Byrnejepsen9708
To assess class I-histone deacetylase (HDAC) inhibition on formation of lipid-accumulating, disease-promoting phagocytes upon myelin load in vitro, relevant for neuroinflammatory disorders like multiple sclerosis (MS) and cerebral X-linked adrenoleukodystrophy (X-ALD).
Immunohistochemistry on postmortem brain tissue of acute MS (n=6) and cerebral ALD (n=4) cases to analyze activation and foam cell state of phagocytes. Litronesib mw RNA-Seq of in vitro differentiated healthy macrophages (n=8) after sustained myelin-loading to assess the metabolic shift associated with foam cell formation. RNA-Seq analysis of genes linked to lipid degradation and export in MS-275-treated human HAP1 cells and RT-qPCR analysis of HAP1 cells knocked out for individual members of class I HDACs or the corresponding enzymatically inactive knock-in mutants. Investigation of intracellular lipid/myelin content after MS-275 treatment of myelin-laden human foam cells. Analysis of disease characteristic very long-chain fatty acid (VLCFA) metabolism and inflammatory state in MS-275-treated X-ALD macrophages.
Enlarged foam cells coincided with a pro-inflammatory, lesion-promoting phenotype in postmortem tissue of MS and cerebral ALD patients. Healthy in vitro myelin laden foam cells upregulated genes linked to LXRα/PPARγ pathways and mimicked a program associated with tissue repair. Treating these cells with MS-275, amplified this gene transcription program and significantly reduced lipid and cholesterol accumulation and, thus, foam cell formation. In macrophages derived from X-ALD patients, MS-275 improved the disease-associated alterations of VLCFA metabolism and reduced the pro-inflammatory status of these cells.
These findings identify class I-HDAC inhibition as a potential novel strategy to prevent disease promoting foam cell formation in CNS inflammation.
These findings identify class I-HDAC inhibition as a potential novel strategy to prevent disease promoting foam cell formation in CNS inflammation.
The Getting It Right First Time programme aims to reduce variation in clinical practice that unduly impacts on outcomes for patients in the National Health Service (NHS) in England; often termed "unwarranted variation." However, there is no "gold standard" method for detecting unwarranted variation. The aim of this study was to describe a method to allow such variation in recorded practice or patient outcomes between NHS trusts to be detected using data over multiple time periods. By looking at variation over time, it was hoped that patterns that could be missed by looking at data at a single time point, or averaged over a longer time period, could be identified.
This was a retrospective time-series analysis of observational administrative data. Data were extracted from the Hospital Episodes Statistics database for two exemplar aspects of clinical practice within the field of urology (a) use of ureteric stents on first emergency admission to treat urinary tract stones and (b) waiting times for definitive surgery for urinary retention. Data were categorized into 3-month time periods and three rules were used to detect unwarranted variation in the outcome metric relative to the national average (a) two of any three consecutive values greater than two standard deviations above the mean, (b) four of any five consecutive values greater than one standard deviation above the mean, and (c) eight consecutive values above the mean.
For the urinary tract stones dataset, 24 trusts were identified as having unwarranted variation in the outcomes using funnel plots and 23 trusts using the time-series method. For the urinary retention data, 18 trusted were identified as having unwarranted variation in the outcomes using funnel plots and 22 trusts using the time-series method.
The time-series method may complement other methods to help identify unwarranted variation.
The time-series method may complement other methods to help identify unwarranted variation.
The recent development of ultra-thin delivery systems, which enable simultaneous insertion of two metal stents, has encouraged wider adoption of side-by-side (SBS) stent placement for malignant hilar biliary obstruction (MHBO). However, the management of stent occlusion after SBS placement has not been well-characterized. This study aimed to examine the outcomes of endoscopic reintervention (E-RI) after SBS placement in patients with MHBO.
Sixty-seven patients who underwent E-RI for stent occlusion after SBS placement between 2013 and 2020 at three tertiary-care referral centers were investigated. We evaluated the technical success, clinical success, recurrent biliary obstruction (RBO), and adverse events other than RBO rates associated with E-RI. Furthermore, the factors associated with successful E-RI were also evaluated.
The technical success and clinical success rates were 79.1% (53/67) and 76.1% (51/67), respectively. Early adverse events other than RBO occurred in 4.5% (3/67) and late events in 3.9% (2/51). The RBO rate after E-RI was 52.9% (27/51), and the median time to RBO after E-RI was 85days. Common bile duct (CBD) diameter (odds ratio 2.62; 95% confidence interval, 1.37-5.01; P=0.003) and metastatic disease (odds ratio, 0.11; 95% confidence interval, 0.02-0.64; P=0.015) were independently correlated with E-RI success in the multivariate analysis.
This study demonstrated that E-RI after SBS placement is technically feasible and safe, but the success rate was significantly lower in patients with narrow CBDs and metastatic diseases. These factors may be useful for the selection of the initial stenting method.
This study demonstrated that E-RI after SBS placement is technically feasible and safe, but the success rate was significantly lower in patients with narrow CBDs and metastatic diseases. These factors may be useful for the selection of the initial stenting method.The regio- and stereospecific synthesis of O-methyl-chiro-inositols and O-methyl-scyllo-inositol was achieved, starting from p-benzoquinone. After preparing dimethoxy conduritol-B as a key compound, regiospecific bromination of the alkene moiety of dimethoxy conduritol-B and acid-catalyzed ring opening of dimethoxydiacetate conduritol-B epoxide with Ac2 O afforded the desired new chiro-inositol derivatives and scyllo-inositol derivative, respectively. Spectroscopic methods were employed for the characterization of all synthesized compounds. The novel inositols (11-17) had effective inhibition profiles against human carbonic anhydrase isoenzymes I and II (hCA I and II) and acetylcholinesterase (AChE). The novel inositols 11-17 were found to be effective inhibitors against AChE, hCA I, and hCA II enzymes. Ki values were calculated in the range of 87.59 ± 7.011 to 237.95 ± 17.75 μM for hCA I, 65.08 ± 12.39 to 538.98 ± 61.26 μM for hCA II, and 193.28 ± 43.13 to 765.08 ± 209.77 μM for AChE, respectively. Also, due to the inhibitory effects of the novel inositols 11-17 against the tested enzymes, these novel inositols are potential drug candidates to treat some diseases such as glaucoma, epilepsy, leukemia, and Alzheimer's disease.
