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Biomedical subjects

Glenn D Warden

Publications and source records attributed to Glenn D Warden.

At least 19 recordsLinked to original sources
PubMed2006

Norepinephrine modulates the inflammatory and proliferative phases of wound healing.

BACKGROUND: Injury results in the massive release of norepinephrine (NE) into the peripheral circulation. Recent investigations have demonstrated functional adrenoreceptors on the cellular mediators of cutaneous wound healing and NE-induced phenotypic alterations in immune cells have been demonstrated in vitro. Despite this, there is little description of how NE might alter the phases of wound healing in vivo. The purpose of this study was to compare cutaneous wound healing in norepinephrine-intact and norepinephrine-depleted mice. METHODS: Norepinephrine-depleted (NED) mice were generated by chemical axotomy with 6-hydroxydopamine and compared with norepinephrine-intact (NEI) animals (n = 6-12 per group, per time point). Using an excisional wound model, neutrophil recruitment was measured by myeloperoxidase assay. Macrophage recruitment and angiogenesis were measured by immunohistochemistry and re-epithelialization was determined histologically. The development of incisional wound disruption strength was determined over time. Finally, macrophage scavenger function was assessed by an in vitro latex bead phagocytosis assay. RESULTS: Wounds from NEI mice demonstrated greater neutrophil infiltration than NED wounds (24, 72 hours; p < 0.05). Wound macrophage recruitment was initially higher in NEI animals (24 hours, p < 0.05), but was eventually surpassed by that of NED animals (120 hours, p < 0.05). Angiogenesis was decreased while re-epithelialization was accelerated in NEI animals (p < 0.05). Wound disruption strength and macrophage scavenger function were unaltered between NED and NEI mice. CONCLUSIONS: Norepinephrine modulates the inflammatory and proliferative phases of wound healing in a temporally defined, cell-specific manner. By increasing recruitment of innate immune cells and expediting wound closure, norepinephrine appears to play a protective role in defense against infection.

Animals↗
PubMed2005

Protein breakdown in muscle from burned rats is blocked by insulin-like growth factor i and glycogen synthase kinase-3beta inhibitors.

We reported previously that IGF-I inhibits burn-induced muscle proteolysis. Recent studies suggest that activation of the phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway with downstream phosphorylation of Forkhead box O transcription factors is an important mechanism of IGF-I-induced anabolic effects in skeletal muscle. The potential roles of other mechanisms in the anabolic effects of IGF-I are less well understood. In this study we tested the roles of mammalian target of rapamycin and glycogen synthase kinase-3beta (GSK-3beta) phosphorylation as well as MAPK- and calcineurin-dependent signaling pathways in the anticatabolic effects of IGF-I by incubating extensor digitorum longus muscles from burned rats in the presence of IGF-I and specific signaling pathway inhibitors. Surprisingly, the PI3K inhibitors LY294002 and wortmannin reduced basal protein breakdown. No additional inhibition by IGF-I was noticed in the presence of LY294002 or wortmannin. Inhibition of proteolysis by IGF-I was associated with phosphorylation (inactivation) of GSK-3beta. In addition, the GSK-3beta inhibitors, lithium chloride and thiadiazolidinone-8, reduced protein breakdown in a similar fashion as IGF-I. Lithium chloride, but not thiadiazolidinone-8, increased the levels of phosphorylated Foxo 1 in incubated muscles from burned rats. Inhibitors of mammalian target of rapamycin, MAPK, and calcineurin did not prevent the IGF-I-induced inhibition of muscle proteolysis. Our results suggest that IGF-I inhibits protein breakdown at least in part through a PI3K/Akt/GSK3beta-dependent mechanism. Additional experiments showed that similar mechanisms were responsible for the effect of IGF-I in muscle from nonburned rats. Taken together with recent reports in the literature, the present results suggest that IGF-I inhibits protein breakdown in skeletal muscle by multiple mechanisms, including PI3K/Akt-mediated inactivation of GSK-3beta and Foxo transcription factors.

Animals↗
PubMed2005

Surgical treatment of hidradenitis suppurativa: a 10-year experience.

