Association between cigarette smoking and lipid peroxidation in a controlled feeding study

BACKGROUND: Cigarette smoke may promote atherogenesis by producing oxygen-derived free radicals that damage lipids. However, evidence in support of this hypothesis is inconsistent because most studies did not control for aspects of diet (antioxidants and lipid substrate) that may confound the association between smoking and measures of lipid peroxidation. METHODS AND RESULTS: The relationships between cigarette smoking and two measures of lipid peroxidation, breath ethane (an in vivo assay) and thiobarbituric acid-reactive substances (TBARS, an in vitro assay), were examined in 123 adults (11% of whom were smokers) participating in a controlled feeding study. After 3 weeks of controlled feeding on a common diet (36% total fat, 14% saturated fats, 6% polyunsaturated fats, and 12% monounsaturated fats), breath and fasting serum samples were collected for measurement of ethane and TBARS, respectively. Baseline characteristics of smokers and nonsmokers were similar, including several indices related to diet and nutritional status (albumin, cholesterol, body mass index, and oxygen radical-absorbing capacity). Cigarette smokers had significantly higher breath ethane (8.88 versus 1.71 pmol/L; P<.0001) and TBARS (24.0 versus 20.7 micromol/mL; P=.008) than nonsmokers. The interval between breath collection and the time the last cigarette was smoked was significantly and inversely correlated with breath ethane. Neither measure of lipid peroxidation was associated with measures of serum cholesterol or albumin, body mass index, or serum oxygen radical-absorbing capacity. CONCLUSIONS: Cigarette smokers have higher rates of in vivo and in vitro lipid peroxidation. These results support the hypothesis that the atherogenic effects of smoking are mediated in part by free radical damage to lipids.     

Erythrocyte sodium lithium countertransport in normal and hypertensive pregnancy: relation to haemodynamic changes

OBJECTIVE: To establish the changes in erythrocyte sodium lithium countertransport (SLC) with advancing normal pregnancy and to determine if these changes were different in pregnancy induced hypertension (PIH). The changes in both groups were assessed in relation to haemodynamic changes. DESIGN: SLC, mean arterial pressure (MAP), cardiac output (CO) and total peripheral vascular resistance (TPVR) were determined serially during normal pregnancy and cross-sectionally in PIH. Women were studied again 20 weeks after delivery where possible. SETTING: Routine antenatal clinic and antenatal ward of a regional reference centre. SUBJECTS: Fifty-one normal primigravid women were studied serially and 41 primigravid women with PIH were studied at time of diagnosis. RESULTS: During normal pregnancy SLC (mmol Li/h/l cells) increased from a nonpregnant value of 0.24 +/- 0.02 (mean +/- SEM) to 0.32 +/- 0.02 at 14 weeks, and 0.37 +/- 0.02 at 20 weeks gestation. This was maintained until 38 weeks (0.40 +/- 0.02). The increase until 20 weeks occurred at the time of greatest change in CO (5.10 +/- 0.18 to 6.79 +/- 0.20 l/min) and TPVR (1327 +/- 58 to 969 +/- 33 dyn/s/cm-5). The decrease in TPVR with a rise in SLC is opposite to the relation reported in essential hypertension so that a functional relation is unlikely. However, the changes within pregnancy were positively correlated (r = 0.43, P < 0.01). In hypertensive pregnancies TPVR was elevated compared with normotensive pregnancies (1543 +/- 100 vs 1090 +/- 37) but the SLC was not different from that found in normotensive pregnancies (0.43 +/- 0.02 vs 0.40 +/- 0.02). CONCLUSIONS: The changes in SLC activity suggest dynamic effects on erythrocyte membrane function during pregnancy. However, no differences could be found between normal and hypertensive pregnancy and SLC is unlikely to be of value as a marker of hypertensive risk during pregnancy.     

