bluuebunny/crossref_metadata_2025 huggingface dataset:
Discriminating 310‐ from α‐helices: Vibrational and electronic CD and IR absorption study of related Aib‐containing oligopeptides
Authors: D. Silva R. A. Gangani , Yasui Sritana C. , Kubelka Jan , Formaggio Fernando , Crisma Marco , Toniolo Claudio , Keiderling Timothy A.
Published: October 2002

Model peptides based on ‐(Aib‐Ala)n‐, and (Aib)n‐Leu‐(Aib)2 sequences, which have varying amounts of 310‐helical character, were studied by use of vibrational and electronic circular dichroism (VCD and ECD) and Fourier transform infrared (FTIR) absorption spectroscopies to test the correlation of spectral response and conformation. The data indicate that these peptides, starting from a length of about four to six residues, predominantly adopt a 310‐helical conformation at room temperature. The longest model peptides, depending on the series, may evidence some α‐helical contribution to the spectra, while the shorter ones, with less than six residues, have much less order. The IR absorption spectra (as supported by theory) showed only small frequency changes between 310‐ and α‐helices. By contrast, solvent effects are a source of much bigger perturbations. The ECD results show that the intensity ratio for the ∼ 222‐nm to ∼ 208‐nm bands, while useful for distinguishing between these two helical types in some sequences, may have a narrower range of application than VCD. However, the VCD data presented here continue to support the proposed discrimination between α‐ and 310‐helices based on qualitative amide I and II bandshape differences. The present study shows the intensities of the 310‐helical amide I (peak‐to‐peak) to its amide II VCD to be of the same order and useful for discriminating them from α‐helices, whose amide I dominates the amide II in intensity. This qualitative result is experimentally independent of the amount of αMe‐substituted residues in the sequence. These experimental VCD results are consistent in detail with theoretical spectral simulations for Ac‐(Ala)8‐NH2, Ac‐(Aib‐Ala)4‐NH2, and Ac‐(Aib)8‐NH2 in 310‐ and α‐helical conformations. © 2002 Wiley Periodicals, Inc. Biopolymers 65: 229–243, 2002
Inhibition of human chorionic gonadotropin β‐subunit modulates the mitogenic effect of c‐myc in human prostate cancer cells
Authors: Devi Gayathri R. , Oldenkamp Jennifer R. , London Carla A. , Iversen Patrick L.
Published: October 2002

BACKGROUND

Amplification of the proto‐oncogene c‐myc has been identified as one of the most common genetic alterations in prostate cancer, thus making it an attractive therapeutic target. However, certain prostate cancer cells are unresponsive to c‐Myc inhibition. The purpose of this study was to test the hypothesis that effective growth inhibition in the refractory cancer cells can be achieved by blocking c‐myc along with a growth factor using a novel phosphorodiamidate morpholino antisense oligomer‐based approach. Human chorionic gonadotropin, a growth factor implicated in neoplasm, causes activation of c‐myc through a G‐protein–coupled pathway of signal transduction.

METHODS

In this study, the effect of inhibition of β‐hCG and c‐myc singly or in combination was evaluated in DU145 (RB −/−, p53−/−, androgen‐independent) and LNCaP (Rb+/+, p53 +/+, androgen‐sensitive) human prostate cancer cell lines and in a DU145 subcutaneous xenograft murine model.

RESULTS

Antisense phosphorodiamidate morpholino oligomers directed against β‐hCG and c‐myc caused a specific decrease of the target protein levels. Unlike LNCaP cells, DU145 cell growth was refractory to c‐Myc inhibition. Unresponsiveness to c‐myc inhibition in DU145 cells was overcome by targeting both β‐hCG and c‐myc genes, resulting in potentiation of the antiproliferative effect seen with inhibition of β‐hCG alone.

CONCLUSIONS

The inhibition of β‐hCG sensitizes prostate cancer cells to the antiproliferative effects of c‐Myc inhibition, including tumors that are refractory to c‐Myc decrease alone. Prostate 53: 200–210, 2002. © 2002 Wiley‐Liss, Inc.
Mad2 and BubR1 Function in a Single Checkpoint Pathway that Responds to a Loss of Tension
Authors: Shannon Katie B. , Canman Julie C. , Salmon E. D.
Published: October 2002

The spindle checkpoint monitors microtubule attachment and tension at kinetochores to ensure proper chromosome segregation. Previously, PtK1 cells in hypothermic conditions (23°C) were shown to have a pronounced mitotic delay, despite having normal numbers of kinetochore microtubules. At 23°C, we found that PtK1 cells remained in metaphase for an average of 101 min, compared with 21 min for cells at 37°C. The metaphase delay at 23°C was abrogated by injection of Mad2 inhibitors, showing that Mad2 and the spindle checkpoint were responsible for the prolonged metaphase. Live cell imaging showed that kinetochore Mad2 became undetectable soon after chromosome congression. Measurements of the stretch between sister kinetochores at metaphase found a 24% decrease in tension at 23°C, and metaphase kinetochores at 23°C exhibited higher levels of 3F3/2, Bub1, and BubR1 compared with 37°C. Microinjection of anti-BubR1 antibody abolished the metaphase delay at 23°C, indicating that the higher kinetochore levels of BubR1 may contribute to the delay. Disrupting both Mad2 and BubR1 function induced anaphase with the same timing as single inhibitions, suggesting that these checkpoint genes function in the same pathway. We conclude that reduced tension at kinetochores with a full complement of kinetochore microtubules induces a checkpoint dependent metaphase delay associated with elevated amounts of kinetochore 3F3/2, Bub1, and BubR1 labeling.
Performance comparison and pretreatment evaluation of three water treatment membrane pilot plants treating low turbidity water
Authors: Farahbakhsh K , Smith Daniel W
Published: October 2002

