Modulation of the formation of the amplification convertase of complement, C3b, Bb, by native and commercial heparin.

Native rat mast cell macromolecular heparin proteoglycan and commercial hog heparin glycosaminoglycan chains inhibit generation of the amplification convertase, C3b, Bb. The inhibitory action of heparin is not due to chelation of magnesium. Heparin is most active in inhibiting convertase formation on cellular intermediates formed with the lowest C3b input and developed with the highest B concentration, thereby suggesting the receptor site for B on C3b as the point of heparin action. This interpretation is consistent with the demonstration that heparin prevents B utilization during the fluid phase interaction of C3b, B, and D. Inhibition is observed also when C3b,Bb generation takes place on cellular intermediates in the presence of P or C3NeF, which yield stabilized forms of the convertase. 50 times the concentration of heparin required to inhibit convertase generation does not accelerate the decay of the unstabilized or the C3NeF-stabilized convertases and has only a modest effect on the P-stabilized convertase. An additional effect of heparin is to impair beta1H-mediated decay-dissociation of C3b,Bb. The concentration of native or commercial heparin which prevents convertase formation is in the same range as that required for the demonstration of its anti-coagulant and anti-thrombin III cofactor activities. The additional finding that this inhibitory action of heparin can be expressed by the isolated mast cell granule suggests that native heparin may contribute to the modulation of the amplification pathway of complement.

Decreased wound neutrophils and indiscrete margination in the pathogenesis of wound infection.

To assess the pathogenesis of increased susceptibility to infection and septic death in a rat model, neutrophils (PMNs) in the wound, circulating PMNs, and their in vivo activity were evaluated after 30% and 60% burns. Eight hours after injury there were twice as many PMNs in the wounds of rats that sustained 30% compared with 60% burns. There was no difference between these two groups in the number of circulating PMNs at 2, 4, 6, and 8 hours after injury. In vivo evaluation of PMN response to infusion of F-Met-Leu-Phe revealed that circulating PMNs were more sensitive 4 hours after 60% burns compared with sham burns. At this time PMNs were found to be less sensitive to zymosan-activated serum infusion after 30% burns compared with sham burns. However, the PMNs in rats with 30% burns were more sensitive to this stimulus than were PMNs in rats with 60% injuries. Thus rats with greater injury, known to be more susceptible to wound infection, have fewer PMNs in their wounds 8 hours after injury. This is preceded by an increased sensitivity of PMNs in vivo to bacterial chemotactic factor and a relative increase in sensitivity to wound factors. This unusual finding implicates indiscrete margination as a factor in the pathogenesis of infection.

Effect of blood transfusions on immune function. Part VI. Effect on immunologic response to tumor.

Transfusions are reported to increase the incidence of tumor metastasis in clinical studies and primary tumor growth in animal studies. We evaluated the effect of transfusions on immunologic response to primary and metastatic tumors in multiple rat models. One half of the animals were administered lactated Ringer's solution and one half ACI rat blood at the time of tumor challenge. In 80 rats a slow-growing colon tumor was implanted subcutaneously. At 4 months there were no significant differences in tumor size or leukocyte infiltration of the tumor. Similar results were obtained with a rapidly growing colon cancer. Analysis of T-lymphocyte subpopulations in both groups showed no differences. Rats transfused at the time of intravenous challenge with a suspension of 1 x 10(6) tumor cells had a mean survival time of 38.3 +/- 0.8 days and the control group had a mean survival time of 41.1 +/- 0.8 days (p = 0.016). One week after transfusion, natural killer cell lysis of tumor cells at a 100:1 effector/target cell ratio was 18.0% +/- 1.8% in the transfusion group and 23.0% +/- 1.3% in the control group (p = 0.034). In conclusion, transfusions in multiple rat cancer models did not affect primary tumor growth or the host's immunologic response to it but did significantly impair natural killer cell function and survival with tumor metastases.

Prostaglandin E2 receptors EP2 and EP4 are down-regulated in human mononuclear cells after injury.

