bluuebunny/crossref_metadata_2025 huggingface dataset:
Activation of the systemic and adipose renin-angiotensin system in rats with diet-induced obesity and hypertension
Authors: Boustany Carine M. , Bharadwaj Kalyani , Daugherty Alan , Brown David R. , Randall David C. , Cassis Lisa A.
Published: June 2004

In obesity-related hypertension, activation of the renin-angiotensin system (RAS) has been reported despite marked fluid volume expansion. Adipose tissue expresses components of the RAS and is markedly expanded in obesity. This study evaluated changes in components of the adipose and systemic RAS in diet-induced obese hypertensive rats. RAS was quantified in adipose tissue and compared with primary sources for the circulating RAS. Male Sprague-Dawley rats were fed either a low-fat (LF; 11% kcal as fat) or moderately high-fat (32% kcal as fat) diet for 11 wk. After 8 wk, rats fed the moderately high-fat diet segregated into obesity-prone (OP) and obesity-resistant (OR) groups based on their body weight gain (body weight: OR, 566 ± 10; OP, 702 ± 20 g; P < 0.05). Mean arterial blood pressure was increased in OP rats (LF: 97 ± 2; OR: 97 ± 2; OP: 105 ± 1 mmHg; P < 0.05). Quantification of mRNA expression by real-time PCR demonstrated a selective increase (2-fold) in angiotensinogen gene expression in retroperitoneal adipose tissue from OP vs. OR and LF rats. Similarly, plasma angiotensinogen concentration was increased in OP rats (LF: 390 ± 48; OR: 355 ± 24; OP: 530 ± 22 ng/ml; P < 0.05). In contrast, other components of the RAS were not altered in OP rats. Marked increases in the plasma concentrations of angiotensin peptides were observed in OP rats (angiotensin II: LF: 95 ± 31; OR: 59 ± 20; OP: 295 ± 118 pg/ml; P < 0.05). These results demonstrate increased activity of the adipose and systemic RAS in obesity-related hypertension.
Differential regulation of VEGF by TGF-β and hypoxia in rat proximal tubular cells
Authors: Nakagawa Takahiko , Lan Hui Y. , Zhu Hong J. , Kang Duk-Hee , Schreiner George F. , Johnson Richard J.
Published: June 2004

VEGF expression by proximal tubular epithelial cells may play a critical role in maintaining peritubular capillary endothelium in renal disease. Two major processes involved in renal injury include hypoxia (from vasoconstriction or vascular injury) and transforming growth factor (TGF)-β-dependent fibrosis, both of which are known to stimulate VEGF. Because the TGF-β/Smad pathway is activated in hypoxia, we tested the hypothesis that the induction of VEGF in hypoxia could be partially dependent on TGF-β. Rat proximal tubular (NRK52E) cells treated with TGF-β under normoxic conditions secreted VEGF at 24 h, and this was significantly reduced by blocking Smad activation by overexpressing the inhibitory Smad7 or by blocking p38 and ERK1/2 MAP kinase activation or protein kinase C activation with specific inhibitors. With acute hypoxia, rat proximal tubular cells also express VEGF mRNA and protein as well as TGF-β. However, the induction of VEGF occurs before synthesis of TGF-β and is not blocked by either a TGF-β antagonist, by Smad7 overexpression, or by blockage of ERK1/2, whereas induction is blocked by PKC inhibition or partially blocked by a p38 inhibitor. Finally, the addition of TGF-β with hypoxia results in significantly more VEGF expression than either stimulation alone. Thus TGF-β and hypoxia act via additive/synergistic but distinct pathways to stimulate VEGF in proximal tubular cells, a finding that may be important in understanding how VEGF is stimulated in renal disease.
Active hexose correlated compound enhances the immune function of mice in the hindlimb-unloading model of spaceflight conditions
Authors: Aviles Hernan , Belay Tesfaye , Vance Monique , Sun Buxiang , Sonnenfeld Gerald
Published: June 2004

Hindlimb unloading is a ground-based model that simulates some of the aspects of spaceflight conditions, including lack of load bearing on hindlimbs and a fluid shift to the head. It has been shown that treatment with active hexose correlated compound (AHCC) restores resistance to infection in mice maintained under hindlimb-unloading conditions. The present study was designed to clarify the mechanisms by which AHCC enhances resistance to infection in this model. We hypothesized that oral administration of AHCC will enhance the function of the immune system, which could lead to the increased resistance to infection observed in this model. AHCC or the excipient was orally administered to mice, and the function of the immune system was assessed in spleen and peritoneal cells isolated from those groups. The results of the present study showed that administration of AHCC for 1 wk before and throughout the second day of the hindlimb-unloading period enhanced the function of the immune system assessed by spleen cell proliferation and cytokine production in spleens and nitric oxide and cytokine production in peritoneal cells. These findings suggest that AHCC can be used as a potent immunoenhancer, especially in cases in which the immune system is suppressed by any condition, including diseases such as human immunodeficiency virus infection and cancer.
Fructose feeding and intermittent hypoxia affect ventilatory responsiveness to hypoxia and hypercapnia in rats
Authors: Schlenker Evelyn H. , Shi Yijiang , Wipf Joni , Martin Douglas S. , Kost Curtis K.
Published: June 2004

