bluuebunny/crossref_metadata_2025 huggingface dataset:
GENERALIZED EULERIAN COORDINATES FOR RELATIVISTIC FLUIDS: HAMILTONIAN REST-FRAME INSTANT FORM, RELATIVE VARIABLES, ROTATIONAL KINEMATICS
Authors: ALBA DAVID , LUSANNA LUCA
Published: August 2004

We study the rest-frame instant form of a new formulation of relativistic perfect fluids in terms of new generalized Eulerian configuration coordinates. After the separation of the relativistic center of mass from the relative variables on the Wigner hyper-planes, we define orientational and shape variables for the fluid, viewed as a relativistic extended deformable body, by introducing dynamical body frames. Finally we define Dixon's multipoles for the fluid.
NONPERTURBATIVE SOLUTION OF THE NONCONFINING SCHWINGER MODEL WITH A GENERALIZED REGULARIZATION
Authors: RAHAMAN ANISUR
Published: August 2004

The nonconfining Schwinger model4 is studied with a one-parameter class of kinetic energy-like regularization. It may be thought of as a generalization over the regularization considered in Ref. 4. The phase space structure has been determined in this new situation. The mass of the gauge boson acquires a generalized expression with the bare coupling constant and the parameters involved in the regularization. The confinement and deconfinement scenario has been studied at the quark–antiquark potential level.
COUPLING CONSTANT UNIFICATION IN EXTENSIONS OF STANDARD MODEL
Authors: LI LING-FONG , WU FENG
Published: August 2004

Unification of electromagnetic, weak, and strong coupling constants is studied in the extension of Standard Model with additional fermions and scalars. It is remarkable that this unification in the supersymmetric extension of Standard Model yields a value of Weinberg angle which agrees very well with experiments. We discuss the other possibilities which can also give same result.
IMMERSED AND VIRTUALLY EMBEDDED BOUNDARY SLOPES IN ARITHMETIC MANIFOLDS
Authors: BART ANNEKE
Published: August 2004

Given a Bianchi Group [Formula: see text], and a Hyperbolic manifold M, where π1(M) is of finite index in Γd, we show that all boundary slopes are realized as the boundary slope of an immersed totally geodesic surface and hence are virtually embedded boundary slopes.
REFORMING THE ITALIAN PENSION SYSTEM IN THE XXI CENTURY: THE ISSUE OF SENIORITY PENSIONS ONCE AGAIN
Authors: VAGLIASINDI PIETRO A. , ROMANELLI MARZIA , BIANCHI CARLO
Published: August 2004

Alternative pension schemes, and early retirement provisions in particular, can produce different effects on retirement behavior, with significant economic consequences. This paper presents new evidence on the effect of different seniority pension reforms, considering the evolution of an agent-based economy in Italy, with heterogeneous workers whose retirement age depends on expected lifetime incomes. Using dynamic aging methods, we examine behavioral changes along proposed pension reform paths. Our model — calibrated to replicate the main demographic and economic features and retirement dynamics of the Italian economy — is used to estimate the age of retirement, total pension expenditures, pension benefits and the trend of inequality and poverty among pensioners under different policy scenarios. More precisely, we compare the current state of affairs (B) with a reform proposed by the Italian Welfare Minister (M) and with an early introduction of a mixed regime for seniority pensions (A) according to two limiting "retirement behavioral rules." Under the individual rationality hypothesis, M produces slightly higher savings with minor redistributive effects; although it leads to an increase in income concentration, M mitigates poverty problems after 2008. The reform is more effective under family-bounded rationality, but it leads to permanent and more significant increases in income concentration and aggravates the diffusion and intensity of poverty.
A SEARCH MODEL OF UNEMPLOYMENT AND FIRM DYNAMICS
Authors: RICHIARDI MATTEO
Published: August 2004

An urn-ball probabilistic model of the labor market is developed. Agents can be employed (voluntarily or involuntarily) unemployed, or entrepreneurs. The analytical long-run equilibrium probabilities for each state and the matching function are derived. In equilibrium, a higher reservation wage increases the number of start-ups, but has an overall negative impact on the unemployment rate. A more buoyant economy (higher average growth rate and higher average wages) is shown to be associated with a lower unemployment rate. Higher start-up costs discourage entrepreneurship and increase unemployment. More active search behavior leads first to a decrease in the unemployment rate, and then to a small increase, due to increased coordination failure induced by the higher number of applications sent by job seekers. The out-of-equilibrium dynamics are investigated through an agent-based simulation, which also provides results on firm demography. Important empirical regularities such as the Beveridge and the Okun curve are recovered. Finally, the simulation model is used to investigate departures from maximizing individual behavior and the effects of more realistic assumptions about profits and the business cycle.
BUSINESS CYCLE FLUCTUATIONS AND FIRMS' SIZE DISTRIBUTION DYNAMICS
Authors: DELLI GATTI DOMENICO , DI GUILMI CORRADO , GAFFEO EDOARDO , GIULIONI GIANFRANCO , GALLEGATI MAURO , PALESTRINI ANTONIO
Published: August 2004

Power law behavior is an emerging property of many economic models. In this paper we emphasize the fact that power law distributions are persistent but not time invariant. In fact, the scale and shape of the firms' size distribution fluctuate over time. In particular, on a log–log space, both the intercept and the slope of the power law distribution of firms' size change over the cycle: during expansions (recessions) the straight line representing the distribution shifts up and becomes less steep (steeper). We show that the empirical distributions generated by simulations of the model presented in Ref. 11 mimic real empirical distributions remarkably well.
Gastrin-releasing peptide is a modulatory neurotransmitter of the descending phase of the peristaltic reflex
Authors: Grider John R.
Published: August 2004

