bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of bidirectional pattern synchrony of concentration-secretion pairs: implementation in the human testicular and adrenal axes
Authors: Liu Peter Y. , Pincus Steven M. , Keenan Daniel M. , Roelfsema Ferdinand , Veldhuis Johannes D.
Published: October 2004

The hypothalamo-pituitary-testicular and hypothalamo-pituitary-adrenal axes are prototypical coupled neuroendocrine systems. In the present study, we contrasted in vivo linkages within and between these two axes using methods without linearity assumptions. We examined 11 young (21–31 yr) and 8 older (62–74 yr) men who underwent frequent (every 2.5 min) blood sampling overnight for paired measurement of LH and testosterone and 35 adults (17 women and 18 men; 26–77 yr old) who underwent adrenocorticotropic hormone (ACTH) and cortisol measurements every 10 min for 24 h. To mirror physiological interactions, hormone secretion was first deconvolved from serial concentrations with a waveform-independent biexponential elimination model. Feedforward synchrony, feedback synchrony, and the difference in feedforward-feedback synchrony were quantified by the cross-approximate entropy (X-ApEn) statistic. These were applied in a forward (LH concentration template, examining pattern recurrence in testosterone secretion), reverse (testosterone concentration template, examining pattern recurrence in LH secretion), and differential (forward minus reverse) manner, respectively. Analogous concentration-secretion X-ApEn estimates were calculated from ACTH-cortisol pairs. X-ApEn, a scale- and model-independent measure of pattern reproducibility, disclosed 1) greater testosterone-LH feedback coordination than LH-testosterone feedforward synchrony in healthy men and significant and symmetric erosion of both feedforward and feedback linkages with aging; 2) more synchronous ACTH concentration-dependent feedforward than feedback drive of cortisol secretion, independent of gender and age; and 3) enhanced detection of bidirectional physiological regulation by in vivo pairwise concentration-secretion compared with concentration-concentration analyses. The linking of relevant biological input to output signals and vice versa should be useful in the dissection of the reciprocal control of neuroendocrine systems or even in the analysis of other nonendocrine networks.
Brain region-dependent effects of dexamethasone on counterregulatory responses to hypoglycemia in conscious rats
Authors: Sandoval Darleen A. , Ping Ling , Neill Ray Anthony , Gong Bin , Walsh Kristen , Davis Stephen N.
Published: October 2004

The aim of this study was to determine whether activation of central type II glucocorticoid receptors can blunt autonomic nervous system counterregulatory responses to subsequent hypoglycemia. Sixty conscious unrestrained Sprague-Dawley rats were studied during 2-day experiments. Day 1 consisted of either two episodes of clamped 2-h hyperinsulinemic (30 pmol·kg−1·min−1) hypoglycemia (2.8 ± 0.1 mM; n = 12), hyperinsulinemic euglycemia (6.2 ± 0.1 mM; n = 12), hyperinsulinemic euglycemia plus simultaneous lateral cerebroventricular infusion of saline (24 μl/h; n = 8), or hyperinsulinemic euglycemia plus either lateral cerebral ventricular infusion ( n = 8; LV-DEX group), fourth cerebral ventricular ( n = 10; 4V-DEX group), or peripheral ( n = 10; P-DEX group) infusion of dexamethasone (5 μg/h), a specific type II glucocorticoid receptor analog. For all groups, day 2 consisted of a 2-h hyperinsulinemic (30 pmol·kg−1·min−1) or hypoglycemic (2.9 ± 0.2 mM) clamp. The hypoglycemic group had blunted epinephrine, glucagon, and endogenous glucose production in response to subsequent hypoglycemia. Consequently, the glucose infusion rate to maintain the glucose levels was significantly greater in this group vs. all other groups. The LV-DEX group did not have blunted counterregulatory responses to subsequent hypoglycemia, but the P-DEX and 4V-DEX groups had significantly lower epinephrine and norepinephrine responses to hypoglycemia compared with all other groups. In summary, peripheral and fourth cerebral ventricular but not lateral cerebral ventricular infusion of dexamethasone led to significant blunting of autonomic counterregulatory responses to subsequent hypoglycemia. These data suggest that prior activation of type II glucocorticoid receptors within the hindbrain plays a major role in blunting autonomic nervous system counterregulatory responses to subsequent hypoglycemia in the conscious rat.
Sympathetic neural regulation in endurance-trained humans: fitness vs. fatness
Authors: Alvarez Guy E. , Halliwill John R. , Ballard Tasha P. , Beske Stacy D. , Davy Kevin P.
Published: October 2004

We tested the hypothesis that muscle sympathetic nerve activity (MSNA) would be higher in endurance-trained (ET) compared with sedentary (Sed) men with similar levels of total body and abdominal adiposity. We further hypothesized that sympathetic baroreflex gain would be augmented in ET compared with Sed men independent of the level of adiposity. To address this, we measured MSNA (via microneurography), sympathetic and vagal baroreflex responses (the modified Oxford technique), body composition (dual-energy X-ray absorptiometry), and waist circumference (Gulick tape) in Sed ( n = 22) and ET men ( n = 8). The ET men were also compared with a subgroup of Sed men ( n = 6) with similar levels of total body and abdominal adiposity. Basal MSNA was greater in the ET compared with Sed men with similar levels of total body and abdominal adiposity (28 ± 2.0 vs. 21 ± 2.0 bursts/min; P < 0.05) but similar to the larger group of Sed men ( n = 22) with higher total body and abdominal adiposity (vs. 26 ± 3 bursts/min; P > 0.05). In contrast to our hypothesis, sympathetic baroreflex gain was lower in the ET compared with Sed men (−6.4 ± 0.8 vs. −8.4 ± 0.4 arbitrary integrative units·beat−1·mmHg−1; P < 0.05) regardless of the level of adiposity. Taken together, the results of the present study suggest that MSNA is higher in ET compared with Sed men with similar levels of total body and abdominal adiposity. In addition, sympathetic baroreflex gain is lower in ET compared with Sed men. That sympathetic baroreflex gain was lower in ET compared with Sed men regardless of the level of adiposity suggests an influence of the ET state per se.
Effects of relaxin on systemic arterial hemodynamics and mechanical properties in conscious rats: sex dependency and dose response
Authors: Debrah Dan O. , Conrad Kirk P. , Danielson Lee A. , Shroff Sanjeev G.
Published: October 2004

