***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Objective : To study the association of timing , duration , and intensity of hyperglycemia with pediatric intensive care unit ( PICU ) mortality in critically ill children . Design : Retrospective cohort study . Setting : PICU of a university-affiliated , tertiary care , children 's hospital . Patients : A total of 152 critically ill children receiving vasoactive infusions or mechanical ventilation .  Interventions : None . Methods : With institutional review board approval , we review ed a cohort of 179 consecutive children , 1 mo to 21 yrs of age , treated with mechanical ventilation or vasoactive infusions .  We excluded 18 with <3 μg·kg−1·min−1 dopamine only , diabetes , or solid organ transplant and nine who died within 24 hrs of PICU admission . Peak blood glucose ( BG ) and time to peak BG during PICU admission , duration of hyperglycemia ( percentage of PICU days with any BG of > 126 mg/dL ) , and intensity of hyperglycemia ( median BG during first 48 PICU hours ) were analyzed for association with PICU mortality using chi-square , Student 's t-test , and logistic regression . Measurements and Main Results : Peak BG of > 126 mg/dL occurred in 86 % of patients . Compared with survivors , nonsurvivors had higher peak BG ( 311 ± 115 vs. 205 ± 80 mg/dL , p < .001 ) . Median time to peak BG was similar in nonsurvivors ( 23.5 hrs ; interquartile ratio , 5–236 hrs ) and survivors ( 19 hrs ; inter-quartile ratio , 6–113 hrs ) . Duration of hyperglycemia was longer in nonsurvivors ( 71 % ± 14 % of PICU days ) vs. survivors ( 37 % ± 5 % of PICU days , p < .001 ) . Nonsurvivors had more intense hyperglycemia during the first 48 hrs in the PICU ( 126 ± 38 mg/dL ) vs. survivors ( 116 ± 34 mg/dL , p < .05 ) . Univariate logistic regression analysis showed that peak BG and the duration and intensity of hyperglycemia were each associated with PICU mortality ( p < .05 ) . Multivariate modeling controlling for age and Pediatric Risk of Mortality scores showed independent association of peak BG and duration of hyperglycemia with PICU mortality ( p < .05 ) . Conclusions : Hyperglycemia is common in critically ill children . Peak BG and duration of hyperglycemia are independently associated with mortality in our PICU . A prospect i ve , r and omized trial of strict glycemic control in this subset of critically ill children who are at high risk of mortality is both warranted and feasible A hallmark of the disease state following severe burn injury is decreased liver function , which results in gross metabolic derangements that compromise patient survival . The underlying mechanisms leading to hepatocyte dysfunction after burn are essentially unknown . The aim of the present study was to determine the underlying mechanisms leading to hepatocyte dysfunction and apoptosis after burn . Rats were r and omized to either control ( no burn ) or burn ( 60 % total body surface area burn ) and sacrificed at various time-points . Liver was either perfused to isolate primary rat hepatocytes , which were used for in vitro calcium imaging , or liver was harvested and processed for immunohistology , transmission electron microscopy , mitochondrial isolation , mass spectroscopy or Western blotting to determine the hepatic response to burn injury in vivo . We found that thermal injury leads to severely depleted endoplasmic reticulum ( ER ) calcium stores and consequent elevated cytosolic calcium concentrations in primary hepatocytes in vitro . Burn-induced ER calcium depletion caused depressed hepatocyte responsiveness to signalling molecules that regulate hepatic homeostasis , such as vasopressin and the purinergic agonist ATP . In vivo , thermal injury result ed in activation of the ER stress response and major alterations in mitochondrial structure and function - effects which may be mediated by increased calcium release by inositol 1,4,5-trisphosphate receptors . Our results reveal that thermal injury leads to dramatic hepatic disturbances in calcium homeostasis and result ant ER stress leading to mitochondrial abnormalities contributing to hepatic dysfunction and apoptosis after burn injury Glucose management in patients with burn injury is often difficult because of their hypermetabolic state with associated hyperglycemia , hyperinsulinemia , and insulin resistance . Recent studies suggest that time to glycemic control is associated with improved outcomes . The authors sought to determine the influence of early glycemic