We hypothesized that, in male rats, 10% fructose in drinking water would depress ventilatory responsiveness to acute hypoxia (10% O2 in N2) and hypercapnia (5% CO2 in O2) that would be depressed further by exposure to intermittent hypoxia. Minute ventilation (V̇e) in air and in response to acute hypoxia and hypercapnia was evaluated in 10 rats before fructose feeding (FF), during 6 wk of FF, and after FF was removed for 2 wk. During FF, five rats were exposed to intermittent air and five to intermittent hypoxia for 13 days. Six rats given tap water acted as control and were exposed to intermittent air and subsequently intermittent hypoxia. In FF rats, plasma insulin levels increased threefold in the rats exposed to intermittent hypoxia and during washout returned to levels observed in rats exposed to intermittent air. During FF, ventilatory responsiveness to acute hypoxia was depressed because of decreased tidal volume (Vt) responsiveness. During washout, V̇e decreased as a result of decreased Vt and frequency of breathing, and the ventilatory responsiveness to hypoxia in intermittent hypoxia rats did not recover. In all rats, the ventilatory responses to hypercapnia were decreased during FF and recovered after washout because of an increased Vt responsiveness. In the control group, hypoxic responsiveness was not depressed after intermittent hypoxia and was augmented after washout. Thus FF attenuated the ventilatory responsiveness of conscious rats to hypoxia and hypercapnia. Intermittent hypoxia interacted with FF to increase insulin levels and depress ventilatory responses to acute hypoxia that remained depressed during washout.
Leg glucose and protein metabolism during an acute bout of resistance exercise in humans
Authors: Durham William J. , Miller Sharon L. , Yeckel Catherine W. , Chinkes David L. , Tipton Kevin D. , Rasmussen Blake B. , Wolfe Robert R.
Published: June 2004

The present study investigated the responses of leg glucose and protein metabolism during an acute bout of resistance exercise. Seven subjects (5 men, 2 women) were studied at rest and during a strenuous lower body resistance exercise regimen consisting of ∼8 sets of 10 repetitions of leg press at ∼75% 1 repetition maximum and 8 sets of 8 repetitions of knee extensions at ∼80% 1 repetition maximum. l-[ ring-2H5]phenylalanine was infused throughout the study for measurement of phenylalanine rates of appearance, disappearance, protein synthesis, and protein breakdown across the leg. Femoral arterial and venous blood samples were collected at rest and during exercise for determination of leg blood flow, concentrations of glucose, lactate, alanine, glutamine, glutamate, leucine, and phenylalanine, and phenylalanine enrichments. Muscle biopsies were obtained at rest and immediately after exercise. Leg blood flow was nearly three times ( P < 0.009) higher and glucose uptake more than five times higher ( P = 0.009) during exercise than at rest. Leg lactate release was 86 times higher than rest during the exercise bout. Although whole body phenylalanine rate of appearance, an indicator of whole body protein breakdown, was reduced during exercise; leg phenylalanine rate of appearance, rate of disappearance, protein synthesis, and protein breakdown did not change. Arterial and venous alanine concentrations and glutamate uptake were significantly higher during exercise than at rest. We conclude that lower body resistance exercise potently stimulates leg glucose uptake and lactate release. In addition, muscle protein synthesis is not elevated during a bout of resistance exercise.
Labeled carbon dioxide (C18O2): an indicator gas for phase II in expirograms
Authors: Schulz Holger , Schulz Anne , Eder Gunter , Heyder Joachim
Published: June 2004

Carbon dioxide labeled with 18O (C18O2) was used as a tracer gas for single-breath measurements in six anesthetized, mechanically ventilated beagle dogs. C18O2 is taken up quasi-instantaneously in the gas-exchanging region of the lungs but much less so in the conducting airways. Its use allows a clear separation of phase II in an expirogram even from diseased individuals and excludes the influence of alveolar concentration differences. Phase II of a C18O2 expirogram mathematically corresponds to the cumulative distribution of bronchial pathways to be traversed completely in the course of exhalation. The derivative of this cumulative distribution with respect to respired volume was submitted to a power moment analysis to characterize volumetric mean (position), standard deviation (broadness), and skewness (asymmetry) of phase II. Position is an estimate of dead space volume, whereas broadness and skewness are measures of the range and asymmetry of functional airway pathway lengths. The effects of changing ventilatory patterns and of changes in airway size (via carbachol-induced bronchoconstriction) were studied. Increasing inspiratory or expiratory flow rates or tidal volume had only minor influence on position and shape of phase II. With the introduction of a postinspiratory breath hold, phase II was continually shifted toward the airway opening (maximum 45% at 16 s) and became steeper by up to 16%, whereas skewness showed a biphasic response with a moderate decrease at short breath holding and a significant increase at longer breath holds. Stepwise bronchoconstriction decreased position up to 45 ± 2% and broadness of phase II up to 43 ± 4%, whereas skewness was increased up to twofold at high-carbachol concentrations. Under all circumstances, position of phase II by power moment analysis and dead space volume by the Fowler technique agreed closely in our healthy dogs. Overall, power moment analysis provides a more comprehensive view on phase II of single-breath expirograms than conventional dead space volume determinations and may be useful for respiratory physiology studies as well as for the study of diseased lungs.
Prism Adaptation During Walking Generalizes to Reaching and Requires the Cerebellum
Authors: Morton Susanne M. , Bastian Amy J.
Published: June 2004

