A unique mechanism of desensitization to lipolysis mediated by beta(3)-adrenoceptor in rats with thermal injury.
(17/1867)
Thermal injury causes a hypermetabolic state associated with increased levels of catabolic hormones, but the molecular bases for the metabolic abnormalities are poorly understood. We investigated the lipolytic responses after beta(3)-adrenoceptor (beta(3)-AR) agonists and evaluated the associated changes in beta-AR and its downstream signaling molecules in adipocytes isolated from rats with thermal injury. Maximal lipolytic responses to a specific beta(3)-AR agonist, BRL-37344, were significantly attenuated at post burn days (PBD) 3 and 7. Despite significant reduction of the cell surface beta(3)-AR number and its mRNA at PBD 3 and 7, BRL-37344 and forskolin-stimulated cAMP levels were not decreased. Glycerol production in response to dibutyryl cAMP, a direct stimulant of hormone-sensitive lipase (HSL) via protein kinase A (PKA), was significantly attenuated. Although immunoblot analysis indicated no differences in the expression and activity of PKA or in the expression of HSL, HSL activity showed significant reductions. Finally, beta(3)-AR-induced insulin secretion was indeed attenuated in vivo. These studies indicate that the beta(3)-AR system is desensitized after burns, both in the adipocytes and in beta(3)-AR-induced secretion of insulin. Furthermore, these data suggest a complex and unique mechanism underlying the altered signaling of lipolysis at the level of HSL in animals after burns. (+info)
IGF-I gene transfer in thermally injured rats.
(18/1867)
Exogenous insulin-like growth factor-I (IGF-I) is known to improve the pathophysiology of a thermal injury, however, deleterious side-effects have limited its utility. Cholesterol-containing cationic liposomes that encapsulate complementary DNA (cDNA) are nonviral carriers used for in vivo gene transfection. We propose that liposome IGF-I gene transfer will accelerate wound healing in burned rats and attenuate deleterious side-effects associated with high levels of IGF-I. To test this hypothesis IGF-I gene constructs, encapsulated in liposomes, were studied for their efficacy in modulating the thermal injury response. Thirty adult male Sprague-Dawley rats were given a 60% TBSA scald burn and randomly divided into three groups to receive weekly subcutaneous injections of liposomes plus the lacZ gene coding for beta-galactosidase, liposomes plus cDNA for IGF-I and beta-galactosidase or liposomes plus the rhIGF-I protein. Body weights and wound healing were measured. Muscle and liver dry/wet weights and IGF-I concentrations in serum, skin and liver were measured by radioimmunoassay. Transfection was confirmed by histochemical staining for beta-galactosidase. Rats receiving the IGF-I cDNA constructs exhibited the most rapid wound re-epithelialization and greatest increase in body weight and gastrocnemius muscle protein content (P < 0.05). Local IGF-I protein concentrations in the skin were higher when compared to liposomes containing only the lacZ gene (P < 0.05) Transfection was apparent in the cytoplasm of myofibroblasts, endothelial cells and macrophages of the granulation tissue. Liposomes containing the IGF-I gene constructs proved effective in preventing muscle protein wasting and preserving total body weight after a severe thermal injury. (+info)
Expression of the soxR gene of Pseudomonas aeruginosa is inducible during infection of burn wounds in mice and is required to cause efficient bacteremia.