BACKGROUND: Hidradenitis suppurativa (HS) is a disease of the apocrine sweat glands resulting in chronic wounds with abscesses, sinuses, and fibrosis. Because many patients referred for treatment have both recurrent and progressive disability, we attempted to determine which factors have the greatest impact on outcome so we could develop an operative treatment algorithm. METHODS: We identified 57 patients with HS who underwent operative treatment for chronic recurrent HS from January 1994 through December 2003. Charts were reviewed for demographic, treatment, and outcome data. RESULTS: The mean age at presentation was 34 years and the average duration of symptoms was 6.7 years. Two thirds of the patients had undergone 1 or more incision and drainage procedures and 90% had received long-term antibiotic therapy. Axillary involvement was present in 88% of women and was bilateral in half of all patients. Inguinoperineal involvement was present in 87% of men and was bilateral in 92% of all patients. An algorithm for operative treatment was developed based on the extent of involvement, chronicity, and comorbid conditions. Ninety-two operative procedures were performed, 50% involved the axilla, 36% involved the perineum, and 14% involved the inguinal region. Excision and primary closure was used for localized disease; wide excision with or without skin grafting was used for diffuse disease. CONCLUSIONS: HS is a chronic relapsing disease that frequently causes disabling pain, diminished range of motion, and social isolation. Definitive treatment involves operative excision of the involved apocrine tissue and should be individualized based on the stage and location of the disease.

Adult↗
PubMed2004

Hypovitaminosis D in acutely injured pediatric burn patients.

PROBLEM: The prevalence of vitamin D insufficiency, its etiology, and associated sequelae among acutely injured burn patients is unknown. OBJECTIVE: This study assessed vitamin D and endocrine status, as well as the effect of anabolic agents, in pediatric patients who had sustained burns in excess of 25% total body surface area (TBSA). SUBJECTS: Sixty-nine patients with a mean TBSA burn of 50.6+/-2.2% (range 27% to 94%) and full thickness injury of 41.3+/-3.0% (range 0% to 94%) were studied. Subjects ranged in age from 0.6 to 18 years (mean, 5.8+/-0.6 years). Main outcome measures Blood samples were obtained for serum 25-hydroxyvitamin D (D25), 1,25-dihydroxyvitamin D (D1,25), albumin, cortisol, triiodothyronine (T3), tetraiodothyronine (T(4)), thyroid stimulating hormone (TSH), and parathormone (PTH). RESULTS: Two hundred eighty morning blood samples of D25 and D1,25 demonstrated that 45% and 26.2% were low and 8.9% and 11% were very low, respectively. At least one low D25 or D1,25 level occurred in 62.3% of all subjects. Very low levels were noted in 23.2% of all patients. There was an increased incidence of hyperparathyroidism in patients with very low serum D25. Vitamin D25 and D1,25 levels were lower in subjects with larger burns or inhalation injury, as well as those treated with thyroxine or oxandrolone. Serum albumin, cortisol, T(4), and TSH were not correlated with concentration of vitamin D. CONCLUSIONS: Demonstration of a high incidence of low serum vitamin D indicates vitamin D status may be significantly compromised in burned children. It is unclear why vitamin D deficiency exists in this population. The most effective way to improve vitamin D status remains elusive at this time.

Adolescent↗
PubMed2002

Principles and practices for treatment of cutaneous wounds with cultured skin substitutes.

BACKGROUND: Skin substitutes prepared from cultured skin cells and biopolymers may reduce requirements for donor skin autograft, and have been shown to be effective in treatment of excised burns, burn scars, and congenital skin lesions. DATA SOURCES: Cultured skin substitutes (CSS) generate skin phenotypes (epidermal barrier, basement membrane) in the laboratory, and restore tissue function and systemic homeostasis. Healed skin is smooth, soft and strong, but develops irregular degrees of pigmentation. Quantitative analysis demonstrates that CSS closes 67 times the area of the donor skin, compared to less than 4 times for split-thickness skin autograft. CONCLUSIONS: CSS reduce requirements for donor skin autograft for closure of excised, full-thickness cutaneous wounds, and demonstrate qualitative outcome that is not different from meshed, split-thickness autograft. These results offer reductions in morbidity and mortality for the treatment of burns and chronic wounds, and for cutaneous reconstruction.