Adaptation of arm movements to laterally displacing prism glasses is usually highly specific to body part and movement type and is known to require the cerebellum. Here, we show that prism adaptation of walking trajectory generalizes to reaching (a different behavior involving a different body part) and that this adaptation requires the cerebellum. In experiment 1, healthy control subjects adapted to prisms during either reaching or walking and were tested for generalization to the other movement type. We recorded lateral deviations in finger endpoint position and walking direction to measure negative aftereffects and generalization. Results showed that generalization of prism adaptation is asymmetric: walking generalizes extensively to reaching, but reaching does not generalize to walking. In experiment 2, we compared the performance of cerebellar subjects versus healthy controls during the prism walking adaptation. We measured rates of adaptation, aftereffects, and generalization. Cerebellar subjects had reduced adaptation magnitudes, slowed adaptation rates, decreased negative aftereffects, and poor generalization. Based on these experiments, we propose that prism adaptation during whole body movements through space invokes a more general system for visuomotor remapping, involving recalibration of higher-order, effector-independent brain regions. In contrast, prism adaptation during isolated movements of the limbs is probably recalibrated by effector-specific mechanisms. The cerebellum is an essential component in the network for both types of prism adaptation.
Adrenergic Signaling Plays a Critical Role in the Maintenance of Waking and in the Regulation of REM Sleep
Authors: Ouyang Ming , Hellman Kevin , Abel Ted , Thomas Steven A.
Published: June 2004

Many experiments have suggested that the adrenergic system is important for arousal and the regulation of sleep/wake states. Electrophysiological studies have found strong correlations between the firing of adrenergic neurons and arousal state. Lesions of adrenergic neurons have been reported to cause changes in sleep/wake regulation, although findings have been variable and sometimes transient. To more specifically address the role of adrenergic signaling in sleep/wake regulation, we performed electroencephalographic and electromyographic recordings in mice with a targeted disruption of the gene for dopamine β-hydroxylase, the enzyme that converts dopamine to norepinephrine. These mice are unable to synthesize the endogenous adrenergic ligands norepinephrine and epinephrine. The mutant mice sleep ∼2 h more each day. The decrease in waking is due to a considerable decrease in the duration of waking bouts in spite of an increase in the number of waking bouts and transitions from sleep to waking. In contrast, the amount of rapid-eye-movement (REM) sleep is only half that in control mice due to a decrease in the number and duration of REM sleep bouts. Delta power is selectively increased in the mutant mice, and there is much less variation in non-REM sleep delta power over 24 h. After 6 h of total sleep deprivation during the first half of the light period, there is no rebound recovery of sleep time in the mutant mice. These results provide genetic evidence that adrenergic signaling acts to maintain waking and is important for the regulation of REM sleep and possibly sleep homeostasis.
The Spinal GABAergic System Is a Strong Modulator of Burst Frequency in the Lamprey Locomotor Network
Authors: Schmitt David E. , Hill Russell H. , Grillner Sten
Published: June 2004

The spinal network coordinating locomotion is comprised of a core of glutamate and glycine interneurons. This network is modulated by several transmitter systems including spinal GABA interneurons. The purpose of this study is to explore the contribution of GABAergic neurons to the regulation of locomotor burst frequency in the lamprey model. Using gabazine, a competitive GABAAantagonist more specific than bicuculline, the goal was to provide a detailed analysis of the influence of an endogenous activation of GABAAreceptors on fictive locomotion, as well as their possible interaction with GABABand involvement of GABACreceptors. During N-methyl-d-aspartate (NMDA)-induced fictive locomotion (ventral root recordings in the isolated spinal cord), gabazine (0.1–100 μM) significantly increased the burst rate up to twofold, without changes in regularity or “burst quality.” Gabazine had a proportionately greater effect at higher initial burst rates. Picrotoxin (1–7.5 μM), a less selective GABAAantagonist, also produced a pronounced increase in frequency, but at higher concentrations, the rhythm deteriorated, likely due to the unspecific effects on glycine receptors. The selective GABABantagonist CGP55845 also increased the frequency, and this effect was markedly enhanced when combined with the GABAAantagonist gabazine. The GABACantagonist (1,2,5,6-tetrahydropyridine-4-yl)methylphosphinic acid (TPMPA) had no effect on locomotor bursting. Thus the spinal GABA system does play a prominent role in burst frequency regulation in that it reduces the burst frequency by ≤50%, presumably due to presynaptic and soma-dendritic effects documented previously. It is not required for burst generation, but acts as a powerful modulator.
Hyperthermia Modulates Respiratory Pacemaker Bursting Properties
Authors: Tryba Andrew K. , Ramirez Jan-Marino
Published: June 2004

Most mammals modulate respiratory frequency (RF) to dissipate heat (e.g., panting) and avoid heat stroke during hyperthermic conditions. Respiratory neural network activity recorded in an isolated brain stem-slice preparation of mice exhibits a similar RF modulation in response to hyperthermia; fictive eupneic frequency increases while inspiratory network activity amplitude and duration are significantly reduced. Here, we study the effects of hyperthermia on the activity of synaptically isolated respiratory pacemakers to examine the possibility that these changes may account for the hyperthermic RF modulation of the respiratory network. During heating, modulation of the bursting frequency of synaptically isolated pacemakers paralleled that of population bursting recorded from the intact network, whereas nonpacemaker neurons were unaffected, suggesting that pacemaker bursting may account for the temperature-enhanced RF observed at the network level. Some respiratory neurons that were tonically active at hypothermic conditions exhibited pacemaker properties at approximately the normal body temperature of eutherian mammals (36.81 ± 1.17°C; mean ± SD) and continued to burst at 40°C. At elevated temperatures (40°C), there was an enhancement of the depolarizing drive potential in synaptically isolated pacemakers, while the amplitude of integrated population activity declined. Isolated pacemaker bursting ceased at 41–42°C ( n = 5), which corresponds to temperatures at which hyperthermic-apnea typically occurs in vivo. We conclude that pacemaker properties may play an important role in the hyperthermic frequency modulation and apnea, while network effects may play important roles in generating other aspects of the hyperthermic response, such as the decreased amplitude of ventral respiratory group activity during hyperthermia.
Slow Afterhyperpolarization Governs the Development of NMDA Receptor–Dependent Afterdepolarization in CA1 Pyramidal Neurons During Synaptic Stimulation
Authors: Wu Wendy W. , Chan C. Savio , Disterhoft John F.
Published: June 2004

