bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Oral Administration of Crude Aqueous Extract of Garlic on Pharmacokinetic Parameters of Isoniazid and Rifampicin in Rabbits
Authors: Dhamija P. , Malhotra S. , Pandhi P.
Published: May 2006

Aim: To study the effect of oral administration of crude aqueous extract of garlic for 14 days on pharmacokinetic parameters of isoniazid and rifampicin. Materials and Methods: Crude extract was prepared according to the method described by Fromtling and Bulmer. The study was done on 16 New Zealand white rabbits, divided into two groups of 8 animals each for two drugs. Baseline pharmacokinetic parameters for single-dose isoniazid and rifampicin were calculated from plasma drug concentrations obtained at various time intervals after dosing. The animals were given garlic extract orally for 14 days. Pharmacokinetic parameters were calculated again as done previously. Observations: Administration of crude aqueous extract of garlic significantly altered the pharmacokinetic parameters for isoniazid. Cmax was reduced from 15.4 ± 5.6 to 5.4 ± 3.3 µg/ml. AUC(0–24) was reduced from 76.7 ± 25.0 to 34.3 ± 19.2 µg/ml·h. No significant change in Tmax, kel and AUC(0–α) was seen. Pharmacokinetic parameters of rifampicin were not significantly altered by administration of garlic extract. Conclusions: Oral administration of garlic extract decreased the bioavailability of isoniazid significantly with no change in rate of elimination. Bioavailability of rifampicin is not significantly altered by garlic extract.
Antidiuretic Hormone and Osmolality in Isosorbide Therapy and Glycerol Test
Authors: Kakigi Akinobu , Takeda Taizo , Sawada Shoichi , Taguchi Daizo
Published: May 2006

Changes in plasma antidiuretic hormone (p-ADH) and plasma osmolality (p-Osm) levels were studied in 63 patients with Ménière’s disease before and after isosorbide administration and a glycerol test. Increments in both p-ADH and p-Osm levels were observed after isosorbide administration and the glycerol test. The p-ADH secretion appeared to be secondarily stimulated by an increase in the p-Osm level. This p-ADH level increase affects cochlear fluid homeostasis. Based on these results, we must consider both the p-Osm and p-ADH levels when treating patients with Ménière’s disease by osmotic diuretics.
Speech Recognition at 1-Year Follow-Up in the Childhood Development after Cochlear Implantation Study: Methods and Preliminary Findings
Authors: Eisenberg Laurie S. , Johnson Karen C. , Martinez Amy S. , Cokely Carol G. , Tobey Emily A. , Quittner Alexandra L. , Fink Nancy E. , Wang Nae-Yuh , Niparko John K.
Published: May 2006

The Childhood Development after Cochlear Implantation (CDaCI) study is a longitudinal multicenter investigation designed to identify factors influencing spoken language in young deaf children with cochlear implants. Normal-hearing peers serve as controls. As part of a comprehensive evaluation battery, a speech recognition hierarchy was designed to assess how well these children recognize speech stimuli across developmental stages. Data were analyzed for the earliest measures in 42 pairs of children reaching 1 year of follow-up. A number of children in the cochlear implant group who met criteria for testing approached levels of performance similar to the normal-hearing controls, and some could identify sentences in competition. These results demonstrate the responsiveness of the speech recognition hierarchy in tracking emergent skills from a sample of the CDaCI cohort.
Regulation of Acid-Base Transporters by Vasopressin in the Kidney Collecting Duct of Brattleboro Rat
Authors: Amlal Hassane , Sheriff Sulaiman , Faroqui Somia , Ma Liyun , Barone Sharone , Petrovic Snezana , Soleimani Manoocher
Published: May 2006

Aim: The objective of these studies was to examine the effects of long-term vasopressin treatment on acid-base transporters in the collecting duct of rat kidney. Methods: Brattleboro rats were placed in metabolic cages and treated with daily injections of 1-desamino-8-D-arginine vasopressin (dDAVP), a selective V2-receptor agonist, or its vehicle (control) for up to 8 days. Results: dDAVP treatment resulted in a significant reduction in serum bicarbonate concentration, and caused the upregulation of key ammoniagenesis enzymes, along with increased urinary NH4+ excretion. Northern hybridization and immunofluorescence labeling indicated a significant increase (+80%) in mRNA expression of the apical Cl–/HCO3– exchanger pendrin (PDS), along with a sharp increase in its protein abundance in B-type intercalated cells in the cortical collecting duct in dDAVP-treated rats. In the inner medullary collecting duct, the abundance of basolateral Cl–/HCO3– exchanger (AE1) and apical H+-ATPase was significantly reduced in dDAVP-treated rats. Kidney renin mRNA increased significantly and correlated with an increase in serum aldosterone levels in dDAVP-injected rats. Serum corticosterone levels were, however, reduced and correlated with increased mRNA levels of renal 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2) and decreased mRNA expression of 11β-hydroxylase in the adrenal gland of dDAVP-injected rats. Conclusion: Chronic administration of dDAVP to Brattleboro rats is associated with the upregulation of PDS and downregulation of H+-ATPase and AE1 in the collecting duct, along with increased ammoniagenesis. Stimulation of the renin-angiotensin-aldosterone system and/or decreased glucocorticoid levels likely plays a role in the transduction of these effects.
Relevance of Tenascin-C and Matrix Metalloproteinases in Vascular Abnormalities in Murine Hypoplastic Lungs
Authors: Chinoy Mala R. , Miller Shane A.
Published: May 2006