Biocompatible Materials↗
PubMed2002

Vitamin C regulates keratinocyte viability, epidermal barrier, and basement membrane in vitro, and reduces wound contraction after grafting of cultured skin substitutes.

Cultured skin substitutes have become useful as adjunctive treatments for excised, full-thickness burns, but no skin substitutes have the anatomy and physiology of native skin. Hypothetically, deficiencies of structure and function may result, in part, from nutritional deficiencies in culture media. To address this hypothesis, vitamin C was titrated at 0.0, 0.01, 0.1, and 1.0 mM in a cultured skin substitute model on filter inserts. Cultured skin substitute inserts were evaluated at 2 and 5 wk for viability by incorporation of 5-bromo-2'-deoxyuridine (BrdU) and by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) conversion. Subsequently, cultured skin substitute grafts consisting of cultured human keratinocytes and fibroblasts attached to collagen-glycosaminoglycan substrates were incubated for 5 wk in media containing 0.0 mM or 0.1 mM vitamin C, and then grafted to athymic mice. Cultured skin substitutes (n = 3 per group) were evaluated in vitro at 2 wk of incubation for collagen IV, collagen VII, and laminin 5, and through 5 wk for epidermal barrier by surface electrical capacitance. Cultured skin substitutes were grafted to full-thickness wounds in athymic mice (n = 8 per group), evaluated for surface electrical capacitance through 6 wk, and scored for percentage original wound area through 8 wk and for HLA-ABC-positive wounds at 8 wk after grafting. The data show that incubation of cultured skin substitutes in medium containing vitamin C results in greater viability (higher BrdU and MTT), more complete basement membrane development at 2 wk, and better epidermal barrier (lower surface electrical capacitance) at 5 wk in vitro. After grafting, cultured skin substitutes with vitamin C developed functional epidermal barrier earlier, had less wound contraction, and had more HLA-positive wounds at 8 wk than without vitamin C. These results suggest that incubation of cultured skin substitutes in medium containing vitamin C extends cellular viability, promotes formation of epidermal barrier in vitro, and promotes engraftment. Improved anatomy and physiology of cultured skin substitutes that result from nutritional factors in culture media may be expected to improve efficacy in treatment of full-thickness skin wounds.

Animals↗
PubMed2002

Cultured skin substitutes reduce donor skin harvesting for closure of excised, full-thickness burns.

OBJECTIVE: Comparison of cultured skin substitutes (CSS) and split-thickness skin autograft (AG) was performed to assess whether donor-site harvesting can be reduced quantitatively and whether functional and cosmetic outcome is similar qualitatively in the treatment of patients with massive cutaneous burns. SUMMARY BACKGROUND DATA: Cultured skin substitutes consisting of collagen-glycosaminoglycan substrates populated with autologous fibroblasts and keratinocytes have been shown to close full-thickness skin wounds in preclinical and clinical studies with acceptable functional and cosmetic results. METHODS: Qualitative outcome was compared between CSS and AG in 45 patients on an ordinal scale (0, worst; 10, best) with primary analyses at postoperative day 28 and after about 1 year for erythema, pigmentation, pliability, raised scar, epithelial blistering, and surface texture. In the latest 12 of the 45 patients, tracings were performed of donor skin biopsies and wounds treated with CSS at postoperative days 14 and 28 to calculate percentage engraftment, the ratio of closed wound:donor skin areas, and the percentage of total body surface area closed with CSS. RESULTS: Measures of qualitative outcome of CSS or AG were not different statistically at 1 year after grafting. Engraftment at postoperative day 14 exceeded 75% in the 12 patients evaluated. The ratio of closed wound:donor skin areas for CSS at postoperative day 28 was significantly greater than for conventional 4:1 meshed autografts. The percentage of total body surface area closed with CSS at postoperative day 28 was significantly less than with AG. CONCLUSIONS: The requirement for harvesting of donor skin for CSS was less than for conventional skin autografts. These results suggest that acute-phase recovery of patients with extensive burns is facilitated and that complications are reduced by the use of CSS together with conventional skin grafting.