High affinity hormone binding to the extracellular N-terminal exodomain of the follicle-stimulating hormone receptor is critically modulated by exoloop 3

The human follicle-stimulating hormone receptor (FSH-R) consists of two distinct domains of >330 amino acids, the N-terminal extracellular exodomain and membrane-associated endodomain. The exodomain alone binds hormone with high affinity, whereas the endodomain is the site of receptor activation. Coordination of these two domains is essential for successful hormone action but little is known about their functional and structural relationship. In this communication, we report that exoloop 3 of FSH-R constrains follicle-stimulating hormone binding to the exodomain. When the FSH-R exodomain was prepared by truncating its endodomain, the hormone binding affinity of the exodomain was slightly improved, compared with the wild type receptor. The binding affinity was further improved by >3-fold when the exodomain was attached to the membrane-associated domain of CD8. These results suggest that the FSH-R endodomain attenuates hormone binding at the exodomain. As a first step to test this hypothesis, the 11 amino acids except Ala589 of exoloop 3 were individually substituted with Ala. Ala substitution for Leu583 or Ile584 improved the hormone binding affinity by 4-6-fold while totally abolishing cAMP induction, indicating an inverse relationship. The Ala substitution for Lys580 or Pro582 had a similar trend but to a lesser extent. This significant improvement in the binding affinity suggests that the four residues at the N-terminal region of exoloop 3 interact with the exodomain and constrain the hormone binding in the wild type receptor. This effect is specific since substitutions for other than the 4 residues did not improve the hormone binding affinity. Computer modeling shows that the 4 residues can be positioned on one side of exoloop 3. This result and the apparent inverse relationship of hormone binding and cAMP induction suggest that these two essential functions may work against each other. Therefore, hormone binding might be compromised to preserve cAMP inducibility while maintaining a reasonably high, but below maximum, binding affinity.     

Comparison of orthorhombic and alpha-two titanium aluminides as matrices for continuous SiC-reinforced composites

The attributes of an orthorhombic Ti aluminide alloy, Ti-21Al-22Nb (at. pct), and an alpha-two Ti aluminide alloy, Ti-24Al-11Nb (at. pct), for use as a matrix with continuous SiC (SCS-6) fiber reinforcement have been compared. Foil-fiber-foil processing was used to produce both unreinforced (“neat”) and unidirectional “SCS-6” reinforced panels. Microstructure of the Ti-24A1-11Nb matrix consisted of ordered Ti₃Al (α ₂) + disordered beta(β), while the Ti-21 Al-22Nb matrix contained three phases: α₂, ordered beta (β ₀), and ordered orthorhombic(O). Fiber/ matrix interface reaction zone growth kinetics at 982 °C were examined for each composite system. Although both systems exhibited similar interface reaction products(i.e., mixed Ti carbides, silicides, and Ti-Al carbides), growth kinetics in theα ₂ +β matrix composite were much more rapid than in theO +β ₀ +α ₂ matrix composite. Additionally, interfacial reaction in theα ₂ +β} composite resulted in a relatively large brittle matrix zone, depleted of beta phase, which was not present in theO +β ₀+α ₂ matrix composite. Mechanical property measurements included room and elevated temperature tensile, thermal stability, thermal fatigue, thermo-mechanical fatigue (TMF), and creep. The three-phase orthorhombic-based alloy outperformed the α₂+β alloy in all of these mechanical behavioral areas, on both an absolute and a specific(i.e., density corrected) basis.     

Metabolism of 6-chloro n-butyl phthalide in rat

6-Chloro n-butyl phthalide (CBP) was orally administered to healthy, male Wistar rats pretreated with or without 3-methylcholanthrene (3-MC) by a single dose of 150 mg/kg, and urine samples were collected for 0-24 h. The urine sample was hydrolyzed with beta-glucuronidase, extracted and concentrated for TMS derivatization, and analysed on a GC-MS system for identification of CBP metabolities. Mass spectral analysis suggests that 7 CBP metabolites were present in the urine sample, and similar metabolism patterns were viewed in rats with or without pretreatment with 3-MC. Four main metabolites of CBP in rat urine were identified as alpha-beta oxolate, beta-gamma oxolate, beta-hydroxylate and gamma-hydroxylate, based on their chromatographic and mass spectral properties. Two hydroxylates have been previously identified in CBP metabolism by rat liver microsomes. The other two metabolites with higher polarity were tentatively identified as dihydroxylation products on the n-butyl side chain by the mass spectra of their TMS derivatives. One minor metabolite was found by the isotopic effect of chlorine, but its specific structure was undetermined. The difference between in vivo and in vitro metabolic profiles of CBP is also discussed.     

