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Biomedical subjects

M G Jeschke

Publications and source records attributed to M G Jeschke.

At least 19 recordsLinked to original sources
PubMed2006

Gene therapy in wound healing: present status and future directions.

Gene therapy was traditionally considered a treatment modality for patients with congenital defects of key metabolic functions or late-stage malignancies. The realization that gene therapy applications were much vaster has opened up endless opportunities for therapeutic genetic manipulations, especially in the skin and external wounds. Cutaneous wound healing is a complicated, multistep process with numerous mediators that act in a network of activation and inhibition processes. Gene delivery in this environment poses a particular challenge. Numerous models of gene delivery have been developed, including naked DNA application, viral transfection, high-pressure injection, liposomal delivery, and more. Of the various methods for gene transfer, cationic cholesterol-containing liposomal constructs are emerging as a method with great potential for non-viral gene transfer in the wound. This article aims to review the research on gene therapy in wound healing and possible future directions in this exciting field.

Animals↗
PubMed2005

The structure and composition of liposomes can affect skin regeneration, morphology and growth factor expression in acute wounds.

Liposomal gene transfer is an effective therapeutic approach to improve dermal and epidermal regeneration. The purpose of the present study was to define whether the biological or chemical structure of a liposome influences cellular and biological regeneration in the skin, and to determine by which mechanisms possible changes occur. Rats were inflicted a full-excision acute wound and divided into three groups to receive weekly subcutaneous injections of DMRIE liposomes plus the Lac Z gene, or DOTAP/Chol liposomes plus the Lac Z gene, or saline. Planimetry, immunological assays, histological and immunohistochemical techniques were used to determine cellular responses after gene transfer, protein expression, dermal and epidermal regeneration. DOTAP/Chol increased IGF-I and KGF protein concentration and caused concomitant cellular responses, for example, by increasing IGFBP-3, P<0.05. DOTAP/Chol liposomes improved epidermal regeneration by exhibiting the most rapid area and linear wound re-epithelization compared to DMRIE or control, P<0.001. DOTAP/Chol and DMRIE exerted promitogenic and antiapoptotic effects on basal keratinocytes, P<0.05. Dermal regeneration was improved in DOTAP/Chol-treated animals by an increased collagen deposition and morphology, P<0.001. DOTAP/Chol liposomes increased vascular endothelial growth factor concentrations and thus neovascularization when compared with DMRIE and saline, P<0.001. In the present study, we showed that different liposomes have different effects on intracellular and biological responses based on its chemical and molecular structure. For gene transfer in acute wounds, the administration of DOTAP/Chol liposomes appears to be beneficial.

Animals↗
PubMed2004

Composition and characteristics of an autologous thrombocyte gel.

BACKGROUND: The purpose of the current study was to characterize and compare an autologous thrombocyte gel containing several blood components with a commercially available glue. MATERIALS AND METHODS: Twenty-five volunteers had blood drawn, and lab values, characteristics of the platelet-enriched plasma (PRP), thrombocyte aggregation, electron microscopic examinations, and the breaking strength were determined and compared to a commercial glue. RESULTS: Overall 65% of the total thrombocytes could be isolated from the volunteers and an enrichment of 300% with an autotransfusion device could be achieved. Thrombocyte aggregation as a marker for thrombocyte function decreased from 92% in patients to 71% in the PRP. The autologous glue demonstrated a significant reduced breaking strength (0,76 N/cm(3)) compared to the commercial glue (7.42 N/cm(2)), P < 0.05. The decrease in breaking strength could be correlated with the thrombocyte concentration, P < 0.05. CONCLUSIONS: In the present study we have shown that an autologous platelet-enriched plasma cannot be used as a glue in the common sense to seal stitches or prosthesis. Platelet gels, however, have a high concentration of platelets that release the bioactive proteins and growth factors are necessary to initiate and accelerate tissue repair and enhance dermal and epidermal regeneration. To evaluate the possible clinical implication prospective, randomized studies should be performed to examine the effect of autologous plasma platelet-enriched plasma on wound healing.

