Evaluation and application of static headspace-multicapillary column-gas chromatography-ion mobility spectrometry for complex sample analysis.

An evaluation of static headspace-multicapillary column-gas chromatography-ion mobility spectrometry (SHS-MCC-GC-IMS) has been undertaken to assess its applicability for the determination of 32 volatile compounds (VCs). The key experimental variables of sample incubation time and temperature have been evaluated alongside the MCC-GC variables of column polarity, syringe temperature, injection temperature, injection volume, column temperature and carrier gas flow rate coupled with the IMS variables of temperature and drift gas flow rate. This evaluation resulted in six sets of experimental variables being required to separate the 32 VCs. The optimum experimental variables for SHS-MCC-GC-IMS, the retention time and drift time operating parameters were determined; to normalise the operating parameters, the relative drift time and normalised reduced ion mobility for each VC were determined. In addition, a full theoretical explanation is provided on the formation of the monomer, dimer and trimer of a VC. The optimum operating condition for each VC calibration data was obtained alongside limit of detection (LOD) and limit of quantitation (LOQ) values. Typical detection limits ranged from 0.1ng bis(methylthio)methane, ethylbutanoate and (E)-2-nonenal to 472ng isovaleric acid with correlation coefficient (R(2)) data ranging from 0.9793 (for the dimer of octanal) through to 0.9990 (for isobutyric acid). Finally, the developed protocols were applied to the analysis of malodour in sock samples. Initial work involved spiking an inert matrix and sock samples with appropriate concentrations of eight VCs. The average recovery from the inert matrix was 101±18% (n=8), while recoveries from the sock samples were lower, that is, 54±30% (n=8) for sock type 1 and 78±24% (n=6) for sock type 2. Finally, SHS-MCC-GC-IMS was applied to sock malodour in a field trial based on 11 volunteers (mixed gender) over a 3-week period. By applying the SHS-MCC-GC-IMS database, four VCs were identified and quantified: ammonia, dimethyl disulphide, dimethyl trisulphide and butyric acid. A link was identified between the presence of high ammonia and dimethyl disulphide concentrations and a high malodour odour grading, that is, ≥ 6. Statistical analysis did not find any correlation between the occurrence of dimethyl disulphide and participant gender

Endothelin-Receptor Antagonists beyond Pulmonary Arterial Hypertension: Cancer and Fibrosis.

The endothelin axis and in particular the two endothelin receptors, ETA and ETB, are targets for therapeutic intervention in human diseases. Endothelin-receptor antagonists are in clinical use to treat pulmonary arterial hypertension and have been under clinical investigation for the treatment of several other diseases, such as systemic hypertension, cancer, vasospasm, and fibrogenic diseases. In this Perspective, we review the molecules that have been evaluated in human clinical trials for the treatment of pulmonary arterial hypertension, as well as other cardiovascular diseases, cancer, and fibrosis. We will also discuss the therapeutic consequences of receptor selectivity with regard to ETA-selective, ETB-selective, or dual ETA/ETB antagonists. We will also consider which chemical characteristics are relevant to clinical use and the properties of molecules necessary for efficacy in treating diseases against which known molecules displayed suboptimal efficacy

Evaluation of different metrics as an index for the assessment of arterial stiffness

Elevated intravascular pressure is a contributing factor to increased arterial stiffness, and is a risk factor for cardiovascular morbidity and mortality. Assessment of arterial stiffness is of importance in evaluating cardiovascular risk. Pulse wave velocity (PWV) has been broadly used in the assessment of arterial stiffness. We compared three different metrics of arterial stiffness to PWV. Hemodynamic recordings were carried out in anesthetized hypertensive and normotensive rats (n = 25; 13–14 weeks old). Four parameters were calculated (PWV, elastic modulus (Einc), stiffness index (β), and pressure-strain modulus (Ep)) as metrics of arterial stiffness. Hypertensive in comparison to normotensive rats had significantly higher systolic and diastolic blood pressures. Metric for arterial stiffness were significantly (p < 0.002) higher in hypertensive animals: PWV (8.46 ± 2.01 vs. 6.39 ± 1.28 m/s), Ep (0.246 ± 0.019 vs. 0.137 ± 0.010 dyn/cm2 × 10–6), Einc (17.5 ± 1.8 vs. 10.1 ± 0.9 dyn/cm2 × 10–6), and β (2.43 ± 0.11 vs. 1.98 ± 0.08) (mean±SE). Bland-Altman analysis revealed β as the only metric aligned with PWV in hypertensive state. We find in state of reduced arterial compliance associated with high systemic pressure, β but not Einc or Ep is an index of arterial stiffness showing agreement with PWV