bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulatory response to washout of amniotic fluid in sheep
Authors: Yang Qin , Davis L. , Hohimer A. , Faber J. , Anderson D.
Published: October 2004

To test the hypothesis that a substance present in the amniotic fluid could serve as a regulator of amniotic fluid volume, we drained and discarded amniotic fluid while replacing it with lactated Ringer solution that was isotonic to amniotic fluid. Seven ewes with singleton fetuses at 119 ± 1 days of gestation (mean ± SE) were instrumented with multiple indwelling catheters in the pedal artery, pedal vein, and amniotic cavity. During the exchange periods, an average of 3,019 ± 171 ml/day of lactated Ringer solution was infused into the amniotic cavity while an equal amount of amniotic fluid was pumped out and discarded. During the control period, amniotic fluid composition and volume were not altered. Exchange and control periods started with the same amniotic fluid volume, lasted 3 or 4 days, and were randomized with regard to order. Amniotic fluid volume measured by vacuum drainage was 556 ± 98 ml at the end of the control period and 986 ± 209 ml ( P = 0.03) at the end of the exchange period. Fetal arterial blood gases, hemodynamic parameters and the osmolality gradient between fetal plasma and amniotic fluid were not altered by the exchange process. A linear relationship between the control amniotic fluid volume and the volume at the end of the exchange period ( P = 0.003) suggests that the animals with larger control volumes responded to isovolumic dilution with a larger volume increase. We conclude that amniotic fluid may contain a substance that regulates amniotic volume.
Oxidant stress and constrictor reactivity impair cerebral artery dilation in obese Zucker rats
Authors: Phillips Shane A. , Sylvester Francis A. , Frisbee Jefferson C.
Published: October 2004

This study tested the hypothesis that evolution of the metabolic syndrome in obese Zucker rats (OZR) leads to impaired dilator reactivity of cerebral resistance arteries vs. responses determined in lean Zucker rats (LZR). Middle cerebral arteries (MCA) from 17-wk-old male LZR and OZR were isolated and cannulated with glass micropipettes. Vascular reactivity was assessed in response to challenge with ACh, sodium nitroprusside (SNP), reductions and elevations in Po2, 5-HT, and increased intralumenal pressure. Vessels were treated with the free radical scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (tempol) to assess the role of superoxide production in altering reactivity, and passive vascular wall mechanics was assessed in each vessel. Vascular superoxide production was assessed in isolated arteries using fluorescence microscopy. Vessel dilation to ACh and hypoxia was impaired in OZR vs. LZR, although responses to SNP were normal. Vessel constriction to 5-HT, elevated Po2, and elevated intralumenal pressure was enhanced in OZR vs. LZR. Fluorescence microscopy demonstrated an increased superoxide production in arteries of OZR vs. LZR, correctable by incubation with tempol. Although treatment of vessels from OZR with tempol improved dilation to ACh and hypoxia, constrictor responses to 5-HT, elevated Po2, and pressure were not altered by tempol treatment. Indexes of vessel wall mechanics were comparable between groups. These results suggest that vasodilator reactivity of MCA of OZR in response to endothelium-dependent dilator stimuli is impaired vs. LZR and that this may represent a reduced bioavailability of signaling molecules due to oxidant scavenging. However, oxidative stress-independent increases in myogenic tone and constrictor reactivity may contribute to blunted dilator responses of cerebral microvessels.
Statins Inhibit Synthesis of an Oxysterol Ligand for the Liver X Receptor in Human Macrophages With Consequences for Cholesterol Flux
Authors: Wong Jenny , Quinn Carmel M. , Brown Andrew J.
Published: October 2004

Objective—

Cholesterol efflux from macrophages in the artery wall, a key cardioprotective mechanism, is largely coordinated by the nuclear oxysterol-activated liver X receptor, LXRα. We investigated the effect of statins on LXR target gene expression and cholesterol efflux from human macrophages.

Methods and Results—

In human macrophages (THP-1 cell line and primary cells), the archetypal statin, compactin, greatly reduced mRNA levels of 2 LXR target genes, ABCA1 and ABCG1 mRNA, as well as decreased cholesterol efflux. Commonly prescribed statins also downregulated LXR target gene expression in THP-1 cells. We provide several lines of evidence indicating that statins decrease expression of LXR target genes by inhibiting the synthesis of an oxysterol ligand for LXR, 24(
S
),25-epoxycholesterol. When THP-1 cells were cholesterol-loaded via incubation with acetylated low-density lipoprotein, synthesis of 24(
S
),25-epoxycholesterol was greatly reduced and the downregulatory effect of compactin on ABCA1 mRNA levels and cholesterol efflux was lost.

Conclusions—

Our results suggest that statins may downregulate cholesterol efflux from nonloaded human macrophages by inhibiting synthesis of an oxysterol ligand for LXR. Further work is needed to determine how relevant our observations are to arterial foam cells in vivo.
Effect of Low Dose Atorvastatin Versus Diet-Induced Cholesterol Lowering on Atherosclerotic Lesion Progression and Inflammation in Apolipoprotein E*3–Leiden Transgenic Mice
Authors: Verschuren Lars , Kleemann Robert , Offerman Erik H. , Szalai Alexander J. , Emeis Sjef J. , Princen Hans M. G. , Kooistra Teake
Published: October 2004

Objective—

To evaluate whether low-dose atorvastatin suppresses atherosclerotic lesion progression and inflammation in apolipoprotein E*3 (apoE*3)–Leiden mice beyond its cholesterol-lowering effect.