The performance of three different low-pressure water treatment membrane pilot plants was evaluated on a low-turbidity, low-colour water in British Columbia. All membrane units were hollow-fibre, hydrophilic membranes with nominal pore sizes of 0.01 to 0.2 µm. In addition to finished water quality, specific flux of each membrane was used to compare the performance of the three membrane units. The effect of feed pretreatment on the performance of the membranes and removal of disinfection byproduct (DBP) precursors was evaluated using chemical coagulation and powdered activated carbon (PAC) addition. Chemical coagulation proved to be very effective in removing DPB precursors and reducing the rate of membrane fouling. Powdered activated carbon addition, on the other hand, resulted in moderate removal of DBP precursors but increased the rate of membrane fouling. The nature and causes of membrane fouling as well as the impact of pretreatment methods on membrane fouling are discussed. Key words: ultrafiltration, microfiltration, coagulation, PAC, fouling, hollow fibre membranes, pretreatment, water treatment.
The influence of pH and temperature changes on the adsorption behavior of organophilic clays used in the stabilization/solidification of hazardous wastes
Authors: Uribe A , Bishop Paul L , Pinto N G
Published: October 2002

The effect of temperature, pH, and Na+/Ca2+ concentration on the adsorptive behavior of organophilic clay used in the solidification/stabilization of hazardous wastes was addressed. The organophilic clay used was montmorillonite type clay modified by cation exchange with a mixed tallow amine as the sorbent. The contaminants used in this work were phenol, 2-chlorophenol, aniline, and chlorobenzene. 2-Butanone (also known as methyl ethyl ketone, MEK) was initially studied, but preliminary work showed that the organophilic clay poorly sorbed it and it was not studied further. A group of isothermal tests were performed to clarify specific sorption behaviors due to temperature effects, high pH, and concentration of the cations Na+ and Ca2+. The adsorption capacity of the organophilic clay decreased as follows: chlorobenzene > 2-chlorophenol > phenol > aniline. Desorption in high pH environments was seen for phenol and 2-chlorophenol. Changes in temperature, rise in the pH, or increases in Na+/Ca2+ concentrations had no effect on the adsorption of either aniline or chlorobenzene.Key words: organophilic clay, adsorption, hazardous wastes, solidification/stabilization, isotherm.
Wastewater biosolids: an overview of processing, treatment, and management
Authors: Oleszkiewicz J A , Mavinic D S
Published: October 2002

Treated as a valuable resource, municipal sludge, often today referred to as biosolids, is processed through a variety of novel unit operations leading to a safe, aesthetically pleasing, and sought-after product. The design engineer is concerned first with the ultimate disposal and utilization of the biosolids, providing at least two options for the final disposal. Volume reduction, stabilization or vector attraction reduction, and pathogen inactivation are the key goals; process trains combining them into one unit process are the target technologies. Drying and pelletization are now being applied at much smaller plants because of the introduction of indirect dryers, which have fewer air pollution problems than the direct dryers still used at some larger plants. Stabilization of biosolids in newer plants is more often combined with disinfection at thermophillic temperatures, in anaerobic and particularly in aerobic regimes. For the smallest plants, dewatering is now available in drying bags or vacuum drying beds, and larger plants benefit from an array of new devices offering sludge cakes as dry as 22 to [Formula: see text]40% total solids. The ultimate dryness will depend on the quality of sludge, polymer conditioning program, and machine parameters. Emphasis on cost reduction, with simultaneous demand for an excellent quality end product, calls for innovative and case-specific solutions that go beyond the treatment plant and also address the quality of industrialcommercial discharges to the municipal sewers. Key words: sludge, biosolids, process design, dewatering, digestion.
MUON CAPTURE IN DEUTERIUM
Authors: HWANG W.-Y. P. , LIN B.-J.
Published: October 2002

Muon capture in deuterium, μ-+ D →νμ+n+n, is a weak process of fundamental importance. The capture rate depends critically on the spin configuration of the initial (μ D ) state, which is in turn related closely to the availability of having two nearby deuteron nuclei. In this paper, we calculate the capture rates from the doublet [Formula: see text] and quartet [Formula: see text] hyperfine states. In addition to using the gaseous or liquid deuterium target, we wish also to propose to employ the deuterated target such as PdD or TiD to carry out the muon capture measurement, since it is known that the transition metals such as palladium (Pd) or titanium (Ti) has unusually high deuteron (hydrogen) absorption properties.
PROTON ELASTIC SCATTERING AND NEUTRON DISTRIBUTION OF UNSTABLE NUCLEI
Authors: KAKI K. , HIRENZAKI S.
Published: October 2002

We study theoretically how we can determine the neutron density distributions of unstable nuclei from proton elastic scattering. We apply the relativistic impulse model to study the sensitivities of the observables to the density distributions which are expressed in Woods-Saxon form. We find that both the radius and diffuseness of densities can be determined from restricted elastic scattering data in principle. We think this result is helpful to design future experiments.
NUCLEON ELECTROMAGNETIC FORM FACTORS AND CHIRAL SINGULARITIES
Authors: JOHNSON C. D. , TEGEN R.
Published: October 2002

Chiral singularities in both nucleon isovector radii are calculated in closed form. Within a one-meson-loop approximation we implement in an explicitly gauge invariant manner quark substructure in the γ π π and πNN vertex functions. The coefficients of log mπ and [Formula: see text] terms are directly related to gA and to the threshold behaviour of the πN amplitude A(-)(ν,0) which are 1 and 0, respectively, if only the N pole is considered in the πN scattering amplitude. This result is remarkably independent of the cut-off procedure. If mesonic substructure at the γ π π vertex is included, however, gA becomes slightly smaller than 1 and [Formula: see text] becomes moderately negative. This hints at important contributions to both gA and [Formula: see text] from the Δ(1232) and possibly other N*, Δ* resonances in this approach.
A common unique fixed point theorem for two random operators in Hilbert spaces
Authors: Choudhury Binayak S.
Published: October 2002

