involved four children and was related to graft artery stenosis in two. Growth improved by 0.24 +/- 0.48 SD score of height per year.(ABSTRACT TRUNCATED AT 250 WORDS)

Cadaver↗

Vascularised bone grafting for fibrous dysplasia of the upper limb.

We describe our experience with vascularised bone grafting for the treatment of fibrous dysplasia of the upper limb in eight patients, five men and three women, aged between 17 and 36 years. The site was in the humerus in six and the radius in two. Persistent pain, progression of the lesion and pathological fracture with delayed union were the indications for surgical intervention. We used a vascularised fibular graft after curettage of the lesion. Function and radiological progress were serially monitored. Early radiological union of the graft occurred at periods ranging from 8 to 14 weeks. The mean period for reconstitution of the diameter of the bone was 14 months (12 to 18) predominantly through inductive formation of bone around the vascularised graft, which was a prominent feature in all patients. There were no recurrences and none of the grafts sustained a fracture or failed to unite. After operation function was excellent in three patients and good in five. Vascularised bone grafts provide a safe and reliable means of ensuring good continuity of bone with little risk of recurrence and failure.

Adolescent↗

Donor and preservation factors.

1. In nonsensitized, white recipients of first cadaver donor transplants, 1-year graft survival was: 13% lower when the donor was black than when the donor was white; 7-9% lower when the kidney was from a pediatric (under 15) or older (over 50) donor than from a donor aged 21-50; 8% lower when the donor was a female over 30 than when the donor was a male under 30; 4% lower when the cause of donor death was a cerebrovascular accident than when the death was a closed head injury; 6% lower when the kidney was transplanted with more than 36 hours of cold ischemia time than when ischemia was less than 24 hours; 3% lower if the kidney had been transported more than 50 miles to the transplant center. 2. The lower graft survival rates associated with the race, sex, age and cause of death of the donor were generally reflected in a higher incidence of early nonfunction and poorer quality of function. 3. Preservation related factors, long cold ischemia and sharing were associated with an increase in delayed onset of function, but there was no difference in the proportion of kidneys that never functioned during the follow-up period. 4. There was a 9% difference in 1-year graft survival between kidneys obtained from centers more than 50 miles from the transplant center and with more than 36 hours of cold ischemia and those transplanted locally with less than 24 hours of cold ischemia. 5. Long cold ischemia, even in excess of 48 hrs, had no effect on graft survival when the kidney was procured locally. Long cold ischemia in the absence of sharing was not an apparent risk factor. 6. Rather than concluding that distant sharing results in kidneys of poor quality, we may have to consider that kidneys of poor quality are sometimes shared. 7. Cadaver kidneys from female donors over 30 had 80% 1-year survival when transplanted to recipients who weighed between 41 and 75 kg, a result comparable to that obtained with young male donor organs. In recipients over 75 kg, survival of the older female kidneys was 70% vs 80% for young male donor kidneys. Recipient "size" may be a nonimmunological risk factor.

Adult↗

Hypoglossal-facial nerve side-to-end anastomosis for preservation of hypoglossal function: results of delayed treatment with a new technique.

This report describes a new surgical technique to improve the results of conventional hypoglossal-facial nerve anastomosis that does not necessitate the use of nerve grafts or hemihypoglossal nerve splitting. Using this technique, the mastoid process is partially resected to open the stylomastoid foramen and the descending portion of the facial nerve in the mastoid cavity is exposed by drilling to the level of the external genu and then sectioning its most proximal portion. The hypoglossal nerve beneath the internal jugular vein is exposed at the level of the axis and dissected as proximally as possible. One-half of the hypoglossal nerve is transected: use of less than one-half of the hypoglossal nerve is adequate for approximation to the distal stump of the atrophic facial nerve. The nerve endings, the proximally cut end of the hypoglossal nerve, and the distal stump of the facial nerve are approximated and anastomosed without tension. This technique was used in four patients with long-standing facial paralysis (greater than 24 months), and it provided satisfactory facial reanimation, with no evidence of hemitongue atrophy or dysfunction. Because it completely preserves glossal function, the hemihypoglossal-facial nerve anastomosis described here constitutes a successful approach in patients with long-standing facial paralysis who do not wish to have tongue function compromised.