We previously showed that chronic administration of recombinant human relaxin (rhRLX; 4 μg/h) to conscious female, nonpregnant rats to reach serum levels corresponding to early to midgestation (∼20 ng/ml) increases cardiac output (CO) and global arterial compliance (AC) and decreases systemic vascular resistance (SVR), comparable to changes observed in midterm pregnancy. The goals of this study were to test whether chronic administration of rhRLX (4 μg/h) to conscious male rats will yield similar changes in CO and systemic arterial load and to determine whether higher infusion rates of rhRLX (50 μg/h) administered to nonpregnant female rats yielding serum concentrations corresponding to late pregnancy (∼80 ng/ml) will further modify CO and SVR and global AC comparable to late gestation. CO and systemic arterial load, as quantified by SVR and AC, were obtained by using the same methods as in our previous studies. With respect to baseline, chronic rhRLX administration to male rats over 10 days at 4 μg/h increased both CO (20.5 ± 4.2%) and AC (19.4 ± 6.9%) and reduced SVR (12.7 ± 3.9%). These results were comparable to those elicited by the hormone in nonpregnant female rats. In contrast, neither acute (over 4 h) nor chronic (over 6 days) infusion of the higher dose of rhRLX administered to conscious female rats resulted in significant changes in CO, AC, or SVR from baseline. We conclude that 1) rhRLX increases CO and AC and reduces SVR irrespective of sex, and 2) the rhRLX dose response is biphasic insofar as significant alterations in CO and systemic arterial load fail to occur at high serum concentrations.
Processing of Frequency-Modulated Sounds in the Lateral Auditory Belt Cortex of the Rhesus Monkey
Authors: Tian Biao , Rauschecker Josef P.
Published: October 2004

Single neurons were recorded from the lateral belt areas, anterolateral (AL), mediolateral (ML), and caudolateral (CL), of nonprimary auditory cortex in 4 adult rhesus monkeys under gas anesthesia, while the neurons were stimulated with frequency-modulated (FM) sweeps. Responses to FM sweeps, measured as the firing rate of the neurons, were invariably greater than those to tone bursts. In our stimuli, frequency changed linearly from low to high frequencies (FM direction “up”) or high to low frequencies (“down”) at varying speeds (FM rates). Neurons were highly selective to the rate and direction of the FM sweep. Significant differences were found between the 3 lateral belt areas with regard to their FM rate preferences: whereas neurons in ML responded to the whole range of FM rates, AL neurons responded better to slower FM rates in the range of naturally occurring communication sounds. CL neurons generally responded best to fast FM rates at a speed of several hundred Hz/ms, which have the broadest frequency spectrum. These selectivities are consistent with a role of AL in the decoding of communication sounds and of CL in the localization of sounds, which works best with broader bandwidths. Together, the results support the hypothesis of parallel streams for the processing of different aspects of sounds, including auditory objects and auditory space.
Processing of Retinal and Extraretinal Signals for Memory-Guided Saccades During Smooth Pursuit
Authors: Blohm Gunnar , Missal Marcus , Lefèvre Philippe
Published: October 2004

It is an essential feature for the visual system to keep track of self-motion to maintain space constancy. Therefore the saccadic system uses extraretinal information about previous saccades to update the internal representation of memorized targets, an ability that has been identified in behavioral and electrophysiological studies. However, a smooth eye movement induced in the latency period of a memory-guided saccade yielded contradictory results. Indeed some studies described spatially accurate saccades, whereas others reported retinal coding of saccades. Today, it is still unclear how the saccadic system keeps track of smooth eye movements in the absence of vision. Here, we developed an original two-dimensional behavioral paradigm to further investigate how smooth eye displacements could be compensated to ensure space constancy. Human subjects were required to pursue a moving target and to orient their eyes toward the memorized position of a briefly presented second target (flash) once it appeared. The analysis of the first orientation saccade revealed a bimodal latency distribution related to two different saccade programming strategies. Short-latency (<175 ms) saccades were coded using the only available retinal information, i.e., position error. In addition to position error, longer-latency (>175 ms) saccades used extraretinal information about the smooth eye displacement during the latency period to program spatially more accurate saccades. Sensory parameters at the moment of the flash (retinal position error and eye velocity) influenced the choice between both strategies. We hypothesize that this tradeoff between speed and accuracy of the saccadic response reveals the presence of two coupled neural pathways for saccadic programming. A fast striatal-collicular pathway might only use retinal information about the flash location to program the first saccade. The slower pathway could involve the posterior parietal cortex to update the internal representation of the flash once extraretinal smooth eye displacement information becomes available to the system.
Contrast Dependence of Suppressive Influences in Cortical Area MT of Alert Macaque
Authors: Pack Christopher C. , Hunter J. Nicholas , Born Richard T.
Published: October 2004

