Alternative complement pathway activation increases mortality in a model of burn injury in mice.

We have studied the role of the complement system in burn injury in an experimental model in mice. A 25% body surface area, full-thickness scald wound was produced in anesthetized animals. Massive activation of the alternative complement pathway, but not the classical pathway, was seen. This activation was associated with the generation of neutrophil aggregating activity in the plasma, neutrophil aggregates in the lungs, increased pulmonary vascular permeability, and increased lung edema formation. Decomplementation with cobra venom factor (CVF) or genetic C5 deficiency diminished these pathologic changes, and CVF pretreatment substantially reduced burn mortality in the first 24 h. Preliminary data show that human burn patients have a similar pattern of complement activation involving predominantly the alternative pathway, indicating the possible relevance of the murine model to human disease.

A low-affinity Ca2+-dependent association of calmodulin with the Rab3A effector domain inversely correlates with insulin exocytosis.

The stimulus-response coupling pathway for glucose-regulated insulin secretion has implicated a rise in cytosolic [Ca2+]i as a key factor to induce insulin exocytosis. However, it is unclear how elevated [Ca2+]i communicates with the pancreatic beta-cell's exocytotic apparatus. As Rab3A is a model protein involved in regulated exocytosis, we have focused on its role in regulating insulin exocytosis. By using a photoactivatable cross-linking synthetic peptide that mimics the effector domain of Rab3A and microsequence analysis, we found calmodulin to be a major Rab3A target effector protein in pancreatic beta-cells. Coimmunoprecipitation analysis from pancreatic islets confirmed a Rab3A-calmodulin interaction in vivo, and that it inversely correlated with insulin exocytosis. Calmodulin affected neither GTPase nor guanine nucleotide exchange activity of Rab3A. The calmodulin-Rab3A interaction was pH- and Ca2+-dependent, and it was preferential for GTP-bound Rab3A. However, Rab3A affinity for calmodulin was relatively low (Kd = 18-22 micromol/l at 10(-5) mol/l [Ca2+]) and competed by other calmodulin-binding proteins that had higher affinity (e.g., Ca2+/calmodulin-dependent protein kinase-2 [CaMK-2] [Kd = 300-400 nmol/l at 10(-5) mol/l [Ca2+]]). Moreover, the Ca2+ dependence of the calmodulin-Rab3A interaction (K0.5 = 15-18 micromol/l [Ca2+], maximal at 100 micromol/l [Ca2+]) was significantly lower compared with that of the calmodulin-CaMK-2 association (K0.5 = 40 micromol/l [Ca2+], maximal at 1 mmol/l [Ca2+]). The data suggested that a transient Rab3A-calmodulin interaction might represent a means of directing calmodulin to the cytoplasmic face of a beta-granule, where it can be subsequently transferred for activation of other beta-granule-associated calmodulin-binding proteins as local [Ca2+]i rises to promote insulin exocytosis.

Pooling 12 nomifensine studies for efficacy generalizability.

Twelve parallel group, randomized, double-blind studies of nomifensine's safety and efficacy in the treatment of depressed patients were combined into three pools according to common protocols. This approach permitted evaluation of 1) efficacy results for studies with moderate-sized pools of patients, 2) the degree to which efficacy was generalizable to depressed patients in the general population, and 3) the conditions under which pooled active vs. active (imipramine vs. nomifensine) studies could be regarded as pivotal in support of efficacy. Results showed that nomifensine's superiority over placebo was generalizable to patients with a wide range of characteristics, including age 60 years or older. An appropriate statistical profile of more pronounced nomifensine responders would include patients with a duration of present episode less than 4 months who are acutely depressed, exhibit more severe symptoms, and have been previously hospitalized or treated with other psychotropic medications. A comprehensive assessment and power analysis of the pooled active vs. active studies provided strong evidence for comparability of nomifensine and imipramine.

The index of deep burn injury: an analysis of 66 extremity sites in 15 children.

The group of burn injuries generally classified as 'fourth degree' vary enormously in extent and severity. This fact, and the absence of a widely accepted grading system for these relatively uncommon injuries, has hindered our ability to learn from the experiences of others as reported in the literature. Based on a series of cadaver dissections, the Index of Deep Burn Injury (IDBI) was developed to provide such a classification scheme. The initial experience with the IDBI in a group of locally destructive "fourth degree' wounds is presented. It is believed that this index has the potential to improve our ability to describe highly destructive wounds.

