Grace (Germany)

Synthetic amorphous silica (SAS) is industrially relevant material whose bioactivity in vitro is strongly diminished, for example, by protein binding to the particle surface. Here, we investigated the in vitro bioactivity of fourteen SAS (pyrogenic, precipitated, or colloidal), nine of which were surface-treated with organosilanes, using alveolar macrophages as a highly sensitive test system. Dispersion of the hydrophobic SAS required pre-wetting with ethanol and extensive ultrasonic treatment in the presence of 0.05% BSA (Protocol 1). Hydrophilic SAS was suspended by moderate ultrasonic treatment (Protocol 2) and also by Protocol 1. The suspensions were administered to NR8383 alveolar macrophages under serum-free conditions for 16 h, and the release of LDH, GLU, H2O2, and TNFα was measured in cell culture supernatants. While seven surface-treated hydrophobic SAS exhibited virtually no bioactivity, two materials (AEROSIL® R 504 and AEROSIL® R 816) had minimal effects on NR8383 cells. In contrast, non-treated SAS elicited considerable increases in LDH, GLU, and TNFα, while the release of H2O2 was low except for CAB-O-SIL® S17D Fumed Silica. Dispersing hydrophilic SAS with Protocol 1 gradually reduced the bioactivity but did not abolish it. The results show that hydrophobic coating reagents, which bind covalently to the SAS surface, abrogate the bioactivity of SAS even under serum-free in vitro conditions. The results may have implications for the hazard assessment of hydrophobic surface-treated SAS in the lung.

Three H-Oil gas oils,heavy atmospheric gas oil (HAGO), light vacuumgas oil (LVGO), heavy vacuum gas oil (HVGO), and two their blendswith hydrotreated straight run vacuum gas oils (HTSRVGOs) were crackedon two high unit cell size (UCS) lower porosity commercial catalystsand two low UCS higher porosity commercial catalysts. The crackingexperiments were performed in an advanced cracking evaluation fluidcatalytic cracking (FCC) laboratory unit at 527 °C, 30 s catalysttime on stream, and catalyst-to-oil (CTO) variation between 3.5 and7.5 wt/wt The two high UCS lower porosity catalysts were more activeand more coke selective. However, the difference between conversionof the more active high UCS lower porosity and low UCS higher porositycatalysts at 7.5 wt/wt CTO decreased in the order 10% (HAGO) >9%(LVGO) > 6% (HVGO) > 4% (80% HTSRVGO/20% H-Oil VGO). Therefore,thecatalyst performance is feedstock-dependent. The four studied catalystsalong with a blend of one of them with 2% ZSM-5 were examined in acommercially revamped UOP FCC VSS unit. The lower UCS higher porositycatalysts exhibited operation at a higher CTO ratio achieving a similarconversion level with more active higher UCS lower porosity catalysts.However, the higher UCS lower porosity catalysts made 0.67% Δcoke that was higher than the maximum acceptable limit of 0.64% forthis particular commercial FCC unit (FCCU), which required excludingthe HVGO from the FCC feed blend. The catalyst system containing ZSM-5increased the LPG yield but did not have an impact on gasoline octane.It was found that the predominant factor that controls refinery profitabilityrelated to the FCCU performance is the FCC slurry oil (bottoms) yield.

