RESUMO
BACKGROUND: Cardiac point of care ultrasound (POCUS) has shown increasing utility as a tool for diagnosing and managing heart failure (HF). Within cardiology, intravascular volume assessment leveraging visualization of the inferior vena cava (IVC) is a central aspect of care, as IVC size correlates with central venous pressure. This targeted literature review aimed to examine the existing literature assessing the use of POCUS in diagnosis and management of HF patients utilizing POCUS-based IVC measurement either alone or in combination with secondary methods. METHODS: A targeted PubMed and Ovid database search up until August 28, 2023 using a keyword search was completed. Studies that did not include IVC assessment with POCUS in HF were excluded. RESULTS: The initial search using both PubMed and Ovid resulted in 370 journal publications. After exclusion criteria were used 15 studies were included in the review. Studies were grouped into three categories: 1) how well POCUS was able to identify HF, 2) whether POCUS-based findings correlated with other measures evaluating HF and was able to predict the effect of diuretic administration, and 3) whether POCUS-based findings served as a good prognostic indicator. The 5 studies that evaluated HF identification with POCUS found that both diagnostic sensitivity and specificity may reach 90%-100% when IVC measurement was coupled with a lung ultrasound assessing the presence of B-lines or pleural effusion. Five studies assessing POCUS findings correlating with other HF measures and diuretic effect found that IVC diameter changed significantly with diuretic administration (p<0.05). All 6 studies assessing POCUS as a predictor of long-term mortality or hospital readmission found measures that achieved statistical significance with p<0.05. CONCLUSIONS: Including POCUS as standard-of-care - both as a diagnostic tool in the emergency department and a management tool in in-patient and out-patient facilities - may improve the treatment of HF.
RESUMO
AIMS/HYPOTHESIS: Diabetes is associated with epigenetic modifications including DNA methylation and miRNA changes. Diabetic complications in the cornea can cause persistent epithelial defects and impaired wound healing due to limbal epithelial stem cell (LESC) dysfunction. In this study, we aimed to uncover epigenetic alterations in diabetic vs non-diabetic human limbal epithelial cells (LEC) enriched in LESC and identify new diabetic markers that can be targeted for therapy to normalise corneal epithelial wound healing and stem cell expression. METHODS: Human LEC were isolated, or organ-cultured corneas were obtained, from autopsy eyes from non-diabetic (59.87±20.89 years) and diabetic (71.93±9.29 years) donors. The groups were not statistically different in age. DNA was extracted from LEC for methylation analysis using Illumina Infinium 850K MethylationEPIC BeadChip and protein was extracted for Wnt phospho array analysis. Wound healing was studied using a scratch assay in LEC or 1-heptanol wounds in organ-cultured corneas. Organ-cultured corneas and LEC were transfected with WNT5A siRNA, miR-203a mimic or miR-203a inhibitor or were treated with recombinant Wnt-5a (200 ng/ml), DNA methylation inhibitor zebularine (1-20 µmol/l) or biodegradable nanobioconjugates (NBCs) based on polymalic acid scaffold containing antisense oligonucleotide (AON) to miR-203a or a control scrambled AON (15-20 µmol/l). RESULTS: There was significant differential DNA methylation between diabetic and non-diabetic LEC. WNT5A promoter was hypermethylated in diabetic LEC accompanied with markedly decreased Wnt-5a protein. Treatment of diabetic LEC and organ-cultured corneas with exogenous Wnt-5a accelerated wound healing by 1.4-fold (p<0.05) and 37% (p<0.05), respectively, and increased LESC and diabetic marker expression. Wnt-5a treatment in diabetic LEC increased the phosphorylation of members of the Ca2+-dependent non-canonical pathway (phospholipase Cγ1 and protein kinase Cß; by 1.15-fold [p<0.05] and 1.36-fold [p<0.05], respectively). In diabetic LEC, zebularine treatment increased the levels of Wnt-5a by 1.37-fold (p<0.01)and stimulated wound healing in a dose-dependent manner with a 1.6-fold (p<0.01) increase by 24 h. Moreover, zebularine also improved wound healing by 30% (p<0.01) in diabetic organ-cultured corneas and increased LESC and diabetic marker expression. Transfection of these cells with WNT5A siRNA abrogated wound healing stimulation by zebularine, suggesting that its effect was primarily due to inhibition of WNT5A hypermethylation. Treatment of diabetic LEC and organ-cultured corneas with NBC enhanced wound healing by 1.4-fold (p<0.01) and 23.3% (p<0.05), respectively, with increased expression of LESC and diabetic markers. CONCLUSIONS/INTERPRETATION: We provide the first account of epigenetic changes in diabetic corneas including dual inhibition of WNT5A by DNA methylation and miRNA action. Overall, Wnt-5a is a new corneal epithelial wound healing stimulator that can be targeted to improve wound healing and stem cells in the diabetic cornea. DATA AVAILABILITY: The DNA methylation dataset is available from the public GEO repository under accession no. GSE229328 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE229328 ).