control on the outcomes of critically ill patients with burn injury . A retrospective analysis was performed at the Ohio State University Medical Center . Patients hospitalized with burn injury were enrolled if they were admitted to the intensive care unit between March 1 , 2006 , and February 28 , 2009 . Early glycemic control was defined as the achievement of a mean daily blood glucose of ≤150 mg/dl for at least two consecutive days by postburn day 3 . Forty-six patients made up the study cohort with 26 achieving early glycemic control and 20 who did not . The two groups were similar at baseline with regard to age , pre-existing diabetes , APACHE II score and burn size and depth . There were no differences in number of surgical interventions , infectious complications , or length of stay between patients who achieved or failed early glycemic control . Failure of early glycemic control was , however , associated with significantly higher mortality both by univariate ( 35.0 vs 7.7 % , P = .03 ) and multivariate analyses ( hazard ratio 6.754 [ 1.16–39.24 ] , P = .03 ) adjusting for age , TBSA , and inhalation injury . Failure to achieve early glycemic control in patients with burn injury is associated with an increased risk of mortality . However , further prospect i ve controlled trials are needed to establish causality of this association Burn injury causes hepatic dysfunction associated with endoplasmic reticulum ( ER ) stress and induction of the unfolded protein response ( UPR ) . ER stress/UPR leads to hepatic apoptosis and activation of the Jun-N-terminal kinase ( JNK ) signaling pathway leading to vast metabolic alterations . Insulin has been shown to attenuate hepatic damage and to improve liver function . We therefore hypothesized that insulin administration exerts its effects by attenuating postburn hepatic ER stress and subsequent apoptosis . Male Sprague Dawley rats received a 60 % total body surface area ( TBSA ) burn injury . Animals were r and omized to receive saline ( controls ) or insulin ( 2.5 IU/kg q. 24 h ) and euthanized at 24 and 48 h postburn . Burn injury induced dramatic changes in liver structure and function , including induction of the ER stress response , mitochondrial dysfunction , hepatocyte apoptosis , and up-regulation of inflammatory mediators .  Insulin decreased hepatocyte caspase-3 activation and apoptosis significantly at 24 and 48 h postburn . Furthermore , insulin administration decreased ER stress significantly and reversed structural and functional changes in hepatocyte mitochondria . Finally , insulin attenuated the expression of inflammatory mediators IL-6 , MCP-1 , and CINC-1 .  Insulin alleviates burn-induced ER stress , hepatocyte apoptosis , mitochondrial abnormalities , and inflammation leading to improved hepatic structure and function significantly . These results support the use of insulin therapy  after traumatic injury to improve patient outcomes Background Wound healing is impaired in diabetes mellitus , but the mechanisms involved in this process are virtually unknown . Proteins belonging to the insulin signaling pathway respond to insulin in the skin of rats . Objective The purpose of this study was to investigate the regulation of the insulin signaling pathway in wound healing and skin repair of normal and diabetic rats , and , in parallel , the effect of a topical insulin cream on wound healing and on the activation of this pathway . Research Design and Methods We investigated insulin signaling by immunoblotting during wound healing of control and diabetic animals with or without topical insulin .  Diabetic patients with ulcers were r and omized to receive topical insulin or placebo in a prospect i ve , double-blind and placebo-controlled , r and omized clinical trial ( NCT 01295177 ) of wound healing . Results and Conclusions Expression of IR , IRS-1 , IRS-2 , SHC , ERK , and AKT are increased in the tissue of healing wounds compared to intact skin , suggesting that the insulin signaling pathway may have an important role in this process . These pathways were attenuated in the wounded skin of diabetic rats , in parallel with an increase in the time of complete wound healing . Upon topical application of insulin cream , the wound healing time of diabetic animals was normalized , followed by a reversal of defective insulin signal transduction . In addition , the treatment also increased expression of other proteins , such as eNOS ( also in bone marrow ) , VEGF , and SDF-1α in wounded