We construct a sequence of measurable functions and consider its
convergence to the unique common random fixed point of two random operators defined on a nonempty closed subset of a separable Hilbert space. The corresponding result in the nonrandom case is also obtained.
Boundedness and surjectivity in normed spaces
Authors: Nygaard Olav
Published: October 2002

We define the (w*   ‐) boundedness property and the (w*   ‐) surjectivity property for sets in normed spaces. We
show that these properties are pairwise equivalent in complete
normed spaces by characterizing them in terms of a category‐like
property called (w*   ‐) thickness. We give examples of
interesting sets having or not having these properties. In
particular, we prove that the tensor product of two
w*‐thick sets in X** and Y* is a w*‐thick subset in L(X,Y)* and obtain as a consequence that the set w*‐ is w*‐thick.
On inclusion relations for absolute summability
Authors: Rhoades B. E. , Savaş Ekrem
Published: October 2002

We obtain necessary
and (different) sufficient conditions for a series summable
, 1 < k ≤ s < ∞, to imply that the series is summable |T|s, where is a weighted mean matrix and T is a lower triangular matrix. As corollaries of this result, we obtain several inclusion theorems.
Fibrillar Collagen Regulation of Plasminogen Activator Inhibitor-1 Is Involved in Altered Smooth Muscle Cell Migration
Authors: Tanaka Shinji , Koyama Hidenori , Ichii Takuya , Shioi Atsushi , Hosoi Masayuki , Raines Elaine W. , Nishizawa Yoshiki
Published: October 2002

Objective—

Vascular smooth muscle cells (SMCs) cultured on polymerized type I collagen fibrils are arrested in the G
1
phase of the cell cycle, and their phenotypic markers and pattern of expressed genes are markedly altered. In this study, we examined polymerized collagen regulation of plasminogen activator inhibitor (PAI)-1 and its involvement in SMC migration.

Methods and Results—

We demonstrate that secretion and cell surface accumulation of PAI-1 are suppressed in SMCs cultured on polymerized collagen compared with SMCs cultured on monomer collagen. SMCs replated on vitronectin after culture on monomer collagen result in PAI-1 accumulation at focal adhesions and colocalization with α
v
β
3
integrins. In contrast, polymerized collagen inhibits PAI-1 accumulation at focal adhesions when the SMCs are replated on vitronectin. Furthermore, for SMCs cultured on polymerized collagen, platelet-derived growth factor-stimulated migration on vitronectin is enhanced by PAI-1, with its function counteracted by urinary plasminogen activator. Finally, exogenous addition of PAI-1 appears to partly restore platelet-derived growth factor-stimulated α
v
β
3
-dependent SMC migration that is specifically suppressed by polymerized collagen.

Conclusions—

Polymerized type I collagen fibrils dynamically regulate PAI-1, which may be involved in altered α
v
β
3
integrin-dependent SMC migration.
Altered Tetrahydrobiopterin Metabolism in Atherosclerosis
Authors: Vásquez-Vivar Jeannette , Duquaine Damon , Whitsett Jennifer , Kalyanaraman B. , Rajagopalan Sanjay
Published: October 2002

Objective—

Tetrahydrobiopterin (BH
4
) is of fundamental importance for the normal function of endothelial NO synthase. The purpose of this study was to investigate the effects of hyperlipidemia on vascular BH
4
levels and the effect of supplementation with sepiapterin in the presence and absence of
N
-acetylcysteine (NAC).

Methods and Results—

New Zealand White rabbits were fed normal chow (normocholesterolemic [NC] group) or hyperlipidemic chow (hyperlipidemic [HL] group) for 8 to 10 weeks. Mean cholesterol levels were 1465±333 and 53±17 mg/dL in the HL and NC group, respectively. Markedly diminished BH
4
levels were found in the HL group compared with the NC group, but these levels could be restored after 6 hours of incubation with sepiapterin. Peak relaxations to acetylcholine and A23187 were impaired in the HL group. Supplementation with sepiapterin resulted in a further diminution of relaxation in the HL but not NC group. Incubation with NAC for 6 hours failed to raise BH
4
levels, whereas NAC in conjunction with sepiapterin raised BH
4
levels ≈221-fold. However, this increase did not improve relaxations to A23187 and acetylcholine.

Conclusions—

Prolonged exposure to sepiapterin impairs vasorelaxation in hyperlipidemia despite repletion of endogenous BH
4
. Antioxidant thiols do not correct this impairment. These studies have implications for the use of sepiapterin in the correction of vasomotor tone in atherosclerosis.
Role of Heat Shock Proteins in Atherosclerosis
Authors: Xu Qingbo
Published: October 2002

