bluuebunny/crossref_metadata_2025 huggingface dataset:
Sympathetic hyperreactivity to air-jet stress in the chromosome 1 blood pressure quantitative trait locus congenic rats
Authors: Yamazato Masanobu , Ohya Yusuke , Nakamoto Minori , Sakima Atsushi , Tagawa Tatsuya , Harada Yuji , Nabika Toru , Takishita Shuichi
Published: October 2005

A chromosome 1 blood pressure quantitative trait locus (QTL) was introgressed from the stroke-prone spontaneously hypertensive rats (SHRSP) to Wistar-Kyoto (WKY) rats. This congenic strain (WKYpch1.0) showed an exaggerated pressor response to both restraint and cold stress. In this study, we evaluated cardiovascular and sympathetic response to an air-jet stress and also examined the role of the brain renin-angiotensin system (RAS) in the stress response of WKYpch1.0. We measured mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) responses to air-jet stress in WKYpch1.0, WKY, and SHRSP. We also examined effects of intracerebroventricular administration of candesartan, an ANG II type 1 receptor blocker, on MAP and HR responses to air-jet stress. Baseline MAP in the WKYpch1.0 and WKY rats were comparable, while it was lower than that in SHRSP rats. Baseline HR did not differ among the strains. In WKYpch1.0, air-jet stress caused greater increase in MAP and RSNA than in WKY. The increase in RSNA was as large as that in SHRSP, whereas the increase in MAP was smaller than in SHRSP. Intracerebroventricular injection of a nondepressor dose of candesartan inhibited the stress-induced pressor response to a greater extent in WKYpch1.0 than in WKY. Intravenous injection of phenylephrine caused a presser effect comparable between WKYpch1.0 and WKY. These results suggest that the chromosome 1 blood pressure QTL congenic rat has a sympathetic hyperreactivity to an air-jet stress, which causes exaggerated pressor responses. The exaggerated response is at least partly mediated by the brain RAS.
Functional polymorphisms in the α-subunit of the human epithelial Na+ channel increase activity
Authors: Tong Qiusheng , Menon Anil G. , Stockand James D.
Published: October 2005

Activity of the epithelial Na+ channel (ENaC) is limiting for Na+ reabsorption at the distal nephron. Gain-of-function mutations in ENaC cause Liddle's syndrome: a severe form of inheritable hypertension. Several polymorphisms in α-hENaC possibly associated with abnormal Na+ handling by the kidney and the salt-sensitive hypertension prevalent in black populations have been reported. The functional effects of α-hENaC polymorphisms on channel activity, however, remain controversial and have not been directly tested in a mammalian background. We ask here whether polymorphisms at positions 334, 618, and 663 in α-hENaC influence channel activity. Activity of wild-type (A334, C618, A663) and polymorphic ENaC expressed in Chinese hamster ovary cells was assessed with patch-clamp electrophysiology. While the A334T polymorphism had little effect on macroscopic ENaC currents, the C618F and A663T polymorphisms significantly increased ENaC activity >3.3- and 1.6-fold, respectively. Similarly, polymorphic ENaC had greater activity compared with wild-type channels in excised patches with activity of C618F and A663T channels increased 3.8- and 2.6-fold, respectively. Unitary channel conductances and reversal potentials were not different for polymorphic and wild-type ENaC. Increases in activity resulted primarily from increases in the apparent number of active (polymorphic) channels in the plasma membrane. Moreover, addition of a reducing agent to the cytosol significantly increased activity of wild-type ENaC equal to that of C618F polymorphic channels but had no effect on these latter channels. These results are consistent with the C618F and A663T polymorphisms leading to elevated ENaC activity with the possibility that they facilitate altered Na+ handling by the kidney.
Role of nitric oxide in methacholine-induced sweating and vasodilation in human skin
Authors: Lee Kichang , Mack Gary W.
Published: October 2005