Blood Platelets↗
PubMed2004

Liposomal gene transfer of multiple genes is more effective than gene transfer of a single gene.

Liposomal gene transfer is an effective therapeutic approach for the treatment of several pathophysiologic states. The purpose of the present study was to define whether gene transfer of multiple genes is a feasible approach and whether this approach would be more effective than the single transfer of cDNA. Rats were inflicted an acute wound and divided into four groups to receive weekly subcutaneous injections of liposomes plus the Lac-Z gene (0.22 microg, vehicle), or liposomes plus the insulin like-growth factor-I (IGF-I)cDNA (2.2 microg) and Lac Z gene (0.22 microg), or liposomes plus the keratinocyte growth factor (KGF) cDNA (2.2 microg) and Lac Z gene (0.22 microg), or liposomes plus the IGF-I/KGF cDNA (2.2 microg) and Lac Z gene (0.22 microg). Planimetry, immunological assays, histological and immunohistochemical techniques were used to determine molecular mechanisms after gene transfer, protein expression, dermal and epidermal regeneration. IGF-I/KGF cDNA transfer increased IGF-I and KGF protein concentration and caused concomitant cellular responses, for example,by increasing IGFBP-3, P<0.05. IGF-I/KGF cDNA gene transfer improved epidermal regeneration by exhibiting the most rapid area and linear wound re-epithelization by almost 250% compared to control and each growth factor given individually, P<0.001, which was probably due to promitogenic and antiapoptotic effects on basal keratinocytes when compared to controls, P<0.001. Dermal regeneration was improved in IGF-I/KGF cDNA-treated animals by an increased collagen deposition and morphology when compared with vehicle, IGF-I and KGF, P<0.001. IGF-I/KGF cDNA increased VEGF concentrations and thus neovascularization when compared with vehicle, IGF-I and KGF, P<0.001. In the present study, we showed that exogenous gene transfer of multiple cDNA sequences have an additive effect on intracellular and biological responses when compared to the same gene administered as a single cDNA sequence. Our findings demonstrate that gene therapy with multiple genes is feasible, and that the gene transfer of multiple genes can enhance and accelerate physiologic and biological effects.

Animals↗
PubMed2004

[Indication and clinical results of buried skin grafting to treat problematic wounds].

In 1920 Braun described a technique of skin grafting particularly designed for areas where shearing forces, high pressure and extensive secretion cause repetitive loss of conventionally transplanted skin. During the last 10 years we successfully used this technique when impaired wound healing was encountered due to various reasons. Clinical examples of application and results are presented. By combining this technique with vacuum therapy, formation of granulation tissue can be accelerated, thereby resulting in successful transplantation of problematic and therapy resistant wounds.

Adult↗
PubMed2002

Non-viral liposomal keratinocyte growth factor (KGF) cDNA gene transfer improves dermal and epidermal regeneration through stimulation of epithelial and mesenchymal factors.

