Diabetes mellitus is a morbid condition affecting a growing number of the world population, and approximately one third of diabetic patients are afflicted with diabetic foot ulcers (DFU), which are ...chronic non-healing wounds that frequently progress to require amputation. The treatments currently used for DFU focus on reducing pressure on the wound, staving off infection, and maintaining a moist environment, but the impaired wound healing that occurs in diabetes is a constant obstacle that must be faced. Aberrant angiogenesis is a major contributor to poor wound healing in diabetes and surgical intervention is often necessary to establish peripheral blood flow necessary for healing wounds. Over recent years, microRNAs (miRNAs) have been implicated in the dysregulation of angiogenesis in multiple pathologies including diabetes. This review explores the pathways of angiogenesis that become dysregulated in diabetes, focusing on miRNAs that have been identified and the mechanisms by which they affect angiogenesis.
Acute respiratory distress syndrome (ARDS) has approximately 40% in-hospital mortality, and treatment is limited to supportive care. Pneumonia is the underlying etiology in many cases with ...unrestrained inflammation central to the pathophysiology. We have previously shown that CNP-miR146a, a radical scavenging cerium oxide nanoparticle (CNP) conjugated to the anti-inflammatory microRNA(miR)-146a, reduces bleomycin- and endotoxin-induced acute lung injury (ALI) by decreasing inflammation. We therefore hypothesized that CNP-miR146a would decrease inflammation in murine infectious ALI. Mice were injured with intratracheal (IT) MRSA or saline followed by treatment with IT CNP-miR146a or saline control. Twenty-four hours post-infection, bronchoalveolar lavage fluid (BALF) and whole lungs were analyzed for various markers of inflammation. Compared to controls, MRSA infection significantly increased proinflammatory gene expression (IL-6, IL-8, TNFα, IL-1β;
< 0.05), BALF proinflammatory cytokines (IL-6, IL-8, TNFα, IL-1β;
< 0.01), and inflammatory cell infiltrate (
= 0.03). CNP-miR146a treatment significantly decreased proinflammatory gene expression (IL-6, IL-8, TNFα, IL-1β;
< 0.05), bronchoalveolar proinflammatory protein leak (IL-6, IL-8, TNFα;
< 0.05), and inflammatory infiltrate (
= 0.01). CNP-miR146a decreases inflammation and improves alveolar-capillary barrier integrity in the MRSA-infected lung and has significant promise as a potential therapeutic for ARDS.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Fetal repair of myelomeningocele (MMC) and myeloschisis leads to improved neurologic outcomes compared to postnatal repair, but the effects of modifications in closure techniques have not been ...extensively studied. Previous work has suggested that a watertight repair is requisite for improvement in hindbrain herniation (HBH) and to decrease postnatal hydrocephalus (HCP). Our institution adopted the myofascial closure technique for open fetal MMC repair in July 2019, which we hypothesized would result in decreased need for patch closure, improved HBH, and decreased rate of surgically-treated HCP.
A single-center retrospective study of patients who underwent fetal MMC or myeloschisis repair between March 2013 and February 2022 was performed. Outcomes were evaluated (n = 70 prior to July 2019, n = 34 after July 2019). Statistical significance was determined by Fisher's exact and Chi square tests (p < 0.05 significant).
Patients who underwent myofascial closure were less likely to require a patch for skin closure (14.7% vs 58.6%, p < 0.0001). Myofascial closure was also associated with an increased rate of HBH improvement on two-week postoperative fetal MRI (93.9% vs 65.7%, p = 0.002). Surgically-treated HCP at one year was lower in the myofascial closure group (n = 21), however this did not reach statistical significance (23.8% vs 41.9%, p = 0.19).
We conclude that the myofascial closure technique for repair of fetal MMC and myeloschisis is associated with significantly decreased need for patch closure and improvement in hindbrain herniation compared to our previous skin closure technique. These results support a surgical approach that employs a multilayer watertight closure.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
B. B. Poindexter, C. A. Karn, J. A. Ahlrichs, J. Wang, C. A. Leitch, E. A. Liechty and S. C. Denne
Department of Pediatrics, Indiana University School of Medicine, Indianapolis 46202, USA.