Visual neurons are often characterized in terms of their tuning for various stimulus properties, such as shape, color, and velocity. Generally, these tuning curves are further modulated by the overall intensity of the stimulus, such that increasing the contrast increases the firing rate, up to some maximum. In this paper, we describe the tuning of neurons in the middle temporal area (MT or V5) of macaque visual cortex for moving stimuli of varying contrast. We find that, for some MT neurons, tuning curves for stimulus direction, speed, and size are shaped in part by suppressive influences that are present at high stimulus contrast but weak or nonexistent at low contrast. For most neurons, the suppression is direction-specific and strongest for large, slow-moving stimuli. The surprising consequence of this phenomenon is that some MT neurons actually fire more vigorously to a large low-contrast stimulus than to one of high contrast. These results are consistent with recent perceptual observations, as well as with information-theoretic models, which hypothesize that the visual system seeks to reduce redundancy at high contrast while maintaining sensitivity at low contrast.
Modulation of Parabrachial Taste Neurons by Electrical and Chemical Stimulation of the Lateral Hypothalamus and Amygdala
Authors: Li Cheng-Shu , Cho Young K. , Smith David V.
Published: October 2004

The lateral hypothalamus (LH) and the central nucleus of the amygdala (CeA) exert an influence on ingestive behavior and are reciprocally connected to gustatory and viscerosensory areas, including the nucleus of the solitary tract (NST) and the parabrachial nuclei (PbN). We investigated the effects of LH and CeA stimulation on the activity of 101 taste-responsive neurons in the hamster PbN. Eighty three of these neurons were antidromically activated by stimulation of these sites; 57 were antidromically driven by both. Of these 83 neurons, 21 were also orthodromically activated—8 by the CeA and 3 by the LH. Additional neurons were excited ( n = 5) or inhibited ( n = 8) by these forebrain nuclei but not antidromically activated. Taste stimuli were: 0.032 M sucrose, 0.032 M sodium chloride (NaCl), 0.032 M quinine hydrochloride (QHCl), and 0.0032 M citric acid. Among the 34 orthodromically activated neurons, more sucrose-best neurons were excited than inhibited, whereas the opposite occurred for citric-acid- and QHCl-best cells. Neurons inhibited by the forebrain responded significantly more strongly to citric acid and QHCl than cells excited by these sites. The effects of electrical stimulation were mimicked by microinjection of dl-homocysteic acid, indicating that cells at these forebrain sites were responsible for these effects. These data demonstrate that many individual PbN gustatory neurons project to both the LH and CeA and that these areas modulate the gustatory activity of a subset of PbN neurons. This neural substrate is likely involved in the modulation of taste activity by physiological and experiential factors.
Intracellular Labile Iron Modulates Adhesion of Human Monocytes to Human Endothelial Cells
Authors: Kartikasari Apriliana E.R. , Georgiou Niki A. , Visseren Frank L.J. , van Kats-Renaud Henny , van Asbeck B. Sweder , Marx Joannes J.M.
Published: October 2004

Objective—Elevated iron stores and high plasma iron concentration have been linked to an increased risk of atherosclerosis. Iron may thereby affect the interaction of monocytes to endothelium, an initial event in the formation of atherosclerotic plaques.

Methods and Results—Addition of 10 μmol/L non–transferrin-bound iron to the incubation medium caused a 2-fold increase in monocyte adhesion to human umbilical vein endothelial cells (HUVECs). A concordant increase in the expression of the following adhesion molecules was observed: vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and endothelial selectin on HUVECs as well as very late antigen-4, and lymphocyte function–associated antigen-1 on monocytes. The inclusion of either deferiprone or salicylaldehyde isonicotinoylhydrazone counteracted these effects. Intracellular iron chelation by deferoxamine was completed only after 10 hours of incubation, shown by reversal of iron-quenched intracellular calcein signal, and concurrently the effects of iron were blunted. The membrane-impermeable chelator, diethylenetriamine pentaaceticacid, failed to negate iron effects, even after 48 hours of treatment. Furthermore, only membrane-permeable superoxide or hydroxyl radical scavengers were capable of preventing HUVEC activation by iron.

Conclusions—Non–transferrin-bound iron increases the level of intracellular labile iron, which promotes monocyte recruitment to endothelium and may thereby contribute to the pathogenesis of atherosclerosis. Iron-induced adhesion molecule expression was observed, and this event may involve the production of oxygen radicals.
Ultrasensitive Confocal Fluorescence Microscopy of C-Reactive Protein Interacting With FcγRIIa
Authors: Manolov Dimitar E. , Röcker Carlheinz , Hombach Vinzenz , Nienhaus G. Ulrich , Torzewski Jan
Published: October 2004

Background—C-Reactive protein (CRP) is an acute phase protein with a suggested pathogenic role in cardiovascular disease. Previous reports proposed that the low-affinity IgG receptor FcγRIIa is the major receptor for CRP. However, these reports were met with criticism because the use of anti-CRP antibodies in the detection of CRP binding to FcγRIIa may have caused false-positive results.

Methods and Results—To resolve this controversy, we used ultrasensitive fluorescence microscopy to study the association, dissociation, and equilibrium of CRP binding to FcγRIIa. CRP indeed binds to FcγRIIa, with low association rates and dissociation rates. Anti-CRP antibodies markedly enhance binding, as is evident from the decrease of the equilibrium dissociation coefficient by 2 orders of magnitude.

Conclusions—Our study demonstrates the virtues of single fluorophore labeling and highlights the pitfalls of immunolabeling in investigating CRP/Fc receptor interactions. Importantly, this article provides the first quantitative characterization of CRP binding to FcγRIIa and explains and reconciles the diverse and conflicting data presented in the literature.
Molecular Evaluation of Endothelial Progenitor Cells in Patients With Ischemic Limbs
Authors: Yamamoto Koji , Kondo Takahisa , Suzuki Satoshi , Izawa Hideo , Kobayashi Masayoshi , Emi Nobuhiko , Komori Kimihiro , Naoe Tomoki , Takamatsu Junki , Murohara Toyoaki
Published: October 2004

Objective—

Although some patients with limb ischemia have recently undergone therapeutic angiogenesis by cell transplantation, their angiogenic potential has not been well characterized. It is also important to evaluate endothelial progenitor cell (EPC) contents in different stem cell sources to choose the best material for therapeutic angiogenesis.