Proteoglycan synthesis in human skin and burn scar explant cultures.

The synthesis of proteoglycans (PG) by normal human skin, and normal and hypertrophic scars were compared using tissue explants in culture. Newly synthesized PG were labelled with [35S]Na2SO4. Significant differences were found in the proportion of [35S]-radio-labelled incorporation of PG in the tissue and accumulation of [35S]PG in culture medium in the different tissues. The rate of PG biosynthesis in all three tissue types occurred in two phases. There was an initial phase of PG synthesis occurring at 0-3 h and a later phase that occurred at 3-18 h [35S]-labelled PG were isolated and characterized by Sepharose CL-6B chromatography and cellulose acetate electrophoresis. The results showed that the hypertrophic scar tissue and its culture medium contained higher proportions of dermatan sulphate (DS), chondroitin sulphate (CS) and DS' PG than the normal skin fractions. These results suggest that abnormal scarring is related to a change in the level of PG synthesis during the burn injury repair process.

Reconstruction of electrical burns of the oral commissure with a ventral tongue flap.

Reconstruction of the oral commissure following electrical burn injury is a challenging problem. The commissure is a thin, delicate structure that is highly mobile and essential to normal facial appearance and expression. When there is full-thickness destruction of vermilion, mucosa, skin, and orbicularis muscle, the resulting contracture alters adjacent structures, displaces the commissure, and distorts facial animation. Utilizing a composite ventral tongue flap of mucosa and muscle in the reconstruction of the commissure permits effective release of scar contracture and replaces destroyed mucosa and muscle bulk. Remaining structures can be returned to their normal location, and the three-dimensional contours of the oral commissure can be better restored. The use of this flap in 21 patients has resulted in improved mobility, more normal facial expression, and more consistent results in the reconstruction of a wide range of commissure deformities.

Conchal transposition flap for postburn ear deformities.

Severe thermal injuries to the external ear often lead to extensive loss of peripheral structures such as helix and lobule but frequently spare the more central parts of the ear, even though they may be grossly deformed by scar contracture. The use of spared conchal structures as a transposition flap in combination with remodeling of the residual auricle and release of surrounding scar when indicated has been a useful technique in the reconstruction of a frequently occurring type of postburn ear deformity. Twenty-four ears have been reconstructed in 18 patients over the past 5 years using a conchal transposition flap. The residual concha with its overlying skin can be transposed superiorly, based on a very narrow pedicle in the area of the crus helicis. The raw central area remaining is then resurfaced with a split-thickness skin graft. This technique maximally utilizes the unique remaining auricular elements and can provide a satisfactory reconstruction in selected patients without resorting to more complex and extensive procedures. There have been no significant complications in this series, and patient acceptance of the results has been excellent.

Skin sensation after suction lipectomy: a prospective study of 50 consecutive patients.

Using a reproducible pain stimulus, skin sensation was evaluated in a prospective study of 50 consecutive patients who underwent suction lipectomy. A total of 294 anatomic areas were evaluated and treated. Before operation, many patients were found to have patchy areas of decreased sensation, a condition that was unknown to them. Initially after surgery, all patients had decreased sensation in the treated areas. However, sensation usually returned to normal in 6 to 8 months. In some patients, sensory return to preoperative levels took as long as 1 year, and in a few, patchy areas of decreased sensation were present even longer. In general, the larger the treated area, the larger are the area and degree of sensory loss and the slower is the return of sensation.

Large-volume suction lipectomy: an analysis of 108 patients.