Background: Minority and socioeconomically disadvantaged individuals are underrepresented in secondary stroke prevention trials. Little is known about factors associated with study retention in these populations. Objective: To evaluate the impact of sociodemographic characteristics on retention in the Secondary stroke prevention by Uniting Community and Chronic care model teams Early to End Disparities (SUCCEED) trial. Methods: 487 participants ≥40 years with stroke/TIA were recruited from 4 safety-net hospitals and 1 stroke center serving low income zip codes. Strategies for boosting retention included: having bilingual research assistants from similar cultures establish rapport and follow participants; culturally and linguistically tailoring materials; arranging visits around participants’ schedules; offering transportation, and conducting assessments in the home and community. We compared sociodemographic characteristics among those retained at 12 months (n=412) vs. those not retained (n=75) using t-test, Chi Square, and Fisher exact tests. Independent factors associated with retention were determined using logistic regression. Results: Average age was 57 years, 18% were black, 71% were Hispanic, 58% were Spanish-speaking, and 72% were born outside the US. 12-month retention was 85%. On bivariate analysis, factors associated with retention were: Spanish-speaking, Hispanic ethnicity, younger age, born outside the US, and married status (all p<0.05). After multivariate analysis, study site, younger age (<64 vs ≥65 years OR 2.2, 95% CI 1.1,4.4), married status (OR 2.0, 1.0,4.2), government insurance (vs uninsured OR 25.1, 1.2,5.1), private insurance (vs uninsured, OR 4.6, 1.3,16.4), and inability to afford medical care (OR 2.9, 1.3,6.7) were associated with retention. Discussion: In this secondary prevention trial of stroke survivors from predominantly minority backgrounds, younger age, marriage, and insurance were associated with retention, suggesting that addressing barriers in the elderly, and those without insurance or spousal support may be beneficial. Financial constraints were associated with retention suggesting that study participation appealed to more socioeconomically vulnerable individuals.

Introduction: The liver X receptors (LXRs) are members of the nuclear receptor superfamily that regulate sterol metabolism and inflammation. Knockout of LXRs in macrophages greatly accelerates the development of atherosclerosis whereas pharmacological LXR activation has potent athero-protective effects. Previous studies have shown that deletion of LXR target genes in hematopoietic cells can have opposing effects on atherosclerosis development. For example, deletion of ABCA1 using bone marrow transfer in atherogenic mouse models showed increases atherosclerotic plaque burden where as knockout studies of ABCG1 and Aim1 decreased lesion formation in bone marrow transplantation experiments owing to an increase in macrophage apoptosis. Rationale: We sought to identify previously unknown genes regulated by LXRs in macrophages and to determine their contribution to atherogenesis. Methods & Results: We demonstrate that the lipopolysaccharide binding protein (LBP), a secreted glycoprotein, is an LXR target gene in macrophages. Treatment of mouse peritoneal macrophages with modified LDL or oxysterols induces LBP expression, an effect that was lost in LXRαβ-/- macrophages, consistent with a role for LBP in the cellular response to cholesterol overload. To investigate this further, we performed bone marrow transplant studies using WT or LBP-/- donors and LDLR-/- recipients. After 18 weeks of western diet feeding atherosclerotic lesion burden was assessed by en face and aortic root section analysis. LDLR-/- mice receiving LBP-/- bone marrow had markedly smaller lesions compared to those receiving WT (P<0.0001 in en face analysis; P<.01 in root section analysis). Furthermore, loss of bone marrow LBP expression led to a strong increase in apoptosis in atherosclerotic lesions as determined by TUNEL staining. In vitro studies with isolated macrophages and stable cell lines showed that LBP expression does not affect cholesterol efflux but promotes the survival of macrophages in the setting of cholesterol loading. Conclusions: The LBP gene is a macrophage LXR target that promotes foam cell survival and atherogenesis. Our study identifies LBP as a potential diagnostic and therapeutic target in human cardiovascular disease.

Background: Patients with chronic kidney disease (CKD) often have heart failure with reduced left ventricular ejection fraction (HF-REF), and previous work has shown that the co-occurrence of those conditions confers a higher rate of poor outcomes than either condition alone. But few studies have examined whether CKD confers a clinically meaningful difference in outcomes among heart failure patients with preserved left ventricular ejection fraction (HF-PEF). Compared to previous work, our study uses more granular renal function estimates and a large, contemporary cohort. Methods: Using data from the NHLBI-sponsored Cardiovascular Research Network (CVRN), we identified a community-based cohort of patients with HF. Electronic medical record data, including manual review where necessary, were used to classify heart failure type (HF-PEF and HF-REF), based on quantitative and qualitative estimates. Renal function was assessed by estimated glomerular filtration rate (eGFR) and by dipstick proteinuria. We followed patients between 2005 and 2008 for a median of 22.1 months for outcomes of death and hospitalization (HF-specific and all cause). We used Cox regression with time-updated covariates to estimate relative-risk of outcomes by level of CKD, separately for HF-PEF and HF-REF. Results: We identified 14,579 patients with HF-PEF and 9,762 with HF-REF. Compared to patients with eGFR between 60-89 ml/min/1.73m2, lower eGFR was associated with an independent graded increased risk of death and hospitalization; this relation did not meaningfully differ by type of heart failure. For example, among patients with HF-PEF, compared to patients with eGFR 60-89 ml/min/1.73m2, the relative risk of death was 1.57 (95% CI 1.41, 1.76) for eGFR 15-29 ml/min/1.73m2; for those with HF-REF the same relative risk was 2.15 (95% CI 1.87, 2.48). Results were similar with renal function estimates using dipstick proteinuria. Conclusions: Renal dysfunction is common among patients with heart failure, and is an important independent predictor of death and hospitalization across the spectrum of left ventricular systolic function. Whether patients with heart failure respond differentially to treatments by level of renal function is not clear; Our study highlights the need to develop new and effective interventions for the growing number of patients with heart failure complicated by CKD.