Keratinocyte growth factor (KGF) stimulates epithelial cell differentiation and proliferation, which are of major importance for wound healing. Local protein administration, however, has been shown to be ineffective due to enzymes and proteases in the wound fluid. We hypothesized that delivering KGF as a non-viral liposomal cDNA gene complex is a new approach that would effectively enhance dermal and epidermal regeneration. Twenty-two rats were given an acute wound and divided into two groups to receive weekly subcutaneous injections of liposomes plus the LacZ gene (0.2 microg, vehicle), or liposomes plus the KGF cDNA (2.2 microg) and LacZ cDNA (0.2 microg). Transfection was confirmed by histochemical assays for beta-galactosidase. Planimetry, histological and immunohistochemical techniques were used to determine protein expression, dermal and epidermal regeneration. Transfection and subsequent KGF expression was found in diving cells in the granulation tissue. Epidermal regeneration was improved by 170% in rats receiving the KGF cDNA constructs by exhibiting the most rapid area and linear wound re-epithelialization, P < 0.0001. KGF improved epidermal cell net balance by increasing skin cell proliferation and decreasing skin cell apoptosis, P < 0.0001. Dermal regeneration was further improved in KGF cDNA treated animals by an increased collagen deposition and morphology, P < 0.0001. KGF cDNA increased neo-vascularization and concomitant VEGF concentrations when compared with vehicle, P < 0.01. KGF cDNA did not only stimulate epithelial cells, but also mesenchymal cells through increases in IGF-I concentration, P < 0.005. Liposomes containing the KGF cDNA gene constructs were effective in improving epidermal and dermal regeneration. KGF gene transfer to acute wounds may represent a new therapeutic strategy to enhance wound healing.

Animals↗
PubMed2001

Nutritional intervention high in vitamins, protein, amino acids, and omega3 fatty acids improves protein metabolism during the hypermetabolic state after thermal injury.

HYPOTHESIS: Characteristic of the hypermetabolic response to a thermal injury is the massive protein catabolism and compromised structure and function of essential organs. Nutrition has been suggested to affect protein metabolism and clinical outcome after a severe injury but published studies show controversial data. The purpose of this study was to determine the effect of enriched nutritional support during the postburn hypermetabolic state on protein metabolism in serum, liver, muscle, and skin. SETTING: Laboratory. INTERVENTION: Twenty-two rats were given burns covering 60% of their total body surface area and randomized to receive either standard rat chow (control) or a diet high in vitamins, protein, amino acids, and omega3 fatty acids. MAIN OUTCOME MEASURES: Five weeks after injury, body weight, serum, muscle, and hepatic protein content, insulin-like growth factor I concentration, and wound healing (reepithelization) were determined. RESULTS: Rats receiving the enriched diet showed a gradual improvement in body weight 1, 2, 3, 4, and 5 weeks postburn compared with controls (P< .001). Diet-fed rats demonstrated higher protein and insulin-like growth factor 1 content in serum, muscle, and liver 5 weeks after trauma (P< .001). Serum protein, albumin, and transferrin levels were significantly increased in rats receiving the diet compared with control rats (P< .001). Reepithelization was accelerated in rats receiving the enriched diet 4 (diet-fed, mean +/- SD, 23% +/- 1% vs controls, 17% +/- 1%; P< .001) and 5 (diet-fed, 24% +/- 1% vs controls, 18% +/- 1%; P< .001) weeks postburn compared with control rats. CONCLUSIONS: Nutritional intervention high in protein, vitamins, amino acids, and omega3 fatty acids improves protein net balance during the hypermetabolic response to thermal injury. Compromised organ function and structure and clinical outcome during the hypermetabolic response may be improved.

Animals↗
PubMed2001

Effect of varying burn sizes and ambient temperature on the hypermetabolic rate in thermally injured rats.

BACKGROUND: Small animals with scald covering 50% of their total body surface area (TBSA) have been used to study the hypermetabolic burn response. In the 50% TBSA burn rat model, the area of normal skin that is available for animal instrumentation is restricted and the mortality rate has been high. The purpose of this study was to determine whether a smaller burn size can induce a similar hypermetabolic response with mortality rates lower than those of the 50% TBSA model. METHODS: Rats were randomly divided into four groups to receive a 0% (sham nonburned), 30%, 40%, or 50% TBSA third-degree scald burn. The hypermetabolic response was determined by measuring changes in body weight and oxygen consumption at ambient temperatures of 21, 26, and 31 degrees C for each burn size. Weight measurements were made daily while oxygen consumption was measured 7, 11, and 14 days after thermal injury. RESULTS: All thermally injured rats lost body weight; however, there were no significant differences between the 30, 40, and 50% TBSA burn groups. Burn induced a hypermetabolic response as indicated by an increase in oxygen consumption from 130 to 200% that of sham nonburned rats. No significant difference in oxygen consumption could be shown over the study period between the three burn sizes at different ambient temperatures. Mortality was 0% in the sham and 30% group, 10% for the 40% group, and 50% for the 50% TBSA burn group. CONCLUSIONS: From our study we conclude that a burn size covering 30% of the TBSA induces the same hypermetabolic response as a 50% TBSA burn.