Adult↗

Pig xenogeneic antigen modification with green coffee bean alpha-galactosidase.

Green coffee bean alpha-galactosidase can cleave the terminal alpha-galactose (alphaGal) on oligosaccharides that form the major antigen on pig endothelial cells recognized by primate-specific antibodies. Studies have been made of the conditions under which it is functional (e.g. temperature, pH) and of its biochemical and immunologic effects. Pig-to-rhesus monkey vein transplants were studied to identify the efficiency of the enzyme in delaying hyperacute rejection. When a graft became occluded, biopsies were taken for light microscopy (hematoxylin and eosin), scanning electron microscopy (SEM) and immunostaining with Griffonia simplicifolia IB4 lectin (GSIB4), and for IgM, IgG and C3. alpha-Galactosidase was stable for 72-96 h and was effective at 4 degrees C and pH 6.9 (conditions of human liver graft storage), although better function was obtained at 20 degrees C and pH 6.5. Using the porcine PK15 cell assay, the cytotoxicity of human serum was reduced after treatment of the pig cells with the enzyme. In vitro studies demonstrated that porcine veins treated with alpha-galactosidase lost endothelial expression of the Gal epitope within 30 min. SEM, however, demonstrated endothelial damage beginning within 2 h, probably caused by the alpha-galactosidase, as no damage was found in phosphate-buffered saline-treated veins, where the Gal epitope was preserved for >3 h. No change was found in either group on light microscopy. In vivo studies demonstrated that patency of the alpha-galactosidase-treated veins (mean 2.5 h) was longer than that of untreated veins (0.23 h) (P < 0.01). Biopsies showed no GSIB4 lectin staining for alpha-Gal epitopes and much less IgM and C3 deposition in the treated group. Light microscopy and SEM demonstrated more severe endothelial damage, hemorrhage, and fibrin formation in the untreated group. Galactosidase is effective in removing the terminal alphaGal and delays the onset of hyperacute rejection of pig veins transplanted into monkeys. However, its effect is temporary and, on its own, its use is unlikely to prolong survival of pig organs transplanted into primates sufficiently to be of clinical value.

Animals↗

Recovery of biceps function after delayed repair for brachial plexus injury.

BACKGROUND: In many cases of severe closed injury involving the upper trunk of the brachial plexus, the proximal stump is too damaged to permit direct repair. Under these circumstances, several alternative sources of neurotization have been described, three of which are analyzed here. METHODS AND RESULTS: Thirteen patients with brachial plexus injury had paralysis of elbow flexion owing to damage of either the upper trunk or the lateral cord. In four patients, the musculocutaneous nerve was reinnervated through cross-union with the thoracodorsal nerve; all regained strong elbow flexion. One of three the patients with cross-union between the lateral or medial pectoral nerve regained useful elbow flexion. Of six patients with nerve grafting between spinal accessory and musculocutaneous nerves, four regained useful elbow flexion. CONCLUSION: Cross-union between thoracodorsal and musculocutaneous nerves appears to be a reliable method of restoring elbow function even when delayed for 2 years after injury. Return of elbow flexion should be an obtainable goal in most brachial plexus injuries.

Adolescent↗

ICAM-1 affects reperfusion injury and graft function after cardiac transplantation.