Burns↗
PubMedDate not supplied

Multicenter postapproval clinical trial of Integra dermal regeneration template for burn treatment.

The safety and effectiveness of Integra Dermal Regeneration Template was evaluated in a postapproval study involving 216 burn injury patients who were treated at 13 burn care facilities in the United States. The mean total body surface area burned was 36.5% (range, 1-95%). Integra was applied to fresh, clean, surgically excised burn wounds. Within 2 to 3 weeks, the dermal layer regenerated, and a thin epidermal autograft was placed. The incidence of invasive infection at Integra-treated sites was 3.1% (95% confidence interval, 2.0-4.5%) and that of superficial infection 13.2% (95% confidence interval, 11.0-15.7%). Mean take rate of Integra was 76.2%; the median take rate was 95%. The mean take rate of epidermal autograft was 87.7%; the median take rate was 98%. This postapproval study further supports the conclusion that Integra is a safe and effective treatment modality in the hands of properly trained clinicians under conditions of routine clinical use at burn centers.

Adolescent↗
PubMedDate not supplied

The 2002 Moyer Award. Metabolic effects of vitamin D on serum calcium, magnesium, and phosphorus in pediatric burn patients.

Severe burn injury results in profound metabolic derangements. Recently, we have shown that vitamin D metabolism is disturbed after burn injury. Vitamin D is essential for calcium and phosphorus homeostasis and skeletal bone integrity. The role of vitamin D on magnesium homeostasis is not well understood. The purpose of this study was to assess the effects of vitamin D deficiency on serum electrolytes. Forty-one pediatric burn patients with a mean (+/- SEM) total body surface area burn of 53.1 +/- 2.9% and full-thickness injury of 44.2 +/- 4.1% were studied from July 1996 to December 2000. The mean age of the patients was 6.5 +/- 0.8 years. Patients were studied for 6 weeks after admission to the hospital. Blood samples were obtained weekly for serum 25-hydroxycholecalciferol (25D), 1,25-dihydroxycholecalciferol (1,25D), and daily for calcium, magnesium, and phosphorus. Total intravenous (IV) replacement of calcium, magnesium, and phosphorus was also quantitated retrospectively. Bivariate and multivariate correlational analysis was used for statistical comparison. For the study duration, multivariate analysis demonstrated a positive correlation between 25D and serum calcium (r =.47, P <.05) and 1,25D and calcium (r =.27, P <.05). Overall, calcium had a positive correlation with phosphorus and a negative correlation with IV calcium replacement (ie, patients with lower calcium received more IV replacement). During the initial week of hospitalization (week 0), decreased 25D (mean 11.6 ng/ml; normal range 15-57 ng/ml) and 1,25D (mean 13.9 pg/ml; normal range 15-75 pg/ml) did not correlate with any other measured variable. In week 1, 1,25D (mean 15.2 ng/ml) had a positive correlation (r =.410, P <.05) with calcium (mean 7.70 mg/dl). Hypovitaminosis D observed in burn injury correlates with serum calcium and phosphorus abnormalities. Early after injury (<1 week) there was no observed correlation between vitamin D and other variables possibly because of the effects of burn shock. After 1 week, vitamin D appears to significantly effect phosphorus homeostasis. The relationship between vitamin D and magnesium is not well established. These results may indicate a role for vitamin D replacement therapy during the initial phase of burn resuscitation.

Burns↗
PubMedDate not supplied

The 2002 Clinical Research Award. An evaluation of the safety of early vs delayed enteral support and effects on clinical, nutritional, and endocrine outcomes after severe burns.