The physiological role of gastrin-releasing peptide (GRP) and of its cognate receptors in regulating the intestinal peristaltic reflex was examined in a three-compartment flat-sheet preparation of rat colon. Mucosal stimulation applied to the central compartment at high, but not low levels of intensity, induced GRP release in the caudad compartment where descending relaxation was measured, but not into the ascending compartment where ascending contraction was measured or into the central compartment where the stimuli were applied. The selective GRP (BB2) receptor antagonist, [d-Phe6,des-Met14]bombesin6–14, inhibited descending relaxation and VIP release in the caudad compartment induced by high but not by low levels of stimulation applied to the mucosa in the central compartment. The selective neuromedin B (BB1) receptor antagonist, BIM-23127, had no effect on descending relaxation or VIP release. Neither the BB1 nor the BB2 antagonist had any effect on ascending contraction or substance P release in the orad compartment. Consistent with the effects of the antagonists on the peristaltic reflex, the BB2 antagonist but not the BB1 antagonist decreased the velocity of propulsion of artificial fecal pellets through isolated segments of guinea pig distal colon. The results indicate that GRP is selectively released from myenteric neurons in descending pathways during the peristaltic reflex and that it acts via BB2 receptors to augment the descending phase of the peristaltic reflex and propulsion.
Local and global calcium signals and fluid and electrolyte secretion in mouse submandibular acinar cells
Authors: Harmer A. R. , Smith P. M. , Gallacher D. V.
Published: August 2004

Polarized Ca2+signals that originate at and spread from the apical pole have been shown to occur in acinar cells from lacrimal, parotid, and pancreatic glands. However, “local” Ca2+signals, that are restricted to the apical pole of the cell, have been previously demonstrated only in pancreatic acinar cells in which the primary function of the Ca2+signal is to regulate exocytosis. We show that submandibular acinar cells, in which the primary function of the Ca2+signal is to drive fluid and electrolyte secretion, are capable of both Ca2+waves and local Ca2+signals. The generally accepted model for fluid and electrolyte secretion requires simultaneous Ca2+-activation of basally located K+channels and apically located Cl−channels. Whereas a propagated cell-wide Ca2+signal is clearly consistent with this model, a local Ca2+signal is not, because there is no increase in intracellular Ca2+concentration at the basal pole of the cell. Our data provide the first direct demonstration, in submandibular acinar cells, of the apical and basal location of the Cl−and K+channels, respectively, and confirm that local Ca2+signals do not Ca2+-activate K+channels. We reevaluate the model for fluid and electrolyte secretion and demonstrate that Ca2+-activation of the Cl−channels is sufficient to voltage-activate the K+channels and thus demonstrate that local Ca2+signals are sufficient to support fluid secretion.
The gene transfer of soluble VEGF type I receptor (Flt-1) attenuates peritoneal fibrosis formation in mice but not soluble TGF-β type II receptor gene transfer
Authors: Motomura Y. , Kanbayashi H. , Khan W. I. , Deng Y. , Blennerhassett P. A. , Margetts P. J. , Gauldie J. , Egashira K. , Collins S. M.
Published: August 2004

Peritoneal fibrosis formation is a consequence of inflammation/injury and a significant medical problem to be solved. The effects of soluble VEGF receptor type I (sFlt-1) gene transfer on experimental peritoneal fibrosis were examined and compared with soluble transforming growth factor-β (TGF-β) receptor type II (sTGFβRII) gene transfer. Male C57BL/6 mice were injected with 1.5 × 108plaque-forming unit of adenovirus encoding active TGF-β (AdTGFβ) intraperitoneally. Some mice had been treated with sTGFβRII or sFlt-1 plasmid injection into skeletal muscle with electroporation 4 days before virus administration. Mice were euthanized at day 14 after virus administration. AdTGFβ induced significant elevation of serum active TGF-β, caused significant inflammatory response [weight loss, elevation of serum amyloid-P (SAP) and IL-12, increased expression of monocyte chemoattractant protein-1 (MCP-1) mRNA], and induced marked thickening of the peritoneum and collagen deposition. Gene transfer of sFlt-1 reduced the collagen deposition ∼81% in mesenteric tissue. Treatment with sFlt-1 decreased ICAM-1 and MCP-1 mRNA expression significantly. Significant negative correlation between serum sFlt-1 and placental growth factor level was observed, whereas there was no significant negative correlation between sFlt-1 and VEGF. On the other hand, sTGFβRII treatment enhanced the AdTGFβ-induced inflammation (significant elevation of SAP, TNF-α, and IL-12 levels and upregulation of ICAM-1 and MCP-1 mRNA expressions) and failed to prevent collagen deposition. These observations indicate that sFlt-1 gene transfer might be of therapeutic benefit in peritoneal fibrosis.
Membrane-bound ICAM-1 is upregulated by trypsin and contributes to leukocyte migration in acute pancreatitis
Authors: Hartwig Werner , Werner Jens , Warshaw Andrew L. , Antoniu Bozena , Castillo Carlos Fernandez-del , Gebhard Martha-Maria , Uhl Waldemar , Büchler Markus W.
Published: August 2004