The purpose of this study was to determine whether the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME) demonstrates significant muscarinic-receptor antagonism during methacholine (MCh)-stimulated sweating in human forearm skin. Three intradermal microdialysis probes were placed in the skin of eight healthy adults (4 men and 4 women). MCh in the range of 0.033–243 mM in nine steps was perfused through a microdialysis probe with and without the presence of the nitric oxide synthase inhibitor l-NAME (10 mM) or the l-arginine analog NG-monomethyl-l-arginine (l-NMMA; 10 mM). Local sweat rate (sweat rate) and skin blood flow (laser-Doppler velocimetry) were measured directly over each microdialysis probe. We observed similar resting sweat rates at MCh only, MCh and l-NAME, and MCh and l-NMMA sites averaging 0.175 ± 0.029, 0.186 ± 0.034, and 0.139 ± 0.027 mg·min−1·cm−2, respectively. Peak sweat rate (0.46 ± 0.11, 0.56 ± 0.16, and 0.53 ± 0.16. mg·min−1·cm−2) was also similar among all three sites. MCh produced a sigmoid-shape dose-response curve and 50% of the maximal attainable response (0.42 ± 0.14 mM for MCh only) was shifted rightward shift in the presence of l-NAME or l-NMMA (2.88 ± 0.79 and 3.91 ± 1.14 mM, respectively; P < 0.05). These results indicate that nitric oxide acts to augment MCh-stimulated sweat gland function in human skin. In addition, l-NAME consistently blunted the MCh-induced vasodilation, whereas l-NMMA did not. These data support the hypothesis that muscarinic-induced dilation in cutaneous blood vessels is not mediated by nitric oxide production and that the role of l-NAME in attenuating acetylcholine-induced vasodilation may be due to its potential to act as a muscarinic-receptor antagonist.
Recovery from contraction-induced injury is impaired in weight-bearing muscles of old male mice
Authors: Rader Erik P. , Faulkner John A.
Published: October 2005

With aging, the skeletal muscles of humans sustain decreases of ∼30% in mass and maximum force. Contraction-induced injury may contribute to these declines. When a 225 lengthening contraction protocol (LCP) was administered to small, non-weight-bearing muscles of mice, muscles of young/adult mice recovered completely, whereas those of old mice sustained permanent deficits of 20% in muscle mass and maximum force. Despite these observations, whether a large, frequently recruited, weight-bearing muscle sustains such permanent damage is not known. The hypothesis tested is that after a severe contraction-induced injury, large, weight-bearing muscles of old mice sustain permanent reductions in mass and force. The LCP was administered to plantar flexor muscles of adult and old, male C57BL/6 mice. At 3 days, 1 mo, and 2 mo after the LCP, maximum isometric forces were measured, anesthetized mice were euthanized, and muscles were removed and weighed. Two months after the LCP, the muscles of the adult mice regained control values of mass and force, whereas for muscles of old mice the mass decreased by 24% and the maximum force decreased by 32%. We conclude that a severe contraction-induced injury to large, weight-bearing muscles of old mice causes permanent deficits in mass and force.
Viscoelasticity of the trachea and its effects on flow limitation
Authors: Aljuri Nikolai , Venegas Jose G. , Freitag Lutz
Published: October 2005

To test the hypothesis that peak expiratory flow is determined by the wave-speed-limiting mechanism, we studied the time dependency of the trachea and its effects on flow limitation. For this purpose, we assessed the relationship between transmural pressure and cross-sectional area [the tube law (TL)] of six excised human tracheae under controlled conditions of static (no flow) and forced expiratory flow. We found that TLs of isolated human tracheae followed quite well the mathematical representation proposed by Shapiro (Shapiro AH. J Biomech Eng 99: 126–147, 1977) for elastic tubes. Furthermore, we found that the TL measured at the onset of forced expiratory flow was significantly stiffer than the static TL. As a result, the stiffer TL measured at the onset of forced expiratory flow predicted theoretical maximal expiratory flows far greater than those predicted by the more compliant static TL, which in all cases studied failed to explain peak expiratory flows measured at the onset of forced expiration. We conclude that the observed viscoelasticity of the tracheal walls can account for the measured differences between maximal and “supramaximal” expiratory flows seen at the onset of forced expiration.
Contractile dysfunction and altered metabolic profile of the aging rat thyroarytenoid muscle
Authors: McMullen Colleen A. , Andrade Francisco H.
Published: October 2005