CA1 pyramidal neurons from animals that have acquired a hippocampus-dependent task show a reduced slow postburst afterhyperpolarization (sAHP). To understand the functional significance of this change, we examined and characterized the sAHP activated by different patterns of synaptic stimuli and its impact on postsynaptic signal integration. Whole cell current-clamp recordings were performed on rat CA1 pyramidal neurons, and trains of stratum radiatum stimuli varying in duration, frequency, and intensity were used to activate the AHP. At −68 mV, a short train of subthreshold stimuli (20–150 Hz) generated only the medium AHP. In contrast, just two suprathreshold stimuli >50 Hz triggered a prominent sAHP sensitive to bath-applications of isoproterenol, carbachol, or intracellularly applied BAPTA, suggesting that the underlying current is the Ca2+-activated K+ current, the s IAHP. The sAHP magnitude was positively related to stimulus train duration and frequency, consistent with its dependence on intracellular Ca2+ accumulation for activation. About 20% of neurons recorded did not have a sAHP. In response to high-frequency suprathreshold stimuli, these neurons developed a pronounced afterdepolarization (ADP) and multiple action potential firing. The ADP magnitude increased with successive stimuli and was positively related to stimulus intensity and frequency. It was sensitive to bath-applications of thapsigargin and nitrendipine, and abolished by d-AP5, indicating that it is supported by intracellular Ca2+ release, the L-type Ca2+ influx, and N-methyl-d-aspartate (NMDA) receptor–mediated influx. In the presence of d-AP5, we were unable to trigger an ADP with maximal stimulus intensity. Pharmacologically eliminating the sAHP allowed neurons to develop an ADP with the original stimulus train. We propose that the slow AHP acts to facilitate Mg2+ re-block of the activated NMDA receptors, thereby reducing temporal summation and preventing an NMDA receptor–dependent ADP during intense synaptic events. Neuromodulation of the sAHP may thus affect information throughput and regulate NMDA receptor–mediated plasticity.
Proteolysis of the Pericellular Matrix
Authors: Lindstedt Ken A. , Leskinen Markus J. , Kovanen Petri T.
Published: June 2004

The 2 major general concepts about the cell biology of atherogenesis, growth of smooth muscle cells, and lipid accumulation in macrophages, ie, foam cell formation, have not been able to satisfactorily explain the genesis of acute coronary syndromes. Rather, the basic pathology behind the acute atherothrombotic events relates to erosion and rupture of unstable coronary plaques. At the cellular level, we now understand that a switch from cellular growth to cellular death, notably apoptosis, could be involved in turning at least some types of atherosclerotic plaques unstable. Because intimal cells require a proper matrix environment for normal function and survival, the vulnerability of an atherosclerotic plaque may critically depend on the integrity of the pericellular matrix of the plaque cells. In vitro studies have revealed that plaque-infiltrating inflammatory cells, such as macrophages, T-lymphocytes, and mast cells, by secreting a variety of proteases capable of degrading pericellular matrix components, induce death of endothelial cells and smooth muscle cells, and so provide a mechanistic explanation for inflammation-dependent plaque erosion and rupture. Thus, a novel link between inflammation and acute coronary syndromes is emerging. For a more explicit understanding of the role of proteases released by inflammatory cells in the conversion of a clinically silent plaque into a dangerous and potentially killing plaque, animal models of plaque erosion and rupture need to be established.
HDL Cholesterol and Protective Factors in Atherosclerosis
Authors: Assmann Gerd , Gotto Antonio M.
Published: June 2004

A low level of high-density lipoprotein cholesterol (HDL-C) is an important risk factor for cardiovascular disease. Epidemiological and clinical studies provide evidence that HDL-C levels are linked to rates of coronary events. The cardioprotective effects of HDL-C have been attributed to its role in reverse cholesterol transport, its effects on endothelial cells, and its antioxidant activity. Although some clinical trials suggest a benefit of raising HDL-C to reduce risk, further studies are needed, and HDL-C is still not considered a primary target of therapy in the National Cholesterol Education Program guidelines. However, HDL-C should be considered as part of the patient’s overall profile of established risk factors in determining treatment strategies.
Inflammation in Atherosclerosis and Implications for Therapy
Authors: Paoletti Rodolfo , Gotto Antonio M. , Hajjar David P.
Published: June 2004

Atherosclerosis is now understood to be a disease characterized by inflammation that results in a host of complications, including ischemia, acute coronary syndromes (unstable angina pectoris and myocardial infarction), and stroke. Inflammation may be caused by a response to oxidized low-density lipoproteins, chronic infection, or other factors; and markers of this process, such as C-reactive protein, may be useful to predict an increased risk of coronary heart disease. Thus, we believe that inflammatory processes may be potential targets of therapy in preventing or treating atherosclerosis and its complications.
Should C-Reactive Protein Be Added to Metabolic Syndrome and to Assessment of Global Cardiovascular Risk?
Authors: Ridker Paul M , Wilson Peter W.F. , Grundy Scott M.
Published: June 2004