(19/1867)
Burn wounds are prone to infection by Pseudomonas aeruginosa, which is an opportunistic pathogen causing various human diseases. During infection, the bacterium senses environmental changes and regulates the expression of genes appropriate for survival. A purine-auxotrophic mutant of P. aeruginosa was unable to replicate efficiently on burn wounds, suggesting that burn wounds are purine-deficient environments. An in vivo expression technology based on purEK gene expression was applied to the burned mouse infection model to isolate P. aeruginosa genes that are specifically induced during infection. Four such in vivo-inducible (ivi) genetic loci were identified, including the gene for a superoxide response regulator (soxR), the gene for a malate synthase G homologue (glcG), an antisense transcript of a putative regulator responding to copper (copR), and an uncharacterized genetic locus. SoxR of Escherichia coli is known to regulate genes involved in protecting the bacterium against oxidative stress. The expression of soxR was proven to be highly inducible during the infection of burned mice and also inducible by treatment with paraquat, which is a redox-cycling reagent generating intracellular superoxide. The SoxR protein functions as an autorepressor in the absence of paraquat, whereas in the presence of paraquat, this autorepression is diminished. Furthermore, a soxR null mutant was shown to be much more sensitive than wild-type P. aeruginosa to macrophage-mediated killing. In support of this observation, a soxR null mutant exhibited a significant delay in causing systemic infections in the burned mice. Since most mortality in burn patients is caused by systemic infection, the defect in the ability to cause efficient bacteremia in burned mice suggests an important role of the soxR gene in the infection of burn wounds. (+info)
Pharmacokinetics of antibiotics in burn patients.
(20/1867)
Drug pharmacokinetics are significantly altered in the burned patient but the interplay of a large number of variables is involved in deciding how an individual will deal with a drug. Consequently the burn patient population shows significant inter- and intrapatient variation. In 1976 altered aminoglycoside pharmacokinetics and the need for increased dosage in burn patients was reported but, despite this early study, a review of the currently available literature shows that for many drugs there is a paucity of information to support current dosage recommendations. In addition, many reports are based upon small numbers of patients, and even in larger studies there is no standardization of the study population with regard to the important variables known to affect drug handling. For the sub-population of burn patients who eliminate drugs extremely rapidly, a concern exists over the adequacy of antibiotic dosing. It is suggested that antibiotic serum concentrations be measured for all drugs in every patient to ascertain whether there is a significant problem with dosing. Additionally, future pharmacokinetic studies need to be standardized in burn patients. (+info)
The "Let's Get Alarmed!" initiative: a smoke alarm giveaway programme.
(21/1867)
OBJECTIVES: To reduce fires and fire related injuries by increasing the prevalence of functioning smoke alarms in high risk households. SETTING: The programme was delivered in an inner London area with above average material deprivation and below average smoke alarm ownership. The target population included low income and rental households and households with elderly persons or young children. METHODS: Forty wards, averaging 4000 households each, were randomised to intervention or control status. Free smoke alarms and fire safety information were distributed in intervention wards by community groups and workers as part of routine activities and by paid workers who visited target neighbourhoods. Recipients provided data on household age distribution and housing tenure. Programme costs were documented from a societal perspective. Data are being collected on smoke alarm ownership and function, and on fires and related injuries and their costs. RESULTS: Community and paid workers distributed 20,050 smoke alarms, potentially sufficient to increase smoke alarm ownership by 50% in intervention wards. Compared with the total study population, recipients included greater proportions of low income and rental households and households including children under 5 years or adults aged 65 and older. Total programme costs were 145,087 Pounds. CONCLUSIONS: It is possible to implement a large scale smoke alarm giveaway programme targeted to high risk households in a densely populated, multicultural, materially deprived community. The programme's effects on the prevalence of installed and functioning alarms and the incidence of fires and fire related injuries, and its cost effectiveness, are being evaluated as a randomized controlled trial. (+info)
House fire injury prevention update. Part II. A review of the effectiveness of preventive interventions.
(22/1867)
OBJECTIVE: To evaluate and summarize the house fire injury prevention literature. METHODS: MEDLINE (1983 to March 1997) was searched by keyword: fire, burn, etiology, cause, prevention, epidemiology, and smoke detector/alarm. ERIC (1966 to March 1997) and PSYCLIT (1974 to June 1997) were searched by keyword: as above, and safety, skills, education, and training. Other sources included references of retrieved publications, review articles, and books; Injury Prevention hand search; government documents; and internet sources. Sources relevant to residential fire injury prevention were selected, evaluated, and summarized. RESULTS: Forty three publications were selected for review, including seven randomized controlled trials, nine quasiexperiments, two natural experiments, 21 prospective cohort studies, two cross sectional surveys, one case report, and one program evaluation. These studies examined the following types of interventions: school (9), preschool (1), and community based educational programs (5); fire response training programs for children (7), blind adolescents (2), and mentally retarded adults (5) and children (1); office based counseling (4); home inspection programs (3); smoke detector giveaway campaigns (5); and smoke detector legislation (1). CONCLUSIONS: This review of house fire prevention interventions underscores the importance of program evaluation. There is a need for more rigorous evaluation of educational programs, particularly those targeted at schools. An evidence based, coordinated approach to house fire injury prevention is critical, given current financial constraints and the potential for program overload for communities and schools. (+info)
Role of protein kinase C in cyclic AMP-mediated suppression of T-lymphocyte activation following burn injury.