Background: Tenascin-C (TN-C), an extracellular matrix glycoprotein, is crucial to cell-migration, proliferation, apoptosis and remodeling of tissues, with a potential role in pathobiology of pulmonary hypertension. Matrix metallopro-teinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are crucial to the integrity of the extracellular matrix. TN-C and MMPs are counter-regulatory molecules, which influence the vascular integrity through modulations of elastin. We have a murine model of pulmonary hypoplasia with coexistent diaphragmatic hernia, vascular abnormalities and excessive arterial smooth muscle cell (SMC) proliferation. Objectives: Our objective was to investigate modulations of TN-C and MMPs in hypoplastic lungs and their possible contribution to the observed pulmonary vascular abnormalities. Methods: We addressed our objectives by pursing immunoblotting and immunohistochemistry and zymography/reverse zymography to assess the alterations in activities of MMPs and their inhibitors. Results: We observed significant down-regulation of MMP-9 activity in hypoplastic lungs at the later fetal developmental stages, whereas MMP-2 activity assessed by gelatin zymography remained unaltered. Reverse zymography revealed up-regulation of activities of TIMP-1, -2, -3 and -4 in hypoplastic lungs during later fetal development, with pronounced increases in TIMP-3 and -4 activities. Furthermore, immunoblot analyses and immunohistochemistry revealed that TN-C protein was down-regulated in developing hypoplastic lungs, compared to normal lungs. Conclusions: (1)TN-C is known to inhibit vascular SMC proliferation. But, decrease in TN-C in hypoplastic lungs may support the observed arterial SMC proliferation. (2) Our studies showed that in hypoplastic lungs the SMC apoptosis is not affected, thus suggesting that SMC proliferation and apoptosis may be two separate processes in pulmonary hypoplasia with coexistent diaphragmatic hernia. Together, our data showed an imbalance in the extracellular matrix proteins, which may contribute to the pulmonary vascular abnormalities.
Association of Estrogen Receptor α (ESR1) PvuII and XbaI Polymorphisms with Sporadic Alzheimer’s Disease and Their Effect on Apolipoprotein E Concentrations
Authors: Corbo Rosa Maria , Gambina Giuseppe , Ruggeri Maria , Scacchi Renato
Published: May 2006

Background: Many studies have shown that estrogen replacement therapy may improve cognitive function in women and reduce the risk of Alzheimer’s disease (AD). Because most of the estrogen neuroprotective effect is mediated by receptors, we studied the associations between estrogen receptor α (ESR1) polymorphisms (PvuII and XbaI) and AD, and their interactions with apolipoprotein E (APOE) polymorphism and plasma levels. Methods: ESR1 genotypes and APOE plasma concentrations were determined in a sample of AD patients and controls. Results: ESR1 PP and XX genotypes were associated with an increased risk for AD only in males (OR = 3.6, 95% CI = 1.2–10.9) and conferred a relevant additional risk of AD to subjects also carrying APOE e*4 allele (OR = 13.3, 95% CI = 1.7–103.6). Mean APOE concentrations were lower in AD patients; the lowest levels were observed in male patients carrying PP and/or XX genotypes (p = 0.006) and in patients carrying PP and/or XX genotypes together with the e*4 allele (p = 0.003). In AD women, ESR1 PP and XX genotypes were also associated with lower MMSE values (p = 0.0007). Conclusion: The present data suggest that the involvement of ESR1 polymorphisms in AD onset is mediated by the regulation of apoE expression. ESR1 polymorphisms are also associated with a faster cognitive decline in the women AD patients.
Tension-Free Vaginal Tape versus Tension-Free Vaginal Tape Obturator in Women with Stress Urinary Incontinence
Authors: Liapis Angelos , Bakas Panagiotis , Giner Maria , Creatsas Georgios
Published: May 2006

Background: To assess the efficacy and complications of tension-free vaginal tape (TVT) versus tension-free vaginal tape obturator in women with urodynamic stress incontinence. Methods: Prospective, randomized study. Initially, 91 patients were included in the study and 89 of them were available at 12 months follow-up. Forty-six patients were subjected to classic TVT procedure and 43 to transobturator vaginal tape from inside to outside (TVT-O) operation. There was no significant difference between the groups for age, BMI, menopausal status and prolapse. No patients had cystocele greater than stage I. Subjective and objective cure and improvement rate, mean operative time, hospital stay and complications incidence were assessed. Results: Mean operative time was significant shorter in the TVT-O group (17.4 ± 6.9 min) compared to the TVT group (26.7 ± 8.6 min). There was no significant difference in the duration of hospital stay between two groups. The objective cure rate for TVT group was 89%, the improvement rate was 6.5%, the failure rate was 4.3% and the subjective cure rate 73.9%. The objective cure rate for TVT-O group was 90%, the improvement rate was 7.6%, the failure rate was 2.5% and the subjective cure rate 76.7%. The hemoglobin loss ranged between 1.0 ± 0.5 g/dl for TVT group and 0.9 ± 0.4 g/dl for TVT-O group. Conclusion: The TVT-O technique presents success rates comparable to the classic TVT method in the short term.
Characteristics of Poststroke Depression in Japanese Patients
Authors: Kaji Yoshiaki , Hirata Koichi , Ebata Atsuko
Published: May 2006

Poststroke depression (PSD) has an important impact on the quality of life of patients with stroke. We studied 100 stroke patients (mean age ± SD: 64.6 ± 11.6, range: 32–85 years) in the subacute phase (2–5 weeks after onset) and investigated the prevalence and clinical correlates of PSD in the subacute phase. The prevalences of PSD and major depression in the subacute phase evaluated by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, were 20.0 and 5.0%, respectively. These values were lower than those reported in Caucasian studies. The Zung Self-Rating Depression Scale (SDS) did not underestimate the presence of PSD and was thus considered valuable for the initial screening of PSD. However, SDS may overestimate PSD especially in patients with anxiety disorders or somatoform disorders and vice versa. Apathy was observed in 40.2% of patients; however, it was widely distributed and observed even in patients without serious depression.
BDNF Val66Met Polymorphism Is Associated with Body Mass Index in Healthy Adults
Authors: Gunstad John , Schofield Peter , Paul Robert H. , Spitznagel Mary Beth , Cohen Ronald A. , Williams Leanne M. , Kohn Michael , Gordon Evian
Published: May 2006