BACKGROUND: Recent characterization of prostaglandin receptor subtypes shows that each is critical to cellular functions and operates through separate signaling pathways that may explain differing effects of prostanoids. This study aimed to determine whether prostaglandin receptors EP2 and EP4 are modulated after injury and to evaluate the effect of prostaglandin E(2) (PGE(2)) addition and blockade on EP receptor expression. METHODS: Peripheral blood mononuclear cells (PBMCs) isolated from 10 patients sustaining fracture or burn injury and 10 control subjects were stimulated with lipopolysaccharide +/- NS-398, an inhibitor of PGE(2) production. Samples were evaluated for production of PGE(2), tumor necrosis factor--alpha, and leukotriene B(4) as well as mRNA expression of EP receptors and COX-2. EP receptor expression was also evaluated after treating control PBMCs with PGE(2). RESULTS: PBMCs from injured patients exhibited significant increases in PGE(2) production and COX-2 mRNA compared with control subjects, and these increases were inhibited by NS-398. In contrast, EP2 and EP4 receptors were markedly down-regulated after injury and NS-398 restored expression to control levels. Decreased EP2 and EP4 receptor expression after injury was replicated by coincubation of PBMCs with PGE(2). CONCLUSIONS: Specific PGE(2) receptors are down-regulated after injury and NS-398 reverses this response. Furthermore, PGE(2) mediates EP2 and EP4 down-regulation. These data suggest that specific EP receptor subtypes may provide critical targets for augmenting the immune response after injury in humans.

Household oven doors: a burn hazard in children.

Contact with hot oven doors is an important cause of burns in pediatric patients. These burns are of particular concern because of their frequent localization to the hands, with the resulting negative implications for financial cost, long-term cosmesis, and hand function. A 5-year review of pediatric oven door burn cases admitted to a burn referral center was conducted. Of the 14 cases identified, the median age was 12 months. The median total body surface area (TBSA) was 1.75% (range, 0.5%-4.5%). Twelve of 14 cases involved 1 or both hands. The median length of hospital stay was 10 days. In 7 cases, burns were sustained from contact to an external surface of the oven. Based on the results obtained, we propose several prevention strategies.

Base-line and postthermal injury plasma histamine in rats.

Although plasma histamine concentration has been reported to increase after thermal injury in the rat to as much as 100-fold over normal human plasma levels, the pathophysiological significance and relevance to human disease is questionable. Lack of confidence in the rat as a model of histamine-mediated disease is based on reports that normal rat base-line plasma histamine concentration exceeds that of human plasma by 20- to 70-fold. The present study confirms that high concentrations of histamine (20-68.9 ng/ml) are found in rat plasma obtained in an uncontrolled manner; but concentrations are lower (1.17 +/- 0.49 ng/ml) or undetectable in a sensitive radioenzymatic assay when sampling technique and plasma isolation are controlled. The primary cause for falsely elevated values for plasma histamine concentration appeared to be due to manipulation of the rat. Plasma histamine concentration increased within 1 min after thermal injury and the increase was proportional to extent of surface area injured. In contrast to the finding of a single time-related peak of plasma histamine concentration after partial-thickness burn, a biphasic elevation was found after full-thickness injury. Thus the data indicate that normal rat plasma histamine concentration is similar to that of the human and below the reported threshold for modulation of a variety of immune responses. Furthermore, the data support a role for histamine and other mast-cell mediators in the local and systemic responses to injury.

Increased susceptibility to infection due to infusion of exogenous chemotaxin.

Previous studies indicate that endogenous chemotaxins, such as the chemotactic factor C5a, may modulate the function of neutrophils (PMNs) and account for increased susceptibility to infection after injury. These effects were investigated by continuously infusing rats with saline or the chemotaxin formyl-methionyl-leucyl-phenylalanine (FMLP). Rats that sustained a full-thickness burn covering 30% of total body surface area and whose wounds were inoculated with Pseudomonas aeruginosa had a significantly shorter survival when FMLP was infused (6.5 +/- 0.91 days) than did saline-infused rats (9.9 +/- 0.83 days). Rats infused with FMLP had significantly more leukocytes in their burn wounds, significantly fewer PMNs in the circulating pool, and the same number of PMNs at the site of FMLP infusion compared with the saline-treated group. These findings support the hypothesis that chemotaxins generated by tissue injury or sepsis contribute to increased susceptibility to infection.

Effect of prostaglandin E on immune function in multiple animal models.

The immunosuppression seen following major trauma and burns has long been attributed in part to prostaglandin E (PGE). This has been due primarily to the demonstration that PGE levels are elevated following burns and that when PGE is added to leukocyte cultures, it impairs multiple types of leukocyte functions. We investigated the effect of a new long-acting PGE derivative, 16,16-dimethyl-PGE, on immune function in multiple animal models. The PGE derivative had no effect on mortality in burn sepsis models but improved mean survival times in an Escherichia coli peritonitis model. The PGE derivative impaired neutrophil migration into burn wounds at lower dosages. In a rat burn model, when PGE was administered parenterally, it failed to impair cell-mediated immunity at any dosage and improved lymphocyte function at certain dosages. These data indicate that PGE may not be as immunosuppressive in in vivo models as it has been shown to be in in vitro models.