Heat shock proteins (HSPs) are present in most cells, serving as molecular chaperones, and they play a role in cell protection from damage in response to stress stimuli. However, accumulating data indicate the involvement of HSPs in the pathogenesis of diseases. The aim of this article is to update the progress concerning the role of HSPs in atherosclerosis. It has been demonstrated that HSPs are highly expressed in the atherosclerotic lesions of humans, rabbits, and apolipoprotein E–deficient mice. Risk factors for atherosclerosis, eg, infections, oxidized low density lipoprotein, oxidative stress, hypertension, and biomechanical stress, evoke HSP overexpression in endothelial cells, macrophages, and smooth muscle cells via activation of heat shock transcription factor 1. Interestingly, HSPs, normally localized within the cell, have been found as a soluble form in the blood, which is positively correlated with atherosclerosis in humans. Recently, several groups have reported that soluble HSPs specifically bind to the Toll-like receptor 4/CD14 complex, initiating an innate immune response, including the production of proinflammatory cytokines by macrophages and adhesion molecules in endothelial cells via nuclear factor-κB activation. Furthermore, the titers of autoantibodies against HSPs are significantly elevated in patients with atherosclerosis, and T lymphocytes specifically responding to HSPs have been found in atherosclerotic plaques. These proinflammatory responses and autoimmune reactions to HSPs in the vessel wall can contribute to the initiation and perpetuation of atherosclerosis. Thus, HSPs have a general role in the response of the arterial wall to stress and may serve as a mediator/inducer of atherosclerosis in particular circumstances.
Interrelationships Among Circulating Interleukin-6, C-Reactive Protein, and Traditional Cardiovascular Risk Factors in Women
Authors: Bermudez Edmund A. , Rifai Nader , Buring Julie , Manson JoAnn E. , Ridker Paul M.
Published: October 2002

Objective—

Interleukin-6 (IL-6) and C-reactive protein (CRP) are markers of systemic vascular inflammation that herald atherothrombosis and may have important interrelationships with traditional cardiovascular risk factors.

Methods and Results—

We conducted a cross-sectional analysis among 340 apparently healthy women enrolled in the Women’s Health Study. In unadjusted analyses, higher levels of IL-6 and CRP were seen with increasing body mass index (BMI), systolic and diastolic blood pressure, and smoking exposure. IL-6 levels were related to the frequency of alcohol intake (
P
=0.002) and showed an inverse relationship with exercise frequency and hormone replacement therapy (
P
<0.0001 for both). CRP levels increased with hormone replacement therapy (
P
=0.0002). Associations among IL-6, CRP, and lipid levels were minimal. Overall, mean levels of IL-6 and CRP increased with increasing numbers of clinical risk factors (
P
<0.0001). In multivariate analyses, independent relationships were seen between levels of IL-6 and age, BMI, smoking, systolic blood pressure, alcohol use, presence of diabetes, and frequency of exercise. CRP was associated with age, BMI, systolic blood pressure, high density lipoprotein, smoking, and hormone replacement therapy in adjusted analyses.

Conclusions—

Plasma levels of IL-6 and CRP are independently related to several clinical cardiovascular risk factors in women.
Common Promoter Variant in Cyclooxygenase-2 Represses Gene Expression
Authors: Papafili Anastasia , Hill Michael R. , Brull David J. , McAnulty Robin J. , Marshall Richard P. , Humphries Steve E. , Laurent Geoffrey J.
Published: October 2002

Objective—Cyclooxygenase (COX)-2 is a key regulatory enzyme in the synthesis of prostanoids associated with trauma and inflammation. We investigated the COX-2 gene for functional variants that may influence susceptibility to disease.

Methods and Results—The promoter of COX-2 was screened for variants in healthy subjects by use of polymerase chain reaction-based methods. Promoter activity was investigated by using reporter expression experiments in human lung fibroblasts. Patients undergoing coronary artery bypass graft surgery, with measurements of plasma markers linked to COX-2 activity, were genotyped for association studies. A common COX-2 promoter variant, −765G>C, was found and shown to be carried by >25% of a group of healthy UK subjects. The −765C allele had significantly lower promoter activity compared with −765G, basally (28±3% lower,P<0.005) and in serum-stimulated cells (31±2% lower,P<0.005). In patients subjected to coronary artery bypass graft surgery, the magnitude of rise in levels of C-reactive protein (CRP) was strongly genotype dependent. Compared with −765G homozygotes, patients carrying the −765C allele had significantly lower plasma CRP levels at 1 to 4 days after surgery (14% lower at the peak of CRP levels on day 3,P<0.05 for all time points).

Conclusions—For several acute and chronic inflammatory diseases, −765G>C may influence the variability of response observed.
Life-Course Perspective on Socioeconomic Differences in Carotid Atherosclerosis
Authors: Rosvall Maria , Östergren Per-Olof , Hedblad Bo , Isacsson Sven-Olof , Janzon Lars , Berglund Göran
Published: October 2002

Objective—Socioeconomic status (SES) in adulthood is known to be related to carotid atherosclerosis. However, few studies have tried to assess its association with SES from a life-course perspective.

Methods and Results—We examined the relationship between SES in childhood and in adulthood and carotid atherosclerosis in a general population of Swedish men and women. Carotid stenosis was determined by B-mode ultrasound. Results showed that women whose fathers’ occupations involved unskilled manual labor had higher odds of carotid stenosis than did women whose fathers’ occupations involved high- or medium-level nonmanual labor, even after adjustment for adult occupational status and risk factors (odds ratio 1.8, 95% CI 1.1 to 2.8). No such association appeared in men. Furthermore, the impact of life-course SES on atherosclerosis was examined by using an additive measure of one’s combined SES during childhood and adulthood. Among women, the odds of carotid stenosis increased with a rise in exposure to low SES during the life-course (Pfor trend <0.001). In men, no such trend was found.