Methods and Results—

ApoE*3–Leiden mice were fed a high-cholesterol (HC) diet until mild atherosclerotic lesions had formed. Subsequently, HC diet feeding was continued or mice received HC supplemented with 0.002% (w/w) atorvastatin (HC+A), resulting in 19% plasma cholesterol lowering, or mice received a low-cholesterol (LC) diet to establish a plasma cholesterol level similar to that achieved in the HC+A group. HC+A and LC diet reduced, significantly and to the same extent, lesion progression and complication in the aortic root, as assessed by measuring total atherosclerotic lesion area, lesion severity, and macrophage and smooth muscle cell area. In the aortic arch, HC+A but not LC blocked lesion progression. HC+A and LC reduced vascular inflammation (ie, expression of macrophage migration inhibitory factor , plasminogen activator inhibitor- 1, matrix metalloproteinase-9), but HC+A additionally suppressed vascular cell adhesion molecule-1 expression and, in parallel, monocyte adhesion. In contrast, low-dose atorvastatin showed no antiinflammatory action toward hepatic inflammation markers (serum amyloid A, C-reactive protein [CRP]) in apoE*3–Leiden mice and human CRP transgenic mice.

Conclusion—

Low-dose atorvastatin cholesterol-dependently reduces lesion progression in the aortic root but shows antiinflammatory vascular activity and tends to retard atherogenesis in the aortic arch beyond its cholesterol-lowering effect.
No Association Between Plasma Levels of Plant Sterols and Atherosclerosis in Mice and Men
Authors: Wilund Kenneth R. , Yu Liqing , Xu Fang , Vega Gloria L. , Grundy Scott M. , Cohen Jonathan C. , Hobbs Helen H.
Published: October 2004

Objective—

Sitosterolemia is characterized by elevated plasma levels of plant sterols, hypercholesterolemia and premature coronary heart disease (CHD). CHD develops in some subjects with sitosterolemia, despite having normal plasma cholesterol levels, suggesting that high circulating levels of plant sterols may be atherogenic. We tested whether elevated plasma levels of plant sterols (sitosterol and campesterol) were associated with atherosclerosis in genetically modified mice and in middle-aged men and women.

Methods and Results—

Wild-type and hypercholesterolemic female mice with >20-fold higher plasma levels of plant sterols because of inactivation of the ATP-binding cassette (ABC) half transporters
G5
and
G8
(
G5G8
−/−mice) were fed chow or Western diets for 7 months. No significant differences in aortic lesion area were found when the sitosterolemic mice were compared with littermate controls. To determine whether plasma levels of plant sterols were associated with coronary atherosclerosis in humans, the relationship between plasma plant sterols and coronary calcium (detected by electron beam computer tomography) was examined in 2542 subjects aged 30 to 67 years. Plasma levels of cholesterol, but not sitosterol or campesterol, were significantly higher in subjects with coronary calcium.

Conclusions—

The results of this study do not support an association between elevated plasma levels of plant sterols and atherosclerosis.
Low-Density Lipoprotein From Apolipoprotein E-Deficient Mice Induces Macrophage Lipid Accumulation in a CD36 and Scavenger Receptor Class A-Dependent Manner
Authors: Zhao Zhenze , de Beer Maria C. , Cai Lei , Asmis Reto , de Beer Frederick C. , de Villiers Willem J.S. , van der Westhuyzen Deneys R.
Published: October 2004

Objective—

To investigate the potential of circulating low-density lipoprotein (LDL), isolated from apolipoprotein E (apoE)-deficient mice (E−/−LDL) and from LDL receptor-deficient mice (Lr−/−LDL), to induce foam cell formation.

Methods and Results—

Binding studies using COS-7 cells overexpressing CD36, J774 cells, and mouse peritoneal macrophages (MPMs) unexpectedly showed for the first time that E−/−LDL, which is enriched in cholesterol, is a high-affinity ligand for CD36 and exhibited greater macrophage uptake than Lr−/−LDL or normal LDL. Minimal copper-mediated oxidization of Lr−/−LDL or C57LDL in vitro resulted in increased ligand internalization, although cell uptake of these oxidized LDLs was lower than that of E−/−LDL, even at oxidation levels similar to that found in E−/−LDL. Treatment of MPMs with E−/−LDL and Lr−/−LDL (to a 2- to 3-fold lesser extent), but not normal LDL, resulted in significant cellular cholesteryl ester accumulation and foam cell formation. Experiments using MPMs lacking CD36, scavenger receptor class A (SR-A), or both, indicated a major contribution of CD36 (≈50%), and to a lesser extent, SR-A (24% to 30%), to E−/−LDL uptake.

Conclusions—

Because of its increased state of oxidation and high cholesterol content, LDL in apoE-deficient mice acts in a proatherogenic manner, without requiring further modification in the vascular wall, to induce foam cell formation through its uptake by scavenger receptors.
RNA-Binding Proteins Heterogeneous Nuclear Ribonucleoprotein A1, E1, and K Are Involved in Post-Transcriptional Control of Collagen I and III Synthesis
Authors: Thiele Bernd-Joachim , Doller Anke , Kähne Thilo , Pregla Reinhard , Hetzer Roland , Regitz-Zagrosek Vera
Published: October 2004

