bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence for Persistent Flow and Aqueous Sedimentation on Early Mars
Authors: Malin Michael C. , Edgett Kenneth S.
Published: November 2003

Landforms representative of sedimentary processes and environments that occurred early in martian history have been recognized in Mars Global Surveyor Mars Orbiter Camera and Mars Odyssey Thermal Emission Imaging System images. Evidence of distributary, channelized flow (in particular, flow that lasted long enough to foster meandering) and the resulting deposition of a fan-shaped apron of debris indicate persistent flow conditions and formation of at least some large intracrater layered sedimentary sequences within fluvial, and potentially lacustrine, environments.
Bose-Einstein Condensation of Molecules
Authors: Jochim S. , Bartenstein M. , Altmeyer A. , Hendl G. , Riedl S. , Chin C. , Hecker Denschlag J. , Grimm R.
Published: November 2003

We report on the Bose-Einstein condensation of more than 10
5
Li
2
molecules in an optical trap starting from a spin mixture of fermionic lithium atoms. During forced evaporative cooling, the molecules are formed by three-body recombination near a Feshbach resonance and finally condense in a long-lived thermal equilibrium state. We measured the characteristic frequency of a collective excitation mode and demonstrated the magnetic field–dependent mean field by controlled condensate spilling.
Parameters affecting germinability and seed bank dynamics in dimorphic achenes of Centaurea solstitialis in California
Authors: Joley D B , Maddox D M , Schoenig S E , Mackey B E
Published: November 2003

Yellow starthistle (Centaurea solstitialis L.) is a major rangeland weed pest in California and other western states. Two complementary aspects of seed biology were examined: germination and seed bank dynamics. Achenes were tested for changes in germinability over time using various light, temperature, and moisture treatments. Soil cores were collected over time to monitor changes in achene density. Both plumed and nonplumed achenes exhibited photo reversible responses to red and far-red light. White and red light enhanced germination above that occurring in darkness. Achenes showed seasonal changes in germinability, which were characteristic of conditional dormancy. Exposure of achenes to field conditions during summer alleviated primary dormancy, allowing germination to occur at higher temperatures and lower substrate moisture. Nonplumed achenes collected in winter showed reduced germinability at or above moderate temperatures under both single and multiple light exposures. Imbibition and moderately low temperatures with subsequent drying induced secondary conditional dormancy in some achenes. Plumed achenes dominated the soil seed bank before the rainy season, then declined rapidly following rain. Nonplumed achenes peaked after rains began, then declined. Although nearly all achenes were depleted after 4 years, both types remained, showing annual cycles of high and low germinability in autumn and late spring, respectively.Key words: light, phytochrome, conditional dormancy, longevity.
The formation of mixed metal aminophosphinidene clusters via reactions of terminal chloroaminophosphido complexes with Co2(CO)8
Authors: Sánchez-Nieves Javier , Sterenberg Brian T , Udachin Konstantin A , Carty Arthur J
Published: November 2003

Reactions of terminal chloroaminophosphido complexes with Co2(CO)8 have been examined. The ruthenium phosphido complexes [Cp*Ru(CO)2{P(Cl)TMP}] (1a) and [CpRu(CO)2{P(Cl)TMP}] (1b) (TMP = 2,2,6,6-tetramethylpiperidinyl) react with Co2(CO)8 to form the cobalt cluster [Co4(CO)7(µ-CO)3{µ3-P(TMP)}] (2) with complete transfer of the phosphinidene unit to cobalt. In contrast, the phosphido complex [Cp*Ru(CO)2{P(Cl)N-i-Pr2}] (1c) affords the spiked-triangular cluster [Cp*RuCo3(CO)8(µ-CO)2(µ3-PN-i-Pr2)] (3), which retains the Cp*Ru unit upon reaction with Co2(CO)8. The molybdenum phosphido complex [CpMo(CO)2{P(Cl)TMP}] (4) reacts with Co2(CO)8 to form cluster 2, while [Cp*Mo(CO)3{P(Cl)N-i-Pr2}] (5) generates the mixed metal tetrahedral cluster [Cp*MoCo3(CO)5(µ-CO)4(µ3-PN-i-Pr2)] (6). Key words: phosphido, phosphinidene, cobalt, ruthenium, molybdenum, cluster.
Allylation of aldehydes catalyzed by chiral N,N'-bis(N-methyl-2-methylene-4,5-bisphenyl-imidazole)-1,2-cyclohexane diamine rhodium(III) complexes
Authors: LaRonde Frank J , Brook Michael A
Published: November 2003

Chiral bis-imidazole rhodium(III) complexes catalyze the allylation of aldehydes by allyltributyltin. The pre-catalyst was readily prepared from chiral N,N'-bis(N-methyl-2-methylene-4,5-bisphenylimidazole)-1,2-cyclohexanediamine, potassium carbonate, and rhodium(III) chloride trihydrate. The rhodium(III) complex produced showed no activity in an allyl transfer process in the presence of the allyltin reagent. However, when silver tetrafluoroborate was added to the pre-catalyst and stirred for 1 h, the resulting system became an efficient catalyst for the allyl transfer process. The reductions produced homo-allyl alcohols with good to excellent yield, although generally with poor facial selectivity (810% ee, aryl aldehydes, 4 examples; 99% ee, aliphatic aldehyde, 1 example).Key words: allylation, aldehydes, enantioselectivity, rhodium(III) tetramine complex.
Synthesis and characterization of tantalum(V) metallaheterocycle (Me2N)3 and chloro-mixed-amide (Me2N)3Ta(Cl)[N(SiMe3)2]
Authors: Cai Hu , Yu Xianghua , Chen Tianniu , Chen Xue-Tai , You Xiao-Zeng , Xue Ziling
Published: November 2003

