Low-density lipoprotein aggregation predicts adverse cardiovascular events in peripheral artery disease

Background and aims: Peripheral artery disease (PAD) is a systemic manifestation of atherosclerosis that is associated with a high risk of major adverse cardiovascular events (MACE). LDL aggregation contributes to atherosclerotic plaque progression and may contribute to plaque instability. We aimed to determine if LDL aggregation is associated with MACE in patients with PAD undergoing lower extremity revascularization (LER). Methods: Two hundred thirty-nine patients with PAD undergoing LER had blood collected at baseline and were followed prospectively for MACE (myocardial infarction, stroke, cardiovascular death) for one year. Nineteen age, sex and LDL-C-matched control subjects without cardiovascular disease also had blood drawn. Subject LDL was exposed to sphingomyelinase and LDL aggregate size measured via dynamic light scattering. Results: Mean age was 72.3 10.9 years, 32.6% were female, and LDL-cholesterol was 68 +/- 25 mg/dL. LDL aggregation was inversely associated with triglycerides, but not associated with demographics, LDL-cholesterol or other risk factors. Maximal LDL aggregation occurred significantly earlier in subjects with PAD than in control subjects. 15.9% of subjects experienced MACE over one year. The 1st tertile (shortest time to maximal aggregation) exhibited significantly higher MACE (25% vs. 12.5% in tertile 2 and 10.1% in tertile 3, p = 0.012). After multivariable adjustment for demographics and CVD risk factors, the hazard ratio for MACE in the 1st tertile was 4.57 (95% CI 1.60-13.01; p = 0.004) compared to tertile 3. Inclusion of LDL aggregation in the Framingham Heart Study risk calculator for recurrent coronary heart disease events improved the c-index from 0.57 to 0.63 (p = 0.01). Conclusions: We show that in the setting of very well controlled LDL-cholesterol, patients with PAD with the most rapid LDL aggregation had a significantly elevated MACE risk following LER even after multivariable adjustment. This measure further improved the classification specificity of an established risk prediction tool. Our findings support broader investigation of this assay for risk stratification in patients with atherosclerotic CVD.Peer reviewe

The identification of intracellular molecular targets for the chemopreventive retinoid N-(4-Hydroxyphenyl)retinamide

published_or_final_versionDentistryDoctoralDoctor of Philosoph

Droplet impact on the super-hydrophobic surface with micro-pillar arrays fabricated by hybrid laser ablation and silanization process

A super-hydrophobic aluminum alloy surface with decorated pillar arrays was obtained by the hybrid laser ablation and further silanization process. The as-prepared surface showed a high apparent contact angle of 158.2 ± 2.0° and low sliding angle of 3 ± 1°. Surface morphologies and surface chemistry were explored to account for the generation process of super-hydrophobicity. The main aim of this current work is to investigate the maximum spreading factor of water droplets impacting on the pillar-patterned super-hydrophobic surface based on the energy conservation concept. Although many previous studies have investigated the droplet impacting behavior on flat solid surfaces, the empirical models were proposed based on few parameters of the Reynolds number (Re), Weber number (We) as well as the Ohnesorge number (Oh), causing the limitation for the super-hydrophobic surfaces due to the ignorance of geometrical parameters of the pillars and viscous energy dissipation for liquid flow within the pillar arrays. In this paper, the maximum spreading factor was deduced from the perspective of energy balance, and the predicated results were in good consistent with our experimental data with a mean error of 4.99% and standard deviation of 0.10

