To determine to what extent intravenous nutrition can reduce proteolysis in very immature and normal newborns, and to assess the capacity of preterm and normal newborns to convert phenylalanine to ...tyrosine, phenylalanine and leucine kinetics were measured under basal conditions and during parenteral nutrition in clinically stable, extremely premature (approximately 26 wk of gestation) infants and in normal term newborns. In response to parenteral nutrition, there was significantly less suppression (P < 0.001) of endogenous leucine and phenylalanine rate of appearance in extremely premature infants compared with term infants. Phenylalanine utilization for protein synthesis during parenteral nutrition increased significantly (P < 0.01) and by the same magnitude (approximately 15%) in both extremely premature and term infants. Phenylalanine was converted to tyrosine at substantial rates in both extremely premature and term infants; however, this conversion rate was significantly higher (P < 0.05) in extremely premature infants during both the basal and parenteral nutrition periods. These data provide clear evidence that there is no immaturity in the phenylalanine hydroxylation pathway. Furthermore, although parenteral nutrition appears to produce similar increases in protein synthesis in extremely premature and term infants, proteolysis is suppressed much less in extremely premature newborns. The factors responsible for this apparent resistance to suppression of proteolysis in the very immature newborn remain to be elucidated.
(Lancet. 2015;385(9968):629–639)Administration of antenatal corticosteroids (ACTs) is one of the most effective interventions to reduce neonatal mortality of premature infants, and is strongly ...recommended by national and international health organizations. However, treatment with ACTs is often limited in low-income countries, and all current evidence showing a reduction in neonatal mortality with ACT therapy comes solely from clinical trials done in hospitals where neonatal intensive care is available.
Diabetic skin is known to have deficient wound healing properties, but little is known of its intrinsic biomechanical properties. We hypothesize that diabetic skin possesses inferior biomechanical ...properties at baseline, rendering it more prone to injury. Skin from diabetic and nondiabetic mice and humans underwent biomechanical testing. Real-time PCR was performed for genes integral to collagen synthesis and degradation. MMP-2 and MMP-9, and TIMP-1 protein levels were assessed by ELISA and zymography. Collagen I and III content was assessed using Western blot analysis. At baseline, both murine and human diabetic skin was biomechanically inferior compared to nondiabetic skin, with decreased maximum stress and decreased modulus (P < 0.001 and < 0.05, respectively). Surprisingly, the expression of genes involved in collagen synthesis were significantly up-regulated, and genes involved in collagen degradation were significantly down-regulated in murine diabetic skin (P < 0.01). In addition, MMP-2 and MMP-9/TIMP-1 protein ratios were significantly lower in murine diabetic skin (P < 0.05). Collagen I levels and I:III ratios were lower in diabetic skin (P < 0.05). These findings suggest that the predisposition of diabetics to wounds may be the result of impaired tissue integrity at baseline, and are due, in part, to a defect in the regulation of collagen protein synthesis at the post-transcriptional level.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Background
Skin aging is an inevitable process with one of the key features of aging being dryness or flakiness of the skin. Previous in vivo and in vitro testing has highlighted that a silk‐based ...product may be effective in improving moisture retention in skin.
Methods
We evaluated the safety and efficacy of our silk‐based product through a combination of objective‐ including scanning electron microscopy (SEM) and EpiDerm Skin Irritation tests ‐ and subjective tests – including direct evaluation of patient’s own perception of their skin.
Results
In alignment with previous studies, patients reported significant concerns about aging, wrinkling, or saggy skin. We found that our silk‐based product was safe and effective in improving hydration and resilience of facial skin and a majority of participants stated they would continue to use this product, when commercially available.
Conclusion
Our novel silk‐based product, NanoSilk Cosmo, is safe for use on human facial skin and it improves skin resiliency and hydration.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
The impact of antiretroviral therapy (ART) on sexual risk behavior and HIV transmission among HIV-infected persons in Africa is unknown.
To assess changes in risky sexual behavior and estimated HIV ...transmission from HIV-infected adults after 6 months of ART.