Collagen types I and III, coded by COL1A1/COL1A2 and COL3A1 genes, are the major fibrillar collagens produced by fibroblasts, including cardiac fibroblasts of the adult heart. Characteristic for different cardiomyopathies is a remodeling process associated with an upregulation of collagen synthesis, which leads to fibrosis. We report identification of three mRNA-binding proteins, heterogeneous nuclear ribonucleoprote (hnRNP) A1, E1, and K, as positive effectors of collagen synthesis acting at the post-transcriptional level by interaction with the 3′-untranslated regions (3′-UTRs) of COL1A1, 1A2, and 3A1 mRNAs. In vitro, binding experiments (electromobility shift assay and UV cross-linking) reveal significant differences in binding to CU- and AU-rich binding motifs. Reporter gene cell transfection experiments and RNA stability assays show that hnRNPs A1, E1, and K stimulate collagen expression by stabilizing mRNAs. Collagen synthesis is activated via the angiotensin II type 1 (AT
1
) receptor. We demonstrate that transforming growth factor-β1, a major product of stimulated AT
1
receptor, does not activate solely collagen synthesis but synergistically the synthesis of hnRNP A1, E1, and K as well. Thus, post-transcriptional control of collagen synthesis at the mRNA level may substantially be caused by alteration of the expression of RNA-binding proteins. The pathophysiological impact of this finding was demonstrated by screening the expression of hnRNP E1 and K in cardiovascular diseases. In the heart muscle of patients experiencing aortic stenosis, ischemic cardiomyopathy, or dilatative cardiomyopathy, a significant increase in the expression of hnRNP E1, A1, and K was found between 1.5- and 4.5-fold relative to controls.
Internal Carotid Artery Stenosis Measurement
Authors: Hyde Derek E. , Fox Allan J. , Gulka Irene , Kalapos Paul , Lee Don H. , Pelz David M. , Holdsworth David W.
Published: October 2004

Background and Purpose—

Clinical trials have shown that carotid endarterectomy reduces stroke risk in symptomatic individuals with severe internal carotid artery (ICA) stenosis. As a result of these trials, digital subtraction angiography (DSA) became a standard of reference for ICA stenosis diagnosis. Newer 3D techniques provide a larger number of views than DSA, which may influence the estimated degree of stenosis. We evaluate this possibility by directly comparing stenosis grades from 3D computed rotational angiography (CRA) and DSA.

Methods—

As a prospective diagnostic study, we performed CRA and DSA on 26 consecutive symptomatic patients. Only 1 angiographic procedure was performed on normal asymptomatic arteries, yielding 42 arteries for comparison. Four neuroradiologists graded the CRA maximum intensity projections (MIPs) and DSA images, according to the North American Symptomatic Carotid Endarterectomy Trial guidelines. CRA studies included a search for the narrowest view by evaluating 60 MIPs generated at 3° intervals and measurement of actual artery diameters. Artery diameters and stenosis grades were analyzed graphically; statistical significance was determined using a paired
t
test.

Results—

The mean difference of 1.2% (CI, −18%, 21%) between CRA and DSA stenosis grades was not statistically significant (
P
=0.55). Agreement of the optimal CRA viewing angle was limited, with an interobserver variability of 24±13°. The interobserver variability of DSA and CRA stenosis grades, 9.1% (CI, 0%, 21%) and 9.4% (CI, 0%, 22%), respectively, was not significantly different (
P
=0.79).

Conclusion—

CRA provides stenosis grades equivalent to DSA, as well as absolute measurements, providing a comparison for newer 3D techniques.
Sex Difference in the Effect of Time From Symptoms to Surgery on Benefit From Carotid Endarterectomy for Transient Ischemic Attack and Nondisabling Stroke
Authors: Rothwell P.M. , Eliasziw M. , Gutnikov S.A. , Warlow C.P. , Barnett H.J.M.
Published: October 2004

Background and Purpose—

Early studies showed that carotid endarterectomy (CEA) carried a high risk if performed within days after a large ischemic stroke. Therefore, many surgeons delay CEA for 4 to 6 weeks after any stroke. To determine the effect of delay to CEA on operative risk and benefit, we pooled data from the North American Symptomatic Carotid Endarterectomy Trial and the European Carotid Surgery Trial.

Methods—

Risk of ipsilateral ischemic stroke in the medical group, operative risk of stroke and death, and overall benefit from surgery were determined in relation to the time from the last symptomatic event to randomization. Operative risk of stroke and death was also determined in relation to the time to surgery. Analyses were stratified by sex and type of presenting event.

Results—

The 30-day perioperative risk of stroke and death was unrelated to the time since the last symptomatic event and was not increased in patients operated <2 weeks after nondisabling stroke. In contrast, the risk of ipsilateral ischemic stroke in the medical group fell rapidly with time since event (
P
<0.001), as did the absolute benefit from surgery (
P
=0.001). This decline in benefit with time was unrelated to the type of presenting event but was more pronounced in women than men (difference
P
<0.001). Benefit in women was confined to those randomized <2 weeks after their last event, irrespective of severity of stenosis.

Conclusions—

CEA can be performed safely within 2 weeks of nondisabling ischemic stroke. Benefit from endarterectomy declines rapidly with increasing delay, particularly in women.
Interaction Between Inducible Nitric Oxide Synthase and Poly(ADP-ribose) Polymerase in Focal Ischemic Brain Injury
Authors: Park Eun-Mi , Cho Sunghee , Frys Kelly , Racchumi Gianfranco , Zhou Ping , Anrather Josef , Iadecola Costantino
Published: October 2004

Background and Purpose—

Overactivation of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) contributes to ischemic brain injury. Because PARP upregulates proinflammatory genes, we investigated whether inducible nitric oxide synthase (iNOS), a gene involved in the deleterious effects of postischemic inflammation, participates in the mechanisms by which PARP activation contributes to cerebral ischemic injury.