Enterococcal burn sepsis. A highly lethal complication in severely burned patients.

A retrospective study was undertaken to examine the incidence and clinical significance of enterococcal bacteremia in burned patients with enterococcal burn-wound infections. During a 26-month period from 1983 to 1985, 38 patients were found to have enterococcal burn-wound infections. Twenty of these patients developed positive blood cultures for enterococcus with no other identifiable source for the bacteremia. Cases occurred sporadically during the study period without evidence of a specific epidemic. Ten patients died within ten days of the bacteremia, while nine others eventually died from other complications. Only one patient survived to discharge. Prior antibiotic therapy did not appear to increase the risk for enterococcal infection, and specific therapy against the enterococcus after the bacteremia was identified appeared to have no effect on mortality. Mortality was significantly greater for bacteremic patients than for patients with enterococcal wound infection alone or for burned patients without enterococcal infections. Although previously not considered pathogenic, enterococcal burn-wound infections should prompt aggressive therapy to prevent the development of enterococcal sepsis with its associated high mortality.

Increased susceptibility to infection related to extent of burn injury.

A model of burn wound sepsis in which the mortality caused by infection was significantly greater after a 60% total body surface area (TBSA) burn than after a 30% TBSA burn was developed in the rat. In rats that sustained a 60% TBSA burn (30% partial plus 30% full thickness), the 30% TBSA partial-thickness burn that was inoculated with Pseudomonas aeruginosa strain 59-1244 developed invasive wound infection (greater 10(5) colony-forming units per gram of tissue). Infection did not develop in rats that had a 30% TBSA partial-thickness burn inoculated, without additional injury. The additional burn in the rats with a 60% TBSA burn seemed to affect the development of infection in the partial-thickness wound and the overall outcome by a mechanism other than by infection of the full-thickness wound itself. Autopsy confirmed that mortality was caused by sepsis.

Leukotriene B4 generation in patients with established pulmonary failure.

We investigated the cause of the reduced leukotriene B4 (LTB4) production seen in neutrophils from patients with established adult respiratory distress syndrome compared with control neutrophils. Lymphocytes/monocytes from controls were found to synergistically enhance the amount of LTB4 produced when incubated with neutrophils. This synergistic effect was not seen in cells from patients with adult respiratory distress syndrome. Fatty-acid analysis of neutrophils from patients with adult respiratory distress syndrome and controls showed remarkable similarity in all quantities of fatty acids measured except for arachidonic acid, where there was a 22% reduction in patients' cells compared with controls. Assay of the rate of generation of LTB4 and its degradation product, 20-hydroxy LTB4, revealed that reduced LTB4 generation in patients' neutrophils was not due to increased degradation of LTB4 by hydroxylase enzymes. When the amount of LTB4 being generated per milliliter of whole blood was analyzed in the patients with adult respiratory distress syndrome and compared with controls, it was determined that the potential to generate LTB4 in patients in the intensive care unit was three to five times greater than in controls.

Tumor necrosis factor-enhanced leukotriene B4 generation and chemotaxis in human neutrophils.

In an in vivo study of five normal volunteers infused with endotoxin (20 U/kg of US reference endotoxin lot EC-5), increased neutrophil (PMN) generation of leukotriene B4 and chemotaxis to leukotriene B4 were found concomitantly with elevated plasma tumor necrosis factor (TNF) levels. To clarify the role of TNF in PMN activation, neutrophil responsiveness after in vitro treatment with TNF was examined. Neutrophils from seven normal subjects were incubated with TNF for 30 minutes and tested for chemotaxis to leukotriene B4, formyl-methionyl-leucyl-phenylalanine and zymosan-activated serum, or the calcium ionophore A23187 to assess leukotriene B4 generation. A range of 10(-13) to 10(-9) mol/L of TNF was used for these assays. When 10(-9) mol/L of TNF was used, the amount of leukotriene B4 that was produced was significantly greater than in control cells. The effect of TNF on PMN chemotaxis was uniformly inhibitory for the three stimuli at 10(-10) mol/L compared with untreated cells. At a picomolar range, PMN migration to leukotriene B4, but not to zymosan-activated serum or formyl-methionyl-leucyl-phenylalanine, was significantly increased over that of PMNs not exposed to TNF. This suggests that TNF has a specific facilitatory effect on PMN responsiveness for both leukotriene B4 production and chemotaxis to leukotriene B4 and may be the same signal for this phenomenon in endotoxemic patients.