To ...determine how increased amino acid availability alters rates of whole
body proteolysis and the irreversible catabolism of the essential amino
acids leucine and phenylalanine throughout the neonatal period, leucine and
phenylalanine kinetics were measured under basal conditions and in response
to intravenous amino acids in two separate groups of healthy, full-term
newborns (at 3 days and 3 wk of age). The endogenous rates of appearance of
leucine and phenylalanine (reflecting proteolysis) were suppressed equally
in both groups and in a dose-dependent fashion (by approximately 10% with
1.2 g x kg(-1) x day(-1) and by approximately 20% with 2.4 g x kg(-1) x
day(-1)) in response to intravenous amino acid delivery. Insulin
concentrations remained unchanged from basal values during amino acid
administration. The irreversible catabolism of leucine and phenylalanine
increased in a stepwise fashion in response to intravenous amino acids;
again, no differences were observed between the two groups. This study
clearly demonstrates that the capacity to acutely increase rates of leucine
oxidation and phenylalanine hydroxylation is fully present early in the
neonatal period in normal newborns. Furthermore, these data suggest that
amino acid availability is a primary regulator of proteolysis in normal
newborns throughout the neonatal period.
The insulin-like growth factors (IGF) are important anabolic hormones in the mammalian fetus; their anabolic actions are potentially modulated by alterations in the IGF-binding proteins (IGFBP). We ...have previously shown that the nutritional state of the fetus affects both IGF-I and the IGFBP concentrations. The present study was designed to determine the effect of alterations in insulin and IGF-I circulating concentrations on the IGFBPs. Because both insulin and IGF-I elicit decreases in glucose and amino acid concentrations, the concentrations of these substrates were clamped during the hormone infusions. Sixteen ovine fetuses were chronically catheterized at approximately 115 days of gestation, and experimental procedures performed at approximately 130 days of gestation. Insulin, IGF-I or both were infused for an 8-h period. Baseline concentrations of hormones and binding proteins were obtained, and concentrations were also obtained at the end of the infusion. Hepatic IGFBP-1 mRNA expression was also determined. Intravenous infusion of IGF-I significantly increased IGF-I concentrations in plasma in the ovine fetus. Intravenous infusion of insulin inhibited hepatic IGFBP-1 gene expression when amino acids and glucose were clamped. In contrast, intravenous infusion of recombinant human IGF-I (rhIGF-I) enhanced hepatic IGFBP-1 gene expression. Neither insulin nor rhIGF-I treatment had an effect on hepatic IGFBP-3 gene expression. Insulin did not alter plasma IGFBP-1 significantly, but it increased IGFBP-3 in plasma. rhIGF-I increased both IGFBP-1 and IGFBP-3 protein levels in plasma. The responses of IGFBP-1 and IGFBP-3 to increased plasma IGF-I and insulin may serve to protect the fetus from exaggerated anabolic effects and to blunt the hypoglycemic potential of circulating IGFs and insulin.
Operating-room procedures canceled due to the COVID-19 pandemic depleted hospital revenue and potentially worsened patient outcomes through disease progression. Despite safeguards to resume elective ...procedures, patients remain apprehensive of contracting COVID-19 during hospitalization and recovery. We investigated symptomatic COVID-19 infection in patients undergoing operating-room procedures during the spring 2020 outbreak in Fairfield County, CT, a heavily affected New York Metropolitan area.
We retrospectively analyzed 419 operating-room patients in Danbury and Norwalk Hospitals between 3/16/20 and 5/19/20. COVID-19 infection was assessed through test results or documented well-being within 2 weeks postdischarge. Variables studied were procedure classification, length of stay, and discharge disposition. Postprocedural COVID-19 infection was analyzed using binomial tests comparing rates to state-mandated infection data.
Six patients developed COVID-19 after 212 urgent-elective and 207 emergent procedures. Overall postprocedural infection risk was equivalent to community infection risk (
> .05). No infections occurred in 1-2 day stays or urgent-elective procedures with discharge home (both
< .05). Discharges home reduced the risk to one-sixth of community spread (
= .03). Risk of infection doubled in hospitalizations > 5 days (
= .05) and quadrupled in discharges to extended care facilities (
= .01).
Operating-room procedures did not increase the risk of symptomatic COVID-19 infection during an outbreak. Urgent-elective and emergent procedures during further outbreaks appear safe when anticipating short stays with discharges home. When anticipating prolonged hospitalization or discharges to facilities, appropriate delay of urgent-elective procedures may minimize risk of infection.
Iron supplementation may have adverse health effects in infants, probably through manipulation of the gut microbiome. Previous research in low-resource settings have focused primarily on anemic ...infants. This was a double blind, randomized, controlled trial of home fortification comparing multiple micronutrient powder (MNP) with and without iron. Six-month-old, non- or mildly anemic, predominantly-breastfed Kenyan infants in a rural malaria-endemic area were randomized to consume: (1) MNP containing 12.5 mg iron (MNP+Fe,
= 13); (2) MNP containing no iron (MNP-Fe,
= 13); or (3) Placebo (CONTROL,
= 7), from 6-9 months of age. Fecal microbiota were profiled by high-throughput bacterial 16S rRNA gene sequencing. Markers of inflammation in serum and stool samples were also measured. At baseline, the most abundant phylum was Proteobacteria (37.6% of rRNA sequences). The proteobacterial genus
was the most abundant genus across all phyla (30.1% of sequences). At the end of the intervention, the relative abundance of
significantly decreased in MNP-Fe (-16.05 ± 6.9%,
= 0.05) and CONTROL (-19.75 ± 4.5%,
= 0.01), but not in the MNP+Fe group (-6.23 ± 9%,
= 0.41). The second most abundant genus at baseline was
(17.3%), the relative abundance of which significantly decreased in MNP+Fe (-6.38 ± 2.5%,
= 0.02) and CONTROL (-8.05 ± 1.46%,
= 0.01), but not in MNP-Fe (-4.27 ± 5%,
= 0.4445).