A new mixed-amido complex (Me2N)3Ta(Cl)[N(SiMe3)2] (1) was prepared from the reaction of (Me2N)3TaCl2 with 1 equiv. of LiN(SiMe3)2. The reactions of 1 with 1 equiv. of LiN(SiMe3)2 or (Me2N)3TaCl2 with 2 equiv. of LiN(SiMe3)2 gave (Me2N)3[Formula: see text] (2) with a four-membered metallaheterocyclic ring through γ-hydrogen abstraction. In the solid state, 1 adopts a distorted trigonal bipyramidal geometry with the -N(SiMe3)2 and -Cl ligands in the equatorial and axial positions, respectively. The X-ray structure of 2 reveals that it is in a distorted trigonal bipyramidal geometry with a planar metallaheterocyclic ring.Key words: tantalum, γ-hydrogen abstraction, C-H activation, amido complexes, metallacycle.
The use of a chiral borate counteranion as a 1H NMR shift reagent for cationic copper(I) complexes
Authors: Llewellyn David B , Arndtsen Bruce A
Published: November 2003

The chiral borate counteranion bis[(R)-1,1′-bi-2-naphtholato]borate (1) has been found to be a competent chiral 1H NMR shift reagent for cationic copper(I) complexes. This has been demonstrated by the addition of the Cu(NCMe)4+ salt of 1 to two classes of common chiral ligands in asymmetric catalysis: 2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl (tol-BINAP) (2) and 2,2′-isopropylidenebis(4-phenyl-2-oxazoline) (3). In the case of ligand 2, the addition of 1 equiv. of either (R,R)-2 or (S,S)-2 to Cu(NCMe)4+1 results in well-resolved 1H NMR resonances for the two enantiomers. Examination of standard solutions of non-enantiopure 2 shows that the copper complex can be an effective NMR shift reagent of a wide range of enantiomeric compositions. Cu(NCMe)4+1 also generates distinct 1H NMR resonances for the two separate enantiomers of 2,2′-isopropylidenebis(4-phenyl-2-oxazoline) (3). However, attempts to employ this copper salt as a chiral NMR shift reagent for rac-3 led to the discovery of a new and unexpected equilibrium: [(R,R)-3]Cu+ + [(S,S)-3]Cu+ [Formula: see text] [(R,R)-3][(S,S)-3]Cu+ + Cu+. Key words: chiral counteranion, copper, chiral NMR shift reagent, ion pairing.
Organometallic reactions in aqueous media  Bismuth-mediated crossed aldol type reactions
Authors: Lee Yoon Joo , Chan Tak Hang
Published: November 2003

Bismuth metal, upon activation by zinc fluoride, can effect the crossed aldol reaction between α-bromocarbonyl compounds and aldehydes in aqueous media. The reaction was found to be regiospecific and syn-diastereoselective.Key words: bismuth, zinc fluoride, aldol reaction, regioselectivity, aqueous media.
Reduction of hafnium(IV) complexes in the presence of molecular nitrogen: Attempts to form dinitrogen complexes of the heaviest group 4 element
Authors: Fryzuk Michael D , Corkin James R , Patrick Brian O
Published: November 2003

The reaction of [P2N2]Li2(dioxane)2 with HfCl4(THF)2 (where [P2N2] = PhP(CH2SiMe2NSiMe2CH2)2PPh) results in the formation of the hafnium dichloride complex [P2N2]HfCl2 (1). The behaviour of 1 as a potential precursor in the generation of a dinitrogen coordination complex is described. Reduction of 1 with potassium-graphite (C8K), under dinitrogen, under a variety of conditions led to a number of products, one of which is the dinuclear derivative with bridging P-phenyl groups that has the general formula {[P2N2]Hf}2 (2). Reduction of the hafnium diiodide [P2N2]HfI2 (3)  prepared via the reaction of 1 with excess Me3SiI  with C8K results in the formation of ([P2N2]Hf)2(µ-η2:η2-N2) (4) as the major product of the reaction, while {[P2N2]Hf}2 (2) and [P2N2]Hf(C7H8) (5) appear to be minor products. Reaction of 1 with 2 equiv of MeMgCl gives [P2N2]HfMe2 (6), which, upon exposure to an atmosphere of H2, gives the hafnium tetrahydride {[P2N2]Hf}2(m-H)4 (7).Key words: hafnium, dinitrogen, reduction, coordination chemistry, hydride, mixed donor ligands.
Solid-state NMR investigations of the polymer route to SiBCN ceramics
Authors: Gervais Christel , Babonneau Florence , Ruwisch Lutz , Hauser Ralf , Riedel Ralf
Published: November 2003

Silicon based polymers obtained by ammonolysis of organochlorosilylboranes and their pyrolytic transformation into Si-B-C-N ceramics were studied by a detailed solid-state NMR investigation. Sol–gel polymerisation/pyrolysis routes were applied to form Si-B-C-N materials with exceptional high-temperature stability. The polymer to ceramic conversion was analyzed by 11B, 13C, 15N, and 29Si MAS NMR spectroscopy as well as by thermal analysis measurements coupled with mass spectroscopy (TGA–MS). The results showed that a significant change in the carbon-, silicon-, and boron-coordination environments occurs during pyrolysis. An evolution of cleavage of silcon–carbon–boron bridges and the formation of new BN3 sites was observed. The NMR data obtained suggest the presence of a rather homogeneous dispersion of the boron atoms in the as synthesized silicon carbonitride phase, supporting the high thermal stability with respect to decomposition found in these compounds.Key words: organosilicon polymers, polymer pyrolysis, SiBCN ceramics, solid-state NMR.
A combined density functional theory and molecular mechanics (QM/MM) study of single site ethylene polymerization catalyzed by [Cp{NC(t-Bu)2}TiR+] in the presence of the counterion (CH3B(C6F5)3)1
Authors: Vanka Kumar , Xu Zhitao , Ziegler Tom
Published: November 2003