Methods—

The middle cerebral artery (MCA) was occluded in mice for 20 minutes using an intravascular filament, and injury volume was measured 72 hours later in Nissl-stained brain sections. mRNA expression was assessed in the postischemic brain by the quantitative “real-time” polymerase chain reaction.

Results—

The PARP inhibitor PJ34 reduced infarct volume and attenuated postischemic iNOS mRNA upregulation by 72%. To determine whether iNOS contributes to the toxicity of PARP, the iNOS inhibitor aminoguanidine was co-administered with PARP inhibitors. Unexpectedly, co-administration of PARP and iNOS inhibitors, or treatment of iNOS-null mice with PARP inhibitors, abrogated the protective effect afforded by iNOS or PARP inhibition alone. The loss of neuroprotection was associated with upregulation of the inflammatory genes iNOS, intercellular adhesion molecule-1, and gp91
phox
.

Conclusions—

The results suggest that iNOS expression contributes to the deleterious effects exerted by PARP activation in cerebral ischemia. However, iNOS activity is required for the protective effect of PARP inhibition and, conversely, PARP activity must be present for iNOS inhibition to be effective. The findings unveil a previously unrecognized deleterious interaction between iNOS and PARP that is relevant to the development of combination therapies for ischemic stroke.
Do Normal D-dimer Levels Reliably Exclude Cerebral Sinus Thrombosis?
Authors: Kosinski Christoph M. , Mull Michael , Schwarz Michael , Koch Benno , Biniek Rolf , Schläfer Joachim , Milkereit Eva , Willmes Klaus , Schiefer Johannes
Published: October 2004

Background and Purpose—

Cerebral sinus thrombosis (CST) needs to be considered in the differential diagnosis of all patients with acute headache. Early diagnosis is essential because early treatment may prevent morbidity and may even be life-saving. Definite exclusion, however, needs advanced neuroradiologic diagnostics, which are not readily available in many hospitals. Because measurement of D-dimers has been demonstrated to be helpful in excluding thromboembolic disease, our aim was to investigate whether D-dimers would be also sensitive enough to exclude CST.

Methods—

We undertook a prospective multicenter study over a 2.5-year period including all patients who came to the emergency departments with symptoms suggestive of CST. All patients were diagnosed either by magnetic resonance venography, spiral computed tomography scan venography, or intra-arterial digital subtraction angiography. D-dimer levels were measured at admission and analyzed by the same method in all patients.

Results—

A total of 343 patients were included. CST was diagnosed in 35 patients, of whom 34 had D-dimers above the cutoff value (>500 μg/L). From the 308 patients not having CST, D-dimers were elevated in 27. Sensitivity of D-dimers was 97.1%, with a negative predictive value of 99.6%. Specificity was 91.2%, with a positive predictive value of 55.7%. D-dimers were positively correlated with the extent of the thrombosis and negatively correlated with the duration of symptoms (Spearman rank correlation coefficients 0.76, −0.58, respectively).

Conclusions—

D-dimer measurement is useful in patients with suspected CST. Normal D-dimers make the presence of CST very unlikely.
Favorable Early Outcome of Carotid Artery Stenting Without Protection Devices
Authors: Sztriha László K. , Vörös Erika , Sas Katalin , Szentgyörgyi Réka , Pócsik Anna , Barzó Pál , Szikra Péter , Makai Attila , Szólics Alex , Elek Péter , Rudas László , Vécsei László
Published: October 2004

Background and Purpose—

Protection devices are increasingly used in carotid artery stenting. However, no randomized trial has been conducted to evaluate the efficacy of such devices, and arguments have also been formulated against their routine use. We set out to investigate the complication rates associated with carotid artery stenting performed without protection devices. Applicability of covered stents in the carotid system was also evaluated.

Methods—

Between January 2001 and July 2003, 245 consecutive patients (260 hemispheres) underwent carotid artery stenting. No protection devices were applied. Covered stents were implanted in 31 (12.1%) cases. The incidence of complications during the intervention and the subsequent 30-day follow-up period was recorded.

Results—

The technical success rate was 98.8%. One postprocedural nonneurological death (0.4%) occurred. Neurological complications (inclusive of transient ischemic attacks) were observed in 14 cases (5.4%). The rate of major complications (death, major stroke, and myocardial infarction) was 1.6% among the symptomatic and 1.5% among the asymptomatic cases. The rate of minor strokes was 3.2% in the symptomatic and 1.5% in the asymptomatic group. Of the neurological complications, 64.3% occurred postprocedurally. No ipsilateral neurological complications were detected in the subgroup treated with covered stents.

Conclusions—

Carotid artery stenting without protection devices appears to be safe. Most of the neurological complications could not have been prevented with protection devices, because they occurred after the intervention. The application of covered stents may reduce the rate of embolization-related complications in the periprocedural period.
Body Mass Index in Mid-Life Is Associated With a First Stroke in Men
Authors: Jood Katarina , Jern Christina , Wilhelmsen Lars , Rosengren Annika
Published: October 2004

Background and Purpose—

Data on the association between obesity and stroke are still limited. We examined the possible association between mid-life body mass index (BMI) and risk of stroke in the prospective Multifactor Primary Prevention Study in Göteborg, Sweden.