In acute pancreatitis, ICAM-1 is upregulated in various organs and contributes to the development of organ injury. To investigate the effects of pancreatic proteases on ICAM-1 expression and their role in the early process of leukocyte migration, human umbilical vein endothelial cells (HUVECs) were incubated with serum subjected to limited trypsin digestion and Wistar rats were injected with trypsin. Significant upregulation of membrane-bound ICAM-1 was seen on HUVECs incubated with trypsinated serum. Likewise, soluble ICAM-1 increased in the supernatant of HUVECs. Changes of membrane-bound ICAM-1 and soluble ICAM-1 were maximal with high concentrations of trypsin. HUVECs incubated with TNF-α (positive control) showed similar changes. In the pancreas and lungs of animals infused with trypsin, ICAM-1 and leukocyte sequestration were increased compared with controls. Reflecting the relevance of protease-induced ICAM-1 expression in leukocyte migration, leukocyte-endothelium interaction, as assessed by intravital microscopy, was markedly increased by trypsin. Inhibition of ICAM-1 ameliorated these changes significantly. In conclusion, trypsinated serum induces the upregulation of both membrane-bound ICAM-1 on endothelial cells and soluble ICAM-1. These changes contribute to the early steps of leukocyte migration in acute pancreatitis. The role of soluble ICAM-1 remains to be investigated.
Vectorial transport of bile salts across MDCK cells expressing both rat Na+-taurocholate cotransporting polypeptide and rat bile salt export pump
Authors: Mita Sachiko , Suzuki Hiroshi , Akita Hidetaka , Stieger Bruno , Meier Peter J. , Hofmann Alan F. , Sugiyama Yuichi
Published: August 2004

Bile salts are predominantly taken up by hepatocytes via the basolateral Na+-taurocholate cotransporting polypeptide (NTCP/SLC10A1) and secreted into the bile by the bile salt export pump (BSEP/ABCB11). In the present study, we transfected rat Ntcp and rat Bsep into polarized Madin-Darby canine kidney cells and characterized the transport properties of these cells for eight bile salts. Immunohistochemical staining demonstrated that Ntcp was expressed at the basolateral domains, whereas Bsep was expressed at the apical domains. Basal-to-apical transport of taurocholate across the monolayer expressing only Ntcp and that coexpressing Ntcp/Bsep was observed, whereas the flux across the monolayer of control and Bsep-expressing cells was symmetrical. Basal-to-apical transport of taurocholate across Ntcp/Bsep-coexpressing monolayers was significantly higher than that across monolayers expressing only Ntcp. Kinetic analysis of this vectorial transport of taurocholate gave an apparent Kmvalue of 13.9 ± 4.7 μM for cells expressing Ntcp alone, which is comparable with 22.2 ± 4.5 μM for cells expressing both Ntcp and Bsep and Vmaxvalues of 15.8 ± 4.2 and 60.8 ± 9.0 pmol·min−1·mg protein−1for Ntcp alone and Ntcp and Bsep-coexpressing cells, respectively. Transcellular transport of cholate, glycocholate, taurochenodeoxycholate, chenodeoxycholate, glycochenodeoxycholate, tauroursodeoxycholate, ursodeoxycholate, and glycoursodeoxycholate, but not that of lithocholate was also observed across the double transfectant. This double-expressing system can be used as a model to clarify vectorial transport of bile salts across hepatocytes under physiological conditions.
Activation of MMP-2 in response to vascular injury is mediated by phosphatidylinositol 3-kinase-dependent expression of MT1-MMP
Authors: Zahradka Peter , Harding Greg , Litchie Brenda , Thomas Shawn , Werner Jeffrey P. , Wilson David P. , Yurkova Natalia
Published: August 2004

Phosphatidylinositol 3-kinase (PI3K) is required for smooth muscle cell (SMC) proliferation. This study reports that inhibitors of PI3K also prevent SMC migration and block neointimal hyperplasia in an organ culture model of restenosis. Inhibition of neointimal formation by LY-294002 was concentration and time dependent, with 10 μM yielding the maximal effect. Continuous exposure for at least the first 4–7 days of culture was essential for significant inhibition. To assess the role of matrix metalloproteinases (MMPs) in this process, we monitored MMP secretion by injured vessels in culture. Treatment with LY-294002 selectively reduced active MMP-2 in media samples according to zymography and Western blot analysis without concomitant changes in latent MMP-2. Parallel results with wortmannin indicate that MMP-2 activation is PI3K dependent. Previous research has shown a role for both furin and membrane-type 1 (MT1)-MMP (MMP-14) in the activation of MMP-2. The furin inhibitor decanoyl-Arg-Val-Lys-Arg-chloromethylketone did not prevent MMP-2 activation after balloon angioplasty. In contrast, balloon angioplasty induced a significant increase in the levels of MT1-MMP, which was suppressed by LY-294002. No change in MT1-MMP mRNA was observed with LY-294002, because equivalent amounts of this mRNA were present in both injured and noninjured vessels. These results implicate PI3K-dependent regulation of MT1-MMP protein synthesis and subsequent activation of latent MMP-2 as critical events in neointimal hyperplasia after vascular injury.
Noninvasive interrogation of microvasculature for signs of endothelial dysfunction in patients with chronic renal failure
Authors: Stewart Julian , Kohen Adam , Brouder Daniel , Rahim Fahim , Adler Stephen , Garrick Renee , Goligorsky Michael S.
Published: August 2004