Calculations have been carried out to investigate the insertion of the ethylene monomer into the Tialkyl bond for the systems CpNC(t-Bu)2RTi-µ-Me-B(C6F5)3 (R = Me and Pr), using density functional theory. A validated QM/MM model was used to represent the counterion. The tertiary butyl groups in the ligands were modeled with QM/MM, with hydrogens being used as the capping atoms. Solvent effects were incorporated with single point solvent calculations done with cyclohexane (ε= 2.023) as the solvent. With R = Me (the initiation step), approach of the ethylene cis and trans to the -µ-Me bridge was considered. Insertion was found to be endothermic, with ΔHtot being 12.7 kcal/mol (cis) and 15.5 kcal/mol (trans). The propagation step was then studied for the contact ion pair CpNC(t-Bu)2PrTi-µ-Me-B(C6F5)3 (4). Different conformations of the propyl chain in 4 were considered by altering θ, the dihedral angle formed between the Cβ-Cα-Ti and the Cα-Ti-µC planes. The resting states were found to be at θ = 69° (4a), 177° (4b), and 53° (4c). A maxima was found near θ = 0° (4d). The cis and trans approaches of the ethylene monomer were considered for each of the four cases. The cis approach towards 4a and trans approach towards 4d led to insertion, with displacement of the counterion from the metal centre. The insertion barriers were found to be 17.8 kcal/mol, for the cis approach towards 4b and 16.4 kcal/mol for the trans approach towards 4d. The cis approaches towards conformers 4a and 4c showed common characteristics, with uptake barriers being higher than the subsequent insertion barriers in the two cases. Uptake barriers were 13.6 kcal/mol {TS(4a7a)} and 10.7 kcal/mol {TS(4c8a)}. The corresponding insertion barriers were 11.8 kcal/mol {TS(7a13a)} and 8.4 kcal/mol {TS(8a13a)}. The trans approaches towards conformers 4a and 4c led to insertion barriers of about 15.1 kcal/mol (lower than for the 4b and 4d cases). The cis approach towards 4d and trans approach towards 4b were found to lead to hydrogen transfer from the propyl chain to monomer, terminating the chain. Termination barriers were high  greater than 19.0 kcal/mol. This suggested that ethylene insertion would be favoured over termination during the propagation step.Key words: homogeneous catalysis, counterion, initiation, propagation, termination.
Insulin Stimulates Glucose Transport Via Nitric Oxide/Cyclic GMP Pathway in Human Vascular Smooth Muscle Cells
Authors: Bergandi L. , Silvagno F. , Russo I. , Riganti C. , Anfossi G. , Aldieri E. , Ghigo D. , Trovati M. , Bosia A.
Published: November 2003

Objective—

In cultured human vascular smooth muscle cells, insulin increases cyclic GMP production by inducing nitric oxide (NO) synthesis. The aim of the present study was to determine whether in these cells the insulin-stimulated NO/cyclic GMP pathway plays a role in the regulation of glucose uptake.

Methods and Results—

Glucose transport in human vascular smooth muscle cells was measured as uptake of 2-deoxy-d-[
3
H]glucose, cyclic GMP synthesis was checked by radioimmunoassay, and GLUT4 recruitment into the plasma membrane was determined by immunofluorescence. Insulin-stimulated glucose transport and GLUT4 recruitment were blocked by an inhibitor of NO synthesis and mimicked by NO-releasing drugs. Insulin- and NO-elicited glucose uptake were blocked by inhibitors of soluble guanylate cyclase and cyclic GMP–dependent protein kinase; furthermore, glucose transport was stimulated by an analog of cyclic GMP.

Conclusions—

Our results suggest that insulin-elicited glucose transport (and the corresponding GLUT4 recruitment into the plasma membrane) in human vascular smooth muscle cells is mediated by an increased synthesis of NO, which stimulates the production of cyclic GMP and the subsequent activation of a cyclic GMP–dependent protein kinase.
Number and Adhesive Properties of Circulating Endothelial Progenitor Cells in Patients With In-Stent Restenosis
Authors: George Jacob , Herz Itzhak , Goldstein Emil , Abashidze Soulico , Deutch Varda , Finkelstein Ariel , Michowitz Yoav , Miller Hylton , Keren Gad
Published: November 2003

Objective—

Intact endothelialization machinery is essential to facilitate vessel healing after stent placement and to prevent restenosis. Circulating endothelial progenitor cells (EPC) have been demonstrated in the peripheral blood and shown to display endothelial functional properties, along with the ability to traffic to damaged vasculature. We reasoned that robust in-stent intimal growth could be partially related to impaired endothelialization resulting from reduced circulating EPC number or function.

Methods and Results—

Sixteen patients with angiographically-demonstrated in-stent restenosis were compared with patients with a similar clinical presentation that exhibited patent stents (n=11). Groups were similar with respect to the use of drugs that could potentially influence EPC numbers. Circulating EPC numbers were determined by the colony-forming unit assay, and their phenotype was characterized by endothelial-cell markers. Adhesiveness of EPC from both groups to extracellular matrix and to endothelial cells was also assayed. Patients with in-stent restenosis and with patent stents displayed a similar number of circulating EPC. Fibronectin-binding was compromised in patients with in-stent restenosis as compared with their controls exhibiting patent stents. Patients with diffuse in-stent restenosis exhibited reduced numbers of EPC in comparison with subjects with focal in-stent lesions.

Conclusion—

Reduced numbers of circulating EPC in patients with diffuse in-stent restenosis and impaired adhesion of EPC from patients with restenosis provides a potential mechanism mediating the exuberant proliferative process. These markers, if further validated, could provide means of risk stratifying patients for likelihood of developing in-stent restenosis.
Reduction of Atherosclerotic Plaques by Lysosomal Acid Lipase Supplementation
Authors: Du Hong , Schiavi Susan , Wan Nick , Levine Mark , Witte David P. , Grabowski Gregory A.
Published: November 2003

Objective—

Proof of principle is presented for targeted enzyme supplementation by using lysosomal acid lipase to decrease aortic and coronary wall lipid accumulation in a mouse model of atherosclerosis.