Suction lipectomy was initially advocated for the treatment of localized collections of fat and for the removal of less than 1500 ml of material. However, many patients wished to have multiple areas treated or had diffuse collections of fat. In such instances, the removal of over 1500 ml of material and circumferential lipectomy are necessary to provide optimal aesthetic results. However, when over 1500 ml of material is removed, anesthetic requirements, fluid replacement, and treatment of blood loss become important if the operation is to be performed safely. We have treated 108 patients who had over 1500 ml of material removed. Eight-eight percent of the patients were female; 12 percent were male. Using the body-mass index, 3 percent of patients were underweight, 70 percent were normal weight, and 27 percent were overweight. Fifty-five patients (51 percent) had 1500 to 2499 ml of material removed, 26 patients (24 percent) had 2500 to 3499 ml removed, 16 patients (15 percent) had 3500 to 4499 ml removed, and 11 patients (10 percent) had over 4500 ml removed. All patients were treated in the hospital; 44 percent were admitted after surgery. A total of 227 units of autologous and 2 units of homologous blood were transfused. As measured by a computerized monitor, the average amount of blood in the material removed from thighs was 30 percent; from abdomens, the blood loss was 45 percent. The aesthetic results were generally excellent. No complications were encountered. A few patients developed undesired sequelae, the most common of which was seroma formation, which occurred in 19 percent of those who had suction of abdominal-wall fat. We believe that large-volume suction lipectomy is safe and efficacious, provided attention is directed to such important aspects of patient care as anesthesia, fluid replacement, and blood loss.

Preoperative magnification angiography of donor and recipient sites for clinical free transfer of flaps or digits.

Based on the 14 free flap transfers we present with full survival, we recommend peroperative magnification angiography of both the recipient and donor sites. In our hands, this type of preoperative assessment seems to increase the margin of safety.

Miniature drag sphere velocity probe.

The development and testing of a miniature drag sphere velocity probe is described. Impetus for its development arose from a need to investigate the flow structure and turbulence beneath breaking surface water waves, i.e., a requirement for a fast-response small velocity probe which is useable in oscillatory flows. However, the presence of both drag (velocity) and inertial (acceleration) forces limits the measurable fluctuations to those having scales at least an order of magnitude larger than the sphere diameter, while the sphere diameter is itself limited by the requirement that the drag coefficient be independent of velocity. The resulting probe, with a sphere diameter of 0.43 cm, while not free of temperature drifts, pressure sensitivity, and cross-channel talk, yields encouraging results.

Management of massive calvarial exposure in young children.

Although small areas of exposed calvaria commonly occur in seriously burned children, these wounds are generally straightforward management problems. In contrast, management of the nearly completely exposed calvaria is an extraordinarily difficult problem--but is fortunately rare. Over the past 15 years, we have treated 119 children with full-thickness calvarial wounds requiring grafting. Four (3.4%) of these patients (average age, 2.9 years; range, 22 months to 5.5 years) had massive exposure of nonviable calvaria, defined as 75% or more of the surface area of the calvaria. These wounds were open an average of 28 months (range, 6 to 45 months). We have concluded that optimal management involves staged debridement of the desiccated outer table with a high-speed drill, taking appropriate precautions to avoid air embolism or inadvertent dural injury in the area of sutures or fontanelles. The resulting wounds quickly granulate and can be autografted.

Acellular allodermis in burns surgery: 1-year results of a pilot trial.

We grafted 10 sites on 6 children with limited (< 25%) areas of body surface available for donor harvest with an acellular allogenic dermis and a thin autograft. Matched control sites were grafted with autograft alone. Study site autografts (0.0074 +/- 0.0007 in, median 0.006 in, range 0.006 to 0.012 in) were thinner than control site autografts (0.0102 +/- 0.0008 in, median 0.012 in, range 0.006 to 0.013 in), with a P value of .015. Endopoints were initial engraftment (in percent) as judged by a blinded experienced observer and Vancouver scar scores. The 6 children (3 girls and 3 boys) had an average age of 5.2 +/- 0.9 years (range 2.8 to 10 years) and an average burn size of 68.7% +/- 6.7% total body surface area (range 47% to 85% total body surface area). The 10 study and control sites were treated with 10 separate procedures; 9 of the procedures were reconstructive and 1 was performed for the excision of an acute burn. Successful initial epithelialization was noted at 7 days postburn for 83% +/- 3.4% (range 60% to 95%) at the cryopreserved acellular human dermis sites and 83.3% +/- 4.3% (range 60% to 98%) at the control sites (not significant, P = .96). At a mean follow-up interval of 43.7 +/- 3.6 weeks (median 52, range 26 to 52 weeks), the differences between the study and control sites in the total mean (pigmentation, vascularity, pliability, and height) of the patients' Vancouver scar scores were not different.

Tunable dye laser neovessel ablation as an adjunct to the management of hypertrophic scarring in burned children: pilot trial to establish safety.