Methods and Results—

We quantitated the mRNA expression of EPC-specific molecules (eg, Flk-1, Flt-1, CD133, VE-cadherin, etc) in bone marrow-derived or peripheral blood-derived mononuclear cells obtained from patients with ischemic limbs, using real-time reverse-transcription polymerase chain reaction technique. The mRNA expression level of EPC markers was significantly lower in the patients than in healthy controls, which was consistent with results of flow cytometric analysis. However, the implantation of autologous bone marrow mononuclear cells increased the circulating EPCs in the peripheral blood of patients. We furthermore revealed the different expression pattern of EPC markers in possible sources for stem cell transplantation, including normal bone marrow, peripheral blood obtained from recombinant granulocyte colony–stimulating factor-treated donor, and umbilical cord blood.

Conclusions—

Patients with peripheral obstructive arterial diseases may have lower angiogenic potential because of decreased expression of EPC specific molecules in their marrow and blood. Therapeutic angiogenesis by transplantation of autologous marrow mononuclear cells increased circulating EPCs in the patients and improved ischemic symptoms.

(
Arterioscler Thromb Vasc Biol
. 2004;24:e192–e196.)
Vein Graft Neointimal Hyperplasia Is Exacerbated by Tumor Necrosis Factor Receptor-1 Signaling in Graft-Intrinsic Cells
Authors: Zhang Lisheng , Peppel Karsten , Brian Leigh , Chien Lynn , Freedman Neil J.
Published: October 2004

Objective—

Vein graft remodeling and neointimal hyperplasia involve inflammation, graft-intrinsic cells, and recruitment of vascular progenitor cells. We sought to examine if the inflammatory cytokine tumor necrosis factor (TNF) affects vein graft remodeling via its p55 TNF receptor-1 (p55).

Methods and Results—

Inferior vena cava-to-carotid artery interposition grafting was performed between p55
−/−
and congenic (C57Bl/6) wild-type (WT) mice. Immunofluorescence revealed TNF in early (2-week) vein grafts. Six weeks postoperatively, luminal and medial areas were indistinguishable among all vein graft groups. However, neointimal area was reduced in p55
−/−
grafts: by 40% in p55
−/−
grafts placed in p55
−/−
recipients, and by 21% in p55
−/−
grafts placed in WT recipients, compared with WT grafts in WT recipients (
P
<0.05). In 2-week-old vein grafts, p55 deficiency reduced intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and monocyte chemoattractant protein-1 expression by 50% to 60%, and increased the extent of graft endothelialization. In vitro, TNF promoted chemokine expression and [
3
H]thymidine incorporation in vascular smooth muscle cells (SMCs) from WT, but not from p55
−/−
mice. However, responses of WT and p55
−/−
SMCs to other growth factors were equivalent.

Conclusions—

Signaling via p55, in vein graft-intrinsic cells, contributes to the pathogenesis of vein graft neointimal hyperplasia.
Increased Vascular Wall Thrombogenicity Combined With Reduced Blood Flow Promotes Occlusive Thrombus Formation in Rabbit Femoral Artery
Authors: Yamashita Atsushi , Furukoji Eiji , Marutsuka Kousuke , Hatakeyama Kinta , Yamamoto Hiroshi , Tamura Shozo , Ikeda Yasuo , Sumiyoshi Akinobu , Asada Yujiro
Published: October 2004

Objective—

Plaque disruption does not always result in complete thrombotic occlusion. The mechanism of arterial thrombus propagation remains unclear.

Methods and Results—

We studied how vascular wall thrombogenicity and blood flow reduction affect thrombus propagation using a rabbit model of single and repeated balloon injury. After balloon injury of the normal femoral artery, the blood flow was reduced to 50%, 25%, or 10% (n=5). Small mural thrombi composed of aggregated platelets were produced, but no occlusive thrombi developed in any flow reduction. Three weeks after the first balloon injury, neointima with tissue factor expression and increased procoagulant activity was developed. Balloon injury of the neointima with the same blood flow reduction (n=5) induced fibrin-rich thrombus formation. Additionally, injury with flow reduced to 25% and 10% promoted thrombus propagation resulting in vessel occlusion within 160±18 and 71±17 seconds, respectively. An injection of anti-von Willebrand factor (vWF) monoclonal antibody (AJW200; 1.0 mg/kg) prevented occlusive thrombus formation.

Conclusions—

Increased vascular wall thrombogenicity together with a substantial blood flow reduction is crucial for occlusive thrombus formation, and vWF plays an important role in thrombus propagation. Reduced blood flow at plaque disruption sites might contribute to thrombus propagation leading to acute coronary syndromes.
Transcription Factor Sterol Regulatory Element Binding Protein 2 Regulates Scavenger Receptor Cla-1 Gene Expression
Authors: Tréguier Morgan , Doucet Chantal , Moreau Martine , Dachet Christiane , Thillet Joëlle , Chapman M. John , Huby Thierry
Published: October 2004

Objective—The human scavenger receptor class B type I (Cla-1) plays a key role in cellular cholesterol movement in facilitating transport of cholesterol between cells and lipoproteins. Indirect evidence has suggested thatCla-1gene expression is under the feedback control of cellular cholesterol content. To define the molecular mechanisms underlying such putative regulation, we evaluated whetherCla-1is a target gene of the sterol regulatory element binding protein (SREBP) transcription factor family.