A prospective cohort study was performed in rural Uganda. Between May 2003 and December 2004 a total of 926 HIV-infected adults were enrolled and followed in a home-based ART program that included prevention counselling, voluntary counseling and testing (VCT) for cohabitating partners and condom provision. At baseline and follow-up, participants' HIV plasma viral load and partner-specific sexual behaviors were assessed. Risky sex was defined as inconsistent or no condom use with partners of HIV-negative or unknown serostatus in the previous 3 months. The rates of risky sex were compared using a Poisson regression model and transmission risk per partner was estimated, based on established viral load-specific transmission rates.
Six months after initiating ART, risky sexual behavior reduced by 70% adjusted risk ratio, 0.3; 95% confidence interval (CI), 0.2-0.7; P = 0.0017. Over 85% of risky sexual acts occurred within married couples. At baseline, median viral load among those reporting risky sex was 122 500 copies/ml, and at follow-up, < 50 copies/ml. Estimated risk of HIV transmission from cohort members declined by 98%, from 45.7 to 0.9 per 1000 person years.
Providing ART, prevention counseling, and partner VCT was associated with reduced sexual risk behavior and estimated risk of HIV transmission among HIV-infected Ugandan adults during the first 6 months of therapy. Integrated ART and prevention programs may reduce HIV transmission in Africa.
Over one-third of infants with congenital diaphragmatic hernia (CDH) eventually require a Nissen fundoplication (NF). We examined pre- and intraoperative predictors for need of a NF in children ...undergoing CDH repair to elucidate, which patients will need a later NF.A retrospective analysis of all consecutive patients undergoing CDH repair at our institution from 2008 to 2018 was performed. Patients who underwent a NF were compared to those who did not (noNissen). Logistic regression analysis was performed to find independent predictors for NF in patients undergoing CDH repair. Severe Defect Grade was defined as defect >50% of the hemidiaphragm and intrathoracic liver.One hundred twenty-six patients were included, 42 (33%) underwent NF at a median of 61 days after CDH repair. Intrathoracic liver was more frequent in the NF (71%) versus noNissen (45%) group (P = .008). Absence of >50% of the hemidiaphragm was more frequent in the NF group (76% vs 31%, P < .001). Severe Defect Grade emerged as independent predictor for NF (odds ratio 7, 95% confidence interval 3-16, P < .001).Severe Defect Grade emerged as independent predictor for NF after CDH repair.
Objective Impaired diabetic wound healing is associated with abnormal stromal cell-derived factor (SDF)-1α production, decreased angiogenesis, and chronic inflammation. Lentiviral-mediated ...overexpression of SDF-1α can correct the impairments in angiogenesis and healing in diabetic wounds. We hypothesized that SDF-1α is a critical component of the normal wound-healing response and that inhibition of SDF-1α would further delay the wound-healing process. Methods dB/Db diabetic mice and Db/+ nondiabetic mice were wounded with an 8-mm punch biopsy and the wounds treated with a lentiviral vector containing either the green fluorescent protein (GFP) or SDF-1α inhibitor transgene. The inhibitor transgene is a mutant form of SDF-1α that binds, but does not activate, the CXCR4 receptor. Computerized planimetry was used to measure wound size daily. Wounds were analyzed at 3 and 7 days by histology and for production of inflammatory markers using real-time polymerase chain reaction. The effect of the SDF-1α inhibitor on cellular migration was also assessed. Results Inhibition of SDF-1α resulted in a significant decrease in the rate of diabetic wound healing, (3.8 vs 6.5 cm2 /day in GFP-treated wounds; P = .04), and also impaired the early phase of nondiabetic wound healing. SDF-1α inhibition resulted in fewer small-caliber vessels, less granulation tissue formation, and increased proinflammatory gene expression of interleukin-6 and macrophage inflammatory protein-2 in the diabetic wounds. Conclusions The relative level of SDF-1α in the wound plays a key role in the wound-healing response. Alterations in the wound level of SDF-1α, as seen in diabetes or by SDF-1α inhibition, impair healing by decreasing cellular migration and angiogenesis, leading to increased production of inflammatory cytokines and inflammation. Inhibition of SDF-1α further impairs diabetic wound healing.