Hypertrophic scarring is a major source of morbidity in patients with burns. The physiologic characteristics are poorly understood, but increased neovascularity is typically seen in those wounds destined to become hypertrophic. We theorize that ablation of the developing neovasculature may favorably influence the development of the hypertrophic scar. The goal of this pilot trial was to establish the practicality and safety of tunable dye laser neovessel ablation at 585 nm. Ten sites of evolving hypertrophic scar in nine children were treated with a series of 450 msec 6.75 J/cm2 pulses at 585 nm. Although all children had the expected transient posttreatment purpura, no pain, ulceration, pruritus, or worsening of the lesions was seen. The technique appears safe and is worthy of continuing investigation. Investigations with higher fluences and multiple treatments are in progress.

Preferential activation and depletion of the alternative complement pathway by burn injury.

Complement levels of eight adult burn patients (25% to 90% body surface area) were studied upon admission to a burn unit and sequentially for one week. Mean classical pathway titers (CH50) were 49% below the normal mean, while hemolytic C4 titers were reduced by 53% and C3 by 43%. However, the alternative pathway titer was reduced by more than 90%, suggesting preferential depletion of this pathway. This depletion was associated with sepsis, pneumonia, and "shock lung." Alternative pathway deficiency was still present one week postburn, and may contribute to the susceptibility of burn patients to bacterial sepsis.

Thumb reconstruction in the burned hand by advancement pollicization of the second ray remnant.

Reconstruction of 15 thumbs in 14 patients with severe postburn deformity has been carried out by advancement and transferral of the second ray remnant onto the remaining proximal thumb metacarpal stump. This technique combines the advantages of thumb lengthening and pollicization procedures in a single operation and has been a useful method for restoration of single hand prehension in the severely burned mitten hand.

Comparison of the effects of interleukin-1 beta on proteoglycan synthesis by human skin and post-burn normal scar explant cultures.

The effect of interleukin (IL)-1 beta on proteoglycan (PG) synthesis and secretion, into culture medium by normal human skin and post-burn human normal scar using tissue explants in culture, was investigated. Following exposure of different tissues to labeling with Na2[35SO4] in the presence and absence of IL-1 beta, the extractable [35SO4]PG (isolated from 0.15 M NaCl and 4 M Gdm. Cl extracts), non-extractable [35SO4]PG (isolated after papain treatment of residual tissue), and [35SO4]PG secreted into culture medium were analyzed for contents and distribution. The contents of [35SO4]PG as measured by [35SO4] incorporation indicate differences in [35SO4]PG production of extractable and non-extractable PGs and also in the PGs released into the culture medium. Examination of the sizes of [35SO4]PGs on Sepharose CL-6 beta columns with and without treatment of IL-1 beta shows that the size of non-extractable [35SO4]PG decreases after IL-1 beta treatment. Cellulose acetate plate electrophoresis of these [35SO4]PG fractions shows that the distribution of PGs alters after treatment with IL-1 beta. These results indicate that burn wound healing abnormalities (scarring) is related to a change in the level of PGs, and may be modified by IL-1 beta treatment.

Acute hand burns in children: management and long-term outcome based on a 10-year experience with 698 injured hands.

OBJECTIVE: To document long-term results associated with an coordinated plan of care for acutely burned hands in children. SUMMARY AND BACKGROUND DATA: Optimal hand function is a crucial component of a high-quality survival after burn injury. This can be achieved only with a coordinated approach to the injuries. Long-term outcomes associated with such a plan of care have not been previously reported. METHODS: Over a 10-year period, 495 children with 698 acutely burned hands were managed at a regional pediatric burn facility; 219 children with 395 injured hands were followed in the authors' outpatient clinic for at least 1 year and an average of >5 years. The authors' approach to the acutely burned hand emphasizes ranging and splinting throughout the hospital stay, prompt sheet autograft wound closure as soon as practical, and the selective use of axial pin fixation and flaps. Long-term follow-up, hand therapy, and reconstructive surgery are emphasized. RESULTS: Normal functional results were seen in 97% of second-degree and 85% of third-degree injuries; in children with burns involving underlying tendon and bone, 70% could perform activities of daily living and 20% had normal function. Reconstructive hand surgery was required in 4.4% of second-degree burns, 32% of third-degree burns, and 65% of those with injuries involving underlying bone and tendon. CONCLUSIONS: When managed in a coordinated long-term program, the large majority of children with serious hand burns can be expected to have excellent functional results.