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Mitigation of hypertrophic scar contraction via an elastomeric biodegradable scaffold. - Biomaterials
Hypertrophic scar (HSc) occurs in 40-70% of patients treated for third degree burn injuries. Current burn therapies rely upon the use of bioengineered skin equivalents (BSEs), which assist in wound healing but do not prevent HSc contraction. HSc contraction leads to formation of a fixed, inelastic skin deformity. We propose that BSEs should maintain their architecture in the wound bed throughout the remodeling phase of repair to prevent HSc contraction. In this work we study a degradable, elastomeric, randomly oriented, electrospun micro-fibrous scaffold fabricated from the copolymer poly(l-lactide-co-Îµ-caprolactone) (PLCL). PLCL scaffolds displayed appropriate elastomeric and tensile characteristics for implantation beneath a human skin graft. InÂ vitro analysis using human dermal fibroblasts demonstrated that PLCL scaffolds decreased myofibroblast formation as compared to an inÂ vitro HSc contraction model. Using a validated immune-competent murine HSc contraction model, we found that HSc contraction was significantly greater in animals treated with standard of care, Integra, as compared to those treated with collagen coated-PLCL (ccPLCL) scaffolds. Finally, wounds treated with ccPLCL were significantly less stiff than control wounds at d30 inÂ vivo. Together, these data suggest that scaffolds which persist throughout the remodeling phase of repair may represent a clinically translatable method to prevent HSc contraction.Copyright Â© 2014 Elsevier Ltd. All rights reserved.
Melatonin and its metabolites as copper chelating agents and their role in inhibiting oxidative stress: a physicochemical analysis. - Journal of pineal research
The copper sequestering ability of melatonin and its metabolites cyclic 3-hydroxymelatonin (3OHM), N(1) -acetyl-N(2) -formyl-5-methoxykynuramine (AFMK), and N(1) -acetyl-5-methoxykynuramine (AMK) was investigated within the frame of the Density Functional Theory. It was demonstrated that these compounds are capable of chelating copper ions, yielding stable complexes. The most likely chelation sites were identified. Two different mechanisms were modeled, the direct-chelation mechanism (DCM) and the coupled-deprotonation-chelation mechanism (CDCM). It is proposed that, under physiological conditions, CDCM would be the main chelation route for Cu(II). It was found that melatonin and its metabolites fully inhibited the oxidative stress induced by Cu(II)-ascorbate mixtures, via Cu(II) chelation. In the same way, melatonin, AFMK, and 3OHM also prevented the first step of the Haber-Weiss reaction, consequently turning off the Ë™OH production via the Fenton reaction. Therefore, it is proposed that, in addition to the previously reported free radical scavenging cascade, melatonin is also involved in a concurrent 'chelating cascade', thereby contributing to a reduction in oxidative stress. 3OHM was identified as the most efficient of the studied compounds for that purpose, supporting the important role of this metabolite in the beneficial effects of melatonin against oxidative stress.Â© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
In vivo analysis of burns in a mouse model using spectroscopic optical coherence tomography. - Optics letters
Spectroscopic analysis of biological tissues can provide insight into changes in structure and function due to disease or injury. Depth-resolved spectroscopic measurements can be implemented for tissue imaging using optical coherence tomography (OCT). Here, spectroscopic OCT is applied to in vivo measurement of burn injury in a mouse model. Data processing and analysis methods are compared for their accuracy. Overall accuracy in classifying burned tissue was found to be as high as 91%, producing an area under the curve of a receiver operating characteristic curve of 0.97. The origins of the spectral changes are identified by correlation with histopathology.