Endothelial cell dysfunction (ECD) has been demonstrated in patients with end-stage renal disease (ESRD) who have cardiovascular disease (CD) or diabetes mellitus (DM). While techniques to examine conduit arteries have been adapted to these patients, evaluation of microvascular function has lagged behind. Therefore, we used laser Doppler flowmetry (LDF) and scanned laser Doppler imaging (LDI) to quantify parameters of the postocclusion reactive hyperemia and thermal hyperemic responses (local heating to 43°C) in ESRD patients ( n = 63) and healthy individuals ( n = 33). Patients with ESRD were partitioned among those with either CD or DM or both (designated CDorDM, n = 30), patients with both CD and DM (designated CD+DM, n = 12, statistically similar to CDorDM), and patients with neither CD or DM (designated ∼CDorDM, n = 33). LDF during thermal hyperemia showed a decrease in the thermal peaks and plateau as well as a delay in plateau compared with control, consistent with ECD. LDF during reactive hyperemia showed a decrease in the pay-back area under the curve, also consistent with ECD. ∼CDorDM were heterogeneous: almost 50% contained flow abnormalities similar to CDorDM. There was also a reduction in the number of functional arterioles on LDI images. Fourier analysis of LDF oscillations showed that low-frequency oscillations characterizing endothelial function were impaired in CDorDM and in many ∼CDorDM. The data demonstrate that ESRD patients with expected ECD (CDorDM) are characterized by distinct abnormalities in LDF parameters. However, similar abnormalities are found in approximately one-half of ESRD patients without evidence for CD or DM. Postocclusive and thermal interrogation of the microvasculature with laser Doppler-resolved parameters of the microcirculation, followed by Fourier analysis of the very slow oscillations, may provide a valuable adjunct to early noninvasive diagnosis of ECD in ESRD, especially important in a subpopulation of ESRD patients with no known CD or DM, which could be at increased risk of impending clinical manifestations of vasculopathy.
Pulmonary vascular effects of red blood cells containing S-nitrosated hemoglobin
Authors: Deem Steven , Kim Seong Su , Min Jin-Hye , Eveland Randy , Moulding Jennifer , Martyr Sabrina , Wang Xunde , Swenson Erik R. , Gladwin Mark T.
Published: August 2004

The role of S-nitrosated hemoglobin (SNO-Hb) in the regulation of blood flow is a central and controversial question in cardiopulmonary physiology. In the present study, we investigate whether intact human red blood cells (RBCs) synthesized to contain high SNO-Hb levels are able to export nitric oxide bioactivity and vasodilate the pulmonary circulation, and whether SNO-Hb dependent vasodilation occurs secondary to an intrinsic oxygen-linked, allosteric function of Hb. RBCs containing supraphysiological concentrations (100–1,000× normal) of SNO-Hb (SNO-RBCs) were synthesized and added to isolated, perfused rat lungs during anoxic or normoxic ventilation, and during normoxic ventilation with pulmonary hypertension induced by the thromboxane mimetic U-46619. SNO-RBCs produced dose-dependent pulmonary vasodilation compared with control RBCs during conditions of both normoxic (U-46619) and hypoxic pulmonary vasoconstriction. These effects were associated with a simultaneous, rapid, and temperature-dependent loss of SNO from Hb. Both vasodilatory effects and the rate of SNO-Hb degradation were independent of oxygen tension and Hb oxygen saturation. Furthermore, these effects were not affected by inhibition of the RBC membrane band 3 protein (anion exchanger-1), a putative membrane facilitator of NO export from RBCs. Whereas these data support observations by multiple groups that synthesized SNO-Hb can vasodilate, this effect is not under intrinsic oxygen-dependent allosteric control, nor likely to be relevant in the pulmonary circulation at normal physiological concentrations.
Flavonoid metabolites and susceptibility of rat lipoproteins to oxidation
Authors: Benito Sonia , Buxaderas Susana , Mitjavila M. Teresa
Published: August 2004

Flavonoids are ingested with vegetables and beverages and exert a beneficial effect on cardiovascular disease. Studies in animals in vitro and in humans ex vivo on the resistance of lipoproteins to oxidation are not consistent and the mechanisms by which flavonoids protect against atherosclerosis are a matter of debate. In the present study, we investigated the effects of administering diets containing 0.3% (wt/wt) quercetin, 0.3% (wt/wt) catechin, or 35% (vol/wt) dealcoholated red wine (DRW) for 10 days in healthy rats on markers of oxidative damage in lipoproteins and in plasma. The antioxidant levels in low-density lipoproteins (LDL) or the lag phase, oxidation rate, and maximum level of conjugated dienes during ex vivo LDL oxidation did not differ between control and treated rats. Plasma levels of α-tocopherol and retinol were similar in all groups. The total antioxidant status of the plasma from rats fed either quercetin or DRW diet was higher than in control rats. Only glucuronide and sulfate compounds of quercetin were detected in plasma from rats fed the quercetin-rich diet, and no flavonoids or their metabolites were detected in plasma or LDL from rats fed the catechin- or the DRW-rich diet. No significant differences in malondialdehyde or in conjugated dienes in plasma were observed. These results indicate that although metabolites from quercetin are present in plasma, they are not detected in lipoproteins and do not modify the level of other antioxidants. In conclusion, in the absence of any pathology or of oxidative stress the intake of quercetin, catechin, or DRW did not protect lipoproteins from oxidation ex vivo.
Dynamic cardiorespiratory interaction during head-up tilt-mediated presyncope
Authors: Krishnamurthy S. , Wang X. , Bhakta D. , Bruce E. , Evans J. , Justice T. , Patwardhan A.
Published: August 2004