Cardiovascular Risk Scores to Predict Perioperative Stroke in Noncardiac Surgery

© 2019 American Heart Association, Inc. Background and Purpose-Perioperative stroke is associated with significant morbidity and mortality. Conventional cardiovascular risk scores have not been compared to predict acute stroke after noncardiac surgery. Methods-Patients undergoing noncardiac surgery between 2009 and 2010 were identified from the US National Surgical Quality Improvement Program (n=540 717). Patients were prospectively followed for 30 days postoperatively for the primary outcome of stroke. Established cardiovascular and perioperative risk scores (CHADS2, CHA2DS2-VASc, Revised Cardiac Risk Index, Mashour et al risk score, Myocardial Infarction or Cardiac Arrest risk score, and National Quality Improvement Project American College of Surgeons surgical risk calculator) were assessed to predict perioperative stroke. Results-Stroke occurred in the perioperative period of 1474 noncardiac surgeries (0.27%). Patients with perioperative stroke were older, more frequently male, had lower body mass index, and were more likely to have undergone vascular surgery or neurosurgery than patients without stroke (P\u3c0.001 for each comparison). All risk prediction models were associated with increased risk of perioperative stroke (C statistic [AUC] range, 0.743-0.836). The Myocardial Infarction or Cardiac Arrest risk score (AUC, 0.833) and American College of Surgeons surgical risk calculator (AUC, 0.836) had the most favorable test characteristics and a greater ability to discriminate perioperative stroke when compared with Revised Cardiac Risk Index, CHADS2, CHA2DS2-VASc, and Mashour risk scores (P for comparison, \u3c0.001; Delong). Risk scores did not provide consistent discriminative ability across surgery types and were least predictive in vascular surgery (AUC range, 0.588-0.672). Conclusions-The Myocardial Infarction or Cardiac Arrest risk score and American College of Surgeons surgical risk calculator surgical risk scores provide excellent risk discrimination for perioperative stroke in most patients undergoing noncardiac surgery. Stroke prediction was less optimal in patients undergoing vascular surgery

Cardiovascular Risk Factors and Perioperative Myocardial Infarction After Noncardiac Surgery

© 2021 Canadian Cardiovascular Society Background: Perioperative cardiovascular events are a leading cause of morbidity and mortality after noncardiac surgery. We propose a simplified method for perioperative risk stratification. Methods: In a retrospective cohort study we identified patients who underwent noncardiac surgery between 2009 and 2015 in the US National Surgical Quality Improvement Program. Multivariable logistic regression models adjusted for age, sex, race, and surgery type were generated to estimate the effect of traditional cardiovascular risk factors (hypertension, diabetes mellitus, current smoking) on odds of perioperative myocardial infarction (MI). Time to event analysis was conducted using competing risk analysis, with MI as the outcome event and death as the competing risk. Results: A total of 3,848,501 noncardiac surgeries were identified. Postoperative MI occurred in 0.37% of patients and 1.04% of patients died. The 30-day event rate of perioperative MI increased in a stepwise fashion with additional risk factors (0.42% for 1, 0.82% for 2, and 1.08% for 3; P for trend \u3c 0.001) after accounting for the competing risk of death. Compared with those with no risk factors, patients with 1, 2, and 3 risk factors had increased odds of MI (adjusted odds ratio [aOR], 2.07 [95% confidence interval (CI), 1.96-2.19]; aOR, 3.63 [95% CI, 3.43-3.85]; and aOR, 5.54 [95% CI, 5.09-6.04], respectively). Perioperative MI was rare (0.10%) in patients without risk factors. Conclusions: Patients with cardiovascular risk factors are at increased risk of perioperative MI, those without risk factors are at low risk. Further evaluation is needed to determine the effect of a simplified risk score in the perioperative setting

Virtual Screening against Phosphoglycerate Kinase 1 in Quest of Novel Apoptosis Inhibitors

Inhibition of apoptosis is a potential therapy to treat human diseases such as neurodegenerative disorders (e.g., Parkinson’s disease), stroke, and sepsis. Due to the lack of druggable targets, it remains a major challenge to discover apoptosis inhibitors. The recent repositioning of a marketed drug (i.e., terazosin) as an anti-apoptotic agent uncovered a novel target (i.e., human phosphoglycerate kinase 1 (hPgk1)). In this study, we developed a virtual screening (VS) pipeline based on the X-ray structure of Pgk1/terazosin complex and applied it to a screening campaign for potential anti-apoptotic agents. The hierarchical filters in the pipeline (i.e., similarity search, a pharmacophore model, a shape-based model, and molecular docking) rendered 13 potential hits from Specs chemical library. By using PC12 cells (exposed to rotenone) as a cell model for bioassay, we first identified that AK-918/42829299, AN-465/41520984, and AT-051/43421517 were able to protect PC12 cells from rotenone-induced cell death. Molecular docking suggested these hit compounds were likely to bind to hPgk1 in a similar mode to terazosin. In summary, we not only present a versatile VS pipeline for potential apoptosis inhibitors discovery, but also provide three novel-scaffold hit compounds that are worthy of further development and biological study