Conclusions—The results indicate that the total life-course exposure to low SES, with contributions from childhood and adulthood, seems to play a role in atherogenesis in women. Such a pattern of association could not be shown in men.
Statin Therapy in Acute Coronary Syndromes
Authors: Sposito Andrei C. , Chapman M. John
Published: October 2002

Randomized trials have established that statin treatment reduces coronary events in primary prevention and in patients with stable coronary artery disease. In unstable coronary artery disease, however, the pathophysiological background is distinct, and the potential benefits of statin therapy have not been evaluated until recently. Data from animal models and clinical studies indicate that statin treatment can influence a spectrum of molecular and cellular mechanisms that are intimately related to the pathogenesis of acute coronary syndromes; these include the reduction of circulating levels of atherogenic lipoproteins (very low density lipoprotein, very low density lipoprotein remnants, intermediate density lipoprotein, and low density lipoprotein) and thus of arterial lipid deposition and the attenuation of inflammation, modulation of thrombogenesis and thrombolysis, improvement of endothelial dysfunction, and reduction of ischemia/reperfusion injury. Indeed, findings from prospective and observational studies have demonstrated that statin treatment significantly improves clinical outcome after acute coronary syndromes. Therefore, early initiation of statin therapy after an acute coronary event not only enhances adherence to treatment but also preempts the occurrence of new events. In this review, we discuss recent important developments in our knowledge of the clinical evidence of the beneficial effects of early statin therapy in acute coronary syndromes and the biological mechanisms that underlie them.
Low Molecular Weight Fucoidan Prevents Neointimal Hyperplasia in Rabbit Iliac Artery In-Stent Restenosis Model
Authors: Deux Jean-François , Meddahi-Pellé Anne , Le Blanche Alain F. , Feldman Laurent J. , Colliec-Jouault Sylvia , Brée Françoise , Boudghène Frank , Michel Jean-Baptiste , Letourneur Didier
Published: October 2002

Objective—

Smooth muscle cell (SMC) proliferation within the intima is regulated by heparan sulfates. We studied a low molecular weight (LMW) fucoidan (sulfated polysaccharide from brown seaweed) on SMC proliferation in vitro and intimal hyperplasia in vivo.

Methods and Results—

In vitro study revealed that LMW fucoidan reduces rabbit SMC proliferation and is internalized in SMC perinuclear vesicles. On rabbit iliac arteries perfused in vivo with fluorolabeled LMW fucoidan after angioplasty, the labeling was mainly located on sites of injury. Pharmacokinetic studies showed that LMW fucoidan exhibited in rats an elimination half-life of 56±25 minutes (n=8) after intravenous administration and a constant plasma rate for ≥6 hours after intramuscular administration. After stent implantation in their iliac arteries, rabbits were also treated with LMW fucoidan (5 mg/kg IM twice a day). Histomorphometric analysis at day 14 indicated that LMW fucoidan reduced intimal hyperplasia by 59% (1.79±0.4 versus 0.73±0.2 mm
2
,
P
<0.0001) and luminal cross-sectional area narrowing by 58% (0.38±0.08 versus 0.16±0.04,
P
<0.0001). Blood samples showed no anticoagulant activity due to LMW fucoidan.

Conclusions—

This natural polysaccharide with high affinity for SMCs and sustained plasma concentration markedly reduced intimal hyperplasia, suggesting its use for the prevention of human in-stent restenosis.
Locus Controlling LDL Cholesterol Response to Dietary Cholesterol Is on Baboon Homologue of Human Chromosome 6
Authors: Kammerer Candace M. , Rainwater David L. , Cox Laura A. , Schneider Jennifer L. , Mahaney Michael C. , Rogers Jeffrey , VandeBerg John L.
Published: October 2002

Objective—

Cholesterolemic responses to dietary lipids are known to be heritable, but the genes that may affect this response have yet to be identified. Using segregation analysis, we previously detected a potential quantitative trait locus (QTL) in baboons that influenced low density lipoprotein cholesterol response to dietary cholesterol. We performed linkage analyses to locate this QTL by using data on the baboon genetic linkage map.

Methods and Results—

We obtained evidence for linkage of this potential QTL to the same locus (D6S311) on the baboon homologue of human chromosome 6 by using variance components and parametric linkage analysis methods (2-point lod scores 4.17 [genomic probability value 0.008] and 2.81 [genomic
P
=0.10], respectively). Linkage analyses of serum levels of apolipoprotein B dietary response, a correlated trait, also gave weak suggestive evidence of linkage to this chromosomal region (maximum 2-point lod score 1.91). Although the
LPA
locus is nearby, we found no evidence of linkage with
LPA.

Conclusions—

This report is the first to localize, in any primate species, a potential QTL that influences low density lipoprotein cholesterol response to dietary cholesterol.
Early Kinetic Abnormalities of ApoB-Containing Lipoproteins in Insulin-Resistant Women With Abdominal Obesity
Authors: Pont Frédéric , Duvillard Laurence , Florentin Emmanuel , Gambert Philippe , Vergès Bruno
Published: October 2002

Objective—

The kinetic abnormalities of apolipoprotein B (apoB)-containing lipoproteins in abdominally obese insulin-resistant individuals remain poorly understood. To determine the influence of insulin resistance, linked with abdominal obesity, on apoB metabolism at an early stage, we performed a stable isotope kinetic study of apoB in very low density lipoproteins (VLDLs), intermediate density lipoproteins (IDLs), and low density lipoproteins (LDLs) in 5 abdominally obese insulin-resistant women with normal fasting triglyceride levels and without impaired glucose tolerance and in 5 age-matched control women.

Methods and Results—

Each subject received an intravenous injection of a 0.7 mg/kg bolus of
l
-[1-
13
C]leucine, immediately followed by a 16-hour constant infusion at 0.7 mg/kg per hour. Compared with control women, insulin-resistant women with abdominal obesity showed a significant 84% increase of the VLDL apoB production rate (27.18±11.53 versus 14.80±1.94 [control] mg/kg per day,
P
=0.009), a significant 54% increase of the IDL apoB production rate (20.63±3.66 versus 13.39±3.99 [control] mg/kg per day,
P
=0.009), and a significant 63% increase of the LDL apoB production rate (18.49±1.70 versus 11.33±3.79 [control] mg/kg per day,
P
=0.009), leading to significantly higher VLDL, IDL, and LDL apoB concentrations. The fractional catabolic rates of VLDL, IDL, and LDL apoB were not significantly different between abdominally obese insulin-resistant women and control women.