Angiotensin II stimulates canonical TGF-Î² signaling pathway through angiotensin type 1 receptor to induce granulation tissue contraction. - Journal of molecular medicine (Berlin, Germany)
Hypertrophic scar contraction (HSc) is caused by granulation tissue contraction propagated by myofibroblast and fibroblast migration and contractility. Identifying the stimulants that promote migration and contractility is key to mitigating HSc. Angiotensin II (AngII) promotes migration and contractility of heart, liver, and lung fibroblasts; thus, we investigated the mechanisms of AngII in HSc. Human scar and unwounded dermis were immunostained for AngII receptors angiotensin type 1 receptor (AT1 receptor) and angiotensin type 2 receptor (AT2 receptor) and analyzed for AT1 receptor expression using Western blot. In vitro assays of fibroblast contraction and migration under AngII stimulation were conducted with AT1 receptor, AT2 receptor, p38, Jun N-terminal kinase (JNK), MEK, and activin receptor-like kinase 5 (ALK5) antagonism. Excisional wounds were created on AT1 receptor KO and wild-type (WT) mice treated with AngIIâ€‰Â±â€‰losartan and ALK5 and JNK inhibitors SB-431542 and SP-600125, respectively. Granulation tissue contraction was quantified, and wounds were analyzed by immunohistochemistry. AT1 receptor expression was increased in scar, but not unwounded tissue. AngII induced fibroblast contraction and migration through AT1 receptor. Cell migration was inhibited by ALK5 and JNK, but not p38 or MEK blockade. In vivo experiments determined that absence of AT1 receptor and chemical AT1 receptor antagonism diminished granulation tissue contraction while AngII stimulated wound contraction. AngII granulation tissue contraction was diminished by ALK5 inhibition, but not JNK. AngII promotes granulation tissue contraction through AT1 receptor and downstream canonical transforming growth factor (TGF)-Î² signaling pathway, ALK5. Further understanding the pathogenesis of HSc as an integrated signaling mechanism could improve our approach to establishing effective therapeutic interventions.AT1 receptor expression is increased in scar tissue compared to unwounded tissue. AngII stimulates expression of proteins that confer cell migration and contraction. AngII stimulates fibroblast migration and contraction through AT1 receptor, ALK5, and JNK. AngII-stimulated in vivo granulation tissue contraction is AT1 receptor and ALK5 dependent.
A novel immune competent murine hypertrophic scar contracture model: a tool to elucidate disease mechanism and develop new therapies. - Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society
Hypertrophic scar (HSc) contraction following burn injury causes contractures. Contractures are painful and disfiguring. Current therapies are marginally effective. To study pathogenesis and develop new therapies, a murine model is needed. We have created a validated immune-competent murine HSc model. A third-degree burn was created on dorsum of C57BL/6 mice. Three days postburn, tissue was excised and grafted with ear skin. Graft contraction was analyzed and tissue harvested on different time points. Outcomes were compared with human condition to validate the model. To confirm graft survival, green fluorescent protein (GFP) mice were used, and histologic analysis was performed to differentiate between ear and back skin. Role of panniculus carnosus in contraction was analyzed. Cellularity was assessed with 4',6-diamidino-2-phenylindole. Collagen maturation was assessed with Picro-sirius red. Mast cells were stained with Toluidine blue. Macrophages were detected with F4/80 immune. Vascularity was assessed with CD31 immune. RNA for contractile proteins was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Elastic moduli of skin and scar tissue were analyzed using a microstrain analyzer. Grafts contracted to âˆ¼45% of their original size by day 14 and maintained their size. Grafting of GFP mouse skin onto wild-type mice, and analysis of dermal thickness and hair follicle density, confirmed graft survival. Interestingly, hair follicles disappeared after grafting and regenerated in ear skin configuration by day 30. Radiological analysis revealed that panniculus carnosus doesn't contribute to contraction. Microscopic analyses showed that grafts show increase in cellularity. Granulation tissue formed after day 3. Collagen analysis revealed increases in collagen maturation over time. CD31 stain revealed increased vascularity. Macrophages and mast cells were increased. qRT-PCR showed up-regulation of transforming growth factor beta, alpha smooth muscle actin, and rho-associated protein kinase 2 in HSc. Tensile testing revealed that human skin and scar tissues are tougher than mouse skin and scar tissues.Â© 2014 The Authors. Wound Repair and Regeneration published by Wiley Periodicals, Inc. on behalf of Wound Healing Society.