Engineering Corynebacterium glutamicum for de novo production of 2-phenylethanol from lignocellulosic biomass hydrolysate

Abstract Background 2-Phenylethanol is a specific aromatic alcohol with a rose-like smell, which has been widely used in the cosmetic and food industries. At present, 2-phenylethanol is mainly produced by chemical synthesis. The preference of consumers for “natural” products and the demand for environmental-friendly processes have promoted biotechnological processes for 2-phenylethanol production. Yet, high 2-phenylethanol cytotoxicity remains an issue during the bioproduction process. Results Corynebacterium glutamicum with inherent tolerance to aromatic compounds was modified for the production of 2-phenylethanol from glucose and xylose. The sensitivity of C. glutamicum to 2-phenylethanol toxicity revealed that this host was more tolerant than Escherichia coli. Introduction of a heterologous Ehrlich pathway into the evolved phenylalanine-producing C. glutamicum CALE1 achieved 2-phenylethanol production, while combined expression of the aro10. Encoding 2-ketoisovalerate decarboxylase originating from Saccharomyces cerevisiae and the yahK encoding alcohol dehydrogenase originating from E. coli was shown to be the most efficient. Furthermore, overexpression of key genes (aroG fbr, pheA fbr, aroA, ppsA and tkt) involved in the phenylpyruvate pathway increased 2-phenylethanol titer to 3.23 g/L with a yield of 0.05 g/g glucose. After introducing a xylose assimilation pathway from Xanthomonas campestris and a xylose transporter from E. coli, 3.55 g/L 2-phenylethanol was produced by the engineered strain CGPE15 with a yield of 0.06 g/g xylose, which was 10% higher than that with glucose. This engineered strain CGPE15 also accumulated 3.28 g/L 2-phenylethanol from stalk hydrolysate. Conclusions In this study, we established and validated an efficient C. glutamicum strain for the de novo production of 2-phenylethanol from corn stalk hydrolysate. This work supplied a promising route for commodity 2-phenylethanol bioproduction from nonfood lignocellulosic feedstock. Graphical Abstrac

Determinants of Surgical Remission in Prolactinomas: A Systematic Review and Meta-Analysis

Objective: Prolactin-secreting tumors respond well to medical management, with a few patients requiring surgery. We conducted a systematic review and meta-analysis to study the determinants of surgical remission in these tumors. Methods: We searched PubMed to identify eligible studies reporting postoperative remission in patients treated with transsphenoidal surgery for prolactinoma. Primary outcomes included postoperative remission, follow-up remission, and recurrence. Postoperative and follow-up remission were defined as normoprolactinemia at 1 year after operation, respectively. Recurrence was defined as hyperprolactinemia after initial normalization of prolactin levels. Odds ratios (ORs) were calculated, stratified by radiologic size, tumor extension, and tumor invasion, and analyzed using a random-effects model meta-analysis. Results: Thirty-five studies were included. Macroadenomas were associated with lower rates of postoperative remission (OR, 0.20; 95% confidence interval [CI], 0.16–0.24) and lower rates of remission at follow-up (OR, 0.11; 95% CI, 0.053–0.22). Postoperative remission was less likely in tumors with extrasellar or suprasellar extension (OR, 0.16; 95% CI, 0.06–0.43) and tumors with cavernous sinus invasion (OR, 0.03; 95% CI, 0.01–0.13). Female gender and absence of preoperative dopamine agonist treatment were also associated with higher remission rates. Across the included studies, there was considerable heterogeneity in each primary outcome (postoperative remission, I2 = 94%; follow-up remission, I2 = 86%; recurrence, I2 = 68%). Conclusions: Transsphenoidal surgery for prolactinomas may be particularly effective in small, noninvasive, treatment-naive tumors and may provide a viable first-line alternative to dopamine agonist therapy in such patients