Methods and Results—Transient transfections demonstrated that SREBP factors induce Cla-1 promoter activity and that SREBP-2 is a more potent inducer than the SREBP-1a isoform. The 5′-deletion analysis of 3 kb of the 5′-flanking sequence of theCla-1gene, combined with site-directed mutagenesis and electrophoretic mobility shift assay, allowed identification of a unique sterol responsive element. SREBP-mediated Cla-1 regulation was confirmed in stably transfected human embryonic kidney 293 cells expressing the active form of SREBP-2 at incremental levels. In these cell lines, Cla-1 mRNA and protein levels were increased in direct proportion to the level of SREBP-2 expression.

Conclusions—These findings provide evidence that SREBP-2, a key regulator of cellular cholesterol uptake through modulation of the expression of the low-density lipoprotein receptor gene, may influence cellular cholesterol homeostasis via regulation ofCla-1gene expression.
Inhibitory Effect of High Concentration of Glucose on Relaxations to Activation of ATP-Sensitive K
+
Channels in Human Omental Artery
Authors: Kinoshita Hiroyuki , Azma Toshiharu , Nakahata Katsutoshi , Iranami Hiroshi , Kimoto Yoshiki , Dojo Mayuko , Yuge Osafumi , Hatano Yoshio
Published: October 2004

Objective—

The present study was designed to examine in the human omental artery whether high concentrations of D-glucose inhibit the activity of ATP-sensitive K
+
channels in the vascular smooth muscle and whether this inhibitory effect is mediated by the production of superoxide.

Methods and Results—

Human omental arteries without endothelium were suspended for isometric force recording. Changes in membrane potentials were recorded and production of superoxide was evaluated. Glibenclamide abolished vasorelaxation and hyperpolarization in response to levcromakalim. D-glucose (10 to 20 mmol/L) but not
l
-glucose (20 mmol/L) reduced these vasorelaxation and hyperpolarization. Tiron and diphenyleneiodonium, but not catalase, restored vasorelaxation and hyperpolarization in response to levcromakalim in arteries treated with D-glucose. Calphostin C and Gö6976 simultaneously recovered these vasorelaxation and hyperpolarization in arteries treated with D-glucose. Phorbol 12-myristate 13 acetate (PMA) inhibited the vasorelaxation and hyperpolarization, which are recovered by calphostin C as well as Gö6976. D-glucose and PMA, but not
l
-glucose, significantly increased superoxide production from the arteries, whereas such increased production was reversed by Tiron.

Conclusions—

These results suggest that in the human visceral artery, acute hyperglycemia modulates vasodilation mediated by ATP-sensitive K
+
channels via the production of superoxide possibly mediated by the activation of protein kinase C.
Stem Cell Transplantation Reveals That Absence of Macrophage CD36 Is Protective Against Atherosclerosis
Authors: Febbraio Maria , Guy Ella , Silverstein Roy L.
Published: October 2004

Objective—

CD36 is expressed on multiple cell types and has numerous functions, a subset of which can impact on atherogenesis. In previous work, we demonstrated that CD36 absence was protective against lesion formation. The current objective was to determine whether absence of macrophage CD36 alone was protective.

Methods and Results—

Lethal irradiation and stem cell transfer were used to create chimeric mice that did or did not express macrophage CD36 in the context of the Apo E-null model of atherosclerosis. After engraftment, mice were fed a Western diet for 12 weeks. White cell counts, plasma levels of lipoproteins, triacylglycerol, and nonesterified fatty acids were determined, and glucose tolerance tests were preformed. Lesion area was assessed quantitatively after oil red O staining. Mice lacking CD36 in macrophages alone were profoundly protected against atherosclerosis (88.1% reduction of lesion area throughout the aortic tree). Re-introduction of macrophage CD36 resulted in a 2.11-fold increase in lesion area. There were no differences in engraftment, macrophage recruitment, glucose tolerance, weight, and total, low-density lipoprotein, and high-density lipoprotein cholesterol among the groups. Lesions contained similar percent macrophage antigen-positive area.

Conclusion—

Protection in this model is primarily caused by loss of CD36 macrophage function.
A G/C Element Mediates Repression of the SM22α Promoter Within Phenotypically Modulated Smooth Muscle Cells in Experimental Atherosclerosis
Authors: Wamhoff B.R. , Hoofnagle M.H. , Burns A. , Sinha S. , McDonald O.G. , Owens G.K.
Published: October 2004

A hallmark of smooth muscle cell (SMC) phenotypic switching in atherosclerotic lesions is suppression of SMC differentiation marker gene expression. Yet little is known regarding the molecular mechanisms that control this process. Here we show that transcription of the SMC differentiation marker gene SM22α is reduced in atherosclerotic lesions and identify a
cis
regulatory element in the SM22α promoter required for this process. Transgenic mice carrying the SM22α promoter–β-galactosidase (β-gal) reporter transgene were crossed to apolipoprotein E (ApoE)
−/−
mice. Cells of the fibrous cap, intima, and underlying media showed complete loss of β-gal activity in advanced atherosclerotic lesions. Of major significance, mutation of a G/C-rich
cis
element in the SM22α promoter prevented the decrease in SM22α promoter–β-gal reporter transgene expression, including in cells that compose the fibrous cap of the lesion and in medial cells in proximity to the lesion. To begin to assess mechanisms whereby the G/C repressor element mediates suppression of SM22α in atherosclerosis, we tested the hypothesis that effects may be mediated by platelet-derived growth factor (PDGF)-BB–induced increases in the G/C binding transcription factor Sp1. Consistent with this hypothesis, results of studies in cultured SMCs showed that: (1) PDGF-BB increased expression of Sp1; (2) PDGF-BB and Sp1 profoundly suppressed SM22α promoter activity as well as smooth muscle myosin heavy chain promoter activity through mechanisms that were at least partially dependent on the G/C
cis
element; and (3) a short interfering RNA to Sp1 increased basal expression and attenuated PDGF-BB induced suppression of SM22α. Together, these results support a model whereby a G/C repressor element within the SM22α promoter mediates transcriptional repression of this gene within phenotypically modulated SMCs in experimental atherosclerosis and provide indirect evidence implicating PDGF-BB and Sp1 as possible mediators of these effects.
Transactivation of Epidermal Growth Factor Receptor Mediates Catecholamine-Induced Growth of Vascular Smooth Muscle
Authors: Zhang Hua , Chalothorn Dan , Jackson Leslie F. , Lee David C. , Faber James E.
Published: October 2004