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Wound size impacts the threshold between scarless regeneration and reparative healing in the fetus with increased inflammation showed in fetal scar formation. We hypothesized that increased fetal ...wound size increases pro‐inflammatory and fibrotic genes with resultant inflammation and fibroplasia and that transition to scar formation could be reversed by overexpression of interleukin‐10 (IL‐10). To test this hypothesis, 2‐mm and 8‐mm dermal wounds were created in mid‐gestation fetal sheep. A subset of 8‐mm wounds were injected with a lentiviral vector containing the IL‐10 transgene (n = 4) or vehicle (n = 4). Wounds were harvested at 3 or 30 days for histology, immunohistochemistry, analysis of gene expression by microarray, and validation with real‐time polymerase chain reaction. In contrast to the scarless 2‐mm wounds, 8‐mm wounds showed scar formation with a differential gene expression profile, increased inflammatory cytokines, decreased CD45+ cells, and subsequent inflammation. Lentiviral‐mediated overexpression of the IL‐10 gene resulted in conversion to a regenerative phenotype with decreased inflammatory cytokines and regeneration of dermal architecture. In conclusion, increased fetal wounds size leads to a unique gene expression profile that promotes inflammation and leads to scar formation and furthermore, these results show the significance of attenuated inflammation and IL‐10 in the transition from fibroplasia to fetal regenerative healing.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Wound healing is of major clinical concern and is constantly being explored for early restoration and enhanced recovery. While the etiology of the wound healing is multifactorial, high inflammation ...and increased oxidative stress which results in chronic inflammation, endothelial dysfunction and collagen degradation, delay the overall healing process. Thus, visual sensing of the oxidative stress would be highly informative in the successful implementation of wound healing therapies based on specific requirements. In this study, electrospinning was used to fabricate silk fibroin nanofibrous mats infused with Amplex red capable of detecting hydrogen peroxide, a reactive oxygen molecule. These mats produced a visible change in color with the limit of detection at 1 μM H
2
O
2
concentration.
In vivo
studies carried out in diabetic mice with impaired wounds also displayed a visible change in color of the mats infused with Amplex red within 24 hours. These electrospun silk fibroin nanofibrous Amplex infused mats has the potential to enable a futuristic platform where decisions can be made for enhanced wound healing therapy.
Amplex red infused silk mats in visible detection of oxidative stress in the cutaneous wound over time.
The design of intracellular drug delivery vehicles demands an in‐depth understanding of their internalization and function upon entering the cell to tailor the physicochemical characteristics of ...these platforms and achieve efficacious treatments. Polymeric cationic systems have been broadly accepted to be membrane disruptive thus being beneficial for drug delivery inside the cell. However, if excessive destabilization takes place, it can lead to adverse effects. One of the strategies used to modulate the cationic charge is the incorporation of hydrophobic moieties, thus increasing the hydrophobic content. We have demonstrated the successful synthesis of nanogels based on diethylaminoethyl methacrylate and poly(ethylene glycol) methyl ether methacrylate. Addition of the hydrophobic monomers tert‐butyl methacrylate or 2‐(tert‐butylamino)ethyl methacrylate shows improved polymer hydrophobicity and modulation of the critical swelling pH. Here, we evaluate the cytocompatibility, uptake, and function of these membrane‐destabilizing cationic methacrylated nanogels using in vitro models. The obtained results suggest that the incorporation of hydrophobic monomers decreases the cytotoxicity of the nanogels to epithelial colorectal adenocarcinoma cells. Furthermore, analysis of the internalization pathways of these vehicles using inhibitors and imaging flow cytometry showed a significant decrease in uptake when macropinocytosis/phagocytosis inhibitors were present. The membrane‐disruptive abilities of the cationic polymeric nanogels were confirmed using three different models. They demonstrated to cause hemolysis in sheep erythrocytes, lactate dehydrogenase leakage from a model cell line, and disrupt giant unilamellar vesicles. These findings provide new insights of the potential of polymeric nanoformulations for intracellular delivery.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
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