In 28 healthy adults, we compared the dynamic interaction between respiration and cerebral autoregulation in 2 groups of subjects: those who did and did not develop presyncopal symptoms during 70° passive head-up tilt (HUT), i.e., nonpresyncopal (23 subjects) and presyncopal (5 subjects). Airflow, CO2, cerebral blood flow velocity (CBF), ECG, and blood pressure (BP) were recorded. To determine whether influences of mean BP (MBP) and systolic SP (SBP) on CBF were altered in presyncopal subjects, coherencies and transfer functions between these variables and mean and peak CBF (CBFm and CBFp) were estimated. To determine the influence of end-tidal CO2 (ETco2) on CBF, the relative CO2 reactivity (%change in CBFm per mmHg change in ETco2) was calculated. We found that in presyncopal subjects before symptoms during HUT, coherence between SBP and CBFp was higher ( P = 0.02) and gains of transfer functions between BP (MBP and SBP) and CBFm were larger (MBP, P = 0.01; SBP, P = 0.01) in the respiratory frequency region. In the last 3 min before presyncope, presyncopals had a reduced relative CO2 reactivity ( P = 0.005), likely a consequence of the larger decrease in ETco2. We hypothesize that the CO2-mediated increase in resistance attenuates autoregulation such that the relationship between systemic and cerebral hemodynamics is enhanced. Our results suggest that an altered cardiorespiratory interaction involving cerebral hemodynamics may contribute in the cascade of events during tilt that culminate in unexplained syncope.
Spinal CSF absorption in healthy individuals
Authors: Edsbagge Mikael , Tisell Magnus , Jacobsson Lars , Wikkelso Carsten
Published: August 2004

The present study examines the extent of spinal cerebrospinal fluid (CSF) absorption in healthy individuals in relation to physical activity, CSF production, intracranial pressure (ICP), and spinal CSF movement. Thirty-four healthy individuals aged 21–35 yr were examined by lumbar puncture and radionuclide cisternography with repeated imaging. ICP was registered before and after CSF drainage, and CSF production was calculated. Spinal CSF absorption was calculated as reduction in spinal radionuclide activity. The radionuclide activity in the spinal subarachnoidal space was gradually decreased by 20 ± 13% (mean ± SD) during 1 h. The reduction was higher in active than in resting individuals (27 ± 12% vs. 13 ± 9%). The mean ICP in 19 of the individuals was 13.6 ± 3.1 cmH2O. B-waves were found in 79% of the individuals, with a mean frequency of 0.6 ± 0.3 min−1. The mean CSF production rate was 0.34 ± 0.13 ml/min. There were no correlations between radionuclide reduction, spinal movement of the radionuclide, and CSF production rate. The spinal radionuclide reduction found in this study indicates a spinal CSF absorption of 0.11–0.23 ml/min, more pronounced in active than in resting individuals.
Programmed obesity in intrauterine growth-restricted newborns: modulation by newborn nutrition
Authors: Desai Mina , Gayle Dave , Babu Jooby , Ross Michael G.
Published: August 2004

The degree of nutrient enhancement during the newborn period may modulate programming of appetite-regulating hormones, body composition, and propensity to adult obesity in intrauterine growth-restricted (IUGR) newborns. Pregnant rats received, from day 10 to term gestation and throughout lactation, ad libitum food (AdLib) or 50% food restriction (FR) to produce IUGR newborns. AdLib vs. FR offspring were studied at day 1, and, to create two distinct groups of newborn catch-up growth (immediate, delayed) among the IUGR newborns, cross-fostering techniques were employed. The four groups of pups at 3 wk were IUGR immediate catch-up growth (FR/AdLib), IUGR delayed catch-up growth (FR/FR), control (AdLib/AdLib), and lactation FR control (AdLib/FR). From 3 wk to 9 mo, all offspring had AdLib rat chow. Maternal FR during pregnancy resulted in IUGR pups (6.0 ± 0.3 vs. 7.1 ± 0.3 g, P < 0.01) with decreased leptin (0.66 ± 0.03 vs. 1.63 ± 0.12 ng/ml, P < 0.001) and increased ghrelin (0.43 ± 0.03 vs. 0.26 ± 0.02 ng/ml, P < 0.001). Maternal FR during lactation (FR/FR) further impaired IUGR offspring growth at 3 wk. However, by 9 mo, these pups attained normal body weight, percent body fat, and plasma leptin levels. Conversely, IUGR offspring nursed by AdLib dams (FR/AdLib) exhibited rapid catch-up growth at 3 wk and continued accelerated growth, resulting in increased weight, percent body fat, and plasma leptin levels. Thus the degree of newborn nutrient enhancement and timing of IUGR newborn catch-up growth may determine the programming of orexigenic hormones and offspring obesity.
Cardiovascular control during voluntary static exercise in humans with tetraplegia
Authors: Takahashi Makoto , Sakaguchi Akihiro , Matsukawa Kanji , Komine Hidehiko , Kawaguchi Kotaro , Onari Kiyoshi
Published: August 2004

The purpose of the present study was 1) to investigate whether an increase in heart rate (HR) at the onset of voluntary static arm exercise in tetraplegic subjects was similar to that of normal subjects and 2) to identify how the cardiovascular adaptation during static exercise was disturbed by sympathetic decentralization. Mean arterial blood pressure (MAP) and HR were noninvasively recorded during static arm exercise at 35% of maximal voluntary contraction in six tetraplegic subjects who had complete cervical spinal cord injury (C6-C7). Stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR) were estimated by using a Modelflow method simulating aortic input impedance from arterial blood pressure waveform. In tetraplegic subjects, the increase in HR at the onset of static exercise was blunted compared with age-matched control subjects, whereas the peak increase in HR at the end of exercise was similar between the two groups. CO increased during exercise with no or slight decrease in SV. MAP increased approximately one-third above the control pressor response but TPR did not rise at all throughout static exercise, indicating that the slight pressor response is determined by the increase in CO. We conclude that the cardiovascular adaptation during voluntary static arm exercise in tetraplegic subjects is mainly accomplished by increasing cardiac pump output according to the tachycardia, which is controlled by cardiac vagal outflow, and that sympathetic decentralization causes both absent peripheral vasoconstriction and a decreased capacity to increase HR, especially at the onset of exercise.
Cloning and sequencing of myosin heavy chain isoform cDNAs in golden-mantled ground squirrels: effects of hibernation on mRNA expression
Authors: Rourke Bryan C. , Qin Anqi , Haddad Fadia , Baldwin Kenneth M. , Caiozzo Vincent J.
Published: August 2004