skin . In diabetic patients , topical insulin cream markedly improved wound healing , representing an attractive and cost-free method for treating this devastating complication of diabetes . Trial Registration Clinical Trials.gov The aim of the present study was to investigate the effect of local insulin injection on granulation tissue formation in the wounds of patients with diabetic foot ulcer . Thirty-two patients with diabetic foot ulcer were r and omly divided into an insulin ( n=18 ) and a control ( n=14 ) group . In the diabetic foot ulcer wound , the insulin group were administered insulin and the control group were administered an equal volume of saline . Prior to injection and at 0.5 , 1.0 , 2.0 and 4.0 h after injection , the fingertip blood glucose levels were determined . The growth of granulation tissue was assessed continuously for 12 days . Wound tissue was harvested at 0 , 5 , 7 and 12 days for the detection of CD34 expression by immunohistochemistry . The microvessel density ( MVD ) was calculated . No significant difference in the fasting blood glucose level was found between the two groups at any time-point ( P>0.05 ) . Growth of granulation tissue in the insulin group was more marked from 7 days after local insulin injection ( 24.87±0.24 ) and was significantly different from that in the control group ( 18.66±0.45 ) ( P<0.01 ) . New vessels were observed in the insulin group 3 days after insulin injection ; however , there was no significant difference in MVD compared with the control group ( P>0.05 ) . The MVD in the insulin group increased markedly from 5 days after treatment , and the difference between the two groups was significant ( P<0.01 ) . In conclusion , local injection of insulin into the base of a diabetic foot ulcer has a significant effect on systemic blood glucose and may promote wound healing by improving the growth of granulation tissue OBJECTIVE To investigate the effect of topical application of silymarin on full-thickness cutaneous wounds in rats . METHOD A full-thickness cutaneous defect ( 2 × 2 cm ) was induced on the back of 85 male and female Wister rats . The animals were r and omly divided into four groups ( n=20 in each group ) , treated with 1ml basal cream ( placebo group ) , low-dose ( 6mg/ml/rat ) and high-dose ( 12mg/ml/rat ) silymarin , and untreated ( control ) . Five rats remained uninjured to serve as comparisons for biomechanical analysis . Wounds were evaluated 10 , 20 and 30 days after injury , through histopathologic , biochemical and biomechanical analyses . RESULTS There was a significant ( p < 0.05 ) increase observed in the amount of glycosaminoglycans and collagen present on days 10 , 20 and 30 for both low-dose and high-dose silymarin groups . Low-dose silymarin reduced the number of lymphocytes and enhanced the number of fibrocytes at the earlier stages of wound healing ; however , high-dose silymarin reduced both lymphocytes and macrophages , and increased number of fibrocytes at the later stages of wound healing . Silymarin significantly improved alignment of the healing tissue , enhanced maturity of the collagen fibres and fibroblasts ( p < 0,05 ) , and increased the ultimate tensile strength and stress of the healing tissue . CONCLUSION The results suggest that topical application of silymarin improved the morphological , biochemical and biomechanical properties of experimentally-induced wound defects in rats . DECLARATION OF INTEREST There were no external sources of funding for this study . The authors have no conflicts of interest to declare When wounds are treated with regular insulin , they are also being treated with zinc ; used in the formula to crystallize insulin molecules . It is not clear if regular insulin-accelerated  wound healing is due to insulin , the zinc it contains , or both . Thus , we aim ed to compare topical regular crystalline insulin ( containing z 
    Output:
    
Key findings : The animal studies revealed that treatment with topical insulin lead to faster wound contraction and re‐epithelialization .
Meta‐ analysis of wound studies revealed that insulin therapy is significantly favored for growth of granulation tissue .
Based on these findings , insulin  enhanced development of granulation tissue on day 7 after treatment .
The meta‐ analysis studies indicated significant reduction in time of healing in the patients treated with insulin .
Significance : Insulin is a low cost growth factor and can be considered as a therapeutic agent in wound healing .