Stimulation of α
1
-adrenoceptors induces proliferation of vascular smooth muscle cells (SMCs) and contributes to arterial remodeling. Although activation of NAD(P)H oxidase and generation of reactive oxygen species (ROS) are required, little is known about this pathway. In this study, we examined the hypothesis that epidermal growth factor receptor (EGFR) transactivation and extracellular regulated kinases (ERK) are involved in α
1
-adrenoceptor–mediated SMC growth. Phenylephrine increased protein synthesis in association with a rapid (≤5 minutes) and sustained (≥60 minutes) doubling of phosphorylation of EGFR and ERK1/2, but not p38 or JNK in the media of rat aorta maintained in organ culture. Antagonists of EGFR phosphotyrosine activity (AG-1478) and ERK phosphorylation (PD-98059, U-0126) abolished phenylephrine-induced protein synthesis, whereas antagonists of p38 or JNK phosphorylation had no specific effect. A competitive antagonist (P22) for heparin binding EGF-like growth factor (HB-EGF) blocked phenylephrine-induced protein synthesis, as did downregulation of pro-HB-EGF (CRM197). Phenylephrine-induced protein synthesis was inhibited by neutralizing antibody to HB-EGF and absent in HB-EGF
−/−
SMCs. Inhibitors of metalloproteinases (BiPS, KB-R7785) also blocked adrenergic growth. The neutralizing antibody against HB-EGF had no effect on the two-fold increase in ROS generation induced by phenylephrine (DCF fluorescence), suggesting that stimulation of NAD(P)H oxidase by α
1
-adrenoceptor occupation precedes HB-EGF release. Cell culture studies confirmed and extended these findings. These data suggest that α
1
-adrenoceptor–mediated SMC growth requires ROS-dependent shedding of HB-EGF, transactivation of EGFR, and activation of the MEK1/2-dependent MAP kinase pathway. This trophic pathway may link sympathetic activity to arterial wall growth in adaptive remodeling and hypertrophic disease.
Brain–Machine and Brain–Computer Interfaces
Authors: Friehs Gerhard M. , Zerris Vasilios A. , Ojakangas Catherine L. , Fellows Mathew R. , Donoghue John P.
Published: October 2004

The idea of connecting the human brain to a computer or machine directly is not novel and its potential has been explored in science fiction. With the rapid advances in the areas of information technology, miniaturization and neurosciences there has been a surge of interest in turning fiction into reality. In this paper the authors review the current state-of-the-art of brain–computer and brain–machine interfaces including neuroprostheses. The general principles and requirements to produce a successful connection between human and artificial intelligence are outlined and the authors’ preliminary experience with a prototype brain–computer interface is reported.
Molecular Identification of the Ischemic Penumbra
Authors: Weinstein Philip R. , Hong Shwuhuey , Sharp Frank R.
Published: October 2004

Review of results of experimental and clinical studies indicates that the penumbra of physiologically impaired but potentially salvageable tissue surrounding the central core of focal cerebral ischemia that develops shortly after onset of major conducting vessel occlusion is complex and dynamic with severity and duration thresholds for hypoxic stress and injury that are specific to tissue site, cell type, molecular pathway or gene expression investigated and efficiency of collateral or residual flow and reperfusion. Imaging methods that have been utilized in vivo to identify penumbra and predict response to reperfusion and other protective therapies include magnetic resonance spectroscopy, diffusion- and perfusion-MRI as well as positron emission tomography. However, resolution of focal lesions characterized by lactic acidosis or cellular edema does not predict tissue survival, and imaging thresholds for resuscitation after reperfusion have not been determined experimentally. HSP-70 stress protein induction represents an endogenous protective mechanism that occurs in penumbra but not core neurones. A robust protective effect has been demonstrated during focal ischemia in transgenic mice overexpressing HSP-70 perhaps by suppressing early cytochrome
c
release. Delayed manganese mediated striatal neurodegeneration can be detected with T1 MRI after brief episodes of transient focal ischemia. Future studies may define endogenous cytotoxic and cytoprotective molecular penumbras that can be exploited to improve outcome after temporary focal ischemia.
ASPECTS on CTA Source Images Versus Unenhanced CT
Authors: Coutts Shelagh B. , Lev Michael H. , Eliasziw Michael , Roccatagliata Luca , Hill Michael D. , Schwamm Lee H. , Pexman J.H. Warwick , Koroshetz Walter J. , Hudon Mark E. , Buchan Alastair M. , Gonzalez R. Gilberto , Demchuk Andrew M.
Published: October 2004

Background and Purpose—

The Alberta Stroke Program Early CT Score (ASPECTS) is a grading system to assess ischemic changes on CT in acute ischemic stroke. CT angiography–source images (CTA-SI) predict final infarct volume. We examined whether the final infarct ASPECTS and clinical outcome were more related to acute CTA-SI ASPECTS than to the acute noncontrast CT (NCCT) ASPECTS.