Of novel risk factors for cardiovascular disease currently under investigation, high-sensitivity C-reactive protein (hsCRP) is the most promising. To date, more than 20 prospective epidemiologic studies have demonstrated that hsCRP independently predicts vascular risk, 6 cohort studies have confirmed that hsCRP evaluation adds prognostic information beyond that available from the Framingham Risk Score, and 8 cohort studies have demonstrated additive prognostic value at all levels of metabolic syndrome or in the prediction of type 2 diabetes. In contrast to several other biomarkers that also reflect biological aspects of inflammation, hypofibrinolysis, and insulin resistance, hsCRP measurement is inexpensive, standardized, widely available, and has a decade-to-decade variation similar to that of cholesterol. Given the consistency of prognostic data for hsCRP and the practicality of its use in outpatient clinical settings, we believe the time has come for a careful consideration of adding hsCRP as a clinical criterion for metabolic syndrome and for the creation of an hsCRP-modified coronary risk score useful for global risk prediction in both men and women. Toward this end, we believe experts in the fields of epidemiology, prevention, vascular biology, and clinical cardiology should be convened to begin discussing the merits of this proposal.
Oral D-4F Causes Formation of Pre-β High-Density Lipoprotein and Improves High-Density Lipoprotein–Mediated Cholesterol Efflux and Reverse Cholesterol Transport From Macrophages in Apolipoprotein E–Null Mice
Authors: Navab Mohamad , Anantharamaiah G.M. , Reddy Srinivasa T. , Hama Susan , Hough Greg , Grijalva Victor R. , Wagner Alan C. , Frank Joy S. , Datta Geeta , Garber David , Fogelman Alan M.
Published: June 2004

Background—

These studies were designed to determine the mechanism of action of an oral apolipoprotein (apo) A-I mimetic peptide, D-4F, which previously was shown to dramatically reduce atherosclerosis in mice.

Methods and Results—

Twenty minutes after 500 μg of D-4F was given orally to apoE-null mice, small cholesterol-containing particles (CCPs) of 7 to 8 nm with pre-β mobility and enriched in apoA-I and paraoxonase activity were found in plasma. Before D-4F, both mature HDL and the fast protein liquid chromatography fractions containing the CCPs were proinflammatory. Twenty minutes after oral D-4F, HDL and CCPs became antiinflammatory, and there was an increase in HDL-mediated cholesterol efflux from macrophages in vitro. Oral D-4F also promoted reverse cholesterol transport from intraperitoneally injected cholesterol-loaded macrophages in vivo. In addition, oral D-4F significantly reduced lipoprotein lipid hydroperoxides (LOOH), except for pre-β HDL fractions, in which LOOH increased.

Conclusions—

The mechanism of action of oral D-4F in apoE-null mice involves rapid formation of CCPs, with pre-β mobility enriched in apoA-I and paraoxonase activity. As a result, lipoprotein LOOH are reduced, HDL becomes antiinflammatory, and HDL-mediated cholesterol efflux and reverse cholesterol transport from macrophages are stimulated.
Papillary Muscles Do Not Attach Directly to the Solid Heart Wall
Authors: Axel Leon
Published: June 2004

Background—

The papillary muscles (PMs) play an important role in normal cardiac function, helping to prevent leakage through the AV valves during systole. The nature of their attachment to the heart wall can affect the understanding of their function. This attachment is conventionally portrayed as a direct connection of their bases to the solid portion of the heart wall. X-ray multidetector CT provides a new, noninvasive way to investigate this connection in vivo.

Methods and Results—

With the use of x-ray multidetector CT with interactive 3D reconstruction, the bases of the PMs are seen to attach to the trabeculae carneae lining the ventricular wall rather than directly to the solid portion of the wall, as has been conventionally believed. This is true for both the left and right ventricular PMs.

Conclusions—

This new picture of the geometry of the attachment of the PMs to the heart wall may have important implications for the understanding of their function, including the nature of the transmission of the forces between the PMs and the heart wall.
Macrophage Migration Inhibitory Factor Deficiency Impairs Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice
Authors: Pan Jie-Hong , Sukhova Galina K. , Yang Jing-Tian , Wang Bing , Xie Tao , Fu Huanxiang , Zhang Yaou , Satoskar Abhay R. , David John R. , Metz Christine N. , Bucala Richard , Fang Kenneth , Simon Daniel I. , Chapman Harold A. , Libby Peter , Shi Guo-Ping
Published: June 2004

Background—

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine expressed widely by vascular cells. However, scant in vivo evidence supports direct participation of MIF in atherogenesis. Therefore, we investigated whether deficiency of MIF modulates atherosclerotic lesion formation and composition in low-density lipoprotein receptor-deficient (LDLr
−/−
) mice.

Methods and Results—

MIF
−/−
LDLr
−/−
and LDLr
−/−
mice were generated and consumed an atherogenic diet for 12 or 26 weeks. MIF
−/−
LDLr
−/−
mice had significantly reduced abdominal aorta lipid deposition and intimal thickening from aortic arch throughout the abdominal aorta compared with LDLr
−/−
mice. Marked retardation of atherosclerosis over time in MIF-deficient mice accompanied decreased lesion cell proliferation. At 26 weeks, 20% of MIF-deficient mice developed only early, fatty streak-like lesions, whereas >80% of LDLr
−/−
mice developed advanced lesions containing calcification and lipid cores. Analysis of smooth muscle cells from mouse aortae demonstrated that MIF deficiency reduced smooth muscle cell proliferation, cysteine protease expression, and elastinolytic and collagenolytic activities.