Effectiveness of an intervention designed to optimize statins use: a primary prevention randomized clinical trial. - BMC family practice
Although hypercholesterolemia is considered a cardiovascular risk factor, in isolation it is not necessarily sufficient cause for a cardiovascular event. To improve event prediction, cardiovascular risk calculators have been developed; the REGICOR calculator has been validated for use in our population. The objective of this project is to develop an intervention with general practitioners (GPs) and evaluate its impact on prescription adequacy of cholesterol-lowering drugs in primary prevention of cardiovascular disease and in controlling the costs associated with this disease.This nonblinded, cluster-randomized clinical trial analyzes data from primary care electronic medical records (ECAP) and other databases. Inclusion criteria are patients aged 35 to 74Â years with no known cardiovascular disease and a new prescription for cholesterol-lowering drugs during the 2-year study period. Dependent variables include the following: RETIRA, defined as new cholesterol-lowering drugs initiated during the year preceding the intervention, considered inadequate, and withdrawn during the study period; EVITA, defined as new cholesterol-lowering drugs initiated during the study period and considered inadequate; COST, defined as the total cost of inadequate new treatments prescribed; and REGISTER, defined as the recording of cardiovascular risk factors. Independent variables include the GP's quality-of-care indicators and randomly assigned study group (intervention vs control), patient demographics, and clinical variables. Aggregated descriptive analysis will be done at the GP level and multilevel analysis will be performed to estimate the intervention effect, adjusted for individual and GP variables.The study objective is to generate evidence about the effectiveness of implementing feedback information programs directed to GPs in the context of Primary Care. The goal is to improve the prescription adequacy of lipid-lowering therapies for primary prevention.ClinicalTrials.gov Identifier: NCT01997671. November 28, 2013.
Theoretical study on the peroxyl radicals scavenging activity of esculetin and its regeneration in aqueous solution. - Physical chemistry chemical physics : PCCP
The study of the Ë™OOH, Ë™OOCH3 and Ë™OOCHCH2 radicals scavenging processes by esculetin (ES) was carried out in aqueous and lipid media, using the density functional theory. Three reaction mechanisms were considered: single electron transfer (SET), hydrogen transfer (HT) and radical adduct formation (RAF). Rate constants and branching ratios for the different paths are reported. It was found that in lipid media the main mechanism of reaction is HT, while in aqueous solution it depends on the predominant acid-base form of esculetin. HT was found to be the main mechanism involved in the free radical scavenging activity of neutral esculetin (H2ES), while for anionic esculetin (HES(-)) the relative importance of the different mechanisms changes with the reacting radical. Based on the calculated rate constants, it is proposed that esculetin has moderate peroxyl scavenging activity in lipid media while in aqueous solution, at physiological pH, it is excellent for that purpose. In addition, the possible regeneration of ES, after scavenging the first radical, was investigated in aqueous solution, at physiological pH. It was found that regeneration is very likely to occur, which suggests that this compound has the ability to scavenge several radical equivalents (two per cycle), under such conditions.
Antioxidant activity of propyl gallate in aqueous and lipid media: a theoretical study. - Physical chemistry chemical physics : PCCP
In this work, we have carried out a quantum chemistry and computational kinetics study on the reactivity of propyl gallate towards Ë™OOH, Ë™OOCH3 and Ë™OOCHCH2 radicals, in aqueous and lipid media. We have considered three reaction mechanisms: hydrogen transfer (HT), radical adduct formation (RAF) and single electron transfer (SET). Rate constants and relative branching ratios for the different paths contributing to the overall reaction, at 298.15 K, are reported. Our results show that propyl gallate reacts mainly through the HT mechanism, independently of the solvent or the peroxyl radical, contrary to other phenols such as catechols and guayacols previously studied, which react mainly via the SET mechanism. In aqueous media at physiological pH, the calculated rate constants towards the Ë™OOH, Ë™OOCH3 and Ë™OOCHCH2 radicals are 4.56 Ã— 10(8), 1.59 Ã— 10(6) and 4.05 Ã— 10(8) M(-1) s(-1), while in lipid media the rate constants are 2.94 Ã— 10(4), 7.73 Ã— 10(3) and 9.94 Ã— 10(5) M(-1) s(-1). Thus, a propyl gallate molecule acts as a very efficient peroxyl radical scavenger, both in aqueous and lipid media. Since the gallate moiety is a part of other naturally occurring polyphenols such as aflavine gallates and epigallocatechin gallates, the results of this study could be extrapolated to these compounds. Even if these compounds have other antioxidant structures or enhancers, the activity of the gallate moiety could be considered as a lower limit to their antioxidant activity.