Methods—

ASPECTS was assigned by 2 raters on the acute NCCT, CTA-SI, and follow-up imaging. The mean baseline ASPECTS of acute NCCT and CTA-SI was compared with the follow-up ASPECTS. Rate ratios (RRs) were used to quantify the relationship between the dichotomized baseline ASPECTS (categorized as 0 to 7 versus 8 to 10) and favorable patient outcome.

Results—

Thirty-nine patients were recruited. Proximal occlusion (internal carotid artery or middle cerebral artery) was seen in 62%, M2 occlusion in 18%, and no occlusion was seen in 20% of patients. The median time between symptom onset and imaging was 1.9 (1.2 to 2.5) hours. There was a significantly larger difference of 1.4 between the mean baseline NCCT and CTA-SI ASPECTS in patients who had more ischemic changes (follow-up ASPECTS=0 to 3) than a difference of 0.6 in patients who had near-to-normal CT scans (follow-up ASPECTS=8 to 10). The rate of favorable outcome for acute NCCT ASPECTS of 8 to 10 was 51.8% versus 25.0% for 0 to 7 (RR, 2.1, 95% CI: 0.7 to 5.9,
P
=0.12). For acute CTA-SI ASPECTS of 8 to 10, the rate of favorable outcome was 58.8% versus 31.8% for 0 to 7 (RR, 1.8, 95% CI: 0.9 to 3.8,
P
=0.09).

Conclusions—

CTA-SI ASPECTS provides added information in the prediction of final infarct size.
Die Symbolik chthonischer Götter in Sophokles' Ödipus auf Kolonos
Authors: Tilg Stefan
Published: October 2004

The significant import of chthonic elements, especially chthonic deities, in Sophocles' Oedipus Coloneus has been widely noticed and variously discussed. The focus of this discussion traced, however, historical cult and religion without regard to a possible literary aspect. This paper tries to show how Sophocles throughout the play intentionally associates his protagonist with the sphere of the chthonic and dark as a means of creating a symbolic language and as a device of personal characterization.
Hera in Sappho, fr. 17 L-P, V—and Aeneid I?
Authors: Lidov Joel
Published: October 2004

In current commentaries and translations, the first stanza of Sappho fr. 17 is read as a prayer for Hera's presence. This understanding was created by modifying Wilamowitz's interpretation of the fragment as a dream narrative, but it depends on an improbable use of the opening word πλασιον involves an awkward third-person periphrasis for the second-person appeal, and creates insoluble difficulties of supplementation and usage in the third line. It is more fruitful to read the stanza as a deprecation of the god's anger, as in fr. 1.1-4; a suggested reading of χαλεπην ϑυελλαν (cf.Il. 21.335) gives αραταν a meaning within its normal, somewhat pejorative connotation, and allows a more plausible reconstruction of the end of line 3; attributing the source of the Atridae's distress to Hera is consistent with a number of indications of a narrative pattern in which Hera sends disruptive storms.
An Evolutionary Social Science? A Skeptic’s Brief, Theoretical and Substantive
Authors: Bryant Joseph M.
Published: October 2004

So-called grand or paradigmatic theories—structural functionalism, psychoanalysis, Marxism, rational-choice theory—provide their proponents with a conceptual vocabulary and syntax that allows for the classification and configuring of wide ranges of phenomena. Advocates for any particular “analytical grammar” are accordingly prone to conflating the internal coherence of their paradigm—its integrated complex of definitions, axioms, and inferences—with a corresponding capacity for representational verisimilitude. The distinction between Theory-as-heuristic and Theory-as-imposition is of course difficult to negotiate in practice, given that empirical observation and measurement are not entirely “theory neutral” or independent of prior analytical conceptualization. Nonetheless, the scientific cogency of any theory is ultimately evaluated by the substantive realism of its foundational assumptions and categorical designations; that is, the accuracy with which it identifies and tracks the determinant properties and processes of the phenomena to be explicated. The paradigm of sociocultural evolutionism—despite extensive revamping by contemporary proponents—does not carry warrant in this regard, as its recourse to an analytical grammar fashioned and derived from another discipline raises doubts about its empirical veridicality. This article revisits the contentious issue of remodeling social phenomena in accordance with biological categories and offers both a theoretical and a substantive critique of the “selectionist” paradigm. The transdisciplinary program of historical social science is affirmed by way of counterpoint.
A Place for Aesthetics
Authors: Schlenker Emily Catherine
Published: October 2004

This article explores the relationship between aesthetics and the activities of daily life for nurses and for other human beings. The author relates a personal experience and describes some definitions and history surrounding our need for beauty.
Activation of the PI3K/mTOR pathway by BCR-ABL contributes to increased production of reactive oxygen species
Authors: Kim Jeong H. , Chu Stephanie C. , Gramlich Jessica L. , Pride Yuri B. , Babendreier Emily , Chauhan Dharminder , Salgia Ravi , Podar Klaus , Griffin James D. , Sattler Martin
Published: October 2004