Animals↗
PubMed2001

Selective decontamination of the digestive tract in severely burned pediatric patients.

Infection is still one of the leading causes of morbidity and mortality in severely burned patients. Evidence suggests that many of the responsible organisms are endogenous. Systemic antibiotic prophylaxis is not effective, and produces resistant strains of microorganisms. SDD has been postulated to be beneficial for controlling and decreasing infections in critically ill patients. Its efficacy in severely burned patients, however, remains controversial. In order to analyze the efficacy of selective decontamination of the digestive (SDD) tract, to decrease the bacterial colonization of the aerodigestive tract and burn wounds, and the incidence of septic complications in severely burned children, 23 pediatric patients affected of severe burns were prospectively randomized in a double-blinded study. Eleven patients received SDD (Polymyxin E, Tobramycin, and Amphotericin B), and 12 placebo. Demographics, hospital course, microbiology results, complications, infectious episodes, and serum levels of IL-1beta, IL-6, IL-10, and TNF-alpha were compared to determine the efficacy of SDD. Colonization rates to the wound, sputum, nasogastric aspirates, and feces were similar. Pneumonia, sepsis and other complications had similar incidence in both groups. Serum levels of all cytokines studied were also comparable, suggesting a similar inflammatory status in all patients, regardless of the treatment received. Patients in the SDD group, however, had a significantly higher incidence of diarrhea (P=0.003). We can conclude that selective decontamination of the digestive tract with Polymixin E, Tobramycin and Amphotericin B is not effective to decrease bacterial colonization and infectious episodes in severely burned pediatric patients.

Amphotericin B↗
PubMed2001

The effect of short-term growth hormone treatment on growth and energy expenditure in burned children.

Delays in growth are commonly observed in children who have sustained a severe cutaneous burn. The reasons for this growth delay are not completely known, but in adults, plasma growth hormone (GH) levels have been shown to decrease after thermal injury. If this is also the case in severely burned children, the low GH levels may contribute to their chronic growth delay. We propose that treatment with rhGH may prevent this burn-induced growth delay. Height velocities were measured for up to 2 years after injury in 38 burned children (age 7+/-1 years) with a 64+/-2% total burn surface area (TBSA) burn and a 59+/-3% third-degree burn who received 0.2 mg/kg/day rhGH during hospitalization. These height velocities were compared to 41 burned children (age 8+/-1 years) with a 64+/-3% TBSA burn and a 60+/-3% TBSA third-degree burn who were treated similarly but did not receive rhGH. Height velocities and height percentiles were compared to standard height velocity and percentile nomograms of unburned children. To determine the effect of rhGH on energy requirements, resting energy expenditures (REE) were measured by indirect calorimetry and compared to values calculated from the Harris-Benedict equation. All data are presented as mean+/-S.E.M. No differences in average height percentile could be shown between those receiving GH and controls at admission and 6 months after burn. There was, however, a significant difference (P<0.05) in height velocity during the first 2 years after burn between GH (47th+/-6 percentile) and controls (32nd+/-5 percentile). For rhGH-treated children, the REE was elevated by 34+/-4% versus 35+/-5% for controls. Recombinant human GH, given during acute hospitalization, maintained growth in severely burned children who would otherwise experience a significant growth delay. Treatment with rhGH did not atttenuate their elevated REE.

Adolescent↗
PubMed2001

Therapeutic success and efficacy of nonviral liposomal cDNA gene transfer to the skin in vivo is dose dependent.