Although recent studies suggest a possible relationship between the brain-derived neurotrophic factor Val66Met polymorphism and eating disorders, no study has examined the possibility that the Met-Met genotype is associated with a lower body mass index (BMI) in healthy individuals. We examined this possibility in 481 adults (age range 18–82 years) without significant medical or psychiatric history. After adjusting for gender, analysis of covariance showed that persons with the Met-Met genotype had a lower BMI than those with the Val-Met/Val-Val genotypes (22.28 ± 3.77 vs. 24.72 ± 4.81). A similar, though nonsignificant, trend emerged when comparing all three genotypes separately. These findings suggest a possible relationship between Val66Met polymorphism and BMI in healthy adults. Further work is needed to clarify possible mechanisms for this relationship.
Positron Emission Tomography Imaging of Risperidone Augmentation in Serotonin Reuptake Inhibitor-Refractory Patients
Authors: Buchsbaum Monte S. , Hollander Eric , Pallanti Stefano , Baldini Rossi Nicolò , Platholi Jimcy , Newmark Randall , Bloom Rachel , Sood Erica
Published: May 2006

We studied 15 nondepressed patients with obsessive-compulsive disorder (OCD) who were nonresponders to serotonin reuptake inhibitors with an additive trial of risperidone. Positron emission tomography with 18F-deoxyglucose and magnetic resonance imaging was obtained at baseline and following 8 weeks of either risperidone or placebo in a double-blind parallel group design. Risperidone treatment was associated with significant increases in relative metabolic rate in the striatum, cingulate gyrus, the prefrontal cortex, especially in the orbital region, and the thalamus. Four of 9 patients who received risperidone showed clinical improvement (CGI score of 1 or 2 at 8 weeks) while none of the 6 patients who received placebo showed improvement. Patients with low relative metabolic rates in the striatum and high relative metabolic rates in the anterior cingulate gyrus were more likely to show a clinical response. These metabolic predictors of clinical response are consistent with earlier PET studies showing similar prediction when either neuroleptics or serotonin reuptake inhibitor treatments are administered individually. Our results are consistent with a frontostriatal circuit change related to both dopaminergic and serotonergic systems and with the presence of psychopharmacological subtypes within OCD.
Inheritance of Olfactory Preferences I. Pheromone-Mediated Behavioral Responses of Heliothis subflexa × Heliothis virescens Hybrid Male Moths
Authors: Vickers Neil J.
Published: May 2006

Shifts in male preference for qualitatively different pheromone blends appear to have played a fundamental role in the divergence of olfactory communication and evolution of moth species. As an initial step in documenting the genetic complexity underlying such shifts, we characterized the behavioral responses of hybrid male moths created by mating two heliothine moth species, Heliothis subflexa and Heliothis virescens. Between 67 and 96% of hybrid males flew upwind and contacted the pheromone source when presented with a blend consisting of (Z)-11-hexadecenal (Z11–16:Ald), (Z)-9-hexadecenal (Z9–16:Ald), and (Z)-11-hexadecenol (Z11–16:OH) in a 1:0.5:0.1 ratio that has previously been shown to be attractive to H. subflexa males. In addition, an H. virescens blend of Z11–16:Ald and (Z)-9-tetradecenal (Z9–14:Ald) enhanced by the addition of Z11–16:OH (in a 1:0.05:0.1 mixture) was attractive to hybrid males (26–64% source contact), but significantly fewer males reached the odor source compared to the blend containing Z9–16:Ald. A blend in which the dosage of Z9–14:Ald was doubled, however, was equally attractive (75–77% source contact) as the Z9–16:Ald-containing blend. Consecutive presentation of two blends revealed that individual hybrid males responded equally well to blends containing either Z9–14:Ald or Z9–16:Ald. Together these results suggest that in addition to Z11–16:Ald, hybrid males: (1) required either Z9–16:Ald (likeH. subflexamales) or Z9–14:Ald (like H. virescens males); (2) required the presence of Z11–16:OH (H. subflexa dominant); (3) were not adversely affected by the presence of Z11–16:Ac (H. subflexa dominant). The behavioral response phenotype of hybrid males was therefore influenced by genetic factors inherited from both parental species.
Inheritance of Olfactory Preferences II. Olfactory Receptor Neuron Responses from Heliothis subflexa × Heliothis virescens Hybrid Male Moths
Authors: Baker T.C. , Quero C. , Ochieng’ S.A. , Vickers N.J.
Published: May 2006