Performance optimization of multidisciplinary mechanical systems subject to uncertainties

This paper presents a methodology to solve a new class of stochastic optimization problems for multidisciplinary systems (multidisciplinary stochastic optimization or MSO) wherein the objective is to maximize system mechanical performance (e.g. aerodynamic efficiency) while satisfying reliability-based constraints (e.g. structural safety). Multidisciplinary problems require a different solution approach than those solved in earlier research in reliability-based structural optimization (single discipline) wherein the goal is usually to minimize weight (or cost) for a structural configuration subject to a limiting probability of failure or to minimize probability of failure subject to a limiting weight (or cost). For the problems solved herein, the objective is to maximize performance over the range of operating conditions, while satisfying constraints that ensure safe and reliable operation. Because the objective is performance based and because the constraints are reliability based, the random variables used in the objective must model variability in operating conditions, while the random variables used in the constraints must model uncertainty in extreme values (to ensure safety). Thus, the problem must be formulated to treat these two different types of variables at the same time, including the case when the same physical quantity (e.g. a particular load) appears in both the objective function and the constraints. In addition, the problem must be formulated to treat multiple load cases, which can again require modeling the same physical quantity with different random variables. Deterministic multidisciplinary optimization (MDO) problems have advanced to the stage where they are now commonly formulated with multiple load cases and multiple disciplines governing the objective and constraints. This advancement has enabled MDO to solve more realistic problems of much more practical interest. The formulation used herein solves stochastic optimization problems that are posed in this same way, enabling similar practical benefits but, in addition, producing optimum designs that are more robust than the deterministic optimum designs (since uncertainties are accounted for during the optimization process). The methodology has been implemented in the form of a baseline MSO shell that executes on both a massively parallel computer and a network of workstations. The MSO shell is demonstrated herein by a stochastic shape optimization of an axial compressor blade involving fully coupled aero-structural analysis.     

Design of high-power multiplexers with interacting,synchronously tunable channels

A novel circuit configuration is presented for tunable combining multiplexers. Using reciprocal devices, the new circuit enables any channel to be tuned without the adverse effect of frequency pulling on the other channels. Experimental results in the 900 MHz band using dual-mode dielectric resonators are in close agreement with theory.     

A model agreement for genetic research in socially identifiable populations

Genetic research increasingly focuses on population-specific human genetic diversity. However, the naming of a human population in public databases and scientific publications entails collective risks for its members. Those collective risks can be evaluated and protections can be put in place by the establishment of a dialogue with the subject population, before a research study is initiated. Here we describe an agreement to undertake genetic research with a Native American tribe. We identified the culturally appropriate public and private social units within which community members are accustomed to make decisions about health. We then engaged those units in a process of communal discourse. In their discourses about our proposed study, community members expressed most concern about culturally specific implications. We also found that, in this population, private social units were more influential in communal decision making than were public authorities. An agreement was reached that defined the scope of research, provided options for naming the population in publications (including anonymity), and addressed the distribution of royalties from intellectual property, the future use of archival samples, and specific cultural concerns. We found that informed consent by individuals could not fully address these collective issues. This approach may serve as a general model for the undertaking of population-specific genetic studies.     

Effect of pulmonary artery stenoses on the cardiopulmonary response to exercise following repair of tetralogy of Fallot

Data from exercise tests, echocardiograms, and lung perfusion scans were analyzed to determine whether the excessive minute ventilation (VE) often encountered among patients with tetralogy of Fallot is due to ventilation-perfusion mismatch secondary to branch pulmonary artery stenoses. Patients with branch PA stenoses had lower peak oxygen consumptions and higher VE during exercise than did patients without stenoses, and a strong correlation existed between the degree of pulmonary blood flow maldistribution on lung perfusion scan and the amount of excessive VE during exercise.