It is well documented that responses to growth factor treatment typically display bell-shaped dose responses that can significantly affect efficacy. Here we tested the hypothesis that nonviral liposomal gene delivery also displays this characteristic. We chose two different growth factors, keratinocyte growth factor (KGF) and insulin-like growth factor-I (IGF-I) CMV-driven transfecting constructs at three different concentrations and assessed efficacy on several physiological parameters that are descriptive of wound healing progress in a burn-wound healing model. Rats were given a 60% TBSA scald burn and randomly divided into one of seven groups to receive weekly subcutaneous injections of liposomes containing the cDNA for KGF (0.2 microg, 2.2 microg, or 22.2 microg), or liposomes containing the cDNA for IGF-I (0.2 microg, 2.2 microg, or 22.2 microg) at various concentrations, but constant liposome:DNA ratios and a LacZ gene (0.2 microg) CMV-driven construct for beta-galactosidase as vehicle and marker gene. Transfection was confirmed by histology for beta-galactosidase. Physiological efficacy was evaluated by measuring the wound healing parameters that define dermal and epidermal regeneration. Transfection products were found in the cytoplasm of rapidly dividing cells of the granulation tissue. Different doses of the nonviral cDNA gene transfer coding for KGF or IGF-I resulted in different outcomes for dermal and epidermal regeneration. There was a dose-dependent response to both growth factor gene transfers that was not dissimilar from that typically displayed by treatment with growth factor proteins. Both concentrations below and above the optimal concentration of DNA:liposomal preparations did not yield the results observed at the optimal concentration.

Animals↗
PubMed2001

Fatty infiltration of the liver in severely burned pediatric patients: autopsy findings and clinical implications.

BACKGROUND: Trauma induces hypermetabolic responses that are characterized by the mobilization of all available substrates. The marked increase of peripheral lipolysis after a burn can lead to the development of fatty liver, which has been associated with immunodepression and increased mortality. METHODS: All autopsies of pediatric burn patients between January 1988 and January 1998 were reviewed. Patient demographics, hospital course, cause of death, and hepatic and septic macroscopic and microscopic findings were recorded. RESULTS: Thirty-seven pediatric patients (4 +/- 1 years old) were included in the study. The mean burn size was 69% +/- 5% total body surface area burned. Eighty percent of the patients presented with fatty infiltration of the liver. Liver weight/body weight ratio was 77 +/- 5 gm/kg, representing 2.1 times the liver weight of age- and sex-matched controls (p < 0.001). Patients with severe fatty infiltration of the liver had a higher incidence of sepsis (p < 0.001). CONCLUSION: Fatty infiltration of the liver is a common condition in fatal burns. Severe fatty infiltration of the liver is associated with an increased incidence of sepsis, although a causative effect could not be found. It is notable that fatty infiltration of the liver occurred in the complete absence of parenteral nutrition.

Burns↗
PubMed2001

IGF-I/BP-3 administration preserves hepatic homeostasis after thermal injury which is associated with increases in no and hepatic NF-kappa B.