Hypoplastic left heart syndrome is a rare condition requiring major cardiac surgery during the neonatal period to sustain life, with subsequent procedures culminating in completion of the Fontan circulation - the common pathway for all 'single ventricle' conditions. Algorithms for care of these children are now well defined with predictable medium-term outcomes with the majority achieving a Fontan circulation. Hypoplastic left heart syndrome is one of a group of conditions that require complex surgery as a neonate and require a similar perioperative approach. Antenatal diagnosis is common in this patient subgroup, and there is a significant body of work that can be drawn on to inform parental choice.

This chapter contains sections titled: Optimization of Enantiomer Separations in HPLC Introduction Basic Principles of Enantioselective HPLC Thermodynamic Fundamentals of Enantioselective HPLC Adsorption and Chiral Recognition Differences to Reversed-Phase and Normal-Phase HPLC Principles for Optimization of Enantioselective HPLC Separations Selectors and Stationary Phases Method Selection and Optimization Cellulose and Amylose Derivatives Immobilized Cellulose and Amylose Derivatives Stationary Phases Derived from Tartaric Acid π-Acidic and π-Basic Stationary Phases Macrocyclic Selectors, Cyclodextrins, and Antibiotics Proteins and Peptides Ruthenium Complexes Synthetic and Imprinted Polymers Metal Complexation and Ligand-Exchange Phases Chiral Ion Exchangers Avoiding Errors and Troubleshooting Equipment and Columns – Practical Tips Detection Mistakes Originating from the Analyte Preparative Enantioselective HPLC Determination of the Loading Capacity Determination of Elution Volumes and Flow Rates Enantiomer Separation using Simulated Moving Bed (SMB) Chromatography Principles of Simulated Moving Bed Chromatography Separation of Commercial Active Pharmaceutical Ingredients by SMB Enantioselective Chromatography by the Addition of Chiral Additives to the Mobile Phase in HPLC and Capillary Electrophoresis Determination of Enantiomeric Purity Through the Formation of Diastereomers Indirect Enantiomer Separation on a Preparative Scale Enantiomer Separations Under Supercritical Fluid Chromatographic (SFC) Conditions New Chiral Stationary Phases and Information Management Software Summary References Miniaturization mLC/NanoLC – Optimization and Troubleshooting Introduction Sensitivity Influence of Column Length Influence of Column Internal Diameter Influence of Stationary Phase Robustness System Choice Capillary Connections Precautions Against Blocking Testing for Leakages Guard Column Switching and Sample Loading Strategies Sensitivity/Resolution Column Dimensions Packing Materials/Surface Covering Detectors References Microchip-Based Liquid Chromatography – Techniques and Possibilities Introduction Techniques Pressure-Driven Liquid Chromatography (LC) Open-Channel Electrochromatography (OCEC) Packed-Bed Electrochromatography Microfabricated Chromatographic Beds (Pillar Arrays) In Situ Polymerized Monolithic Stationary Phases Optimization and Possibilities Separation Performance Isocratic and Gradient Elution Tailor-Made Stationary Phases Sample Pretreatment and More-Dimensional Separations Issues and Challenges Application Examples Conclusions and Outlook References Ultra-Performance Liquid Chromatography Introduction Isocratic Separations Gradient Separations References