Creation of a synthetic indicator of quality of care as a clinical management standard in primary care. - SpringerPlus
The development of electronic medical records has allowed the creation of new quality indicators in healthcare. Among them, synthetic indicators facilitate global interpretation of results and comparisons between professionals.A healthcare quality standard (EQA, the Catalan acronym for EstÃ ndard de Qualitat Assistencial) was constructed to serve as a synthetic indicator to measure the quality of care provided by primary care professionals in Catalonia (Spain). The project phases were to establish the reference population; select health problems to be included; define, select and deliberate about subindicators; and construct and publish the EQA.Construction of the EQA involved 107 healthcare professionals, and 91 health problems were included. In addition, 133 experts were consulted, who proposed a total of 339 indicators. After systematic paired comparison, 61 indicators were selected to create the synthetic indicator. The EQA is now calculated on a monthly basis for more than 8000 healthcare professionals using an automated process that extracts data from electronic medical records; results are published on a follow-up website. Along with the use of the online EQA results tool, there has been an ongoing improvement in most of the quality of care indicators.Creation of the EQA has proven to be useful for the measurement of the quality of care of primary care services. Also an improvement trend over 5 years is shown across most of the measured indicators.The online version of this article (doi:10.1186/2193-1801-2-51) contains supplementary material, which is available to authorized users.
The impact of bariatric surgery on renal and cardiac functions in morbidly obese patients. - Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
Cardiac adaptation to obesity includes both structural and functional alterations in the heart. The kidneys also suffer the consequence of excessive increase of body weight. This study aims to assess the functional, cardiac and renal changes in a cohort of morbidly obese patients, as well as changes after bariatric surgery-the last therapeutic option for these patients.Patients referred for bariatric surgery were prospectively included. In each case, transthoracic echocardiography and a blood test were performed before the procedure and repeated 1 year after surgery. The estimation of the glomerular filtration rate (GFR) was addressed by the Cockroft-Gault lean body weight formula.Sixty-one patients completed the 1-year follow-up. Of these, 81.9% were female. The mean age was 41.1 Â± 9.8 years and the mean body mass index was 47.4 Â± 5 kg/m(2), decreasing to 30.5 Â± 5.07 kg/m(2) after the procedure. Before surgery, the estimated GFR was 92.7 Â± 25.4 mL/min, with hyperfiltration being present in 14.8% of patients, whereas an impaired GFR was detected in 8.3%. Patients showed preserved systolic function and cardiac remodelling. Diastolic function was abnormal in 27.9% of patients. At the 1-year follow-up, favourable changes in the left ventricular geometry and related haemodynamic status were observed. There was no significant change in the estimated GFR in the overall group, although hyperfiltration was ameliorated in 9.8% and a poor GFR was improved in 3.3.%. The improvement was not associated with changes in either blood pressure or the BMI. However, in this group of patients the amelioration of the GFR was associated with an increased stroke volume and improvement in diastolic function.In morbidly obese patients, GFR is usually normal and only a small percentage of them show hyperfiltration or a reduced GFR. Bariatric surgery has a favourable impact on renal function in only a reduced group of patients who also experience an improvement in cardiac performance.
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