The golden-mantled ground squirrel is a small rodent hibernator that demonstrates unusual myosin heavy chain (MHC) isoform plasticity during several months of torpor, punctuated by bouts of rewarming and shivering thermogenesis. We measured MHC mRNA levels to determine whether pretranslational control mechanisms were responsible for differences in MHC2x protein expression, as we previously observed between active and hibernating ground squirrels. We first cloned cDNA using the 3′ rapid amplification of cDNA ends (3′ RACE) technique and identified three sequences corresponding to MHC1, MHC2x, and MHC2b. A DNA control fragment was developed to be used in conjunction with a coupled RT-PCR reaction to simultaneously measure MHC mRNA levels for each isoform in the skeletal muscle of ground squirrels. MHC mRNA and protein expression were strongly correlated, and type IIx and IIb mRNA levels were significantly different between active and hibernating ground squirrels. Pretranslational control of MHC protein is apparently an important process during hibernation, although the exact stimulus is not known. The techniques presented can be used to obtain MHC cDNA sequences and to measure mRNA expression in many vertebrate groups.
Gene Expression Phenotypes of Atherosclerosis
Authors: Seo David , Wang Tao , Dressman Holly , Herderick Edward E. , Iversen Edwin S. , Dong Chunming , Vata Korkut , Milano Carmelo A. , Rigat Fabio , Pittman Jennifer , Nevins Joseph R. , West Mike , Goldschmidt-Clermont Pascal J.
Published: August 2004

Objective—

Fulfilling the promise of personalized medicine by developing individualized diagnostic and therapeutic strategies for atherosclerosis will depend on a detailed understanding of the genes and gene variants that contribute to disease susceptibility and progression. To that end, our group has developed a nonbiased approach congruent with the multigenic concept of complex diseases by identifying gene expression patterns highly associated with disease states in human target tissues.

Methods and Results—

We have analyzed a collection of human aorta samples with varying degrees of atherosclerosis to identify gene expression patterns that predict a disease state or potential susceptibility. We find gene expression signatures that relate to each of these disease measures and are reliable and robust in predicting the classification for new samples with >93% in each analysis. The genes that provide the predictive power include many previously suspected to play a role in atherosclerosis and additional genes without prior association with atherosclerosis.

Conclusion—

Hence, we are reporting a novel method for generating a molecular phenotype of disease and then identifying genes whose discriminatory capability strongly implicates their potential roles in human atherosclerosis.
Compensatory Vascular Remodeling During Atherosclerotic Lesion Growth Depends on Matrix Metalloproteinase-9 Activity
Authors: Lessner Susan M. , Martinson Deborah E. , Galis Zorina S.
Published: August 2004

Objective—The compensatory arterial remodeling associated with atherosclerotic plaques is thought to rely on the activity of matrix metalloproteinases (MMP). To assess the role of MMP-9, we analyzed the effect of MMP-9 genetic deficiency on the development and remodeling of experimental atherosclerotic lesions induced in the apolipoprotein E (apoE) knockout (−/−) mouse model.

Methods and Results—We analyzed remodeling parameters and cellular composition of experimental carotid artery atherosclerotic lesions in apoE−/− and apoE−/− MMP-9−/− double-knockout (DKO) mice at 0, 3, 7, and 14 days after induction by flow cessation. Morphometric image analysis of arterial tissue sections indicated that overall artery size, measured as area encompassed by the external elastic lamina, increased 3.1-fold in the apoE−/− mice but only 1.6-fold in the DKO mice (P<0.0001) by 14 days. At the same time, the net lesion area occupied by macrophages was similar. Statistical analysis indicated that the overall expansion of the artery was 2.5-fold less sensitive to macrophage content in DKO compared with apoE−/− mice. No compensatory increase in other gelatinolytic activities was detected in the DKO.

Conclusions—MMP-9 deficiency significantly impaired compensatory vessel enlargement during carotid artery lesion development in the apoE−/− mouse, without altering macrophage content of lesions.
C-Reactive Protein, Fibrin D-Dimer, and Risk of Ischemic Heart Disease
Authors: Lowe G.D.O. , Sweetnam P.M. , Yarnell J.W.G. , Rumley A. , Rumley C. , Bainton D. , Ben-Shlomo Y.
Published: August 2004

Background—There is increasing interest in the predictive value of C-reactive protein (CRP) and fibrin D-dimer in the prediction of ischemic heart disease (IHD). We assessed their joint and independent associations with IHD in a large combined analysis of 2 population cohorts.

Methods and Results—Men aged 49 to 66 years from the general populations of Caerphilly and Speedwell were studied between 1982 and 1988 and re-examined for new IHD events at fixed intervals of ≈105 months (Caerphilly) and 75 months (Speedwell). 3213 men had CRP and D-dimer measured at baseline and 351 (11%) had a new IHD event. Mean levels of CRP and D-dimer were significantly higher among men in whom IHD developed. The relative odds of IHD in men in the top 20% of the distribution of CRP was 2.97 (95% CI, 2.04, 4.32) and for D-dimer was 2.40 (95% CI, 1.69, 3.40); CRP and D-dimer had additive effects on risk of IHD. Multivariate analysis reduced the size of the relative odds, which remained significant for D-dimer.

Conclusions—Both inflammatory and thrombogenic markers are important (and potentially additive) predictors of coronary risk.
Carbon Monoxide Protects Against Cardiac Ischemia—Reperfusion Injury In Vivo via MAPK and Akt—eNOS Pathways
Authors: Fujimoto Hajime , Ohno Minoru , Ayabe Seiji , Kobayashi Hisae , Ishizaka Nobukazu , Kimura Hiroko , Yoshida Ken-ichi , Nagai Ryozo
Published: August 2004

Background—

Carbon monoxide (CO) is postulated to protect tissues against several types of injuries. We investigated the role of CO in amelioration of cardiac ischemia–reperfusion injury in vivo and the mechanisms involved in it.