Conclusions—

Deficiency of MIF reduces atherogenesis in LDLr
−/−
mice. These results provide novel insight into inflammatory pathways operating in atheromata and identify a new potential target for modulating atherogenesis.
Electrical Propagation in Synthetic Ventricular Myocyte Strands From Germline Connexin43 Knockout Mice
Authors: Beauchamp Philippe , Choby Cécile , Desplantez Thomas , de Peyer Karin , Green Karen , Yamada Kathryn A. , Weingart Robert , Saffitz Jeffrey E. , Kléber André G.
Published: June 2004

To characterize the role of connexin43 (Cx43) as a determinant of cardiac propagation, we synthesized strands and pairs of ventricular myocytes from germline Cx43
−/−
mice. The amount of Cx43, Cx45, and Cx40 in gap junctions was analyzed by immunohistochemistry and confocal microscopy. Intercellular electrical conductance, g
j
, was measured by the dual-voltage clamp technique (DVC), and electrical propagation was assessed by multisite optical mapping of transmembrane potential using a voltage-sensitive dye. Compared with wild-type (Cx43
+/+
) strands, immunoreactive signal for Cx43 was reduced by 46% in Cx43
+/−
strands and was absent in Cx43
−/−
strands. Cx45 signal was reduced by 46% in Cx43
+/−
strands and to the limit of detection in Cx43
−/−
strands, but total Cx45 protein levels measured in immunoblots of whole cell homogenates were equivalent in all genotypes. Cx40 was detected in ≈ 2% of myocytes. Intercellular conductance, g
j
, was reduced by 32% in Cx43
+/−
cell pairs and by 96% in Cx43
−/−
cell pairs. The symmetrical dependence of g
j
on transjunctional voltage and properties of single-channel recordings indicated that Cx45 was the only remaining connexin in Cx43
−/−
cells. Propagation in Cx43
−/−
strands was very slow (2.1 cm/s versus 52 cm/s in Cx43
+/+
) and highly discontinuous, with simultaneous excitation within and long conduction delays (2 to 3 ms) between individual cells. Propagation was abolished by 1 mmol/L heptanol, indicating residual junctional coupling. In summary, knockout of Cx43 in ventricular myocytes leads to very slow conduction dependent on the presence of Cx45. Electrical field effect transmission does not contribute to propagation in synthetic strands.
Novel Mechanism of Action for Hydralazine
Authors: Knowles Helen J. , Tian Ya-Min , Mole David R. , Harris Adrian L.
Published: June 2004

The vasodilator hydralazine, used clinically in cardiovascular therapy, relaxes arterial smooth muscle by inhibiting accumulation of intracellular free Ca
2+
via an unidentified primary target. Collagen prolyl hydroxylase is a known target of hydralazine. We therefore investigated whether inhibition of other members of this enzyme family, namely the hypoxia-inducible factor (HIF)-regulating O
2
-dependent prolyl hydroxylase domain (PHD) enzymes, could represent a novel mechanism of action. Hydralazine induced rapid and transient expression of HIF-1α and downstream targets of HIF (endothelin-1, adrenomedullin, haem oxygenase 1, and vascular endothelial growth factor [VEGF]) in endothelial and smooth muscle cells and induced endothelial cell-specific proliferation. Hydralazine dose-dependently inhibited PHD activity and induced nonhydroxylated HIF-1α, evidence for HIF stabilization specifically by inhibition of PHD enzyme activity. In vivo, hydralazine induced HIF-1α and VEGF protein in tissue extracts and elevated plasma VEGF levels. In sponge angiogenesis assays, hydralazine increased stromal cell infiltration and blood vessel density versus control animals. Thus, hydralazine activates the HIF pathway through inhibition of PHD activity and initiates a pro-angiogenic phenotype. This represents a novel mechanism of action for hydralazine and presents HIF as a potential target for treatment of ischemic disease.
Racial and Ethnic Disparities in Cardiovascular Risk Factors Among Stroke Survivors
Authors: McGruder Henraya F. , Malarcher Ann M. , Antoine Theresa L. , Greenlund Kurt J. , Croft Janet B.
Published: June 2004

Background and Purpose—

Stroke mortality is higher among US blacks than it is among US whites. Few studies have examined racial and ethnic differences in the prevalence of cardiovascular disease (CVD) risk factors among stroke survivors, especially among Hispanics.

Methods—

Data are from 96 501 persons aged18 years or older who participated in the 1999, 2000, or 2001 National Health Interview Survey, a continuous annual household-based survey of the US population. Participants reported a history of stroke, hypertension, diabetes, myocardial infarction, and coronary heart disease. Other CVD risk factors were current smoking, overweight/obese, inadequate physical activity, and binge drinking.

Results—

Stroke was reported by 2.8% of blacks, 1.3% of Hispanics, and 2.2% of whites. Among 2265 stroke survivors, blacks were 1.65-times more likely (95% CI, 1.55 to 1.75) and Hispanics were 0.73-times less likely (95% CI, 0.69 to 0.78) than whites to report hypertension. Hispanics and blacks were more likely than whites to report diabetes (
P
<0.05). Hispanics and blacks were less likely than whites to report total coronary heart disease (
P
<0.05). Overweight was 1.63-times higher among blacks (95% CI, 1.55 to 1.73) and 1.36-times higher (95% CI, 1.30 to 1.44) among Hispanics than whites. Blacks were 1.82-times more likely (95% CI, 1.71 to 1.94) and Hispanics 2.09-times more likely (95% CI, 1.98 to 2.22) than whites to report inadequate levels of physical activity. Binge drinking and smoking were less common among Hispanics and Blacks than among whites (
P
<0.05).