Methods—

7402 apparently healthy men aged 47 to 55 at baseline were followed-up over a 28-year period. Incidence of fatal and nonfatal stroke was recorded in a local stroke registry through the Swedish National Register on Cause of Death and the Swedish Hospital Discharge Registry.

Results—

A total of 873 first strokes were recorded, including 495 ischemic, 144 hemorrhagic, and 234 unspecified strokes. Compared with men with low normal weight (BMI, 20.0 to 22.49 kg/m
2
), men with BMI >30.0 kg/m
2
had a multiple adjusted hazard ratio of 1.93 (95% CI, 1.44 to 2.58) for total stroke, 1.78 (95% CI, 1.22 to 2.60) for ischemic stroke, and 3.91 (95% CI, 2.10 to 7.27) for unspecified stroke. There was no significant association between BMI and hemorrhagic stroke. Adjustment for potential mediators, eg, hypertension, diabetes and serum cholesterol levels, attenuated but did not eliminate the risk.

Conclusion—

In this prospective population-based study of men, increased BMI in mid-life was associated with an increased risk for total, ischemic, and unspecified stroke, but not with hemorrhagic stroke. The result supports the role of mid-life BMI as a risk factor for stroke later in life and suggests a differentiated effect on stroke subtypes.
Intravenous Administration of a GPIIb/IIIa Receptor Antagonist Extends the Therapeutic Window of Intra-Arterial Tenecteplase–Tissue Plasminogen Activator in a Rat Stroke Model
Authors: Zhang Li , Zhang Zheng Gang , Zhang Chunling , Zhang Rui Lan , Chopp Michael
Published: October 2004

Background and Purpose—

Occlusion of the middle cerebral artery triggers platelet accumulation at the site of occlusion and in downstream microvessels. The platelet-induced secondary thrombosis promotes the progressive development of ischemic brain damage and contributes to the resistance to thrombolysis and to the tight 3-hour therapeutic window. We tested the hypothesis that combination of intravenous (IV) administration of a GPIIb/IIIa receptor antagonist, 7E3 F(ab′)
2
, with intra-arterial (IA) administration of tenecteplase–tissue plasminogen activator (TNK-tPA) increases the efficacy of thrombolysis and extends the therapeutic window of stroke.

Methods—

Rats subjected to embolic stroke were treated with IV 7E3 F(ab′)
2
(6 mg/kg) in combination with IA or IV TNK-tPA (5 mg/kg) at 4 and 6 hours after onset of stroke, respectively; IA TNK-tPA (5 mg/kg) alone at 6 hours after onset of stroke; or saline at 6 hours after onset of stroke.

Results—

The combination of IV 7E3 F(ab′)
2
(4 hours) and IA TNK-tPA (6 hours) significantly (
P
<0.05) reduced infarct volume and improved neurological functional deficits, which was associated with significant (
P
<0.05) reductions in the size of embolus at the origin of the occluded middle cerebral artery and in down-stream microvascular platelet and fibrin deposition, and enhanced microvascular patency compared with saline-treated rats. However, combination of IV 7E3 F(ab′)
2
(4 hours) and IV TNK-tPA (6 hours) or IA TNK-tPA (6 hours) alone failed to reduce infarct volume and improve neurological function compared with the saline-treated rats. No significant differences of the incidence of hemorrhage were detected among groups.

Conclusions—

These data suggest that the combination of IV 7E3 F(ab′)
2
(4 hours) and IA TNK-tPA (6 hours) extends the therapeutic window of thrombolysis to 6 hours after stroke.
Alcohol Consumption and Carotid Artery Structure in Older French Adults
Authors: Zureik Mahmoud , Gariépy Jérôme , Courbon Dominique , Dartigues Jean-François , Ritchie Karen , Tzourio Christophe , Alpérovitch Annick , Simon Alain , Ducimetière Pierre
Published: October 2004

Background and Purpose—

Several epidemiological studies have suggested a U-shaped association between alcohol consumption and cardiovascular risk. However, the modifications of vascular structure associated with alcohol consumption are largely unknown.

Methods—

The study population sample comprised 6216 subjects (3780 women and 2436 men) aged 65 years or older who were recruited from 3 French cities (Bordeaux, Dijon, and Montpellier, which are located in the 3 principal wine-growing regions). Usual alcohol consumption was assessed by a standardized questionnaire. Carotid ultrasound examination included measurements (at sites free of plaques) of intima-media thickness (IMT) at the common carotid arteries (CCA), CCA–lumen diameter, and assessment of atherosclerotic plaques in the extracranial carotid arteries.

Results—

Neither CCA–IMT nor carotid plaques were associated with alcohol consumption categories in the overall population. Weak and marginal positive associations were observed between categories of alcohol consumption and carotid plaques in men (
P
=0.02 for linear trend). CCA–lumen diameter was positively and independently associated with alcohol consumption in overall population and in men and in women. Similar results were found between alcohol consumption and carotid measurements in subjects free of cardiovascular disease (90.1% of the population).