Methods and Results—

Rats inhaled CO (250 ppm, 500 ppm, or 1000 ppm) for 24 hours in a chamber after myocardial ischemia–reperfusion induced by occluding the left anterior descending coronary artery for 30 minutes. Pre-exposure to 1000 ppm of CO significantly reduced the ratio of infarct areas to risk areas and suppressed the migration of macrophages and monocytes into infarct areas, and the expression of tumor necrosis factor (TNF)-α in the heart; however, 250 ppm, 500 ppm of CO, or low barometric pressure hypoxia (0.5 atm) did not affect them. Exposure to 1000 ppm CO resulted in the activation of p38 mitogen-activated protein kinase (p38MAPK), protein kinase Bα(Akt), endothelial nitric oxide synthase (eNOS), and cyclic guanosine monophosphate (cGMP) in the myocardium. Inhibition of p38MAPK, PI3kinase, NO, and soluble guanylate cyclase with SB203580, wortmannin, N(G)-nitro-
l
-arginine methyl ester (
l
-NAME), and methylene blue, respectively, attenuated the cytoprotection by CO.

Conclusion—

CO has beneficial effects on cardiac ischemia–reperfusion injury; this effect is mediated by p38MAPK pathway and Akt–eNOS pathway, including production of cGMP.
REDD2 Gene Is Upregulated by Modified LDL or Hypoxia and Mediates Human Macrophage Cell Death
Authors: Cuaz-Pérolin C. , Furman C. , Larigauderie G. , Legedz L. , Lasselin C. , Copin C. , Jaye M. , Searfoss G. , Yu K.T. , Duverger N. , Nègre-Salvayre A. , Fruchart J.-C. , Rouis M.
Published: August 2004

Objective—

Cholesterol accumulation in macrophages is known to alter macrophage biology. In this article we studied the impact of macrophage cholesterol loading on gene expression and identified a novel gene implicated in cell death.

Methods and Results—

The regulated in development and DNA damage response 2 (REDD2) gene was strongly upregulated as THP-1 macrophages are converted to foam cells. These results were confirmed by Northern blot of RNA from human monocyte-derived macrophages (HMDM) treated with oxidized LDL (oxLDL). Human REDD2 shares 86% amino acid sequence identity with murine RTP801-like protein, which is 33% identical to RTP801, a hypoxia-inducible factor 1-responsive gene involved in apoptosis. Treatment of HMDM with desferrioxamine, a molecule that mimics the effect of hypoxia, increased expression of REDD2 in a concentration-dependent fashion. Transfection of U-937 and HMEC cells with a REDD2 expression vector increased the sensitivity of the cells for oxLDL-induced cytotoxicity, by inducing a shift from apoptosis toward necrosis. In contrast, suppression of mRNA expression using siRNA approach resulted in increased resistance to oxLDL treatment.

Conclusion—

We showed that stimulation of REDD2 expression in macrophages increases oxLDL-induced cell death, suggesting that REDD2 gene might play an important role in arterial pathology.
Ets-1 Stimulates Platelet-Derived Growth Factor A-Chain Gene Transcription and Vascular Smooth Muscle Cell Growth via Cooperative Interactions With Sp1
Authors: Santiago Fernando S. , Khachigian Levon M.
Published: August 2004

The platelet-derived growth factor (PDGF) family of ligands (composed of A-, B-, C-, and D-chains), potent mitogens, and chemoattractants for cells of mesenchymal origin has been implicated in numerous vascular pathologies involving smooth muscle cell (SMC) hyperplasia. Understanding the molecular mechanisms mediating PDGF transcription would provide new insights into strategies to control PDGF-dependent pathophysiologic processes. We demonstrated previously that PDGF-A expression is under the positive regulatory influence of Sp1, Sp3, and Egr-1 and is negatively controlled by GCF2, NF-1(X), and WT-1. In this article, we demonstrate that Ets-1 induces PDGF-A expression in primary rat aortic SMCs at the level of transcription and mRNA expression. Electrophoretic mobility shift, supershift, and mutational analyses revealed a functional role for the
−555
TTCC
−552
motif in the PDGF-A promoter that binds endogenous Ets-1. Chromatin immunoprecipitation analysis showed the interaction of endogenous and exogenous Ets-1 or glutathione
S
-transferase-tagged Ets-1, bearing only the DNA-binding domain with the authentic PDGF-A promoter. Conversely, dominant-negative mutant of Ets-1 blocked the promoter interaction of endogenous Ets-1. Overexpression of Ets-1 but not the mutant form of Ets-1 activates the PDGF-A promoter cooperatively with Sp1. Sp1, which interacts with Ets-1, failed to induce PDGF-A promoter-dependent expression if the promoter contained a site-specific mutation in this novel Ets-binding site. Small interfering RNA to Ets-1 and Sp1 blocked PDGF-BB- and serum-inducible PDGF-A expression. SMC growth was stimulated by Ets-1 and Sp1 separately and further increased by both factors together. Ets-1-inducible mitogenesis is blocked by antibodies neutralizing PDGF-A and involves activation of the PDGF α-receptor, which binds PDGF-A. These findings identify a functional
cis
-acting element for Ets-1 in the PDGF-A promoter and demonstrate that Sp1 and Ets-1 cooperatively activate PDGF-A transcription in vascular SMCs.
Overexpression of Urokinase by Macrophages or Deficiency of Plasminogen Activator Inhibitor Type 1 Causes Cardiac Fibrosis in Mice
Authors: Moriwaki Hideaki , Stempien-Otero April , Kremen Michal , Cozen Aaron E. , Dichek David A.
Published: August 2004