Conclusions—

Racial and ethnic disparities exist in stroke prevalence and CVD risk behaviors and medical history. Targeted secondary prevention will be important in reducing disparities among Hispanic and black stroke survivors.
Ethnic Differences in Risk Factors for Ischemic Stroke
Authors: Hajat Cother , Tilling Kate , Stewart Judy A. , Lemic-Stojcevic Nada , Wolfe Charles D.A.
Published: June 2004

Background and Purpose—

The aim is to estimate the relative risk and population attributable risk (PAR) of risk factors for ischemic stroke by ethnic group.

Methods—

In this case–control study, cases of first ischemic stroke were taken from the South London Stroke Register and controls from a cross-sectional prevalence survey covering the same area. PAR was determined for each risk factor by ethnic group. Multivariable analysis was used to examine the association between risk factors and ischemic stroke across all ethnic groups.

Results—

664 cases and 716 controls aged 45 to 74 years were included, with ethnicity of white 78%:42%, black Caribbean 16%:43%, and black African 6%:15%, respectively. For the white group, high PAR was found for ischemic heart disease (IHD) on ECG (56% [95% CI, 49% to 62%]), obesity (49% [95% CI, 40% to 56%]), hypertension (HT) (38% [95% CI, 29% to 46%]), smoking (31% [95% CI, 19% to 41%]), transient ischemic attack (TIA) (23% [95% CI, 19% to 27%]), and atrial fibrillation (AF) (16% [95% CI, 10% to 21%]). In the black Caribbean compared with the white group, PAR was higher for HT (46% [95% CI, 21% to 63%]) and diabetes mellitus (DM) (29% [95% CI, 14% to 42%]), and lower for current smoking (18% [95% CI, 1% to 32%]) and AF (10% [95% CI, 0% to 18%]). In the black African group HT had a higher PAR (59% [95% CI, 91% to 82%]) than the other groups. PAR for AF (11% [95% CI, −11% to 29%]), obesity (30% [95% CI, −20% to 60%]), and DM (4% [95% CI, −25% to 26%]) was low compared with the other groups. In multivariable analysis, risk factors associated with ischemic stroke included TIA, AF, IHD on ECG, smoking, excess alcohol, obesity, HT, and DM.

Conclusion—

In the first European case-control study examining risk factors for ischemic stroke in black Caribbean and African populations, some differences were demonstrated in the impact of risk factors between these groups. It may be important to address such differences when developing stroke preventative strategies.
Underestimation of the Early Risk of Recurrent Stroke
Authors: Coull Andrew J. , Rothwell Peter M.
Published: June 2004

Background—

There is considerable variation in the definitions used for recurrent stroke. Most epidemiological studies exclude events within the first 28 days (eg, Monitoring Trends and Determinants in Cardiovascular Disease [MONICA]) or events within 21 days in the same territory as the presenting event (eg, most stroke incidence studies). However, recurrence is most common during this early period and these restrictive definitions could underestimate the benefits of early prevention.

Methods—

We determined the 90-day risk of recurrence after incident ischemic stroke in 2 population-based cohorts (Oxford Vascular Study [OXVASC] and Oxfordshire Community Stroke Project [OCSP]) with the 3 most common definitions: any stroke ≥24 hours after the incident event excluding early deterioration not caused by a stroke (definition A); as above, but excluding any stroke within 21 days in the same territory as the incident event (definition B); and any stroke ≥28 days after the incident event (definition C).

Results—

657 patients had 93 recurrent strokes between 24 hours and 90 days after the incident event. The 90-day recurrence risks (95% CI) using definition A were 14.5% (11.5 to 17.5) in the OCSP and 18.3% (10.8 to 25.8) in the OXVASC. The equivalent risks using definitions B and C were 8.3% (5.9 to 10.8) and 4.8% (2.8 to 6.7), respectively, in the OCSP and 7.0% (1.6 to 12.4) and 5.9% (1.0 to 10.9) in the OXVASC. The definition A risk of recurrence was particularly high after partial anterior (22.9%,17.5 to 28.2) and posterior (19.5%,13.0 to 25.9) circulation strokes.

Conclusions—

The 3 most widely used definitions of recurrent stroke yield markedly different 90-day risks. We suggest that, where possible, definition A be adopted as the standard to avoid underestimation of risk and to allow valid comparison of different studies.
Contribution of Susceptibility-Weighted Imaging to Acute Stroke Assessment
Authors: Hermier Marc , Nighoghossian Norbert
Published: June 2004

Background—

Susceptibility-weighted (SW) MRI provides insight into the pathophysiology of acute stroke. We report on the use of SW imaging (SWI) sequences in clinical practice and highlight the future applications.

Summary of Review—

SWI exploits the magnetic susceptibility effects generated by local inhomogeneities of the magnetic field. The paramagnetic properties of deoxyhemoglobin support signal changes related to acute hemorrhage and the intravascular spontaneous blood oxygen level dependent (BOLD) effect. SWI allows the early detection of acute hemorrhage within 6 hours after symptom onset. SWI may also identify previous microbleeds in acute ischemia; however, the impact of these findings on thrombolytic therapy safety has not been definitely established. The diagnosis of arterial occlusion is usually performed by magnetic resonance angiography. SWI allows intravascular clot detection at the acute stage.

Substantial experimental data suggest that spontaneous BOLD contrast may improve tissue viability assessment. The ratio of oxyhemoglobin to deoxyhemoglobin, measured by MRI in the capillary and venous compartments, reflects the oxygen extraction fraction (OEF) and the cerebral metabolic rate of oxygen. The combination of magnetic resonance (MR)-measured OEF and cerebral blood flow, via perfusion studies, may provide information about tissue viability.