Conclusions—

Our study shows that patients at an early stage of insulin resistance linked with abdominal obesity (without glucose intolerance or fasting hypertriglyceridemia) already have an altered metabolism of the VLDL-IDL-LDL cascade (increased VLDL, IDL, and LDL apoB production rates), which is consistent with the augmented risk of atherosclerosis observed in this population.
Excessive Microvascular Adaptation to Changes in Blood Flow in Mice Lacking Gene Encoding for Desmin
Authors: Loufrani Laurent , Li Zhenlin , Lévy Bernard I. , Paulin Denise , Henrion Daniel
Published: October 2002

Objective—

Desmin, an intermediate filament, has a key role in the integrity of myocytes, and its absence induces cardiomyopathies. Mice lacking desmin (Des−/− group) exhibit microvascular dysfunction leading to smooth muscle hyporeactivity. We investigated the effect of the absence of desmin in mice (Des−/− mice versus Des+/+ mice) on the adaptation of mesenteric arteries to changes in blood flow.

Methods and Results—

With the use of selective ligations of second-order mesenteric arteries, blood flow was either diminished (low flow [LF]) or elevated (high flow [HF]); respective LF to HF values were 136±18 to 206±29 μL/min for Des+/+ mice and 119±14 to 189±24 μL/min for Des−/−mice in daughter arteries. Two weeks after ligation, arteries were mounted in an arteriograph, allowing the measurement of diameter under controlled conditions of pressure and flow. In HF arteries, diameter changes in response to increases in pressure were higher in Des−/− mice than in Des+/+ mice. Conversely, in LF arteries, diameter was lower in Des−/− mice. Flow-dependent dilation was higher in HF arteries and lower in LF arteries than in control arteries. This adaptation was lower in Des−/− mice than in Des+/+ mice (11.6±3.1% versus 25.5±4.8% dilation, respectively). Endothelial NO synthase expression increased in HF arteries in both strains.

Conclusions—

These findings provide a demonstration of the role of the intermediate filament desmin in microvascular remodeling. This dysfunction might take place in desmin-related myopathies.
Heritability of Carotid Artery Structure and Function
Authors: North Kari E. , MacCluer Jean W. , Devereux Richard B. , Howard Barbara V. , Welty Thomas K. , Best Lyle G. , Lee Elisa T. , Fabsitz Richard R. , Roman Mary J.
Published: October 2002

Objective—Alterations in carotid artery structure and function may represent phenotypic measures of vascular disease that contain information beyond that which can be inferred from conventional cardiovascular disease risk assessment. However, apart from their associations with cardiovascular disease risk factors and outcome, the genetic basis of variations in carotid artery structure and function is largely unknown. The purpose of this study was to examine the genetic and environmental contributions to carotid artery structure and function in 3 large groups of American Indians.

Methods and Results—Approximately 950 men and women, aged ≥18 years, in 32 extended families were examined between 1997 and 1999. By use of a variance component approach and the program Sequential Oligogenic Linkage Analysis Routines, heritabilities for carotid artery structure and function phenotypes were estimated. After accounting for the effects of covariates (sex, age, diabetes, impaired glucose tolerance, smoking, cholesterol, body surface area, and hypertension), we detected significant heritabilities (given as h2values) for common carotid artery diastolic diameter (h2<0.44), intimal-medial wall thickness (h2<0.21), vascular mass (h2<0.27), arterial stiffness (h2<0.23), and the augmentation index (h2<0.18).

Conclusions—These results suggest that the additive effects of genes explain a moderate proportion of the variability of carotid artery structure and function.
Administration of Recombinant P-Selectin Glycoprotein Ligand Fc Fusion Protein Suppresses Inflammation and Neointimal Formation in Zucker Diabetic Rat Model
Authors: Zhou Zhongmin , Penn Marc S. , Forudi Farhad , Zhou Xiaorong , Tarakji Khaldoun , Topol Eric J. , Lincoff A. Michael , Wang Kai
Published: October 2002

Objective—P-selectin–mediated leukocyte-endothelium and leukocyte-platelet interaction has been reported after vascular injury and has been correlated with neointimal hyperplasia, but its role in neointimal formation after arterial injury in diabetes has not been described.

Methods and Results—Using a Zucker diabetic rat balloon injury model, we examined the role of P-selectin in the vascular inflammatory process and neointimal formation after balloon injury. Immunohistochemistry revealed that P-selectin was intensely expressed and that CD45-positive leukocyte infiltration was significantly increased after arterial injury. A single preprocedural intravenous administration of a recombinant P-selectin–soluble glycoprotein ligand-Ig inhibited CD45-positive leukocyte accumulation and suppressed neointimal formation in the Zucker diabetic rat model.

Conclusions—These results suggest that reduction of P-selectin–mediated leukocyte activation with the use of recombinant P-selectin–soluble glycoprotein ligand-Ig decreases the inflammatory response and limits neointimal formation after balloon injury in diabetes.
Adipocyte Fatty Acid–Binding Protein, aP2, Alters Late Atherosclerotic Lesion Formation in Severe Hypercholesterolemia
Authors: Boord Jeffrey B. , Maeda Kazuhisa , Makowski Liza , Babaev Vladimir R. , Fazio Sergio , Linton MacRae F. , Hotamisligil Gökhan S.
Published: October 2002

Objective—

The adipocyte fatty acid–binding protein, aP2, has important effects on insulin resistance, lipid metabolism, and atherosclerosis. Its expression in macrophages enhances early foam cell formation and atherosclerosis in vivo. This study was designed to determine whether aP2 deficiency has a similar effect in the setting of advanced atherosclerosis and severe hypercholesterolemia.