Methods and Results—

Mice with LDL receptor deficiency were placed on an atherogenic diet and developed predictable aortic and coronary atheroma. α-Mannosyl-terminated human lysosomal acid lipase (phLAL) was produced in
Pichia pastoris
, purified, and administered intravenously to such mice with either early or late lesions. phLAL injections reduced plasma, hepatic, and splenic cholesteryl esters and triglycerides in affected mice. phLAL was detected in hepatic Kupffer cells and in atheromatous foam cells. Repeated enzyme injections were well tolerated, with no obvious adverse effects. In addition, the coronary and aortic atheromatous lesions were (1) eliminated in their early stages and (2) quantitatively and qualitatively reduced in their advanced stages.

Conclusion—

These results support the potential utility of lysosomal acid lipase supplementation for the treatment of atherosclerosis, a leading cause of mortality and morbidity in Westernized nations.
Heritability of Venous Function in Humans
Authors: Brinsuk Marina , Tank Jens , Luft Friedrich C. , Busjahn Andreas , Jordan Jens
Published: November 2003

Objectives—

Venous function contributes to the pathogenesis of thrombophlebitis, venous thrombosis, and possibly to arterial hypertension. Venous disease is presumably heritable; however, the genetic variance of venous function is unknown.

Methods and Results—

We determined the heritability of venous function in 46 twin pairs (24 monozygotic, age 35±11 years, 14 men, 34 women; 22 dizygotic, age 30±8 years, 19 men, 25 women). After a resting phase in the supine position, we determined venous function in both legs by impedance plethysmography. Venous capacity was determined by a standardized protocol. In addition, we obtained venous pressure volume curves by slowly deflating a thigh cuff from 60 to 0 mm Hg. Venous compliance was determined as the steepest part of the venous pressure volume curve. Heritability was estimated using a path modeling approach. Unadjusted heritability was 0.6 (
P
<0.05) for venous capacity and 0.9 (
P
<0.05) for venous compliance. The heritability estimate for venous capacity decreased to 0.3 after adjustment for age, body mass index, and body fat. The heritability estimate for venous compliance remained essentially unchanged after adjustment for sex and age.

Conclusions—

We conclude that venous function is strongly influenced by genetic factors. The genes involved may influence venous disease states.
Noninvasive Arrhythmia Risk Stratification in Idiopathic Dilated Cardiomyopathy
Authors: Grimm Wolfram , Christ Michael , Bach Jennifer , Müller Hans-Helge , Maisch Bernhard
Published: November 2003

Background—

Arrhythmia risk stratification with regard to prophylactic implantable cardioverter-defibrillator therapy is a completely unsolved issue in idiopathic dilated cardiomyopathy (IDC).

Methods and Results—

Arrhythmia risk stratification was performed prospectively in 343 patients with IDC, including analysis of left ventricular (LV) ejection fraction and size by echocardiography, signal-averaged ECG, arrhythmias on Holter ECG, QTc dispersion, heart rate variability, baroreflex sensitivity, and microvolt T-wave alternans. During 52±21 months of follow-up, major arrhythmic events, defined as sustained ventricular tachycardia, ventricular fibrillation, or sudden death, occurred in 46 patients (13%). On multivariate analysis, LV ejection fraction was the only significant arrhythmia risk predictor in patients with sinus rhythm, with a relative risk of 2.3 per 10% decrease of ejection fraction (95% CI, 1.5 to 3.3;
P
=0.0001). Nonsustained ventricular tachycardia on Holter was associated with a trend toward higher arrhythmia risk (RR, 1.7; 95% CI, 0.9 to 3.3;
P
=0.11), whereas β-blocker therapy was associated with a trend toward lower arrhythmia risk (RR, 0.6; 95% CI, 0.3 to 1.2;
P
=0.13). In patients with atrial fibrillation, multivariate Cox analysis also identified LV ejection fraction and absence of β-blocker therapy as the only significant arrhythmia risk predictors.

Conclusions—

Reduced LV ejection fraction and lack of β-blocker use are important arrhythmia risk predictors in IDC, whereas signal-averaged ECG, baroreflex sensitivity, heart rate variability, and T-wave alternans do not seem to be helpful for arrhythmia risk stratification. These findings have important implications for the design of future studies evaluating prophylactic implantable cardioverter-defibrillator therapy in IDC.
Heat Shock Transcription Factor 1 Protects Cardiomyocytes From Ischemia/Reperfusion Injury
Authors: Zou Yunzeng , Zhu Weidong , Sakamoto Masaya , Qin Yingjie , Akazawa Hiroshi , Toko Haruhiro , Mizukami Miho , Takeda Norihiko , Minamino Tohru , Takano Hiroyuki , Nagai Toshio , Nakai Akira , Komuro Issei
Published: November 2003

Background—

Because cardiomyocyte death causes heart failure, it is important to find the molecules that protect cardiomyocytes from death. The death trap is a useful method to identify cell-protective genes.

Methods and Results—

In this study, we isolated the heat shock transcription factor 1 (HSF1) as a protective molecule by the death trap method. Cell death induced by hydrogen peroxide was prevented by overexpression of HSF1 in COS7 cells. Thermal preconditioning at 42°C for 60 minutes activated HSF1, which played a critical role in survival of cardiomyocytes from oxidative stress. In the heart of transgenic mice overexpressing a constitutively active form of HSF1, ischemia followed by reperfusion-induced ST-segment elevation in ECG was recovered faster, infarct size was smaller, and cardiomyocyte death was less than wild-type mice. Protein kinase B/Akt was more strongly activated, whereas Jun N-terminal kinase and caspase 3 were less activated in transgenic hearts than wild-type ones.

Conclusions—

These results suggest that HSF1 protects cardiomyocytes from death at least in part through activation of Akt and inactivation of Jun N-terminal kinase and caspase 3.
Water Ingestion as Prophylaxis Against Syncope
Authors: Lu Chih-Cherng , Diedrich André , Tung Che-Se , Paranjape Sachin Y. , Harris Paul A. , Byrne Daniel W. , Jordan Jens , Robertson David
Published: November 2003

Background—

Water ingestion raises blood pressure substantially in patients with perturbed autonomic control and more modestly in older subjects. It is unclear whether prophylactic water drinking improves orthostatic tolerance in normal healthy adults.