BACKGROUND: The effects of increased expression of intercellular adhesion molecule (ICAM-1), an important mediator of neutrophil-mediated reperfusion injury (RI), were assessed in donor cardiac allografts in a heterotopic rat transplantation model. METHODS: At -24 h, PVG donors were untreated (n = 35) or treated (n = 37) with lipopolysaccharide (LPS, 5 mg/kg ip). Hearts were procured at 0 h, stored at 4 degrees C for 45 min, and grafted heterotopically into ACI recipients pretreated with vehicle or anti-ICAM-1 (1A29) mAb. Intracardiac balloons (n = 8 per group) were used to measure allograft left ventricular function (dP/dt) prior to harvest and following reperfusion. RI was assessed at 6, 12, and 24 h by myeloperoxidase (MPO) levels, percentage wet weight (%w/w), and percentage contraction band necrosis (%CBN). RESULTS: At 12 h, LPS-pretreated grafts showed increased ICAM-1 expression by Northern blot (n = 3) and immunohistochemistry (n = 3) and significantly increased MPO (0.33 +/- 0.2 U/mg vs 0.05 +/- 0.04 U/mg at 12 h), %w/w (81.7 +/- 1.8% vs 79.2 +/- 0.7% at 12 h), and %CBN (15.2 +/- 1. 9% vs 11.4 +/- 2.0% at 24 h). LPS pretreatment had no effect on graft function at early time points (baseline to 2 h) but led to depressed dP/dt at later time points with trends toward significance at 12 h (2101 +/- 1653 mmHg/s vs 173 +/- 201 mmHg/s, P = 0.06, ANOVA). Recipient 1A29 treatment (n = 6 per group) reversed the effects of LPS pretreatment in all three RI parameters and significantly improved functional recovery. CONCLUSIONS: Alteration of cardiac graft phenotype to that likely seen in clinical organ donors leads to increased delayed-onset myocardial RI following transplantation in this model. The blockade of this increased RI following 1A29 mAb treatment supports a central role for ICAM-1 in this process.

Animals↗

Customized treatment algorithm for giant cell tumor of bone: report of a series.

Between 1991 and 2000, 30 patients with 31 resections of giant cell tumors of bone were treated (average followup, 4.9 years; range, 1-9.6 years). Intralesional resection with curettes and a high-speed burr and reconstruction with polymethylmethacrylate cementation or bone grafting was used for salvageable, nonexpendable bones. Wide resection and allograft reconstruction was done in nonexpendable bones that were too destroyed for salvage. Adjuvant treatments were used for all intralesional procedures and when wide resection with a close margin was obtained. Adjuvant treatments included hydrogen peroxide instillation in 30 patients, electrocautery in 27 patients, phenol irrigation in 26 patients, sterile water irrigation in 15 patients, and polymethylmethacrylate cementation in 15 patients. There have been only two (6.4%) local recurrences, one in bone and one in soft tissue. Both patients had intralesional resections initially and both had salvage procedures with wide resections of the recurrent tumors. The 5-year recurrence-free survivorship was 93%. A delayed ray amputation for failed bone graft of the little finger was the only amputation. In all other patients, a functional limb was preserved. Wide resection only is required when bone salvageability is impractical. Intralesional curettage and high-speed burr resection, when supplemented with the adjuvant therapies as described, is adequate for the majority of patients with giant cell tumor of bone. A proposed treatment algorithm is presented.

Adult↗

Antebrachial deformities in the dog: treatment with external fixation.

The results of 12 dogs with antebrachial deformity treated by ulnar ostectomy, radial osteotomy and external skeletal fixation are presented. Postoperative complications were seen in only one dog; a delayed union requiring placement of autogenous cancellous bone graft at a second surgery to achieve healing. Postoperatively, owners reported limb function was good in almost all cases, although they were less pleased with the cosmetic appearance.

Animals↗

Radical excision and delayed reconstruction of a lymphedematous leg with a 15 year follow-up.

An adult female patient with primary lymphedema of the lower extremity was treated with total excision of the subcutaneous tissues followed by delayed reconstruction with a giant full thickness skin graft taken from the excised surgical specimen. The leg has maintained excellent function and contour over the ensuing 15 years. A small area on the dorsum of the foot that initially was covered with a split thickness skin graft required subsequent regrafting using abdominal skin. This area developed verrucoid changes.

Adult↗

Primary liver resection and salvage transplantation or primary liver transplantation in patients with single, small hepatocellular carcinoma and preserved liver function: an outcome-oriented decision analysis.

