Bondeshaw2022

CEAP (clinical, etiologic, anatomic, pathophysiologic) clinical class, supine foot venous pressure, clinical improvement, QOL improvement, stent patency, or reintervention rates after stenting. Patients presenting with QOL-impairing symptoms in whom conservative treatment has failed merit consideration of correction of their obstruction even if the degree of stenosis is less then 50%. The use of a CCVIS might be helpful but requires further study.To determine if wedge resection is equivalent to lobectomy for Stage I Non-Small Cell Lung Cancer (NSCLC) and to evaluate the impact of radiologic and pathologic variables not available in large national databases. Records were reviewed from 2010-2016 for patients with pathologic Stage I NSCLC who underwent wedge resection or lobectomy. Propensity score matching was performed on pre-operative variables and patients with ≥1 lymph node removed. Clinical variables were compared. Kaplan-Meier curves and multivariable Cox proportional hazard models for 5-year overall survival (OS), disease-free (DFS), and locoregional-recurrence-free survival (LRFS) were created. A total of 1086 patients met inclusion criteria; 391 lobectomies and 695 wedge resections. Propensity score matching yielded 167 pairs of lobectomy and wedge resection patients. Rapamycin Complications were fewer for wedge resections than lobectomies, 19.2% for wedge resection patients vs 34.1% for lobectomy patients, p 10 mm and appropriate lymph node dissection is performed.The long-term survival and reoperation rate in chronic renal failure (CRF) on hemodialysis (HD) patients after aortic valve/root replacement (AVR/ARR) with a stentless bioprosthesis is unknown. From 1992-2015, 1941 patients underwent AVR/ARR with stentless valve for primary indications of aortic stenosis/insufficiency, root aneurysm, and acute type A aortic dissection, including 93 CRF-HD (64 new-onset postoperative HD, and 29 preoperative HD) and 1848 non-CRF-HD. Data was obtained from the STS database, retrospective chart review, administered surveys and national death index data. Compared to the non-CRF-HD group, the CRF-HD group had significantly higher incidence of diabetes mellitus (28 vs 18%), CAD (49 vs 38%), COPD (31 vs 16%), NYHA class IV (12 vs 4%), atrial fibrillation (24 vs 12%), and previous cardiac surgery (27 vs 16%). Postoperatively, CRF-HD group had a higher reoperation for bleeding (10 vs 4%), length of hospital stays (20 vs 7 days), and operative mortality (23 vs 2.3%), all p less then 0.01. The odds ratio of CRF-HD for operative mortality was 8.97. The long-term survival was worse in CRF-HD group than that in non-CRF-HD group [8-year survival 31% vs 70%, p less then 0.0001]. The hazard ratio of CRF-HD for long-term mortality was 2.4. The 10-year cumulative reoperation rate for structural valve deterioration in the CRF-HD group was 6.0% vs 5.0% in the non-CRF-HD group, p = 0.74. Surgeons should consider poor short- and long-term outcomes of patients with high risk of being on dialysis when offering aortic valve/root replacement. Bioprosthesis could be a good option in this patient population.

The pathogenesis of Wilson disease (WD) involves hepatic and brain copper accumulation resulting from pathogenic variants affecting the ATP7B gene and downstream epigenetic and metabolic mechanisms. Prior methylome investigations in human WD liver and blood and in the Jackson Laboratory C3He-Atp7b

/J (tx-j) WD mouse model showed an epigenetic signature of WD, including changes in the histone deacetylase (HDAC)5. We tested the hypothesis that histone acetylation is altered with respect to copper overload and aberrant DNA methylation in WD.

We investigated class IIa HDAC4 and HDAC5 and H3K9/H3K27 histone acetylation in tx-j mouse livers compared with C3HeB/FeJ (C3H) control in response to 3 treatments 60% kcal fat diet, D-penicillamine (copper chelator), and choline (methyl group donor). Experiments with copper-loaded HepG2 cells were conducted to validate invivo studies.