Methods and Results—

Mice deficient in aP2 and apolipoprotein E (aP2
−/−
apoE
−/−
mice) and apolipoprotein E–deficient control mice (apoE
−/−
mice) were fed a Western diet for 14 weeks. No significant differences in fasting serum levels of cholesterol, triglycerides, or free fatty acids were found between groups for each sex. Compared with apoE
−/−
control mice, male and female aP2
−/−
apoE
−/−
mice had significant reductions in mean atherosclerotic lesion size in the proximal aorta, en face aorta, and innominate/right carotid artery. Feeding the Western diet in the apoE-deficient background did not cause a significant reduction in insulin sensitivity in vivo, as determined by steady-state serum glucose levels and insulin tolerance testing.

Conclusions—

These data demonstrate an important role for aP2 expression in the advanced stages of atherosclerotic lesion formation. Thus, aP2 provides an important physiological link between different features of the metabolic syndrome and is a potential target for therapy of atherosclerosis.
Effect of Estrogen Plus Progestin on Progression of Carotid Atherosclerosis in Postmenopausal Women With Heart Disease
Authors: Byington Robert P. , Furberg Curt D. , Herrington David M. , Herd J. Alan , Hunninghake Donald , Lowery Maureen , Riley Ward , Craven Timothy , Chaput Lily , Ireland Christine C. , Applegate William B.
Published: October 2002

Objective—

The Heart and Estrogen/Progestin Replacement Study (HERS) found no overall effect of estrogen plus progestin (compared with placebo) on coronary event rates in 2763 postmenopausal women with established coronary disease (mean 4.1 years of follow-up). In addition to the events trial, a carotid ultrasound substudy was established in 1993 to be conducted concurrently to determine whether hormone therapy affects the progression of the underlying atherosclerotic process.

Methods and Results—

Within the larger HERS, a subset of 362 participants underwent carotid B-mode ultrasound examinations at baseline and the end of follow-up. Progression of carotid atherosclerosis was measured as the temporal change in intimal-medial thickness (IMT).

Conclusions—

IMT progressed in the hormone treatment and placebo groups, although there was no statistical difference between the rates: IMT progressed 26 μm/y (95% CI 18 to 34 μm/y) in the hormone group and 31 μm/y (95% CI 21 to 40 μm/y) in the placebo group (
P
=0.44). There were also no significant treatment effects when the results were examined by carotid segment or were adjusted for covariates. These data support the American Heart Association recommendation that women with established coronary disease should not initiate hormone therapy with an expectation of atherosclerotic benefit.
Heme Oxygenase-1 Gene Promoter Polymorphism Is Associated With Coronary Artery Disease in Japanese Patients With Coronary Risk Factors
Authors: Kaneda Hideaki , Ohno Minoru , Taguchi Junichi , Togo Masako , Hashimoto Hideki , Ogasawara Ken , Aizawa Tadanori , Ishizaka Nobukazu , Nagai Ryozo
Published: October 2002

Objective—

Heme oxygenase (HO) is important in the defense against oxidative stress and as a factor in an antiatherogenic mechanism. Compared with long (GT)
n
repeats, short (GT)
n
repeats in the human HO-1 gene promoter were shown to have higher transcriptional activity in response to oxidative stress. There is a strong link between oxidative stress and the pathogenesis of coronary artery disease (CAD).

Methods and Results—

We screened the allelic frequencies of (GT)
n
repeats in the HO-1 gene promoter in 577 patients who underwent coronary angiography. Because the distribution of numbers of (GT)
n
repeats was bimodal, we divided the alleles into 2 subclasses: class S included shorter (<27) repeats, and class L included longer (≥27) repeats. Multivariate logistic regression models including standard coronary risk factors revealed that the genotypes were significantly related to CAD status in hypercholesterolemic, diabetic patients or in smokers. In this study, the patients with shorter GT repeats were less likely to have CAD.

Conclusions—

Length polymorphism in the HO-1 gene promoter is related to CAD susceptibility in Japanese people who also have coronary risk factors such as hypercholesterolemia, diabetes, and smoking. HO-1 may play an antiatherogenic role in Japanese patients with these coronary risk factors.
Impaired Responsiveness to NO in Newly Diagnosed Patients With Rheumatoid Arthritis
Authors: Bergholm Robert , Leirisalo-Repo Marjatta , Vehkavaara Satu , Mäkimattila Sari , Taskinen Marja-Riitta , Yki-Järvinen Hannele
Published: October 2002

Objective—

Cardiovascular disease is the major cause of excessive mortality in patients with rheumatoid arthritis (RA). We determined whether endothelial dysfunction characterizes patients with newly diagnosed RA (n=10) compared with normal subjects (control group, n=33) and whether it is reversible with 6 months of anti-inflammatory therapy.

Methods and Results—

Endothelial function was determined by measuring vasodilatory responses to intrabrachial artery infusions of acetylcholine (ACh at 7.5 and 15 μg/min, low and high dose, respectively), an endothelium-dependent vasodilator, and to sodium nitroprusside (SNP, 3 and 10 μg/min), an endothelium-independent vasodilator. Before treatment, blood flow responses (fold increase in flow) to low-dose SNP were 30% lower in the RA versus the control group (4.1±0.4-fold versus 5.9±0.5-fold, respectively), and responses to high-dose SNP were 34% lower in the RA group versus the control group (5.1±0.6-fold versus 7.7±0.7-fold, respectively;
P
<0.001). The responses to low-dose ACh were 50% lower in the RA group versus the control group (3.0±0.5-fold versus 6.6±0.7-fold, respectively), and responses to high-dose ACh were 37% lower in the RA group versus the control group (5.0±0.4-fold versus 7.9±0.8-fold, respectively;
P
<0.001). After therapy, clinical and laboratory markers of inflammation had significantly decreased. Blood flow responses to ACh increased significantly (
P
=0.02).