Conclusions—

This very large population sample of French older adults shows no marked relationships of alcohol consumption with atherosclerosis. The positive association of alcohol intake with carotid arterial diameter may reflect the ability of alcohol to maintain adaptive enlargement to preserve lumen area.
Nonsteroidal anti-inflammatory drugs inhibit a Fyn-dependent pathway coupled to Rac and stress kinase activation in TCR signaling
Authors: Paccani Silvia Rossi , Patrussi Laura , Ulivieri Cristina , Masferrer Jaime L. , D'Elios Mario Milco , Baldari Cosima T.
Published: October 2004

In addition to their anti-inflammatory properties, nonsteroidal anti-inflammatory drugs (NSAIDs) harbor immunosuppressive activities related to their capacity both to inhibit cyclooxygenases (COXs) and to act as peroxisome proliferator-activated receptor (PPAR) ligands. We have previously shown that the stress-activated kinase p38 is a selective target of NSAIDs in T cells. Here we have investigated the effect of NSAIDs on the signaling pathway triggered by the T-cell antigen receptor (TCR) and leading to stress kinase activation. The results show that nonselective and COX-1–selective NSAIDs also block activation of the stress kinase c-Jun N-terminal kinase (JNK) and that prostaglandin-E2 (PGE2) reverses this block and enhances TCR-dependent JNK activation. Analysis of the activation state of the components upstream of p38 and JNK showed that NSAIDs inhibit the serine-threonine kinase p21-activated protein kinase 1 (Pak1) and the small guanosine 5′-triphosphatase (GTPase) Rac, as well as the Rac-specific guanine nucleotide exchanger, Vav. Furthermore, activation of Fyn, which controls Vav phosphorylation, is inhibited by NSAIDs, whereas activation of lymphocyte-specific protein tyrosine kinase (Lck) and of the Lck-dependent tyrosine kinase cascade is unaffected. Accordingly, constitutively active Fyn reverses the NSAID-dependent stress kinase inhibition. The data identify COX-1 as an important early modulator of TCR signaling and highlight a TCR proximal pathway selectively coupling the TCR to stress kinase activation.
Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness
Authors: Beyth Shaul , Borovsky Zipora , Mevorach Dror , Liebergall Meir , Gazit Zulma , Aslan Hadi , Galun Eithan , Rachmilewitz Jacob
Published: October 2004

Infusion of either embryonic or mesenchymal stem cells prolongs the survival of organ transplants derived from stem cell donors and prevents graft-versus-host-disease (GVHD). An in-depth mechanistic understanding of this tolerization phenomenon could lead to novel cell-based therapies for transplantation. Here we demonstrate that while human mesenchymal stem cells (hMSCs) can promote superantigen-induced activation of purified T cells, addition of antigen-presenting cells (APCs; either monocytes or dendritic cells) to the cultures inhibits the T-cell responses. This contact- and dose-dependent inhibition is accompanied by secretion of large quantities of interleukin (IL)–10 and aberrant APC maturation, which can be partially overridden by the addition of factors that promote APC maturation (ie, lipopolysaccharide [LPS] or anti-CD40 monoclonal antibody [mAb]). Thus, our data support an immunoregulatory mechanism wherein hMSCs inhibit T cells indirectly by contact-dependent induction of regulatory APCs with T-cell–suppressive properties. Our data may reveal a physiologic phenomenon whereby the development of a distinct APC population is regulated by the tissue's cellular microenvironment.
The transcriptional program of terminal granulocytic differentiation
Authors: Theilgaard-Mönch Kim , Jacobsen Lars Christian , Borup Rehannah , Rasmussen Thomas , Bjerregaard Malene Digmann , Nielsen Finn Cilius , Cowland Jack Bernard , Borregaard Niels
Published: October 2004

To characterize the transcriptional program that governs terminal granulocytic differentiation in vivo, we performed comprehensive microarray analyses of human bone marrow populations highly enriched in promyelocytes (PMs), myelocytes/metamyelocytes (MYs), and neutrophils (bm-PMNs). These analyses identified 11 310 genes involved in differentiation, of which 6700 were differentially regulated, including previously unidentified effector proteins and surface receptors of neutrophils. Differentiation of PMs toward MYs was accompanied by a marked decline of proliferative and general cellular activity as defined by down-regulation of E2 promoter binding factor (E2F) target genes; cyclin dependent kinases 2, 4, and 6; and various metabolic, proteasomal, and mitochondrial genes. Expression patterns of apoptosis genes indicated death control by the p53 pathway in PMs and by death receptor pathways in bm-PMNs. Effector proteins critical for host defense were expressed successively throughout granulocytic differentiation, whereas receptors and receptor ligands essential for the activation of the host defense program were terminally up-regulated in bm-PMNs. The up-regulation of ligand-receptor pairs, which are defined inducers as well as target genes of nuclear factor-κB (NF-κB), suggests a constitutive activation of NF-κB in bm-PMNs by autocrine loops. Overall, these results define a granulocytic differentiation model governed by a highly coordinated fail-safe program, which promotes completion of differentiation before cells gain responsiveness toward activating stimuli that accompany infections. (Blood. 2005; 105:1785-1796)
Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3
Authors: George Prince , Bali Purva , Annavarapu Srinivas , Scuto Anna , Fiskus Warren , Guo Fei , Sigua Celia , Sondarva Gautam , Moscinski Lynn , Atadja Peter , Bhalla Kapil
Published: October 2004