In 9-week tx-j mice, HDAC5 levels increased significantly after 8 days of a 60% kcal fat diet compared with chow. In 24-week tx-j micets suggest dietary modulation of class IIa HDAC4/5, and subsequent H3K9/H3K27 acetylation/deacetylation can regulate gene expression in key metabolic pathways in the pathogenesis of WD. The data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO series accession number GSE168972 (https//www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE168972).The phosphatidylinositol transfer protein domain (PITPd) is an evolutionarily conserved protein that is able to transfer phosphatidylinositol between membranes in vitro and in vivo. However some animal genomes also include genes that encode proteins where the PITPd is found in cis with a number of additional domains and recent large scale genome sequencing efforts indicate that this type of multidomain architecture is widespread in the animal kingdom. In Drosophila photoreceptors, the multidomain phosphatidylinositol transfer protein RDGB is required to regulate phosphoinositide turnover during G-protein activated phospholipase C signalling. Recent studies in flies and mammalian cell culture models have begun to elucidate functions for the non-PITPd of RDGB and its vertebrate orthologs. We review emerging evidence on the genomics, functional and cell biological perspectives of these multi-domain PITPd containing proteins.Huntington's disease (HD) is an autosomal neurodegenerative disorder caused by extended trinucleotide CAG repetition in the HTT gene. Wild-type huntingtin protein (HTT) is essential, involved in a variety of crucial cellular functions such as vesicle transportation, cell division, transcription regulation, autophagy, and tissue maintenance. The mutant HTT (mHTT) proteins in the body interfere with HTT's normal cellular functions and cause additional detrimental effects. In this review, we discuss multiple approaches targeting DNA and RNA to reduce mHTT expression. These approaches are categorized into non-allele-specific silencing and allele-specific-silencing using Single Nucleotide Polymorphisms (SNPs) and haplogroup analysis. Additionally, this review discusses a potential application of recent CRISPR prime editing technology in targeting HD.Corneal nerves are instrumental to maintain cornea integrity through regulation of key physiological functions such as tear secretion, blink reflex, and neuropeptide turnover. Corneal nerve injury/stimulation can follow many insults including mechanical/chemical trauma, infections and surgeries. Nerve disruption initiates a process named neurogenic inflammation which leads to edema, pain, and recruitment and activation of leukocytes. Interestingly, leukocyte influx in the cornea can further damage nerves by releasing inflammatory mediators-including neuropeptides. The clinical outcome of neuroinflammation can be beneficial or detrimental to corneal integrity. On one side, it ensures prompt wound healing and prevents infections. On the other, prolonged and/or deranged neuroinflammation can permanently disrupt corneal integrity and impair vision. The cornea is an ideal site to study peripheral neuroinflammation and neurogenic inflammation since it receives the highest density of sensory nerves of the entire body. We will review the corneal nerve anatomy and neurochemistry, discuss the beneficial and detrimental effects of neurogenic inflammation in corneal wound healing, inflammatory processes, and pain. We will also examine the emerging remote impact of corneal nerve disruption on the trigeminal ganglion and the brain, highlighting the key role of neuropeptide Substance P. Finally, we will discuss the clinical relevance of such neuroinflammatory network in the context of severe and highly prevalent ocular diseases, including potential treatments.It has recently become possible to produce hepatocytes from human induced pluripotent stem cells (iPSC-heps), which may offer some advantages over primary human hepatocytes (Prim-heps) in the regulatory environment. The aim of this research was to assess similarities and differences between commercially available iPSC-heps and Prim-heps in preliminary assays of drug metabolism, hepatotoxicity, and drug transport. Hepatocytes were either cultured in collagen-coated 96-well plates (Prim-heps and 2d-iPSC-heps) or in ultra-low adhesion plates as spheroids (3d-iPSC-heps). 3d-iPSC-heps were used to enhance physiological cell-cell contacts, which is essential to maintain the phenotype of mature hepatocytes. Cytochrome P450 (CYP) 3A4, CYP1A2, and CYP2B6 activity levels were evaluated using fluorescent assays. Phase II metabolism was assessed by HPLC measurement of formation of glucuronides and sulfates of 4-methylumbelliferone, 1-naphthol, and estradiol. The toxicity of acetaminophen, amiodarone, aspirin, clozapine, tacrine, tamoxifen, and troglitazone was monitored using a luminescent cell viability assay. Canaliculi formation was monitored by following the fluorescence of 5,6-carboxy-2',7'-dichlorofluorescein diacetate. All culture models showed similar levels of basal CYP3A4, CYP1A2 and CYP2B6 activity. However, while Prim-heps showed a vigorous response to CYP inducing agents, 2d-iPSC-heps showed no response and 3d-iPSC-heps displayed an inconclusive response. 2d-iPSC-heps showed reduced, yet appreciable, glucuronide and sulfate formation compared to Prim-heps. All culture models showed similar activity in tests of hepatotoxicity, with Prim-heps generally being more sensitive. All models formed canaliculi capable of transporting carboxy-2',7'-dichlorofluorescein. The iPSC-heps appear to be useful for toxicity and transport studies, but metabolic activity is not optimum, and metabolism studies would benefit from a more mature model.Acinetobacter baumannii is an opportunistic pathogen that has acquired resistance to all available drugs. The rise in multi-drug resistance in A. baumannii has been exacerbated by its ability to tolerate antibiotics due to the persister cells, which are phenotypic variants of normal cells that can survive various stress conditions, resulting in chronicity of infection. In the present study we observed that A. baumannii formed persister cells against lethal concentration of ciprofloxacin in exponential phase. The transcriptome of A. baumannii was analyzed after exposure to high concentration of ciprofloxacin (50X MIC) to determine the possible mechanisms of survival. Transcriptome analysis showed differential expression of 146 genes, of which 101 were up-regulated and 45 were down-regulated under ciprofloxacin stress. Differentially expressed genes that might be important for persistence against ciprofloxacin were involved in DNA repair, phenylacetic acid degradation, leucine catabolism, HicAB toxin-antitoxin system and ROS response (iron-sulfur clusters, hemerythrin-like metal binding and Kdp). recA, umuD and ddrR genes involved in SOS response were also up-regulated. Knockout of umuD showed significant decrease in persister cells formation while they were completely eradicated in recA mutant strain. The differentially expressed genes highlighted in the study merit further investigation as therapeutic targets for effective control of A. baumannii infections.