Methods and Results—

Twenty-two healthy subjects, 18 to 42 years of age, with no history of syncope underwent head-up tilt-table testing at 60° for 45 minutes or until presyncope or syncope occurred. In their initial test, participants were randomized to either 16 oz (473 mL) of water drinking 5 minutes before tilt-table testing or tilt-table testing alone, with the alternative in a second test on a different day. During the first 30 minutes of tilt, 8 of 22 subjects without water experienced presyncope but only 1 of 22 who had ingested water (
P
=0.016). Water drinking attenuated the heart rate increase associated with tilt (
P
<0.001) while accentuating the increase in total peripheral resistance (
P
=0.012). The average time study participants tolerated head-up tilt was 26% longer after water (41.1±8.1 versus 32.6±14.3 minutes, mean±SD), with a pairwise mean difference of 8.5±14.0 minutes (95% CI, 2.3 to 14.7 minutes;
P
=0.011).

Conclusions—

Water enhances tolerance of upright posture. The effect of water is mediated by increased peripheral vascular resistance. Water ingestion may constitute a simple and effective prophylaxis against vasovagal reactions in healthy subjects, such as those associated with blood donation.
Impact of Time to Treatment on Mortality After Prehospital Fibrinolysis or Primary Angioplasty
Authors: Steg Philippe Gabriel , Bonnefoy Eric , Chabaud Sylvie , Lapostolle Frédéric , Dubien Pierre-Yves , Cristofini Pascal , Leizorovicz Alain , Touboul Paul
Published: November 2003

Background—

CAPTIM was a randomized trial comparing prehospital thrombolysis with transfer to an interventional facility (and, if needed, percutaneous intervention) with primary percutaneous coronary intervention (PCI) in patients with ST-segment-elevation myocardial infarction (STEMI). Because the benefit of thrombolysis is maximal during the first 2 hours after symptom onset, and because prehospital thrombolysis can be implemented earlier than PCI, this analysis studied the relationship between the effect of assigned treatment and the time elapsed from symptom onset.

Methods and Results—

Randomization within 2 hours (n=460) or ≥2 hours (n=374) after symptom onset had no impact on the effect of treatment on the 30-day combined primary end point of death, nonfatal reinfarction, and disabling stroke. However, patients randomized <2 hours after symptom onset had a strong trend toward lower 30-day mortality with prehospital thrombolysis compared with those randomized to primary PCI (2.2% versus 5.7%,
P
=0.058), whereas mortality was similar in patients randomized ≥2 hours (5.9% versus 3.7%,
P
=0.47). There was a significant interaction between treatment effect and delay with respect to 30-day mortality (hazard ratio 4.19, 95% CI 1.033 to 17.004,
P
=0.045). Among patients randomized in the first 2 hours, cardiogenic shock was less frequent with lytic therapy than with primary PCI (1.3% versus 5.3%,
P
=0.032), whereas rates were similar in patients randomized later.

Conclusions—

Time from symptom onset should be considered when one selects reperfusion therapy in STEMI. Prehospital thrombolysis may be preferable to primary PCI for patients treated within the first 2 hours after symptom onset.
Lipid Lowering by Pravastatin Increases Parasympathetic Modulation of Heart Rate
Authors: Welzig C. Michael , Shin Dong-Gu , Park Ho-Jin , Kim Young-Jo , Saul J. Philip , Galper Jonas B.
Published: November 2003

Background—

We have previously demonstrated in an in vitro model for lipid lowering that lipoprotein depletion resulted in a marked increase in the negative chronotropic response to the acetylcholine analogue carbamylcholine. In this study we used heart rate variability analysis to determine the effect of lipid lowering by statins on the response of the heart to parasympathetic stimulation. In parallel, we examined whether changes in parasympathetic responsiveness correlated with changes in the expression of Gα
i2
, a molecular component of the parasympathetic signaling pathway in the heart.

Methods and Results—

Patients were randomized in a crossover study of pravastatin and simvastatin. R-R interval analysis of Holter monitor studies demonstrated that in patients treated initially with pravastatin, the peak high-frequency power fraction during sleep, which reflects parasympathetic modulation of heart rate, increased by 24.0±5.02% (SEM, n=13,
P
<0.001) compared with the untreated control value. Simvastatin had no significant effect. Western blot analysis of lymphocytes from patients treated with pravastatin demonstrated a 90.1±27.3% (n=10,
P
=0.009) increase in Gα
i2
expression, whereas simvastatin had no effect. Relative changes in Gα
i2
correlated significantly with the changes in the fraction of high-frequency power (ρ=0.574,
P
=0.016).

Conclusions—

Taken together with our in vitro data, these data are the first to suggest that cholesterol lowering by pravastatin might increase the response of the heart to parasympathetic stimulation and that changes in Gα
i2
expression might serve as a molecular marker for this effect.
Isolation of a Chromosome 1 Region Affecting Blood Pressure and Vascular Disease Traits in the Stroke-Prone Rat Model
Authors: Kato Norihiro , Nabika Toru , Liang Yi-Qiang , Mashimo Tomoji , Inomata Hyoe , Watanabe Takehiro , Yanai Kazuyuki , Yamori Yukio , Yazaki Yoshio , Sasazuki Takehiko
Published: November 2003