The larynx and its muscles are important for ventilation, coughing, sneezing, swallowing, Valsalva's maneuver, and phonation. Because of their functional demands, the intrinsic laryngeal muscles have a unique phenotype: very small and fast fibers with high mitochondrial content. How aging affects their function is largely unknown. In this study, we tested the hypothesis that an intrinsic laryngeal muscle (thyroarytenoid muscle, a vocal fold adductor) would become weaker, slower, and fatigable with age. Muscles from Fischer 344 × Brown Norway F1 hybrid rats (6, 18, and 30 mo of age) were used for in vitro contractile function and histology. Thyroarytenoid muscles generated significantly lower twitch and tetanic forces at 30 mo vs. 6 and 18 mo. Maximal shortening velocity decreased by 20% at 30 mo (vs. 6 mo), and velocity of unloaded shortening was slower at 18 and 30 mo by 19 and 27% vs. 6 mo. There was no histochemical evidence of altered myosin ATPase activity at 18 or 30 mo of age. Fatigue resistance was significantly decreased at 18 and 30 mo. We also found abundant mitochondrial clusters and ragged red fibers in the muscles of 30-mo-old rats, and there was an age-related increase in glycogen-positive fibers. We conclude that rat thyroarytenoid muscles become weaker, slower, and more fatigable with age. These functional changes are not due to alterations in myosin ATPase activity, but a switch in the expression of myosin isoforms remains a possibility. Finally, the alterations in mitochondrial and glycogen content indicate a shift in the metabolic characteristics of these muscles with age.
Effect of Benzodiazepine Hypnotic Triazolam on Relationship of Blood Pressure and Paco2to Cerebral Blood Flow During Human Non-Rapid Eye Movement Sleep
Authors: Hiroki Masahiko , Kajimura Naofumi , Uema Takeshi , Ogawa Kenichi , Nishikawa Masami , Kato Masaaki , Watanabe Tsuyoshi , Nakajima Toru , Takano Harumasa , Imabayashi Etsuko , Ohnishi Takashi , Takayama Yutaka , Matsuda Hiroshi , Uchiyama Makoto , Okawa Masako , Takahashi Kiyohisa , Fukuyama Hidenao
Published: October 2005

We sought to clarify the effect of short-acting benzodiazepine hypnotic on the relationship of arterial blood pressure and arterial partial pressure of carbon dioxide (Paco2) to regional cerebral blood flow (rCBF) during human non-rapid-eye-movement (non-REM) sleep. Nine young normal volunteers were treated in a randomized, crossover design with triazolam or placebo and underwent positron emission tomography at night. During wakefulness and stage 2 and slow wave (stages 3 and 4) sleep, we measured mean arterial blood pressure (MAP), Paco2, and absolute CBF. With triazolam compared to placebo, MAP reduced gradually. During stage 2 sleep, Paco2increased and whole-brain mean CBF decreased. With triazolam, relative rCBF of the left orbital basal forebrain decreased more during stage 2 than slow wave sleep, whereas absolute CBF of the occipital cortex and cerebral white matter remained constant. During triazolam-induced stage 2 sleep, absolute CBF of the cerebral white matter correlated more strongly to both MAP and Paco2than during placebo sleep and also correlated more strongly to both MAP and Paco2than absolute CBF of the occipital cortex. In the frontal white matter, during triazolam-induced stage 2 sleep compared to wakefulness, absolute CBF was significantly better correlated to MAP, but not to Paco2. During triazolam-induced stage 2, the cerebral white matter may receive a modulated CBF regulation having the strengthened relationship of Paco2to CBF and, more locally, the frontal white matter may depend precariously on CBF regulation.
Central Representation of Dynamics When Manipulating Handheld Objects
Authors: Milner Theodore E. , Franklin David W. , Imamizu Hiroshi , Kawato Mitsuo
Published: October 2005

To explore the neural mechanisms related to representation of the manipulation dynamics of objects, we performed whole-brain fMRI while subjects balanced an object in stable and highly unstable states and while they balanced a rigid object and a flexible object in the same unstable state, in all cases without vision. In this way, we varied the extent to which an internal model of the manipulation dynamics was required in the moment-to-moment control of the object's orientation. We hypothesized that activity in primary motor cortex would reflect the amount of muscle activation under each condition. In contrast, we hypothesized that cerebellar activity would be more strongly related to the stability and complexity of the manipulation dynamics because the cerebellum has been implicated in internal model-based control. As hypothesized, the dynamics-related activation of the cerebellum was quite different from that of the primary motor cortex. Changes in cerebellar activity were much greater than would have been predicted from differences in muscle activation when the stability and complexity of the manipulation dynamics were contrasted. On the other hand, the activity of the primary motor cortex more closely resembled the mean motor output necessary to execute the task. We also discovered a small region near the anterior edge of the ipsilateral (right) inferior parietal lobule where activity was modulated with the complexity of the manipulation dynamics. We suggest that this is related to imagining the location and motion of an object with complex manipulation dynamics.
Excitatory GABAergic Effects in Striatal Projection Neurons
Authors: Bracci Enrico , Panzeri Stefano
Published: October 2005