Several studies implicate elevated matrix metalloproteinase activity as a cause of cardiac fibrosis. However, it is unknown whether other proteases can also initiate cardiac fibrosis. Because absence of urokinase plasminogen activator (uPA) prevents development of cardiac fibrosis after experimental myocardial infarction in mice, we hypothesized that elevated activity of uPA or deficiency of the uPA inhibitor plasminogen activator inhibitor-1 (PAI-1) might cause cardiac fibrosis. We used mice with scavenger-receptor (SR)-directed, macrophage-targeted uPA overexpression (SR-uPA
+/0
mice) and PAI-1 null mice to test these hypotheses. Our studies revealed that SR-uPA
+/0
mice developed cardiac fibrosis beginning between 5 and 10 weeks of age. Fibrosis was preceded by cardiac macrophage accumulation, implicating uPA-secreting macrophages as important contributors to development of fibrosis. A key role for uPA-secreting macrophages in development of cardiac fibrosis was supported by experiments in which recipients of bone marrow transplants from SR-uPA
+/0
donors but not nontransgenic donors developed cardiac macrophage accumulation and fibrosis. SR-uPA
+/0
mice and recipients of SR-uPA
+/0
bone marrow had neither macrophage accumulation nor fibrosis in other major organs despite the presence of higher levels of uPA in these organs than in hearts. PAI-1 null mice but not congenic, age-matched controls also developed macrophage accumulation and fibrosis in hearts but not in other organs. We conclude: (1) either elevated macrophage uPA expression or PAI-1 deficiency is sufficient to cause cardiac macrophage accumulation and fibrosis; (2) macrophages are important contributors to the development of cardiac fibrosis; and (3) the heart is particularly sensitive to the effects of excess uPA activity.
Rho Kinase–Induced Nuclear Translocation of ERK1/ERK2 in Smooth Muscle Cell Mitogenesis Caused by Serotonin
Authors: Liu Yinglin , Suzuki Yuichiro J. , Day Regina M. , Fanburg Barry L.
Published: August 2004

There is now considerable evidence supporting a mitogenic action of serotonin (5-HT) on vascular smooth muscle cells (SMC) that might participate in pulmonary hypertension (PH). Our previous studies have demonstrated that 5-HT–induced proliferation depends on the generation of reactive oxygen species and activation of extracellular signal-regulated kinase (ERK) 1/ERK2. Activation of Rho kinase (ROCK) in SMC also may be important in PH. We undertook the present study to assess the role of Rho A/ROCK and its possible relation to ERK1/ERK2 in 5-HT–induced pulmonary artery SMC proliferation. We found that this stimulation of SMC proliferation requires Rho A/ROCK as inhibition with Y27632, a ROCK inhibitor, or dominant negative (DN) mutant Rho A blocks 5-HT–induced proliferation, cyclin D1 expression, phosphorylation of Elk, and the DNA binding of transcription factors, Egr-1 and GATA-4. 5-HT activated ROCK, and the activation was blocked by GR 55562 and GR127935, 5-HT 1B/1D receptor antagonists, but not by serotonin transport (SERT) inhibitors. Activation of Rho kinase by 5-HT was independent of activation of ERK1/ERK2, and 5-HT activated ERK1/ERK2 independently of ROCK. Treatment of SMC with Y27632 and expression of DNRho A in cells blocked translocation of ERK1/ERK2 to the cellular nucleus. Depolymerization of actin with cytochalasin D (CD) and latrunculin B (latB) failed to block the translocation of ERK, suggesting that the actin cytoskeleton does not participate in the translocation. The studies show for the first time to our knowledge combinational action of SERT and a 5-HT receptor in SMC growth and Rho A/ROCK participation in 5-HT receptor 1B/1D-mediated mitogenesis of vascular SMCs through an effect on cytoplasmic to nuclear translocation of ERK1/ERK2.
Generation of Functional Culture–Derived Platelets From CD34
+
Progenitor Cells to Study Transgenes in the Platelet Environment
Authors: Ungerer Martin , Peluso Mario , Gillitzer Angelika , Massberg Steffen , Heinzmann Ulrich , Schulz Christian , Münch Götz , Gawaz Meinrad
Published: August 2004

Abstract:—

The possibility of evaluating the function of transgenes in platelets requires the generation of platelets from nucleated progenitor cells in vitro. In this article, we provide effective culture conditions for generating functional culture-derived (CD) human and mouse platelets from CD34
+
progenitor cells that allow expression of any foreign protein of interest. We have evolved an effective cytokine cocktail (thrombopoietin, stem cell factor, interleukin [IL]-1β, IL-6) that induces a high yield of CD platelets and optimal shedding from cultivated megakaryocytes generated from CD34
+
progenitor cells. CD platelets showed similar functional and morphological characteristics compared with isolated blood platelets, including surface expression of platelet antigens (CD41, CD42, CD62P), aggregation, release of granule constituents (P-selectin, platelet factor 4, serotonin). Moreover, transmission electron microscopy revealed the presence of typical α- and dense granules and dense tubular system in CD platelets. Additionally, we showed that stable transgene expression in CD platelets can be performed through infection of CD34
+
progenitor cells using adenoviral vectors. Thus, we describe a methodology that enables studying functional consequences of transgenes of interest in the natural environment of platelets that may impose substantial impact on potential future platelet research and therapeutic target evaluation. The full text of this article is available online at http://circres.ahajournals.org.