Present studies show that LBH589, a novel cinnamic hydroxamic acid analog histone deacetylase inhibitor, induces acetylation of histone H3 and H4 and of heat shock protein 90 (hsp90), increases p21 levels, as well as induces cell-cycle G1 phase accumulation and apoptosis of the human chronic myeloid leukemia blast crisis (CML-BC) K562 cells and acute leukemia MV4-11 cells with the activating length mutation of FLT-3. In MV4-11 cells, this was associated with marked attenuation of the protein levels of p-FLT-3, FLT-3, p-AKT, and p-ERK1/2. In K562 cells, exposure to LBH589 attenuated Bcr-Abl, p-AKT, and p-ERK1/2. Treatment with LBH589 inhibited the DNA binding activity of signal transducers and activators of transcription 5 (STAT5) in both K562 and MV4-11 cells. The hsp90 inhibitor 17-allyl-amino-demethoxy geldanamycin (17-AAG) also induced polyubiquitylation and proteasomal degradation of FLT-3 and Bcr-Abl by reducing their chaperone association with hsp90. Cotreatment with LBH589 and 17-AAG exerted synergistic apoptosis of MV4-11 and K562 cells. In the imatinib mesylate (IM)-refractory leukemia cells expressing Bcr-Abl with the T315I mutation, treatment with the combination attenuated the levels of the mutant Bcr-Abl and induced apoptosis. Finally, cotreatment with LBH589 and 17-AAG also induced more apoptosis of IM-resistant primary CML-BC and acute myeloid leukemia (AML) cells (with activating mutation of FLT-3) than treatment with either agent alone. (Blood. 2005;105:1768-1776)
Information assessment on predicting protein-protein interactions
Authors: Lin Nan , Wu Baolin , Jansen Ronald , Gerstein Mark , Zhao Hongyu
Published: October 2004

Background

Identifying protein-protein interactions is fundamental for understanding the molecular machinery of the cell. Proteome-wide studies of protein-protein interactions are of significant value, but the high-throughput experimental technologies suffer from high rates of both false positive and false negative predictions. In addition to high-throughput experimental data, many diverse types of genomic data can help predict protein-protein interactions, such as mRNA expression, localization, essentiality, and functional annotation. Evaluations of the information contributions from different evidences help to establish more parsimonious models with comparable or better prediction accuracy, and to obtain biological insights of the relationships between protein-protein interactions and other genomic information.

Results

Our assessment is based on the genomic features used in a Bayesian network approach to predict protein-protein interactions genome-wide in yeast. In the special case, when one does not have any missing information about any of the features, our analysis shows that there is a larger information contribution from the functional-classification than from expression correlations or essentiality. We also show that in this case alternative models, such as logistic regression and random forest, may be more effective than Bayesian networks for predicting interactions.

Conclusions

In the restricted problem posed by the complete-information subset, we identified that the MIPS and Gene Ontology (GO) functional similarity datasets as the dominating information contributors for predicting the protein-protein interactions under the framework proposed by Jansen et al. Random forests based on the MIPS and GO information alone can give highly accurate classifications. In this particular subset of complete information, adding other genomic data does little for improving predictions. We also found that the data discretizations used in the Bayesian methods decreased classification performance.
PASBio: predicate-argument structures for event extraction in molecular biology
Authors: Wattarujeekrit Tuangthong , Shah Parantu K , Collier Nigel
Published: October 2004

Background

The exploitation of information extraction (IE), a technology aiming to provide instances of structured representations from free-form text, has been rapidly growing within the molecular biology (MB) research community to keep track of the latest results reported in literature. IE systems have traditionally used shallow syntactic patterns for matching facts in sentences but such approaches appear inadequate to achieve high accuracy in MB event extraction due to complex sentence structure. A consensus in the IE community is emerging on the necessity for exploiting deeper knowledge structures such as through the relations between a verb and its arguments shown by predicate-argument structure (PAS). PAS is of interest as structures typically correspond to events of interest and their participating entities. For this to be realized within IE a key knowledge component is the definition of PAS frames. PAS frames for non-technical domains such as newswire are already being constructed in several projects such as PropBank, VerbNet, and FrameNet. Knowledge from PAS should enable more accurate applications in several areas where sentence understanding is required like machine translation and text summarization. In this article, we explore the need to adapt PAS for the MB domain and specify PAS frames to support IE, as well as outlining the major issues that require consideration in their construction.

Results

We introduce PASBio by extending a model based on PropBank to the MB domain. The hypothesis we explore is that PAS holds the key for understanding relationships describing the roles of genes and gene products in mediating their biological functions. We chose predicates describing gene expression, molecular interactions and signal transduction events with the aim of covering a number of research areas in MB. Analysis was performed on sentences containing a set of verbal predicates from MEDLINE and full text journals. Results confirm the necessity to analyze PAS specifically for MB domain.

Conclusions

At present PASBio contains the analyzed PAS of over 30 verbs, publicly available on the Internet for use in advanced applications. In the future we aim to expand the knowledge base to cover more verbs and the nominal form of each predicate.
Extractor for ESI quadrupole TOF tandem MS data enabled for high throughput batch processing
Authors: Boehm Andreas M , Galvin Robert P , Sickmann Albert
Published: October 2004

Background

Mass spectrometry based proteomics result in huge amounts of data that has to be processed in real time in order to efficiently feed identification algorithms and to easily integrate in automated environments. We present wiff2dta, a tool created to convert MS/MS data obtained using Applied Biosystem's QStar and QTrap 2000 and 4000 series.

Results

Comparing the performance of wiff2dta with the standard tools, we find wiff2dta being the fastest solution for extracting spectrum data from ABIs raw file format. wiff2dta is at least 10% faster than the standard tools. It is also capable of batch processing and can be easily integrated in high throughput environments. The program is freely available via http://www.protein-ms.de, http://sourceforge.net/projects/protms/ and is also available from Applied Biosystems.