Single-cell electrophysiological recordings were obtained from olfactory receptor neurons (ORNs) in sensilla trichodea on male antennae of hybrids formed mainly by crossing female Heliothis subflexa with male Heliothis virescens (‘SV hybrids’). We recorded from the A-, B-, and C-type sensilla trichodea, with the latter two types housing ORNs exhibiting response profiles to different pheromone components that we had previously found to be characteristic for each species. For both the B- and the C-type SV hybrid sensilla, most of the ORNs exhibited a spike amplitude and ORN co-compartmentalization within sensilla that more strongly resembled the ORNs of parental H. subflexa rather than those of H. virescens. The overall mean dose-response profiles of the ORNs in hybrid C- and B-type sensilla were intermediate between those of the H. virescens and H. subflexa parental type ORNs. However, not all hybrid ORNs were intermediate in their tuning spectra, but rather ranged from those that closely resembled H. subflexa or H. virescens parental types to those that were intermediate, even on the same antenna. The most noteworthy shift in ORN responsiveness in hybrid males was an overall increase in sensitivity to Z9–14:Ald exhibited by Z9–16:Ald-responsive ORNs. Heightened cross-responsiveness to Z9–14:Ald by hybrid ORNs correlates well with observed behavioral cross-responsiveness of hybrids in which Z9–14:Ald could substitute for Z9–16:Ald in the pheromone blend, a behavior not observed in parental types. The hybrid ORN shifts involving greater sensitivity to Z9– 14:Ald also correlate well with studies of hybrid male antennal lobe interneurons that exhibited a shift toward greater cross-responsiveness to Z9–14:Ald and Z9– 16:Ald. We propose that the differences between parental H. virescens, H. subflexa, and SV hybrid male pheromone ORN responsiveness to Z9–16:Ald and Z9–14:Ald are most logically explained by an increased or decreased co-expression of two different odorant receptors for each of these compounds on the same ORN.
Education and Dementia: A Meta-Analytic Study
Authors: Caamaño-Isorna Francisco , Corral Montserrat , Montes-Martínez Agustín , Takkouche Bahi
Published: May 2006

Considerable controversy exists about the role of education in the risk of dementia. Individual studies have not been conclusive so far. To examine the hypothesis that lower education is associated with a higher risk of dementia, we carried out a meta-analysis. Observational studies published as of October 2005 that examined the association between education and risk of dementia were systematically reviewed. Relative risks (RRs) and odds ratios were extracted from cohort and case-control studies. We first compared the risk of dementia in subjects with high level of education with the risk of dementia in those with low educational level. In a subsequent analysis, we compared the risk of persons with high education with the risk of subjects with education level other than high (medium, low). We weighted log RRs for cohort studies or odds ratios by the inverse of their variances. Nineteen studies were included in our meta-analysis (13 cohort and 6 case-control studies). RRs for low versus high education level were: Alzheimer’s disease (AD) 1.80 (95% CI: 1.43–2.27); non-AD dementias, 1.32 (95% CI: 0.92–1.88), and all dementias 1.59 (95% CI: 1.26–2.01). For low and medium versus high education level, the RRs were: AD 1.44 (95% CI: 1.24–1.67); non-AD 1.23 (95% CI: 0.94–1.61), and all dementias 1.33 (95% CI: 1.15–1.54). These results confirm that low education may be a risk factor for dementia, especially for AD.
Risk Factors for Contrast-Induced Nephropathy
Authors: Toprak Omer , Cirit Mustafa
Published: May 2006

An increasing number of diagnostic imaging and interventional procedures require the use of radiographic contrast agents which has led to a parallel increase in the incidence of contrast-induced nephropathy (CIN). CIN is a serious clinical problem associated with increased morbidity and mortality, particularly in patients with chronic renal failure (see the Case Report). A key step to minimize CIN is to identify patients at risk of CIN. The aim of the present review was to summarize the knowledge about the risk factors of CIN, including the review of ultimate clinical research and developments.
Acceleration of Lung Maturation in a Human Fetus following Maternal Isotretinoin Intake
Authors: Fauchère Jean-Claude , Ersch Jörg , Grant Daniel Allen , Zimmermann Roland , Bucher Hans Ulrich , Stallmach Thomas
Published: May 2006

The viability of the human fetus increases significantly beyond 25 weeks’ gestation as the lung development progresses towards the ‘saccular’ stage. We report on a fetus of 22 weeks’ gestation whose lung maturation was accelerated by 4 weeks, most likely due to the unintentional exposure to the retinoid isotretinoin (13-cis-retinoic acid) during pregnancy. Although retinoids are known to be stored within the lungs and to play a key role in lung differentiation and growth, their storage within the lung is limited during this critical developmental period. Even though glucocorticosteroids are used clinically to enhance lung maturation in the face of impending preterm birth, there are no data yet which demonstrate that glucocorticosteroids, when given alone, are effective in promoting lung maturation prior to 24 weeks’ gestation. Strong evidence however, indicates that glucocorticosteroids promote the utilization of lung retinoids immediately before birth. Our observation of increased lung maturation, in conjunction with the above information suggests that retinoids alone or in combination with glucocorticosteroids might promote lung maturation more effectively than glucocorticosteroids alone when birth seems inevitable at a very early gestational age.
Childhood C-Reactive Protein in Predicting CRP and Carotid Intima-Media Thickness in Adulthood
Authors: Juonala Markus , Viikari Jorma S.A. , Rönnemaa Tapani , Taittonen Leena , Marniemi Jukka , Raitakari Olli T.
Published: May 2006

Background—

Atherosclerosis begins in childhood, and inflammation may contribute to its pathophysiology. The value of measuring inflammatory markers in the pediatric risk assessment, however, is uncertain. We examined whether childhood C-reactive protein (CRP) levels predict CRP and carotid intima-media thickness (IMT) in adulthood.

Methods and Results—

Study cohort included 1617 subjects, aged 3 to 18 years at baseline in 1980. These subjects were reexamined in 2001 at ages 24 to 39 years. In 2001, CRP was measured from fresh samples, and the subjects underwent carotid IMT study to evaluate subclinical atherosclerosis. Baseline (1980) CRP concentrations were measured from frozen samples in 2005. A significant tracking was observed between childhood and adult CRP levels. The age- and sex-specific correlations were the highest in the age group of 18 years at baseline (
r
=0.47 in females,
r
=0.32 in males,
P
<0.0001). The association between childhood and adult CRP levels was independent of serum lipids, blood pressure, smoking, obesity indices, and insulin. In multivariate analysis, childhood risk factors that independently associated with increased adult IMT included elevated systolic blood pressure (
P
<0.0001), high low-density lipoprotein-cholesterol (
P
=0.01) and smoking (
P
=0.049), but not CRP (
P
=0.95).