(23/1867)
Major burn injury induces T-lymphocyte dysfunction. Previous studies suggest that prostaglandin (PG) E2, which is elevated post-burn, is the causative factor via a cyclic AMP-dependent process. The present study was conducted to elucidate the mechanism by which cAMP induces T-lymphocyte dysfunction following burn injury. Splenocytes were isolated from mice 7 days after receiving a scald burn covering 25% of their total body surface or sham procedure. ConA-induced proliferation by splenocytes from burned mice was significantly suppressed. Macrophage depletion of the splenocyte cultures abrogated the suppression. Concanavalin A-stimulated proliferation by macrophage-depleted splenocytes was suppressed by PGE2 and dibutyryl cAMP in both groups. The IC50 of these cAMP-elevating agents, however, was approximately 100-fold lower for cells from burned mice, indicating an increased sensitivity to cAMP. PGE2 did not suppress PMA/Ca2+ ionophore-induced T-lymphocyte activation. Addition of PMA to ConA-stimulated cultures prevented the suppression of proliferative responses by PGE2, whereas Ca2+ ionophore had no effect. Thus, the suppression of T-lymphocyte activation following burn injury is macrophage-dependent, related to an increased sensitivity to cAMP and due to an uncoupling of cell surface receptors from protein kinase C activation. (+info)
Contribution of quorum sensing to the virulence of Pseudomonas aeruginosa in burn wound infections.
(24/1867)
The Pseudomonas aeruginosa quorum-sensing systems, las and rhl, control the production of numerous virulence factors. In this study, we have used the burned-mouse model to examine the contribution of quorum-sensing systems to the pathogenesis of P. aeruginosa infections in burn wounds. Different quorum-sensing mutants of P. aeruginosa PAO1 that were defective in the lasR, lasI, or rhlI gene or both the lasI and rhlI genes were utilized. The following parameters of the P. aeruginosa infection were examined: (i) lethality to the burned mouse, (ii) dissemination of the P. aeruginosa strain within the body of the infected mouse (by determining the numbers of CFU of P. aeruginosa within the liver and spleen), and (iii) spread of the P. aeruginosa strain within the burned skin (by determining the numbers of CFU of P. aeruginosa at the inoculation site and at a site about 15 mm from the inoculation site [distant site]). In comparison with that of PAO1, the in vivo virulence of lasI, lasR, and rhlI mutants was significantly reduced. However, the most significant reduction in in vivo virulence was seen with the lasI rhlI mutant. The numbers of CFU that were recovered from the livers, spleens, and skin of mice infected with different mutants were significantly lower than those of PAO1. At 8 and 16 h post burn infection, comparable numbers of CFU of PAO1 and lasI and rhlI mutants were obtained from both the inoculation and distant sites of the burned skin of infected mice. In contrast, CFU of the lasR mutant and the lasI rhlI double mutant were recovered only from the inoculation site of infected mice at 8 and 16 h post burn infection. The ability of a plasmid carrying either the lasI or rhlI gene or the lasI and rhlI genes to complement the defect of the lasI rhlI double mutant was also examined. The presence of any of these plasmids within the lasI rhlI double mutant significantly enhanced its in vivo virulence, as well as its ability to spread within the burned skin. These results suggest that the quorum-sensing systems play an important role in the horizontal spread of P. aeruginosa within burned skin and in the dissemination of P. aeruginosa within the bodies of burned-and-infected mice and contributed to the overall virulence of P. aeruginosa in this animal model. (+info)