Conclusions

wiff2dta offers the possibility to run as stand-alone application or within a batch process as command-line tool integrated in automation and high-throughput environments. It is more efficient than the state-of-the-art tools provided.
GeneLink: a database to facilitate genetic studies of complex traits
Authors: Gillanders Elizabeth M , Masiello Anthony , Gildea Derek , Umayam Lowell , Duggal Priya , Jones Mary Pat , Klein Alison P , Freas-Lutz Diana , Ibay Grace , Trout Ken , Wolfsberg Tyra G , Trent Jeffrey M , Bailey-Wilson Joan E , Baxevanis Andreas D
Published: October 2004

Background

In contrast to gene-mapping studies of simple Mendelian disorders, genetic analyses of complex traits are far more challenging, and high quality data management systems are often critical to the success of these projects. To minimize the difficulties inherent in complex trait studies, we have developed GeneLink, a Web-accessible, password-protected Sybase database.

Results

GeneLink is a powerful tool for complex trait mapping, enabling genotypic data to be easily merged with pedigree and extensive phenotypic data. Specifically designed to facilitate large-scale (multi-center) genetic linkage or association studies, GeneLink securely and efficiently handles large amounts of data and provides additional features to facilitate data analysis by existing software packages and quality control. These include the ability to download chromosome-specific data files containing marker data in map order in various formats appropriate for downstream analyses (e.g., GAS and LINKAGE). Furthermore, an unlimited number of phenotypes (either qualitative or quantitative) can be stored and analyzed. Finally, GeneLink generates several quality assurance reports, including genotyping success rates of specified DNA samples or success and heterozygosity rates for specified markers.

Conclusions

GeneLink has already proven an invaluable tool for complex trait mapping studies and is discussed primarily in the context of our large, multi-center study of hereditary prostate cancer (HPC). GeneLink is freely available at http://research.nhgri.nih.gov/genelink.
The diagnostic value of endoscopy and Helicobacter pylori tests for peptic ulcer patients in late post-treatment setting
Authors: Maaroos Heidi-Ingrid , Andreson Helena , Lõivukene Krista , Hütt Pirje , Kolk Helgi , Kull Ingrid , Labotkin Katrin , Mikelsaar Marika
Published: October 2004

Background

Guidelines for management of peptic ulcer patients after the treatment are largely directed to detection of H. pylori infection using only non-invasive tests. We compared the diagnostic value of non-invasive and endoscopy based H. pylori tests in a late post-treatment setting.

Methods

Altogether 34 patients with dyspeptic complaints were referred for gastroscopy 5 years after the treatment of peptic ulcer using a one-week triple therapy scheme. The endoscopic and histologic findings were evaluated according to the Sydney classification. Bacteriological, PCR and cytological investigations and 13C-UBT tests were performed.

Results

Seventeen patients were defined H. pylori positive by 13C-UBT test, PCR and histological examination. On endoscopy, peptic ulcer persisted in 4 H. pylori positive cases. Among the 6 cases with erosions of the gastric mucosa, only two patients were H. pylori positive. Mucosal atrophy and intestinal metaplasia were revealed both in the H. pylori positive and H. pylori negative cases. Bacteriological examination revealed three clarithromycin resistant H. pylori strains. Cytology failed to prove validity for diagnosing H. pylori in a post-treatment setting.

Conclusions

In a late post-treatment setting, patients with dyspepsia should not be monitored only by non-invasive investigation methods; it is also justified to use the classical histological evaluation of H. pylori colonisation, PCR and bacteriology as they have shown good concordance with 13C-UBT. Moreover, endoscopy and histological investigation of a gastric biopsy have proved to be the methods with an additional diagnostic value, providing the physician with information about inflammatory, atrophic and metaplastic lesions of the stomach in dyspeptic H. pylori positive and negative patients. Bacteriological methods are suggested for detecting the putative antimicrobial resistance of H. pylori, aimed at successful eradication of infection in persistent peptic ulcer cases.
First successful case of in vitro fertilization-embryo transfer with venom immunotherapy for hymenoptera sting allergy
Authors: Sills Eric Scott , Conway Susan C , Kaplan Carolyn R , Perloe Mark , Tucker Michael J
Published: October 2004

Background

To describe immune and endocrine responses in severe hymenoptera hypersensitivity requiring venom immunotherapy (VIT) during in vitro fertilization (IVF).

Case presentation

A 39-year old patient was referred for history of multiple miscarriage and a history of insect sting allergy. Four years earlier, she began subcutaneous injection of 100 mcg mixed vespid hymenoptera venom/venom protein every 5–6 weeks. The patient had one livebirth and three first trimester miscarriages. Allergy treatment was maintained for all pregnancies ending in miscarriage, although allergy therapy was discontinued for the pregnancy that resulted in delivery. At our institution ovulation induction incorporated venom immunotherapy (VIT) during IVF, with a reduced VIT dose when pregnancy was first identified. Serum IgE was monitored with estradiol during ovulation induction and early pregnancy. Response to controlled ovarian hyperstimulation was favorable while VIT was continued, with retrieval of 12 oocytes. Serum RAST (yellow jacket) IgE levels fluctuated in a nonlinear fashion (range 36–54%) during gonadotropin therapy and declined after hCG administration. A healthy female infant was delivered at 35 weeks gestation. The patient experienced no untoward effects from any medications during therapy.

Conclusion

Our case confirms the safety of VIT in pregnancy, and demonstrates RAST IgE can remain <60% during IVF. With proper monitoring, VIT during IVF can be safe and appropriate for selected patients and does not appear to adversely affect blastocyst implantation, early embryo development or perinatal outcome. Further studies will be needed to develop VIT guidelines specifically applicable to IVF.