Two treatments are accepted for patients with solitary hepatocellular carcinoma </=5 cm in size and with preserved hepatic function: (1) liver resection, which can be performed without delay but has a high recurrence rate, and (2) liver transplantation, which has a better long-term survival, but is not easily available because grafts are scarce. A third possibility is to offer liver resection first and liver transplantation for tumor recurrence or deteriorating liver function ("salvage" transplantation). We investigated the implications of such a strategy with a Markov-based decision analytic model. In a scenario assuming intermediate values for 4 main variables (12-month waiting list; tumor progression outside transplantation criteria: 4% per month; recurrence after resection: 20% per year; recurrences eligible for transplantation: 60%), the life expectancy was 8.8 years for primary transplantation versus 7.8 years for primary resection and salvage transplantation, with a calculated use of grafts at 5 years of 52% for primary transplantation versus 23% for salvage transplantation. This study estimates of the survival and graft-saving of a strategy of primary resection and salvage transplantation according to variables that are to some extent predictable. This strategy may be a rational way to cope with lengthening waiting lists, especially for patients with tumors close to the limit for transplantation criteria, if the results of liver resection are good, if patients with the lowest risks of recurrence can be selected, and if a strict follow-up can detect recurrences when the patients are still transplantable.

Carcinoma, Hepatocellular↗

Postgrafting administration of granulocyte colony-stimulating factor impairs functional immune recovery in recipients of human leukocyte antigen haplotype-mismatched hematopoietic transplants.

In human leukocyte antigen haplotype-mismatched transplantation, extensive T-cell depletion prevents graft-versus-host disease (GVHD) but delays immune recovery. Granulocyte colony-stimulating factor (G-CSF) is given to donors to mobilize stem cells and to recipients to ensure engraftment. Studies have shown that G-CSF promotes T-helper (Th)-2 immune deviation which, unlike Th1 responses, does not protect against intracellular pathogens and fungi. The effect of administration of G-CSF to recipients of mismatched hematopoietic transplants with respect to transplantation outcome and functional immune recovery was investigated. In 43 patients with acute leukemia who received G-CSF after transplantation, the engraftment rate was 95%. However, the patients had a long-lasting type 2 immune reactivity, ie, Th2-inducing dendritic cells not producing interleukin 12 (IL-12) and high frequencies of IL-4- and IL-10-producing CD4(+) cells not expressing the IL-12 receptor beta(2) chain. Similar immune reactivity patterns were observed on exposure of donor cells to G-CSF. Elimination of postgrafting administration of G-CSF in a subsequent series of 36 patients with acute leukemia, while not adversely affecting engraftment rate (93%), resulted in the anticipated appearance of IL-12-producing dendritic cells (1-3 months after transplantation versus > 12 months in transplant recipients given G-CSF), of CD4(+) cells of a mixed Th0/Th1 phenotype, and of antifungal T-cell reactivity in vitro. Moreover, CD4(+) cell counts increased in significantly less time. Finally, elimination of G-CSF-mediated immune suppression did not significantly increase the incidence of GVHD (< 15%). Thus, this study found that administration of G-CSF to recipients of T-cell-depleted hematopoietic transplants was associated with abnormal antigen-presenting cell functions and T-cell reactivity. Elimination of postgrafting administration of G-CSF prevented immune dysregulation and accelerated functional immune recovery.

Acute Disease↗

Analysis of the innate and adaptive phases of allograft rejection by cluster analysis of transcriptional profiles.

Both clinical and experimental observations suggest that allograft rejection is a complex process with multiple components that are, at least partially, functionally redundant. Studies using graft recipients deficient in various genes including chemokines, cytokines, and other immune-associated genes frequently produce a phenotype of delayed, but not indefinitely prevented, rejection. Only a small subset of genetic deletions (for example, TCR(alpha) or beta, MHC I and II, B7-1 and B7-2, and recombinase-activating gene) permit permanent graft acceptance suggesting that rejection is orchestrated by a complex network of interrelated inflammatory and immune responses. To investigate this complex process, we have used oligonucleotide microarrays to generate quantitative mRNA expression profiles following transplantation. Patterns of gene expression were confirmed with real-time PCR data. Hierarchical clustering algorithms clearly differentiated the early and late phases of rejection. Self-organizing maps identified clusters of coordinately regulated genes. Genes up-regulated during the early phase included genes with prior biological functions associated with ischemia, injury, and Ag-independent innate immunity, whereas genes up-regulated in the late phase were enriched for genes associated with adaptive immunity.

Animals↗