Recently, a genome-wide screen has shown a major quantitative trait locus (QTL) for a stroke-associated phenotype on rat chromosome 1 (RNO1) independent of QTL for blood pressure (BP) in the stroke-prone spontaneously hypertensive rat (SHRSP) of a Heidelberg colony. However, it remains to be elucidated whether these observations reflect the existence of different genes predisposing to each of the disorders. To address this issue, we performed comprehensive approaches in a Japanese colony, Izm, as follows. First, we undertook genome-wide searches in F
1
(SHRSP/Izm×WKY/Izm)×SHRSP/Izm back-cross (n=63) to pursue a causal relation between hypertension and stroke. Although the strongest linkage to BP (LOD score of 3.4) was identified on RNO1, its relevance to stroke was not supported in the F
1
back-cross studied. Second, we also investigated linkage to BP in F
2
progeny (n=175) involving the stroke-resistant (or normal) spontaneously hypertensive rat (SHR). In F
2
studies of SHR/Izm, this locus did not appear to constitute a principal BP QTL. Third, we constructed congenic animals with detailed phenotype characterization. Transfer of a chromosomal fragment between markers
Klk1
and
D1Rat116
from WKY/Izm onto the SHRSP/Izm background lowered systolic BP by 20 to 80 mm Hg, prevented development of apparent stroke, and exaggerated impaired glucose tolerance. In conclusion, we have successfully isolated an RNO1 region affecting BP, stroke, and glucose tolerance in SHRSP/Izm-derived congenic rats. The size of the introgressed region is large, but our novel congenic strain should help delineate complex, genetic impairments underlying BP and associated vascular disease phenotypes.
Calcineurin A

β Gene Targeting Predisposes the Myocardium to Acute Ischemia-Induced Apoptosis and Dysfunction
Authors: Bueno Orlando F. , Lips Daniel J. , Kaiser Robert A. , Wilkins Benjamin J. , Dai Yan-Shan , Glascock Betty J. , Klevitsky Raisa , Hewett Timothy E. , Kimball Thomas R. , Aronow Bruce J. , Doevendans Pieter A. , Molkentin Jeffery D.
Published: November 2003

Cardiovascular disease is the leading cause of mortality and morbidity within the industrialized nations of the world, with coronary heart disease (CHD) accounting for as much as 66% of these deaths. Acute myocardial infarction is a typical sequelae associated with long-standing coronary heart disease resulting in large scale loss of ventricular myocardium through both apoptotic and necrotic cell death. In this study, we investigated the role that the calcium calmodulin-activated protein phosphatase calcineurin (PP2B) plays in modulating cardiac apoptosis after acute ischemia-reperfusion injury to the heart.
Calcineurin A
β gene–targeted mice showed a greater loss of viable myocardium, enhanced DNA laddering and TUNEL, and a greater loss in functional performance compared with strain-matched wild-type control mice after ischemia-reperfusion injury. RNA expression profiling was performed to uncover potential mechanisms associated with this loss of cardioprotection. Interestingly,
calcineurin A
β
−/−
hearts were characterized by a generalized downregulation in gene expression representing approximately 6% of all genes surveyed. Consistent with this observation, nuclear factor of activated T cells (NFAT)-luciferase reporter transgenic mice showed reduced expression in
calcineurin A
β
−/−
hearts at baseline and after ischemia-reperfusion injury. Finally, expression of an activated NFAT mutant protected cardiac myocytes from apoptotic stimuli, whereas directed inhibition of NFAT augmented cell death. These results represent the first genetic loss-of-function data showing a prosurvival role for calcineurin-NFAT signaling in the heart.
Behavioral and Neurofunctional Changes Over Time in Healthy and Aphasic Subjects
Authors: Cardebat Dominique , Démonet Jean-François , de Boissezon Xavier , Marie Nathalie , Marié Rose-Marie , Lambert Jany , Baron Jean-Claude , Puel Michèle
Published: November 2003

Background and Purpose—

Follow-up neuroimaging studies of aphasia never addressed a comparison between aphasic and healthy subjects. Investigation of changes over time in healthy subjects during language tasks seems a prerequisite before interpretation of longitudinal changes in aphasic patients.

Methods—

Six healthy subjects and 8 aphasic patients were PET scanned twice (PET1 and PET2) at a 1-year interval during a word generation task. Using SPM99, language-rest main effect was compared at PET1 and PET2 in each group, whereas group effect was assessed at each session. Correlations were analyzed in each group between performance indexes and changes in regional cerebral flood flow (rCBF) between the 2 sessions.

Results—

Language performances were improved in both groups. rCBF decreased from PET1 to PET2 in the healthy group and increased in the aphasic group in perisylvian regions bilaterally. Correlations between performance and rCBF changes across sessions were similar in the 2 groups; positive correlations involved superior temporal cortexes bilaterally, and negative correlations concerned superior frontal and medial temporal regions.

Conclusions—

Increased perisylvian activation over time probably reflects improved performance at the expenses of cognitive effort in aphasic patients. Decreased activation in different neural systems suggests a familiarization effect with reduced emotional load.
Analysis of the biologic functions of H- and L-ferritins in HeLa cells by transfection with siRNAs and cDNAs: evidence for a proliferative role of L-ferritin
Authors: Cozzi Anna , Corsi Barbara , Levi Sonia , Santambrogio Paolo , Biasiotto Giorgio , Arosio Paolo
Published: November 2003

We describe the use of small interfering RNAs (siRNAs) to down-regulate H- and L-ferritin levels in HeLa cells. siRNAs repressed H- and L-ferritin expression to about 20% to 25% of the background level in both stable and transient transfections. HeLa cells transfected with H- and L-ferritin cDNAs were analyzed in parallel to compare the effects of ferritin up- and down-regulation. We found that large modifications of L-ferritin levels did not affect iron availability in HeLa cells but positively affected cell proliferation rate in an iron-independent manner. The transient down-regulation of H-ferritin modified cellular iron availability and resistance to oxidative damage, as expected. In contrast, the stable suppression of H-ferritin in HeLa cell clones transfected with siRNAs did not increase cellular iron availability but made cells less resistant to iron supplementation and chelation. The results indicate that L-ferritin has no direct effects on cellular iron homeostasis in HeLa cells, while it has new, iron-unrelated functions. In addition, they suggest that H-ferritin function is to act as an iron buffer.
Among circulating hematopoietic cells, B-CLL uniquely expresses functional EPAC1, but EPAC1-mediated Rap1 activation does not account for PDE4 inhibitor-induced apoptosis
Authors: Tiwari Sanjay , Felekkis Kyriacos , Moon Eun-Yi , Flies Amanda , Sherr David H. , Lerner Adam
Published: November 2003