Triage, initial assessment, and early treatment of the pediatric trauma patient.

It should be clear from this overview of triage, assessment, and initial care that early involvement by the leader of the trauma team is essential. Because operative intervention is so often necessary, the trauma team leader should be a surgeon with specialized training in trauma. The complex decision-making process involves prioritizing approaches by emergency room physicians, pediatricians, and surgical specialties in patients with multiple injuries. Even with single-system injury a rapid and logical approach to assessment and treatment is necessary in light of an overall longer term management plan.

Major burn injuries among restaurant workers in New York City: an underappreciated public health hazard.

Major burns among food service workers appears to be an underappreciated source of morbidity and public expense in New York City. A retrospective study was conducted to identify workers requiring hospital admission over the past 3 years. Seventy-six restaurant workers (3.8% of all adult admissions) were identified. They averaged 33 years of age, and sustained burns with a mean %TBSA of 12.5, resulting in a mean length of stay of 12.8 days. Scalds predominated, with water/coffee burns most common (n = 29), followed by oil (n = 27), and soup/sauce burns (n = 12). Burns to the extremities occurred in 97% of patients. Surgery was required in 32 of 76 patients (42.1%). Oil burns were more likely to require surgery than aqueous scalds (59 vs 34%; P < 0.01). Hospitalization expenses averaged $1.13 million dollars per year. There were no mortalities. Restaurant-related major burns are a frequent occurrence, particularly scald injuries. Hospital care and further disability result in enormous publicly funded expenses. The morbidity and lost wages are a severe detriment to workers and their families. Greater public health awareness measures are warranted.

Burn injury in patients with early-onset neurological impairments: 2002 ABA paper.

Many patients suffer from sensorimotor deficits that may contribute to burn injury. This retrospective study examines burn injuries in the subgroup of patients that suffer from the early onset neurological impairments of mental retardation, cerebral palsy, spina bifida, autism, and attention deficit-hyperactivity disorder. Fifty-one patients who suffered from the above-mentioned early-onset neurological impairments were admitted to our burn center during a 4-year period. The average TBSA burned was 8.9% yet resulted in prolonged hospitalizations. This study describes our burn center's experience in treating patients admitted with early-onset neurological impairments.

Multiple significant trauma diagnosis related groups: analysis and national projections based on the first year in an all-payor prospective payment system.

To assess the effect of diagnosis related group (DRG) changes on reimbursement for trauma care in New York State (NYS), 840 trauma patients were studied over a 2-year period. Average costs increased moderately ($10,338 vs. $11,646) while average revenues increased dramatically ($6,934 vs. $9,115), leading to a 21% reduction in operating losses ($1,310,625 vs. $1,032,733). This was largely a result of new multiple significant trauma (MST) DRGs. The impact of 1990/1991 DRG changes was assessed; a 39% reduction in operating losses occurred. Regression analysis of 1989 DRG case weight on cost indicated that MST DRGs were better predictors of resource utilization than other trauma DRGs. Review of NYS data affirmed that only 10% of trauma patients were assigned MST DRGs and 63% of trauma patients were discharged from community hospitals. On a national level, the effect of the new Medicare MST DRGs would be minimal, since only 5% of Medicare patients were assigned MST DRGs. Although improvements have been made, reimbursement for trauma care must be addressed further.

Cardiac arrest among geriatric patients.

In a review of 292 hospital patients who had cardiac arrests over a period of two and a half years patients aged 60 and over were contrasted with those under 60, based on a 50-item clinical questionary completed at the time of the episode. Survival rates were identical (23%) in these two groups. On contrasting patients who survived with those who did not it was again found that age did not influence outcome. Patients with multiple arrests or without cardiographic evidence of ventricular standstill were much more likely to recover. Whether or not a doctor initiated therapy did not affect survival.

The effect of blood transfusions on immune function. V. The effect on the inflammatory response to bacterial infections.

Blood transfusions have been shown to be associated with increased bacterial infection rates in colon cancer patients and in multiple animal studies. This increased susceptibility appears due to impairments in the systemic resistance to infections and not to alterations in the local response. Specifically, transfusions in a rat model were not found to alter the peritoneal cavity's response to an Escherichia coli challenge or the burn wound's response to a Pseudomonas aeruginosa challenge. Transfusions did impair the macrophage's ability to phagocytose and kill bacteria. Transfusions also increased the serum level of the immunosuppressive glucocorticoid, corticosterone.