Conclusions—

Childhood CRP values predict weakly but significantly adult CRP, and this association is independent of other metabolic risk factors. Unlike conventional risk factors, however, childhood CRP does not predict adult IMT.
Maternal Diet During Pregnancy and Carotid Intima–Media Thickness in Children
Authors: Gale Catharine R. , Jiang Benyu , Robinson Sian M. , Godfrey Keith M. , Law Catherine M. , Martyn Christopher N.
Published: May 2006

Objective—

Autopsy studies show that intimal lipid accumulations in arteries are often present at birth, suggesting that the prenatal environment plays a role in the pathogenesis of atherosclerosis. In animal models, a restricted or unbalanced maternal diet during gestation can influence susceptibility to atherosclerosis, but the relation in humans between maternal diet during pregnancy and atherogenesis is unknown.

Methods and Results—

We measured carotid intima–media thickness (IMT) in 216 nine-year-old children whose mothers had participated in a study of nutrition during pregnancy. IMT was greater in boys, in children who were heavier, in those with higher systolic blood pressure, and in those who took less exercise. Increased IMT was associated with a lower maternal energy intake in early (
P
=0.029) or late (
P
=0.006) pregnancy, after adjustment for these factors. Mean IMT of children whose mothers were in the lowest quarter of the distribution of energy intake in late pregnancy was 0.027 mm (95% confidence interval, 0.004 to 0.049) greater than that of those whose mothers were in the highest quarter of the distribution.

Conclusion—

Lower maternal energy intake during pregnancy may increase the susceptibility to atherogenesis of the child.
Human Platelets Secrete the Plasma Type of Platelet-Activating Factor Acetylhydrolase Primarily Associated With Microparticles
Authors: Mitsios John V. , Vini Maria P. , Stengel Dominique , Ninio Ewa , Tselepis Alexandros D.
Published: May 2006

Objective—

Platelet-activating factor acetylhydrolase (PAF-AH) expresses a Ca
2+
-independent phospholipase A
2
activity and hydrolyzes platelet-activating factor as well as oxidized phospholipids. Two major types of PAF-AH have been described: the plasma type, which is associated with lipoproteins, and the intracellular type II PAF-AH.

Methods and Results—

We investigated the type(s) of PAF-AH expressed in human platelets as well as the mechanism and the enzyme type secreted from platelets during activation. The majority of the enzyme activity (75.1±14.3% of total) is found in the cytosol, whereas 24.9±7.3% is associated with the membranes. Immunofluorescence microscopy studies and Western blotting analysis showed that platelets contain the plasma type as well as the intracellular type II PAF-AH. Furthermore, platelets contain high levels of the mRNA of plasma PAF-AH, whereas only a small quantity of the type II PAF-AH mRNA was detected. On activation, platelets secrete the plasma type of PAF-AH mainly associated with platelet-derived microparticles (PMPs). The enzyme activity was also detected on circulating PMPs in plasma from normolipidemic healthy subjects.

Conclusion—

This is the first indication that in addition to lipoproteins, PAF-AH in human plasma is carried by PMPs, suggesting that the PMP-associated PAF-AH may play a role in the dissemination of biological activities mediated by these particles.
Increased Expression of Elastolytic Cathepsins S, K, and V and Their Inhibitor Cystatin C in Stenotic Aortic Valves
Authors: Helske Satu , Syväranta Suvi , Lindstedt Ken A. , Lappalainen Jani , Öörni Katariina , Mäyränpää Mikko I. , Lommi Jyri , Turto Heikki , Werkkala Kalervo , Kupari Markku , Kovanen Petri T.
Published: May 2006

Objective—

To investigate the possible role of elastolytic cathepsins S, K, and V and their endogenous inhibitor cystatin C in adverse extracellular matrix remodeling of stenotic aortic valves.

Methods and Results—

Stenotic aortic valves were collected at valve replacement surgery and control valves at cardiac transplantations. The expression of cathepsins S, K, and V and cystatin C was studied by conventional and real-time polymerase chain reaction and by immunohistochemistry. Total cathepsin activity in the aortic valves was quantified by a fluorometric microassay. When compared with control valves, stenotic valves showed increased mRNA expression of cathepsins S, K, and V (
P
<0.05 for each) and a higher total cathepsin activity (
P
<0.001). In stenotic valves, cystatin C mRNA was increased (
P
<0.05), and cystatin C protein was found particularly in areas with infiltrates of inflammatory cells. Both cathepsin S and cystatin C were present in bony areas of the valves, whereas cathepsin V localized to endothelial cells in areas rich of neovascularization. Incubation of thin sections of aortic valves with cathepsins S, K, and V resulted in severe disruption of elastin fibers, and this cathepsin effect could be blocked by adding cystatin C to the incubation system.