Conclusions—

We conclude that newly diagnosed patients with RA have vascular dysfunction, which is reversible with successful therapy. Therefore, early suppression of inflammatory activity may reduce long-term vascular damage.
Human Macrophage-Induced Vascular Smooth Muscle Cell Apoptosis Requires NO Enhancement of Fas/Fas-L Interactions
Authors: Boyle Joseph J. , Weissberg Peter L. , Bennett Martin R.
Published: October 2002

Objective—We have previously shown that macrophages induce vascular smooth muscle cell (VSMC) apoptosis in vitro by cell-cell proximity and Fas-L/Fas interactions. Because NO is a short-range mediator, we tested whether NO mediates macrophage-induced VSMC apoptosis.

Methods and Results—NO synthase (NOS) inhibitors markedly inhibited macrophage-induced apoptosis of carotid plaque VSMCs (apoptotic indices, 81±2.9% for control and 28.2±3.9% forNG-nitro-l-arginine methyl ester [L-NAME] treatment) and coronary medial VSMCs (apoptotic indices, 76±5.5% for control and 3.5±0.8% for L-NAME treatment). Inactive enantiomers were without effect (P>0.05). Cultured macrophages, but not VSMCs, expressed inducible NOS (but not neuronal NOS or endothelial NOS) concomitant with activation and secreted 1.51±0.3 fmol nitrite per cell, which was blocked by L-NAME (100 μmol/L). Diethylene triamine nitric oxide (DETA/NO) and sodium nitroprusside (NO donors) induced VSMC cell-surface Fas and enhanced plaque VSMC apoptosis induced by agonistic anti-Fas antibody (apoptotic indices, 6.6±1.8% for control, 6.3±1.5% for DETA/NO, 26±1.8% for Fas, and 44±6.9% for Fas+DETA/NO). In isolated macrophages, NOS inhibitors reduced and NO donors increased surface Fas-L, indicating an NO-dependent autocrine enhancement of macrophage surface Fas-L.

Conclusions—Together, these data indicate that macrophage-derived NO is required for macrophage-induced VSMC apoptosis and that it acts by enhancing Fas-L/Fas interactions.
Relationship Between Coronary Artery Calcification and Other Measures of Subclinical Cardiovascular Disease in Older Adults
Authors: Newman Anne B. , Naydeck Barbara L. , Sutton-Tyrrell Kim , Edmundowicz Daniel , O’Leary Daniel , Kronmal Richard , Burke Gregory L. , Kuller Lewis H.
Published: October 2002

Background—

In the Cardiovascular Health Study, subclinical cardiovascular disease (CVD) predicted CVD events in older adults. The extent to which this measure or its components reflect calcified coronary disease is unknown.

Methods and Results—

Coronary artery calcium (CAC) was assessed with electron beam tomography in 414 participants without clinical CVD and examined using cut points (CAC≥400 and CAC≥800) and the log(CAC); 274 had subclinical CVD by ankle-arm index, ECG, or carotid ultrasound. Cut points for subclinical disease as previously defined in the Cardiovascular Health Study were examined as well as continuous measures to produce receiver operating characteristic curve curves. A low ankle-arm index was highly specific for a high CAC score. The internal carotid artery intima-media thickness was most strongly correlated with CAC (
r
=0.30) and was significantly related to both CAC cut points and to the log(CAC) score independently of all other measures.

Conclusions—

In these community-dwelling older adults without clinical CVD, internal carotid artery intima-media thickness was most closely related to CAC. However, 17.5% of those with a CAC≥400 would be missed in the ascertainment of subclinical atherosclerosis using the previously published composite of subclinical atherosclerosis. Prospective follow-up will determine whether the CAC score improves prediction of CVD events over other noninvasive measures.
Oxidized LDL in Carotid Plaques and Plasma Associates With Plaque Instability
Authors: Nishi Kyoko , Itabe Hiroyuki , Uno Masaaki , Kitazato Keiko T. , Horiguchi Hidehisa , Shinno Kiyohito , Nagahiro Shinji
Published: October 2002

Objective—

Oxidation of LDL plays a significant pathogenic role in atherosclerosis. In this study, we attempted to clarify the correlation between the morphology of human atherosclerotic plaques and the oxidized LDL (OxLDL) levels in plasma and carotid plaques.

Methods and Results—

OxLDL levels (ng/μg apolipoprotein B) in plasma and carotid plaques from 44 patients undergoing carotid endarterectomy and OxLDL levels in 17 control plasma and 9 normal intima samples were determined by a sandwich ELISA by using specific antibodies against OxLDL (DLH3) and apolipoprotein B. The plaques were immunohistochemically classified as macrophage (Mφ)-rich and Mφ-poor. In paired samples from individual patients, plaque OxLDL was nearly 70 times higher than plasma OxLDL (mean±SEM, 11.9±1.7 vs 0.18±0.01 ng/μg apoB,
P
<0.0001). The OxLDL level was significantly higher in Mφ-rich- than Mφ-poor plaques (19.6±2.8 vs 5.50±0.77ng/μg apoB,
P
<0.0001) and corresponded with DLH3 antigen positivity of the plaques. In patients with Mφ-rich plaques, plasma OxLDL was significantly higher than in the controls (0.20±0.02 vs 0.13±0.01ng/μg apoB,
P
=0.02).

Conclusions—

Our results suggest that LDL undergoes further oxidation in plaques, and that high plasma and plaque levels of OxLDL are correlated with the vulnerability to rupture of atherosclerotic lesions.