Type 4 cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE4) inhibitors and other agents that raise intracellular cAMP levels induce apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) but not in T-CLL or peripheral blood T cells. Two principal effector proteins for cAMP are protein kinase A (PKA) and EPAC (exchange protein directly activated by cAMP), a Rap guanosine 5′-diphosphate (GDP) exchange factor. We here examine whether varying expression of EPAC accounts for the discrepant sensitivity of B-CLL and T cells to PDE4 inhibitor-induced apoptosis. B-CLL and peripheral blood B cells express EPAC1 transcript, whereas T-CLL, peripheral blood T cells, monocytes, and neutrophils do not. Treatment with the PDE4 inhibitor rolipram induces Rap1 activation in B-CLL cells but not in peripheral blood B cells, T-CLL, or any of the normal hematopoietic lineages examined. The EPAC-specific cAMP analog 8CPT-2Me-cAMP (8-(4-chloro-phenylthio)-2′-O-methyladenosine-3′,5′-cAMP) activates Rap1 in B-CLL cells, but, unlike rolipram/forskolin or 8-Bromo-cAMP, it does not induce PKA activation, as judged by phosphorylation of the transcription factor cAMP-response element binding protein (CREB). Unexpectedly, whereas rolipram/forskolin and 8-Bromo-cAMP induce apoptosis in B-CLL cells, 8CPT-2Me-cAMP decreased basal apoptosis in B-CLL cells by an average of 25% (P < .002). Our results demonstrate that B-CLL cells uniquely activate Rap1 in response to PDE4 inhibitors and suggest that physiologic stimuli that activate EPAC may transmit an antiapoptotic signal. (Blood. 2004;103:2661-2667)
Severe hypodysfibrinogenemia in compound heterozygotes of the fibrinogen AαIVS4 + 1G>T mutation and an AαGln328 truncation (fibrinogen Keokuk)
Authors: Lefebvre Phil , Velasco Pauline T. , Dear Amy , Lounes Karim C. , Lord Susan T. , Brennan Stephen O. , Green David , Lorand Laszlo
Published: November 2003

Two siblings with hypofibrinogenemia have lifelong trauma-related bleeding. Recently, the brother experienced recurrent thrombosis after cryoprecipitate infusions following surgery. The sister had 6 miscarriages. Plasma clots in each were resistant to compression and fibrinolysis and were soluble in 5 M urea. Examination by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) revealed only the presence of crosslinked γ–γ fibrin chain dimers without high polymers of αn. Fibrin clots contained an abnormal 35-kDa constituent recognized by an antibody to the mature fibrinogen Aα–chain residues 241-476 but not by antibodies to Aα219-348 or Aα349-406. DNA analysis revealed a heterozygous CAA → TAA mutation at the codon for amino acid 328 of the Aα gene in these siblings and 2 asymptomatic family members. The Gln328stop mutation (fibrinogen Keokuk) predicted a 46% truncation and the production of a 35-kDa Aα chain. Analysis of purified fibrinogen revealed expression of the abnormal Aα chain in 4 family members but found no normal fibrinogen in the 2 hypofibrinogenemic patients. This paradox was resolved when they and their asymptomatic mother were found to be heterozygous for a second Aα mutation, a GT → TT splice site mutation in intron 4 (IVS4 + 1 G> T). However, compound heterozygosity for both mutations was required for the expression of severe hypodysfibrinogenemia and for clinical symptoms.
Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies
Authors: DiJoseph John F. , Armellino Douglas C. , Boghaert Erwin R. , Khandke Kiran , Dougher Maureen M. , Sridharan Latha , Kunz Arthur , Hamann Philip R. , Gorovits Boris , Udata Chandrasekhar , Moran Justin K. , Popplewell Andrew G. , Stephens Sue , Frost Philip , Damle Nitin K.
Published: November 2003

Antibody-targeted chemotherapy with gemtuzumab ozogamicin (CMA-676, a CD33-targeted immunoconjugate of N-acetyl-γ-calicheamicin dimethyl hydrazide [CalichDMH], a potent DNA-binding cytotoxic antitumor antibiotic) is a clinically validated therapeutic option for patients with acute myeloid leukemia (AML). Here, we describe the preclinical profile of another immunoconjugate of CalichDMH, CMC-544, targeted to CD22 expressed by B-lymphoid malignancies. CMC-544 comprises a humanized IgG4 anti-CD22 monoclonal antibody (mAb), G5/44, covalently linked to CalichDMH via an acid-labile 4-(4′-acetylphenoxy) butanoic acid (AcBut) linker. Both CMC-544 and unconjugated G5/44 bound human CD22 with subnanomolar affinity. CMC-544, but not unconjugated G5/44, exerted potent cytotoxicity against CD22+ B-cell lymphoma (BCL) cell lines (inhibitory concentration of 50%: 6-600 pM CalichDMH). CMC-544 caused a potent inhibition of growth of small but established BCL xenografts leading to cures (therapeutic index > 10). CMC-544 prevented the establishment of BCL xenografts and also caused regression of large BCLs (> 1.5 g tumor mass). In contrast, unconjugated CalichDMH, unconjugated G5/44, and an isotype-matched control conjugate, CMA-676, were ineffective against these BCL xenografts. Thus, CD22-targeted delivery of CalichDMH is a potent and effective preclinical therapeutic strategy for BCLs. The strong antitumor profile of CMC-544 supports its clinical evaluation as a treatment option for B-lymphoid malignancies.
Cause-effect relation between hyperfibrinogenemia and vascular disease
Authors: Kerlin Bryce , Cooley Brian C. , Isermann Berend H. , Hernandez Irene , Sood Rashmi , Zogg Mark , Hendrickson Sara B. , Mosesson Michael W. , Lord Susan , Weiler Hartmut
Published: November 2003