Conclusions—

Stenotic aortic valves show increased expression and activity of elastolytic cathepsins S, K, and V. These cathepsins may accelerate the destruction of aortic valvular extracellular matrix, so promoting the progression of aortic stenosis.
Scavenger Receptors in Atherosclerosis
Authors: Moore Kathryn J. , Freeman Mason W.
Published: May 2006

Atherosclerotic vascular disease arises as a consequence of the deposition and retention of serum lipoproteins in the artery wall. Macrophages in lesions have been shown to express ≥6 structurally different scavenger receptors for uptake of modified forms of low-density lipoproteins (LDLs) that promote the cellular accumulation of cholesterol. Because cholesterol-laden macrophage foam cells are the primary component of the fatty streak, the earliest atherosclerotic lesion, lipid uptake by these pathways has long been considered a requisite and initiating event in the pathogenesis of atherosclerosis. Although the removal of proinflammatory modified LDLs from the artery wall via scavenger receptors would seem beneficial, the pathways distal to scavenger receptor uptake that metabolize the modified lipoproteins appear to become overwhelmed, leading to the accumulation of cholesterol-laden macrophages and establishment of a chronic inflammatory setting. These observations have led to the current dogma concerning scavenger receptors, which is that they are proatherogenic molecules. However, recent studies suggest that the effects of scavenger receptors on atherogenesis may be more complex. In addition to modified lipoprotein uptake, these proteins are now known to regulate apoptotic cell clearance, initiate signal transduction, and serve as pattern recognition receptors for pathogens, activities that may contribute both to proinflammatory and anti-inflammatory forces regulating atherogenesis. In this review, we focus on recent advances in our knowledge of scavenger receptor regulation and signal transduction, their roles in sterile inflammation and infection, and the potential impact of these pathways in regulating the balance of lipid accumulation and inflammation in the artery wall.
Hepatic ATP-Binding Cassette Transporter A1 Is a Key Molecule in High-Density Lipoprotein Cholesteryl Ester Metabolism in Mice
Authors: Singaraja Roshni R. , Stahmer Bjorn , Brundert May , Merkel Martin , Heeren Joerg , Bissada Nagat , Kang Martin , Timmins Jenelle M. , Ramakrishnan Rajasekhar , Parks John S. , Hayden Michael R. , Rinninger Franz
Published: May 2006

Objective—

Mutations in ATP-binding cassette transporter A1 (ABCA1), the cellular lipid transport molecule mutated in Tangier disease, result in the rapid turnover of high-density lipoprotein (HDL)–associated apolipoproteins that presumably are cleared by the kidneys. However, the role of ABCA1 in the liver for HDL apolipoprotein and cholesteryl ester (CE) catabolism in vivo is unknown.

Methods and Results—

Murine HDL was radiolabeled with
125
I in its apolipoprotein and with [
3
H]cholesteryl oleyl ether in its CE moiety. HDL protein and lipid metabolism in plasma and HDL uptake by tissues were investigated in ABCA1-overexpressing bacterial artificial chromosome (BAC)–transgenic (BAC
+
) mice and in mice harboring deletions of total (ABCA1
−/−
) and liver-specific ABCA1 (ABCA1
−L/−L
). In BAC
+
mice with elevated ABCA1 expression, fractional catabolic rates (FCRs) of both the protein and the lipid tracer were significantly decreased in plasma and in the liver, yielding a diminished hepatic selective CE uptake from HDL. In contrast, ABCA1
−/−
or ABCA1
−L/−L
mice had significantly increased plasma and liver FCRs for both HDL tracers. An ABCA1 deficiency was associated with increased selective HDL CE uptake by the liver under all experimental conditions.

Conclusions—

Hepatic ABCA1 has a critical role for HDL catabolism in plasma and for HDL selective CE uptake by the liver.
Molecular Profiling Improves Diagnoses of Rejection and Infection in Transplanted Organs
Authors: Morgun Andrey , Shulzhenko Natalia , Perez-Diez Ainhoa , Diniz Rosiane V.Z. , Sanson Gerdine F. , Almeida Dirceu R. , Matzinger Polly , Gerbase-DeLima Maria
Published: May 2006

The monitoring of transplanted hearts is currently based on histological evaluation of endomyocardial biopsies, a method that is fairly insensitive and that does not always accurately discriminate between rejection and infection in the heart. Accurate diagnosis of rejection and infection is absolutely crucial, however, as the respective treatments are completely different. Using microarrays, we analyzed gene expression in 76 cardiac biopsies from 40 heart recipients undergoing rejection, no rejection, or
Trypanosoma cruzi
infection. We found a set of genes whose expression patterns were typical of acute rejection, and another set of genes that discriminated between rejection and
T cruzi
infection. These sets revealed acute rejection episodes up to 2 weeks earlier, and trypanosome infection up to 2 months earlier than did histological evaluation. When applied to raw data from other institutions, the 2 sets of predictive genes were also able to accurately pinpoint acute rejection of lung and kidney transplants, as well as bacterial infections in kidneys. In addition to their usefulness as diagnostic tools, the data suggest that there are similarities in the biology of the processes involved in rejection of different grafts and also in the tissue responses to pathogens as diverse as bacteria and protozoa.
14-3-3 Is a Regulator of the Cardiac Voltage-Gated Sodium Channel Nav1.5
Authors: Allouis Marie , Le Bouffant Françoise , Wilders Ronald , Péroz David , Schott Jean-Jacques , Noireaud Jacques , Le Marec Hervé , Mérot Jean , Escande Denis , Baró Isabelle
Published: May 2006