Conclusions—

SWI offers a spectrum of current clinical applications and may improve our knowledge of the pathophysiology of acute stroke.
Cognitive Functioning in Preclinical Vascular Dementia
Authors: Laukka Erika Jonsson , Jones Sari , Fratiglioni Laura , Bäckman Lars
Published: June 2004

Background and Purpose—

Recent studies have shown that cognitive deficits are present during the years preceding a diagnosis of vascular dementia (VaD). The aims of this study were to (1) extend previous research by examining whether cognitive deficits are already present 6 years before diagnosis, and (2) examine the strength of the association between cognitive performance and a future VaD diagnosis after controlling for previous vascular disorders.

Methods—

Subjects from a population-based study of very old persons (≥75) were examined with a test of global cognitive functioning (the Mini-Mental State Examination [MMSE]) at 3 occasions over a 6-year period. The study sample was nondemented the first 2 measurement times. On the last occasion, 22 individuals were diagnosed with VaD, and 450 persons remained nondemented.

Results—

The preclinical VaD group showed no MMSE deficits 6 years before diagnosis (
P
>0.10) compared with the controls. However, 3 years before diagnosis, poor cognitive performance was significantly associated with forthcoming VaD after controlling for demographic factors and prior vascular disorders (odds ratio, 2.55; 95% CI, 1.67 to 3.89).

Conclusions—

This study extends previous findings on preclinical cognitive deficits in VaD and suggests that cognitive measures can be useful in the process of recognizing individuals at risk for developing VaD to initiate early treatment.
Insular Cortical Ischemia Is Independently Associated With Acute Stress Hyperglycemia
Authors: Allport Louise E. , Butcher Ken S. , Baird Tracey A. , MacGregor Lachlan , Desmond Patricia M. , Tress Brian M. , Colman Peter , Davis Stephen M.
Published: June 2004

Background and Purpose—

Acute poststroke hyperglycemia has been associated with larger infarct volumes and a cortical location, regardless of diabetes status. Stress hyperglycemia has been attributed to activation of the hypothalamic-pituitary-adrenal axis but never a specific cortical location. We tested the hypothesis that damage to the insular cortex, a site with autonomic connectivity, results in hyperglycemia reflecting sympathoadrenal dysregulation.

Methods—

Diffusion-weighted MRI, glycosylated hemoglobin (HbA
1c
), and blood glucose measurements were obtained in 31 patients within 24 hours of ischemic stroke onset. Acute diffusion-weighted imaging (DWI) lesion volumes were measured, and involvement of the insular cortex was assessed on T2-weighted images.

Results—

Median admission glucose was significantly higher in patients with insular cortical ischemia (8.6 mmol/L; n=14) compared with those without (6.5 mmol/L; n=17;
P
=0.006). Multivariate linear regression demonstrated that insular cortical ischemia was a significant independent predictor of glucose level (
P
=0.001), as was pre-existing diabetes mellitus (
P
=0.008). After controlling for the effect of insular cortical ischemia, DWI lesion volume was not associated with higher glucose levels (
P
=0.849). There was no association between HbA
1c
and glucose level (
P
=0.737).

Conclusions—

Despite the small sample size, insular cortical ischemia appeared to be associated with the production of poststroke hyperglycemia. This relationship is independent of pre-existing glycemic status and infarct volume. Neuroendocrine dysregulation after insular ischemia may be 1 aspect of a more generalized acute stress response. Future studies of poststroke hyperglycemia should account for the effect of insular cortical ischemia.
From Perception to Consciousness: An Epistemic Vision of Evolutionary Processes
Authors: Debono Marc-Williams
Published: June 2004

The concept of plasticity provides a unifying hypothesis to account for the natural properties of living systems as well as the different levels of perception and information associated with these systems. Are the metadynamics of evolutionary processes able to describe the nature of consciousness as a whole? The close study of the link between the coherence of emerging objects and the way we think they appear allows us to use the metaphor of a discontinuous bridge linking primitive perceptions to consciousness just as brain plasticity is linked to art.
Orai, or How the Text Got Pleated: A Genealogy of La Plissure du Texte: A Planetary Fairytale
Authors: Ascott Roy
Published: June 2004

This paper is an attempt to make sense of the Japanese word orai and to consider in what way the author's own “comings and goings” across artistic, literary and esoteric pathways led to the formulation of his practice, later to be theorized as telematic art and to be understood as a form of associative connectivism. The paper focuses on La Plissure du Texte, his first project involving distributed authorship.
Creative Aspects of Sonification
Authors: Ben-Tal Oded , Berger Jonathan
Published: June 2004

Agoal of sonification research is the intuitive audio representation of complex, multidimensional data. The authors present two facets of this research that may provide insight into the creative process. First, they discuss aspects of categorical perception in nonverbal auditory scene analysis and propose that these characteristics are simplified models of creative engagement with sound. Second, they describe the use of sonified data in musical compositions by each of the authors and observe aspects of the creative process in the purely aesthetic use of sonified statistical data.
Divisions of the Plane by Computer: Another Way of Looking at Mondrian's Nonfigurative Compositions
Authors: Feijs Loe
Published: June 2004

The article discusses a novel way of looking at Mondrian's nonfigurative paintings. Different periods of Mondrian's life correspond to distinct types of nonfigurative compositions, but can the distinction be formalized? How many bits or numbers are needed to characterize a typical composition? Can the rules of a composition type be expressed in the language of the computer? If distinct composition types require different computer programs, can these be based on a common frame-work, a mechanism, perhaps? The findings presented here are only tentative, but it is interesting to note that some characteristics can be modeled reasonably well, whereas others still resist formalization in the presented framework. The author's approach borrows principles from genetic programming. Employing a built-in random number generator, it can be used to explore a large space of “compositions.”