increased in MNP-Fe only (1.9 ± 0.5%,
= 0.02). No significant differences were observed in inflammation markers, except for IL-8, which decreased in CONTROL. MNP fortification over three months in non- or mildly anemic Kenyan infants can potentially alter the gut microbiome. Consistent with previous research, addition of iron to the MNP may adversely affect the colonization of potential beneficial microbes and attenuate the decrease of potential pathogens.
Background
Over the last two decades, fetal imaging has greatly improved, and new prenatal imaging measurements have been developed to characterize congenital diaphragmatic hernia (CDH) severity.
...Objective
To determine the best prenatal imaging predictor of postnatal CDH outcomes, including use of extracorporeal membrane oxygenation (ECMO) and in-hospital mortality, with particular attention to the percentage of liver herniation (%LH) as a predictor. Additionally, we sought to guide best practices across hospital systems including improved models of prenatal risk assessment.
Materials and methods
We conducted a retrospective review of infants with left CDH who were prenatally diagnosed. We analyzed prenatal imaging measurements including observed-to-expected (O/E) lung-to-head ratio (LHR) on US, percentage predicted lung volume (PPLV) on MRI, and O/E total fetal lung volume (TFLV) and %LH on MRI. We compared prenatal imaging characteristics for infants with (1) in-hospital postnatal mortality and (2) use of ECMO. Then we performed multivariate logistic regression to determine independent predictors of postnatal outcomes.
Results
We included 63 infants with a median gestation of 34 weeks at the time of prenatal MRI. Low O/E LHR (31.2 vs. 50,
P
< 0.0001), PPLV (14.7 vs. 22.6,
P
< 0.0001) and O/E TLFV (24.6 vs. 38.3,
P
< 0.0001) and high %LH (15.1 vs. 2.1,
P
= 0.0006) were associated with worse postnatal outcomes; however, only PPLV was predictive of survival and need for ECMO on multivariable analysis. PPLV survival to discharge model showed an area under the curve (AUC) of 0.93 (95% confidence interval CI: 0.86, 0.99),
P
< 0.0001; and an odds ratio of 68.7 (95% CI: 6.5–2,302),
P
= 0.003. PPLV need for ECMO model showed AUC = 0.87 (95% CI: 0.78, 0.96),
P
< 0.0001; and odds ratio = 20.1 (95% CI: 3.1–226.3),
P
= 0.011.
Conclusion
Low O/E LHR, PPLV and O/E TFLV and high %LH in the third trimester are associated with worse postnatal outcomes. PPLV most strongly predicted outcome using a logistic regression model. Percentage of liver herniation was not an independent predictor of outcomes.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Inflammation and oxidative stress are implicated in the pathogenesis of Crohn's disease. Cerium oxide nanoparticle (CNP) conjugated to microRNA 146a (miR146a) (CNP-miR146a) is a novel compound with ...anti-inflammatory and antioxidative properties. We hypothesized that local administration of CNP-miR146a would improve colitis in a 2,4,6-Trinitrobenzenesulfonic acid (TNBS) mouse model for Crohn's disease by decreasing colonic inflammation. Balb/c mice were instilled with TNBS enemas to induce colitis. Two days later, the mice received cellulose gel enema, cellulose gel with CNP-miR146a enema, or no treatment. Control mice received initial enemas of 50% ethanol and PBS enemas on day two. The mice were monitored daily for weight loss and clinical disease activity. The mice were euthanized on days two or five to evaluate their miR146a expression, inflammation on histology, and colonic IL-6 and TNF gene expressions and protein concentrations. CNP-miR146a enema successfully increased colonic miR146a expression at 12 h following delivery. At the end of five days from TNBS instillation, the mice treated with CNP-miR146a demonstrated reduced weight loss, improved inflammation scores on histology, and reduced gene expressions and protein concentrations of IL-6 and TNF. The local delivery of CNP-miR146a in a TNBS mouse model of acute Crohn's colitis dramatically decreased inflammatory signaling, resulting in improved clinical disease.
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