The voltage-sensitive Na
+
channel Na
v
1.5 plays a crucial role in generating and propagating the cardiac action potential and its dysfunction promotes cardiac arrhythmias. The channel takes part into a large molecular complex containing regulatory proteins. Thus, factors that modulate its biosynthesis, localization, activity, and/or degradation are of great interest from both a physiological and pathological standpoint. Using a yeast 2-hybrid screen, we unveiled a novel partner, 14-3-3η, interacting with the Na
v
1.5 cytoplasmic I interdomain. The interaction was confirmed by coimmunoprecipitation of 14-3-3 and full-length Na
v
1.5 both in COS-7 cells expressing recombinant Na
v
1.5 and in mouse cardiac myocytes. Using immunocytochemistry, we also found that 14-3-3 and Na
v
1.5 colocalized at the intercalated discs. We tested the functional link between Na
v
1.5 and 14-3-3η using the whole-cell patch-clamp configuration. Coexpressing Na
v
1.5, the β1 subunit and 14-3-3η induced a negative shift in the inactivation curve of the Na
+
current, a delayed recovery from inactivation, but no changes in the activation curve or in the current density. The negative shift was reversed, and the recovery from inactivation was normalized by overexpressing the Na
v
1.5 cytoplasmic I interdomain interacting with 14-3-3η. Reversal was also obtained with the dominant negative R56,60A 14-3-3η mutant, suggesting that dimerization of 14-3-3 is needed for current regulation. Computer simulations suggest that the absence of 14-3-3 could exert proarrhythmic effects on cardiac electrical restitution properties. Based on these findings, we propose that the 14-3-3 protein is a novel component of the cardiac Na
+
channel acting as a cofactor for the regulation of the cardiac Na
+
current.
Integrin-Mediated Transcriptional Activation of Inhibitor of Apoptosis Proteins Protects Smooth Muscle Cells Against Apoptosis Induced by Degraded Collagen
Authors: von Wnuck Lipinski Karin , Keul Petra , Ferri Nicola , Lucke Susann , Heusch Gerd , Fischer Jens W. , Levkau Bodo
Published: May 2006

Apoptosis of smooth muscle cells (SMC) and degradation of the extracellular matrix (ECM) have both been implicated in atherosclerotic plaque rupture. We have previously reported that degraded type I collagen fragments induce a rapid but transient apoptotic burst initiated by calpains in SMC. The aim of the current study was to identify the pathway responsible for consecutive SMC survival. We show that exposure of SMC to collagen fragments resulted in a sustained activation of nuclear factor (NF)-κB via phosphorylation and degradation of IκBα. Its prevention through retroviral expression of superrepressor IκBα or proteasome inhibition potently induced apoptosis. In the presence of blocking antibodies to α
v
β
3
integrin and RGD peptides, collagen fragments no longer activated NF-κB and apoptosis was enhanced. The mechanism by which NF-κB was protecting SMC against collagen fragment-induced apoptosis was a transcriptional activation of several endogenous caspase inhibitors of the inhibitor of apoptosis protein (IAP) family as: (1) the expression of xIAP, c-IAP2, and survivin was potently induced by collagen fragments; (2) IAP expression was abrogated by superrepressor IκBα; and (3) knockdown of each of the 3 IAPs by small interfering RNA (siRNA) resulted in enhanced apoptosis after collagen fragment treatment. Our data suggest that SMC exposed to degraded collagen are protected against apoptosis by a mechanism involving α
v
β
3
-dependent NF-κB activation with consequent activation of IAPs. This may constitute a novel antiapoptotic pathway ensuring SMC survival in settings of enhanced ECM degradation such as cell migration, vascular remodeling, and atherosclerotic plaque rupture.
Adrenoceptor Polymorphisms and the Risk of Cardiac Injury and Dysfunction After Subarachnoid Hemorrhage
Authors: Zaroff Jonathan G. , Pawlikowska Ludmila , Miss Jacob C. , Yarlagadda Sirisha , Ha Connie , Achrol Achal , Kwok Pui-Yan , McCulloch Charles E. , Lawton Michael T. , Ko Nerissa , Smith Wade , Young William L.
Published: May 2006

Background and Purpose—Cardiac abnormalities occur commonly after subarachnoid hemorrhage (SAH) and may be caused by excessive release of catecholamines from the myocardial sympathetic nerves. We hypothesized that adrenoceptor polymorphisms resulting in greater catecholamine sensitivity would be associated with an increased risk of cardiac injury.

Methods—This was a prospective cohort study. The primary outcome variables were the serum level of cardiac troponin I (cTi, abnormal if >1.0 μg/L) and the left ventricular ejection fraction (LVEF, abnormal if <50%). Six adrenoceptor polymorphisms were genotyped:β1ARArg389Gly,β1ARSer49Gly,β2ARGly16Arg,β2ARGln27Glu,β2ARThr164Ile, andα2ARdel322-325. The effect of each polymorphism on the risk of developing cardiac abnormalities was quantified using multivariable logistic regression.

Results—The study included 182 patients. The CC genotype (Arg/Arg) ofβ1ARArg389Gly (odds ratio [OR] 3.4,P=0.030) and the CC genotype (Gln/Gln) ofβ2ARGln27Glu (OR 3.1,P=0.032) were predictive of cTi release. The presence of theα2ARdeletion was predictive of reduced LVEF (OR 4.2,P=0.023). The combination of theβ1AR389 CC and theβ2AR27 CC genotypes resulted in a marked increase in the odds of cTi release (OR 15.5,P=0.012). The combination of theβ1AR389 CC and theα2ARdeletion genotypes resulted in a marked increase in the odds of developing a reduced LVEF (OR 10.3,P=0.033).

Conclusions—Genetic polymorphisms of the adrenoceptors are associated with an increased risk of cardiac abnormalities after SAH. These data support the hypothesis that cardiac dysfunction after SAH is a form of neurocardiogenic injury.
Impaired Inhibitory Effect of Interleukin-10 on the Balance Between Matrix Metalloproteinase-9 and Its Inhibitor in Mononuclear Cells From Hyperhomocysteinemic Subjects
Authors: Holven Kirsten B. , Halvorsen Bente , Bjerkeli Vigdis , Damås Jan Kristian , Retterstøl Kjetil , Mørkrid Lars , Ose Leiv , Aukrust Pål , Nenseter Marit S.
Published: May 2006

Background and Purpose—

Homocysteine has been linked to increased risk of ischemic stroke and other cardiovascular events, but the mechanism by which elevated plasma levels of homocysteine promotes atherogenesis remains unclear. Matrix degradation, partly regulated by the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs), plays an important role in atherogenesis and plaque destabilization, and we hypothesized an imbalance between MMPs and TIMPs in hyperhomocysteinemia.