The ability of synaptically released GABA to facilitate action potential generation in striatal projection neurons was studied in brain slices using current-clamp, gramicidin-perforated whole cell recordings. Evoked GABAergic postsynaptic potentials (PSPs) were pharmacologically isolated with ionotropic glutamate receptor antagonists. Subthreshold depolarizing current injections were paired with GABAergic PSPs at different intervals. GABAergic PSPs were able to convert current injection-induced depolarizations from subthreshold to suprathreshold, but only when they preceded the current injection by an appropriate interval; accordingly, action potentials were observed 4–140 ms after the onset of the GABAergic PSP, and their likelihood was maximal after 50–60 ms. The GABAergic excitatory effects were fully blocked by the GABAA receptor antagonist bicuculline. Appropriately timed GABA PSPs decreased the time taken by current injections to depolarize projection neurons, causing an apparent reduction in the spike threshold. In control solution, the ability of evoked PSPs (comprising both glutamatergic and GABAergic components) to reach spike threshold was often impaired by bicuculline. We conclude that GABAergic PSPs can exert excitatory effects on projection neurons and that this ability crucially depends on the timing between the GABAergic event and a concomitant depolarizing input.
Corticospinal Excitability Is Lower During Rhythmic Arm Movement Than During Tonic Contraction
Authors: Carroll Timothy J. , Baldwin Evan R. L. , Collins David F. , Zehr E. Paul
Published: October 2005

Humans perform rhythmic, locomotor movements with the arms and legs every day. Studies using reflexes to probe the functional role of the CNS suggest that spinal circuits are an important part of the neural control system for rhythmic arm cycling and walking. Here, by studying motor-evoked potentials (MEPs) in response to transcranial magnetic stimulation (TMS) of the motor cortex, and H-reflexes induced by electrical stimulation of peripheral nerves, we show a reduction in corticospinal excitability during rhythmic arm movement compared with tonic, voluntary contraction. Responses were compared between arm cycling and tonic contraction at four positions, while participants generated similar levels of muscle activity. Both H-reflexes and MEPs were significantly smaller during arm cycling than during tonic contraction at the midpoint of arm flexion ( F = 13.51, P = 0.006; F = 11.83, P = 0.009). Subthreshold TMS significantly facilitated the FCR H-reflex during tonic contractions, but did not significantly modulate H-reflex amplitude during arm cycling. The data indicate a reduction in the responsiveness of cells constituting the fast, monosynaptic, corticospinal pathway during arm cycling and suggest that the motor cortex may contribute less to motor drive during rhythmic arm movement than during tonic, voluntary contraction. Our results are consistent with the idea that subcortical regions contribute to the control of rhythmic arm movements despite highly developed corticospinal projections to the human upper limb.
Olfactory Cortical Adaptation Facilitates Detection of Odors Against Background
Authors: Kadohisa Mikiko , Wilson Donald A.
Published: October 2005

Detection and discrimination of odors generally, if not always, occurs against an odorous background. On any given inhalation, olfactory receptor neurons will be activated by features of both the target odorant and features of background stimuli. To identify a target odorant against a background therefore, the olfactory system must be capable of grouping a subset of features into an odor object distinct from the background. Our previous work has suggested that rapid homosynaptic depression of afferents to the anterior piriform cortex (aPCX) contributes to both cortical odor adaptation to prolonged stimulation and habituation of simple odor-evoked behaviors. We hypothesize here that this process may also contribute to figure-ground separation of a target odorant from background stimulation. Single-unit recordings were made from both mitral/tufted cells and aPCX neurons in urethan-anesthetized rats and mice. Single-unit responses to odorant stimuli and their binary mixtures were determined. One of the odorants was randomly selected as the background and presented for 50 s. Forty seconds after the onset of the background stimulus, the second target odorant was presented, producing a binary mixture. The results suggest that mitral/tufted cells continue to respond to the background odorant and, when the target odorant is presented, had response magnitudes similar to that evoked by the binary mixture. In contrast, aPCX neurons filter out the background stimulus while maintaining responses to the target stimulus. Thus the aPCX acts as a filter driven most strongly by changing stimuli, providing a potential mechanism for olfactory figure-ground separation and selective reading of olfactory bulb output.
Multiple periodic solutions to a class of second‐order nonlinear mixed‐type functional differential equations
Authors: Shu Xiao-Bao , Xu Yuan-Tong
Published: October 2005

