Risk factors and myocardial infarction in patients with obstructive sleep apnea: impact of β2-adrenergic receptor polymorphisms

BACKGROUND: The increased sympathetic nervous activity in patients with obstructive sleep apnea (OSA) is largely responsible for the high prevalence of arterial hypertension, and it is suggested to adversely affect triglyceride and high-density lipoprotein (HDL) cholesterol levels in these patients. The functionally relevant polymorphisms of the β2-adrenergic receptor (Arg-47Cys/Arg16Gly and Gln27Glu) have been shown to exert modifying effects on these risk factors in previous studies, but results are inconsistent. METHODS: We investigated a group of 429 patients (55 ± 10.7 years; 361 men, 68 women) with moderate to severe obstructive sleep apnea (apnea/hypopnea index (AHI) 29.1 ± 23.1/h) and, on average, a high cardiovascular risk profile (body mass index 31.1 ± 5.6, with hypertension in 60.1%, dyslipidemia in 49.2%, and diabetes in 17.2% of patients). We typed the β2-adrenergic receptor polymorphisms and investigated the five most frequent haplotypes for their modifying effects on OSA-induced changes in blood pressure, heart rate, and lipid levels. The prevalence of cardiovascular risk factors and coronary heart disease (n = 55, 12.8%) and survived myocardial infarction (n = 27, 6.3%) were compared between the genotypes and haplotypes. RESULTS: Multivariate linear/logistic regressions revealed a significant and independent (from BMI, age, sex, presence of diabetes, use of antidiabetic, lipid-lowering, and antihypertensive medication) influence of AHI on daytime systolic and diastolic blood pressure, heart rate, prevalence of hypertension, and triglyceride and HDL levels. The β2-adrenergic receptor genotypes and haplotypes showed no modifying effects on these relationships or on the prevalence of dyslipidemia, diabetes, and coronary heart disease, yet, for all three polymorphisms, heterozygous carriers had a significantly lower relative risk for myocardial infarction (Arg-47Cys: n = 195, odds ratio (OR) = 0.32, P = 0.012; Arg16Gly: n = 197, OR = 0.39, P = 0.031; Gln27Glu: OR = 0.37, P = 0.023). Carriers of the most frequent haplotype (n = 113) (haplotype 1; heterozygous for all three polymorphisms) showed a five-fold lower prevalence of survived myocardial infarction (OR = 0.21, P = 0.023). CONCLUSION: Our study showed no significant modifying effect of the functionally relevant β2-adrenergic receptor polymorphisms on OSA-induced blood pressure, heart rate, or lipid changes. Nevertheless, heterozygosity of these polymorphisms is associated with a lower prevalence of survived myocardial infarction in this group with, on average, a high cardiovascular risk profile

Microstructural evolution during high-temperature oxidation of spark plasma sintered Ti2AlN ceramics

Microstructures of Ti2AlN ceramics synthesized and simultaneously consolidated from starting mixtures of Ti/Al/TiN powders by spark plasma sintering (SPS) were characterized using X-ray diffraction, scanning electron microscopy, focused ion beam (FIB) and transmission electron microscopy (TEM). When sintered for 10 min at 1300 °C, nearly single-phase Ti2AlN ceramics with elongated (∼22 × 6 × 6 μm) grains were obtained. After sintering for 10 min at 1200 °C and chemical etching, Ti2AlN nanowhiskers (150–200 nm dia., 1–5 μm long) were exposed in pores coexisting with TiAl, TiN and Ti2AlN grains. FIB-TEM studies revealed single-crystal Ti2AlN nanowhiskers in a TiAl matrix with orientation relationship [1 1 −2 0]H//[−1 0 1]γ, (0 0 0 1)H//(1 1 1)γ, γ = TiAl, H = Ti2AlN. The nanowhiskers are believed to form by diffusion of TiN into TiAl during SPS and to be exposed during the chemical etch. Microstructural development during high-temperature oxidation of dense Ti2AlN ceramics for 1 h at 1200 °C, more complex layered microstructures containing Al2TiO5, rutile, α-Al2O3 and continuous voids layers form. After heating to 1100 °C for 1 h and cooling to room temperature, planar defects are observed in surface TiO2 grains identified as stacking faults bounded by partial dislocations. After heating for 1 h at 1400 °C and cooling to room temperature, cracks propagate in TiO2 grains. It is believed that planar defects and cracks arise from stress generation in the oxide scale. Thermal stresses formed on cooling may arise from thermal expansion mismatch of phases (TiO2, Al2O3 and Al2TiO5) in the oxide scale, the high anisotropy of thermal expansion in Al2TiO5 and thermal expansion mismatch between the oxide scale and Ti2AlN substrate. Growth stresses formed during the isothermal oxidation treatment may arise from the volume changes associated with oxidation reactions of Ti2AlN. An oxidation mechanism for Ti2AlN ceramics is proposed, which involves initial reaction with atmospheric oxygen to form oxide phases, demixing of the mixed oxide phases, void formation due to the Kirkendall effect and gaseous NOx release. Oxidation of Ti2AlN <1200 °C with 1 h hold times is limited, while above this temperature the oxide scale grows rapidly, and Ti2AlN ceramics undergo heavy oxidation

Fabrication Principles and Their Contribution to the Superior In Vivo Therapeutic Efficacy of Nano-Liposomes Remote Loaded with Glucocorticoids

We report here the design, development and performance of a novel formulation of liposome- encapsulated glucocorticoids (GCs). A highly efficient (>90%) and stable GC encapsulation was obtained based on a transmembrane calcium acetate gradient driving the active accumulation of an amphipathic weak acid GC pro-drug into the intraliposome aqueous compartment, where it forms a GC-calcium precipitate. We demonstrate fabrication principles that derive from the physicochemical properties of the GC and the liposomal lipids, which play a crucial role in GC release rate and kinetics. These principles allow fabrication of formulations that exhibit either a fast, second-order (t1/2 ∼1 h), or a slow, zero-order release rate (t1/2 ∼ 50 h) kinetics. A high therapeutic efficacy was found in murine models of experimental autoimmune encephalomyelitis (EAE) and hematological malignancies