Methods—

Serum MMP-9 and TIMP-1 was measured in 12 hyperhomocysteinemic and 12 control subjects. The release of MMP-9 and TIMP-1, with and without interleukin-10 (IL-10), and the effect of IL-10 on signal transducer and activator of transcription 3 (STAT3) phosphorylation were measured in peripheral blood mononuclear cells (PBMCs) from hyperhomocysteinemic and control subjects.

Results—

Our main findings were: (1) hyperhomocysteinemic subjects had raised serum levels of MMP-9 and MMP-9/TIMP-1 ratio comparing healthy controls; (2) although IL-10 markedly suppressed MMP-9 release from PBMCs in controls, no or only minor effect was seen in hyperhomocysteinemic subjects; (3) although IL-10 enhanced TIMP-1 levels in PBMCs from both hyperhomocysteinemic and control subjects, the increase was more prominent in controls, resulting in a marked difference in IL-10–induced changes in MMP-9/TIMP-1 ratio between these 2 groups; and (4) comparing PBMCs from controls, cells from hyperhomocysteinemic individuals had impaired IL-10–induced STAT3 phosphorylation.

Conclusions—

Our findings suggest an attenuated inhibitory response to IL-10 on MMP-9 activity in hyperhomocysteinemic subjects, potentially promoting atherogenesis and plaque instability, representing a novel explanation for increased risk for atherosclerotic disease in these individuals.
Brain Gray Matter Changes in Migraine Patients With T2-Visible Lesions
Authors: Rocca Maria A. , Ceccarelli Antonia , Falini Andrea , Colombo Bruno , Tortorella Paola , Bernasconi Luca , Comi Giancarlo , Scotti Giuseppe , Filippi Massimo
Published: May 2006

Background and Purpose—

In migraine patients, functional imaging studies have shown changes in several brain gray matter (GM) regions. However, 1.5-T MRI has failed to detect any structural abnormality of these regions. We used a 3-T MRI scanner and voxel-based morphometry (VBM) to assess whether GM density abnormalities can be seen in patients with migraine with T2-visible abnormalities and to grade their extent.

Methods—

In 16 migraine patients with T2-visible abnormalities and 15 matched controls, we acquired a T2-weighted and a high-resolution T1-weighted sequence. Lesion loads were measured on T2-weighted images. An optimized version of VBM analysis was used to assess regional differences in GM densities on T1-weighted scans of patients versus controls. Statistical parametric maps were thresholded at
P
<0.001, uncorrected for multiple comparisons.

Results—

Compared with controls, migraine patients had areas of reduced GM density, mainly located in the frontal and temporal lobes. Conversely, patients showed increased periacqueductal GM (PAG) density. Compared with patients without aura, migraine patients with aura had increased density of the PAG and of the dorsolateral pons. In migraine patients, reduced GM density was strongly related to age, disease duration, and T2-visible lesion load (
r
ranging from −0.84 to −0.73).

Conclusions—

Structural GM abnormalities can be detected in migraine patients with brain T2-visible lesions using VBM and a high-field MRI scanner. Such GM changes comprise areas with reduced and increased density and are likely related to the pathological substrates associated with this disease.
Genetic Analysis of Familial Connective Tissue Alterations Associated With Cervical Artery Dissections Suggests Locus Heterogeneity
Authors: Wiest Tina , Hyrenbach Sonja , Bambul Pinar , Erker Birgit , Pezzini Alessandro , Hausser Ingrid , Arnold Marie-Luise , Martin Juan José , Engelter Stefan , Lyrer Philippe , Busse Otto , Brandt Tobias , Grond-Ginsbach Caspar
Published: May 2006

Background and Purpose—

Cervical artery dissections (CAD) can be associated with connective tissue aberrations in skin biopsies. The analysis of healthy relatives of patients suggested that the connective tissue phenotype is familial with an autosomal dominant inheritance.

Methods—

We performed genetic linkage studies in 3 families of patients with CAD. Connective tissue phenotypes for the patients and all family members were assessed by electron microscopic study of skin biopsies. A genome-wide linkage analysis of 1 family (1 patient with 8 healthy relatives) indicated 2 candidate loci. Three genes were subsequently studied by sequence analysis. Part of the genome was also studied by linkage analysis in 2 further families.

Results—

The genome-wide scan in a single family suggested linkage between the hypothetical mutation causing the connective tissue phenotype and informative genetic markers on chromosome 15q24 (logarithm of the odds score:
Z
= +2.1). A second possible candidate locus (
Z
=+1.9) was found on chromosome 10q26. Sequence analysis of 3 candidate genes in the suggestive locus (chondroitin sulfate proteoglycan4 [
CSPG4
], lysyl oxidase-like1 [
LOXL1
] and fibroblast growth factor receptor2 [
FGFR2
]) did not lead to the identification of a mutation responsible for connective tissue alterations. In 2 additional smaller families the loci on chromosome 15q24 and 10q26 were excluded by linkage analysis.

Conclusions—

Linkage analysis of a large family with CAD-associated connective tissue alterations suggested the presence of a candidate locus on chromosome 15q2 or on chromosome 10q26. Sequence analysis did not lead to the identification of a mutated candidate gene in 1 of these loci. The study of 2 additional pedigrees indicated locus heterogeneity for the connective tissue phenotype of CAD patients.