Early enteral support is believed to improve gastrointestinal, immunological, nutritional, and metabolic responses to critical injury; however, this premise is in need of further substantiation by definitive data. The purpose of this prospective study was to examine the effectiveness and safety of early enteral feeding in pediatric patients who had burns in excess of 25% total body surface area. Seventy-seven patients with a mean percent total body surface area burn of 52.5 +/- 2.3 (range 26-91), percent full thickness injury of 44.7 +/- 2.8 (range 0-90), and age ranging from 3.1 to 18.4 (mean 9.3 +/- 0.5) were randomized to two groups: early (feeding within 24 hours of injury) vs control (feeding delayed at least 48 hours postburn). Nutrient intake was measured daily, indirect calorimetry was performed biweekly, and blood and urine samples were obtained for the assay of cortisol, glucagon, insulin, gastrin, epinephrine, norepinephrine, dopamine, triiodothyronine, tetraiodothyronine, albumin, transferrin, prealbumin, retinol-binding protein, glucose, nitrogen balance, and 3-methylhistidine throughout the study period. Three protocol violations occurred, and two patients were transferred to another hospital; these patients were excluded from the study. No patient in either group experienced tube feeding aspiration. No differences were evident in infection, diarrhea, hospital length of stay, or mortality outcomes. A higher incidence of reportable adverse events coincided with early feeding (22 vs 8%), but this was not statistically significant. The delayed feeding group demonstrated a significant caloric deficit during postburn week (PBW) 1 (P <.0001) and PBW2 (P =.0022). Serum insulin (P =.0004) and triiodothyronine (P =.0162) were higher in the early fed group during PBW1. A decrease in 3-methylhistidine output (suggesting a decrease in protein breakdown) was also evident during PBW1 (P =.0138). No other significant trends in study outcome variables were noted. In conclusion, provision of enteral nutrients shortly after burn injury reduces caloric deficits and may stimulate insulin secretion and protein retention during the early phase postburn. These data, however, do not necessarily reaffirm the safety of early enteral feeding, nor do they associate earlier feeding with a direct improvement in endocrine status or a reduction in morbidity, mortality, hypermetabolism, or hospital stay. Future studies are needed to establish precise feeding implementation times that maximize clinical benefit while minimizing morbidity in the critically injured burn patient.

Adolescent↗
PubMedDate not supplied

Four-year review of burns as an etiologic factor in the development of long bone fractures in pediatric patients.

Reduced bone density has been documented in children after burns. This loss of bone may place children at heightened risk for fractures. The medical records of all acutely injured patients with burns in excess of 40% TBSA burn admitted to our institution between January 1, 1997, through December 31, 2000, were reviewed for fracture incidence. Patients with fractures sustained during the course of initial trauma were not included in the review. One hundred four records were reviewed. These patients had a mean age of 6.7 +/- 0.51 years, (range, 0.2 to 18.0) and a mean %TBSA burn of 59.9 +/- 1.60 (range, 40 to 98) with a mean full-thickness %burn of 51.7 +/- 2.16 (range, 0 to 95). Fifteen long bone fractures were documented in six patients during the review time frame. All fractures were initially suspected by physical therapy personnel upon regularly scheduled therapy sessions and subsequently verified by x-ray. All fractures identified by this review occurred in children less than 3 years of age. Most fractures were noted during the rehabilitation phase of injury (range, 73 to 283 days after burn) once wounds were more than 95% healed, except for one child, who sustained multiple fractures during the acute recovery phase at a referring hospital. A 5.8% incidence of fractures was noted in patients with burns in excess of 40% (6 of 104 admissions). The etiology of the fractures is unknown, although the hormonal milieu postburn, depressed vitamin D status, inadequate protein intake, and decreased weight-bearing activity are potential contributory factors. In addition, infants and toddlers tend to provide more resistance to therapy because of an inherent lack of cognition. This may account for the increased breaks in this population.

Burns↗
PubMedDate not supplied

Home oxygen therapy: adjunct or risk factor?