BCR-ABL oncoprotein-expressing cells are associated with a relative increase of intracellular reactive oxygen species (ROS), which is thought to play a role in transformation. Elevated ROS levels in BCR-ABL-transformed cells were found to be blocked by the mitochondrial complex I inhibitor rotenone as well as the glucose transport inhibitor phloretin, suggesting that the source of increased ROS might be related to increased glucose metabolism. The glucose analog 2-deoxyglucose (2-DOG) reduced ROS to levels found in non-BCR-ABL-transformed cells and inhibited cell growth alone or in cooperation with imatinib mesylate (Gleevec). A mutant of BCR-ABL that is defective in transformation of myeloid cells, Tyr177Phe, was also found to be defective in raising intracellular ROS levels. Glucose metabolism in BCR-ABL-transformed cells is likely to be mediated by activation of the phosphatidylinositol-3′-kinase (PI3K) pathway, which is regulated through this site. Inhibition of PI3K or mTOR led to a significant decrease in ROS levels. Overall, our results suggest that elevated levels of ROS in BCR-ABL-transformed cells are secondary to a transformation-associated increase in glucose metabolism and an overactive mitochondrial electron transport chain and is specifically regulated by PI3K. Finally, these results hint at novel targets for drug development that may aid traditional therapy. (Blood. 2005; 105:1717-1723)
Activated protein C induces the release of microparticle-associated endothelial protein C receptor
Authors: Pérez-Casal Margarita , Downey Colin , Fukudome Kenji , Marx Gernot , Toh Cheng Hock
Published: October 2004

Activated protein C (APC) treatment is now used for patients with severe sepsis. We investigated its effect in vitro on primary, physiologically relevant cells and demonstrate a novel mechanism of endothelial protein C receptor (EPCR) release that is not inhibited by metalloproteinase inhibitors. Exposure of human umbilical vein endothelial cells or monocytes to APC (6.25-100 nM) results in the release of EPCR-containing microparticles, as demonstrated by confocal microscopy and characterized through flow cytometry, enzyme-linked immunosorbent assay quantitation of isolated microparticles, and Western blotting. The phenomenon is time- and concentration-dependent and requires the APC active site, EPCR, and protease activated receptor 1 (PAR1) on endothelial cells. Neither protein C nor boiled or d-Phe-Pro-Arg-chloromethylketone–blocked APC can induce microparticle formation and antibody blockade of EPCR or PAR1 cleavage and activation abrogates this APC action. Coincubation with hirudin does not alter the APC effect. The released microparticle bound is full-length EPCR (49 kDa) and APC retains factor V–inactivating activity. Although tumor necrosis factor-α (10 ng/mL) can also induce microparticle-associated EPCR release to a similar extent as APC (100 nM), it is only APC-induced microparticles that contain bound APC. This novel observation could provide new insights into the consequences of APC therapy in the septic patient.
Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias
Authors: Faderl Stefan , Gandhi Varsha , O'Brien Susan , Bonate Peter , Cortes Jorge , Estey Elihu , Beran Miloslav , Wierda William , Garcia-Manero Guillermo , Ferrajoli Alessandra , Estrov Zeev , Giles Francis J. , Du Min , Kwari Monica , Keating Michael , Plunkett William , Kantarjian Hagop
Published: October 2004

Clofarabine (2-chloro-2′-fluoro-deoxy-9-β-D-arabinofuranosyladenine) is a second-generation nucleoside analog with activity in acute leukemias. As clofarabine is a potent inhibitor of ribonucleotide reductase (RnR), we hypothesized that clofarabine will modulate ara-c triphosphate accumulation and increase the antileukemic activity of cytarabine (ara-C). We conducted a phase 1-2 study of clofarabine plus ara-C in 32 patients with relapsed acute leukemia (25 acute myeloid leukemia [AML], 2 acute lymphoblastic leukemia [ALL]), 4 high-risk myelodysplastic syndrome (MDS), and 1 blast-phase chronic myeloid leukemia (CML).1 Clofarabine was given as a 1-hour intravenous infusion for 5 days (days 2 through 6) followed 4 hours later by ara-C at 1 g/m2 per day as a 2-hour intravenous infusion for 5 days (days 1 through 5). The phase 2 dose of clofarabine was 40 mg/m2 per day for 5 days. Among all patients, 7 (22%) achieved complete remission (CR), and 5 (16%) achieved CR with incomplete platelet recovery (CRp), for an overall response rate of 38%. No responses occurred in 3 patients with ALL and CML. One patient (3%) died during induction. Adverse events were mainly less than or equal to grade 2, including transient liver test abnormalities, nausea/vomiting, diarrhea, skin rashes, mucositis, and palmoplantar erythrodysesthesias. Plasma clofarabine levels generated clofarabine triphosphate accumulation, which resulted in an increase in ara-CTP in the leukemic blasts. The combination of clofarabine with ara-C is safe and active. Cellular pharmacology data support the biochemical modulation strategy.
Anti–human CTLA-4 monoclonal antibody promotes T-cell expansion and immunity in a hu-PBL-SCID model: a new method for preclinical screening of costimulatory monoclonal antibodies
Authors: May Kenneth F. , Roychowdhury Sameek , Bhatt Darshna , Kocak Ergun , Bai Xue-Feng , Liu Jin-Qing , Ferketich Amy K. , Martin Edward W. , Caligiuri Michael A. , Zheng Pan , Liu Yang
Published: October 2004

When adopting basic principles learned in mice to clinical application in humans, it is often difficult to distinguish whether a “translation” fails because of an invalid target in the human disease or because the therapeutic agents are not optimal for the human target. It is, therefore, desirable to develop preclinical models to optimize therapies for human targets using in vivo settings. Although anti–mouse CTLA-4 antibodies are known to enhance immune responses in vivo, their effect on T-cell activation in vitro ranges from enhancement to inhibition. Here we use the hu-PBL-SCID mouse model of Epstein-Barr virus (EBV)–associated lymphoma development to screen a panel of anti–human CTLA-4 monoclonal antibodies (mAbs) for their effect on human lymphocytes in an in vivo “humanized” environment. We report significant heterogeneity of anti–human CTLA-4 mAbs in enhancing the expansion of human T cells in mice, and this heterogeneity cannot be attributed to immunoglobulin isotypes or affinity for CTLA-4. These data validate the development of additional screening tools, such as the one described, to further characterize functional activity of antihuman antibodies before proceeding with clinical translation to human studies.