Elevated plasma levels of fibrinogen are associated with the presence of cardiovascular disease, but it is controversial whether elevated fibrinogen causally imparts an increased risk, and as such is a true modifier of cardiovascular disease, or is merely associated with disease. By investigating a transgenic mouse model of hyperfibrinogenemia, we show that elevated plasma fibrinogen concentration (1) elicits augmented fibrin deposition in specific organs, (2) interacts with an independent modifier of hemostatic activity to regulate fibrin turnover/deposition, (3) exacerbates neointimal hyperplasia in an experimental model of stasis-induced vascular remodeling, yet (4) may suppress thrombin generation in response to a procoagulant challenge. These findings provide direct experimental evidence that hyperfibrinogenemia is more than a by-product of cardiovascular disease and may function independently or interactively to modulate the severity and/or progression of vascular disease.
ICSBP is critically involved in the normal development and trafficking of Langerhans cells and dermal dendritic cells
Authors: Schiavoni Giovanna , Mattei Fabrizio , Borghi Paola , Sestili Paola , Venditti Massimo , Morse Herbert C. , Belardelli Filippo , Gabriele Lucia
Published: November 2003

Interferon consensus sequence-binding protein (ICSBP) is a transcription factor belonging to the interferon regulatory factor (IRF) family, recently shown to play a critical role in dendritic cell (DC) differentiation. Here, we analyzed the role of ICSBP in the development and trafficking of epidermal Langerhans cells (LCs) and dermal DCs and the implications for initiation of a competent immune response. ICSBP-/- mice exhibited a reduced frequency of LCs and a delayed mobility of DCs from skin that reflected a slower turnover rate in lymph nodes during steady-state conditions. Even under inflammatory changes, ICSBP-/- DCs displayed reduced mobility from skin to lymph nodes and, as a consequence, failed to induce a contact hypersensitivity (CHS) response, suggesting that these DCs were unable to initiate a competent antigen (Ag)–specific T-cell–mediated immunity. Moreover, bone marrow (BM)–derived DCs from ICSBP-/- mice exhibited an immature phenotype and a severe reduction of interleukin 12 (IL-12) expression. These BM DCs also showed a marked defect in their migratory response to macrophage inflammatory protein 3α (MIP-3α), MIP-3β, and the CC chemokine CCL21/6Ckine, which was paralleled by an impaired expression of the CC chemokine receptors, CCR6 and CCR7. Together, these results indicate that ICSBP is critically required for the development and trafficking of skin DCs, thus playing a critical role in the DC-mediated initiation of T-cell immunity.
LPS resistance in monocytic cells caused by reverse signaling through transmembrane TNF (mTNF) is mediated by the MAPK/ERK pathway
Authors: Kirchner Silvia , Boldt Simone , Kolch Walter , Haffner Silvia , Kazak Seran , Janosch Petra , Holler Ernst , Andreesen Reinhard , Eissner Günther
Published: November 2003

The transmembrane form of tumor necrosis factor (mTNF), expressed on activated monocytes (MO) and macrophages (MΦ), is able to induce apoptosis in human endothelial cells (EC). Apoptosis is mediated by two distinct mechanisms: direct cell contact and a yet-unidentified soluble protein, death factor X. In addition, mTNF acts as a receptor that transduces a “reverse signal” into MO/MΦ when bound to the TNF receptor on EC. Reverse signaling by mTNF confers resistance to bacterial lipopolysaccharide (LPS). Stimulation of reverse signaling by mTNF blocks the ability of MO/MΦ to produce death factor X and proinflammatory cytokines. We have investigated which signaling pathways are used by mTNF acting as receptor. Reverse signaling triggers two independent pathways that can be distinguished by protein kinase C (PKC) inhibitors. The suppression of LPS-induced death factor X is dependent on PKC, whereas the suppression of LPS-mediated cytokine release is not. LPS and reverse signaling stimulate the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. It is interesting that the activation of reverse signaling by mTNF renders MO/MΦ refractory to a subsequent activation of the MAPK/ERK pathway by LPS. Thus, reverse signaling achieves LPS resistance in monocytic cells through interference with key signal-transduction pathways.
Cyclin D2controls B cell progenitor numbers
Authors: Mohamedali Azim , Soeiro Inês , Lea Nicholas C , Glassford Janet , Banerji Lolita , Mufti Ghulam J , Lam Eric W-F , Thomas N Shaun B
Published: November 2003

Cyclin D2 affects B cell proliferation and differentiation in vivo. It is rate-limiting for B cell receptor (BCR)-dependent proliferation of B cells, and cyclin D2−/− mice lack CD5+(B1) B lymphocytes. We show here that the bone marrow (BM) of cyclin D2−/− mice contains half the numbers of Sca1+B220+ B cell progenitors but normal levels of Sca1+ progenitor cells of other lineages. In addition, clonal analysis of BM from the cyclin D2−/− and cyclin D2+/+ mice confirmed that there were fewer B cell progenitors (B220+) in the cyclin D2−/− mice. In addition, the colonies from cyclin D2−/− mice were less mature (CD19lo) than those from cyclin D2+/+ mice (CD19Hi). The number of mature B2 B cells in vivo is the same in cyclin D2−/− and cyclin D2+/+ animals. Lack of cyclin D2 protein may be compensated by cyclin D3, as cyclin-dependent kinase (cdk)6 coimmunoprecipitates with cyclin D3 but not cyclin D1 from BM mononuclear cells of cyclin D2−/− mice. It is active, as endogenous retinoblastoma protein is phosphorylated at the cdk6/4-cyclin D-specific sites, S807/811. We conclude that cyclin D2 is rate-limiting for the production of B lymphoid progenitor cells whose proliferation does not depend on BCR signaling.