After a severe trauma, such as a cutaneous thermal injury, an increase in hepatocyte apoptosis has been associated with hepatocyte damage and impairment in hepatic function. Insulinlike growth factor-I (IGF-I) exerts antiapoptotic effects in several organs, thus improving organ homeostasis. The purpose of the present study was to determine whether IGF-I in combination with its principle binding protein-3 (BP-3) attenuates liver damage after a burn and whether this attenuation is through signals of the apoptotic-proliferative axis of hepatocytes. Sprague-Dawley rats (56 males) received a 60% total body surface area third-degree scald burn and were randomly divided to receive either rhlGF-I/BP3 (10 mg/kg/day s.c.) or saline (control). Serum aspartate transaminase (AST) and nitric oxide (NO), and hepatocyte proliferation and apoptosis, were measured on postburn days 1, 2, 5, and 7. Hepatic interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) mRNA and hepatic nuclear-factor kappa B (NF-kappa B) were determined at 1 and 2 days postburn. IGF-I/BP-3 decreased serum AST and increased serum NO at 1, 2, and 5 days after burn when compared with controls (P < 0.05). IGF-I/BP-3 increased hepatocyte proliferation on the first day after burn and decreased hepatocyte apoptosis at day 7 postburn when compared with controls (P < 0.05). IGF-I/BP-3 decreased hepatic IL-1 beta and TNF-alpha mRNA 1 day after burn (P < 0.05). IGF-I/BP-3 further increased hepatic NF-kappa B concentration 1 and 2 days postburn when compared with controls (P < 0.05). Recombinant hIGF-I in combination with its principle binding protein conserves hepatic homeostasis, which is associated with a transient increase in hepatocyte proliferation and decrease in hepatocyte apoptosis possibly through NO and hepatic NF-kappa B.

Animals↗
PubMed2001

Serum TGF-beta in thermally injured rats.

A severe thermal injury is commonly associated with immune suppression and increased susceptibility to sepsis, frequently leading to multiple organ failure. Transforming growth factor-beta (TGF-beta) is a potent immunosuppressive cytokine involved in complications associated with major trauma. Interleukin- 4 (IL-4) is thought to synergize the immunosuppressive activity of TGF-beta by promoting naive lymphocytes to differentiate and generate TGF-beta secreting cells. This study examines the alterations in serum levels of TGF-beta and IL-4 after a thermal injury. Male Sprague-Dawley rats (300-400 g) were anesthetized and received a 50% total body surface area full-thickness scald burn followed by fluid resuscitation and analgesia. Control rats were given the same treatment, but were immersed in water at room temperature. Rats were sacrificed from 1 h to 8 days after injury. Blood samples were collected aseptically from the inferior caval vein. Serum levels of TGF-beta and IL-4 were measured by enzyme linked immunosorbent assay. Rats in the control and thermal injury groups showed similar increases in serum TGF-beta 1 h after injury. A progressive increase in serum TGF-beta was observed in burned animals compared to control animals starting on day 3 and continued through day 8 (P < 0.01). Serum IL-4 levels in control and thermally injured animals remained undetectable (< 15.6 pg/mL) throughout the experiment. Thermal injury induces a significant increase in serum TGF-beta, which may contribute to post-burn immunosuppression with an increased susceptibility to sepsis.

Animals↗
PubMed2001

Cell proliferation, apoptosis, NF-kappaB expression, enzyme, protein, and weight changes in livers of burned rats.

Thermal injury has been shown to alter gut epithelium and heart myocyte homeostasis by inducing programmed cell death. The effect of thermal injury on hepatocyte apoptosis and proliferation, however, has not been established. The purpose of this study was to determine whether a large thermal injury increases liver cell apoptosis and proliferation and whether these changes were associated with alterations in hepatic nuclear factor kappaB (NF-kappaB) expression and changes in liver enzymes and amount of protein. Sprague-Dawley rats received a 40% total body surface area scald burn or sham burn. Rats were killed and livers were harvested at 1, 2, 5, and 7 days after burn. Liver cell apoptosis was determined by terminal deoxyuridine nick end labeling (TUNEL) assay and cell proliferation by immunohistochemistry for proliferating cell nuclear antigen. Hepatic NF-kappaB expression was determined by Western blot, and total hepatic protein content was determined by protein assay. Protein concentration decreased after burn compared with sham controls (P < 0.05). Liver cell apoptosis, proliferation, and NF-kappaB expression in hepatocytes increased in burned rats compared with controls (P < 0.05). It was concluded that thermal injury induces hepatic cell apoptosis and proliferation associated with an increase in hepatic NF-kappaB expression and a decrease in hepatic protein concentration.

Alkaline Phosphatase↗