The use of home oxygen therapy has become increasingly commonplace and is frequently prescribed by medical specialists. In this study, we have identified a generally unexpected risk of home oxygen therapy. We performed a retrospective review of 3673 consecutive patients treated at our adult burn center over a 10-year period from 1992 to 2001. We identified 27 patients with burns directly attributable to oxygen therapy and also noted an increased incidence of these injuries over the study period. The average age of the patients was 68.1 +/- 9.2 years (range, 40-82 years). Twenty-three were using oxygen at home, three in nursing homes, and one was an inpatient in an acute care facility. Twenty-five patients (93%) were receiving oxygen therapy for the diagnosis of chronic obstructive pulmonary disease. Twenty-four patients (89%) were smoking while using oxygen, two were lighting pilot lights, and one was lighting his wife's cigarette. Four patients (15%) sustained burns greater than 10% TBSA. Seventeen patients (63%) had only partial thickness burns. Thirteen patients (48%) required admission for treatment of their burn injuries. The average length of stay for those admitted was 4.4 days. The average hospital charge for admitted patients was US dollars 8055. There were four deaths (15%), all of which were correlated only with the extent of injury. Although intuitively obvious to most health care professionals, not all patients understand that oxygen therapy and cigarettes or open flame can result in a significant injury. Although some practitioners have advocated not prescribing home oxygen for those who continue to smoke, an alternative means of reducing the incidence of this preventable complication appears warranted. Prevention efforts should focus on the counseling of patients and their caregivers as well as educating primary care physicians, nurses, and home health providers as to the dangers of oxygen use.

Accident Prevention↗
PubMedDate not supplied

Procalcitonin in pediatric burn patients: an early indicator of sepsis?

To determine whether changes in procalcitonin (PCT) could be used to predict the onset of sepsis, daily PCT levels were monitored in 20 burned children. Analysis indicated a PCT rise of 5 ng/ml or greater as the best indication of sepsis. We compared the surgeons' determination of sepsis, which was based on changes in platelet count, C-reactive protein (CRP), and other clinical manifestations, with the prediction of sepsis from PCT. There were 26 septic episodes and 36 nonseptic episodes in the 20 patients. PCT results were classified as to true positives, false positives, true negatives, and false negatives. As an indicator of sepsis, the PCT assay had a sensitivity of 42%, a specificity of 67%, and an efficiency of 57%. Even when the assay correctly identified sepsis, the determination was made an average of 0.8 days after the surgeon had already made the diagnosis based on CRP and/or platelet count. We conclude that PCT is not as effective as CRP and/or platelet count in the early detection of sepsis in burned children.

Burns↗
PubMedDate not supplied

Insulin-like growth factor-I blocks dexamethasone-induced protein degradation in cultured myotubes by inhibiting multiple proteolytic pathways: 2002 ABA paper.

In previous studies, insulin-like growth factor-I (IGF-I) inhibited glucocorticoid-induced muscle protein breakdown, but the intracellular mechanisms of this effect of IGF-I are not well understood. The purpose of the present study was to test the hypothesis that IGF-I inhibits multiple proteolytic pathways in dexamethasone-treated cultured L6 myotubes. Myotubes were treated with 1 microM dexamethasone for 6 hours in the absence or presence of 0.1 microg/ml of IGF-I. Protein degradation was determined by measuring the release of trichloroacetic acid-soluble radioactivity from proteins prelabeled with 3H-tyrosine. The contribution of lysosomal, proteasomal-dependent, and calpain-dependent proteolysis to the inhibitory effect of IGF-I on protein degradation was assessed by using inhibitors of the individual proteolytic pathways (methylamine, beta-lactone, and E64, respectively). In addition, the influence of IGF-I on cathepsin B, proteasome, and calpain activities was determined. Treatment of L6 myotubes with dexamethasone resulted in an approximately 20% increase in protein degradation. This effect of dexamethasone was completely blocked by IGF-I. When the different protease inhibitors were used, results showed that IGF-I inhibited lysosomal, proteasomal-dependent, and calpain-dependent proteolysis by 70, 44, and 41%, respectively. Additionally, IGF-I blocked the dexamethasone-induced increase in cathepsin B, proteasome, and calpain activities. The present results suggest that IGF-I inhibits glucocorticoid-induced muscle proteolysis by blocking multiple proteolytic pathways.

Animals↗