By means of variational structure and Z2 group index theory, we obtain multiple periodic solutions to a class of second‐order mixed‐type differential equations x′′(t − τ) + f(t, x(t), x(t − τ), x(t − 2τ)) = 0 and x′′(t − τ) + λ(t)f1(t, x(t), x(t − τ), x(t − 2τ)) = x(t − τ).
Iterative approximation of fixed point for Φ‐hemicontractive mapping without Lipschitz assumption
Authors: Zhiqun Xue
Published: October 2005

Let E be an arbitrary real Banach space and let K be a nonempty closed convex subset of E such that K + K ⊂ K. Assume that T : K → K is a uniformly continuous and Φ‐hemicontractive mapping. It is shown that the Ishikawa iterative sequence with errors converges strongly to the unique fixed point of T.
On Lax pairs and matrix extended simple Toda systems
Authors: Legaré M.
Published: October 2005

A A1 Toda system is extended via Lax pair formulations in order to probe noncommutative variables extensions. Systems, some solvable, are built using matrix generalizations.
The Kreps‐Yan theorem for L∞
Authors: Rokhlin D. B.
Published: October 2005

We prove the following version of the Kreps‐Yan theorem. For any norm‐closed convex cone C ⊂ L∞ such that and , there exists a strictly positive continuous linear functional, whose restriction on C is nonpositive. The technique of the proof differs from the usual approach, applicable to a weakly Lindelöf Banach space.
Structured lattices and ground categories of L‐sets
Authors: Frascella A. , Guido C.
Published: October 2005

Complete lattices are considered with suitable families of lattice morphisms that provide a structure (L, Φ), useful to characterize ground categories of L‐sets by means of powerset operators associated to morphisms of these categories. The construction of ground categories and powerset operators presented here extends and unifies most approaches previously considered, allowing the use of noncrisp objects and, with some restriction, the change of base. A sufficiently large category of L‐sets that includes all possible ground categories on a structured lattice (L, Φ) is provided and studied, and its usefulness is justified. Many explanatory examples have been given and connection with the categories considered by J. A. Goguen and by S. E. Rodabaugh are stated.
Riemann boundary value problem for hyperanalytic functions
Authors: Blaya Ricardo Abreu , Reyes Juan Bory , Peña Dixan Peña
Published: October 2005

We deal with Riemann boundary value problem for hyperanalytic functions. Furthermore, necessary and sufficient conditions for solvability of the problem are derived. At the end the explicit form of general solution for singular integral equations with a hypercomplex Cauchy kernel in the Douglis sense is established.
On a subclass of n‐starlike functions
Authors: Acu Mugur , Owa Shigeyoshi
Published: October 2005

In 1999, Kanas and Rønning introduced the classes of starlike and convex functions, which are normalized with f(w) = f′(w) − 1 = 0 and w a fixed point in U. In 2005, the authors introduced the classes of functions close to convex and α‐convex, which are normalized in the same way. All these definitions are somewhat similar to the ones for the uniform‐type functions and it is easy to see that for w = 0, the well‐known classes of starlike, convex, close‐to‐convex, and α‐convex functions are obtained. In this paper, we continue the investigation of the univalent functions normalized with f(w) = f′(w) − 1 = 0 and w, where w is a fixed point in U.
EphA2 as a Novel Molecular Marker and Target in Glioblastoma Multiforme
Authors: Wykosky Jill , Gibo Denise M. , Stanton Constance , Debinski Waldemar
Published: October 2005

We investigated the presence of EphA2, and its ligand, ephrinA1, in glioblastoma multiforme (GBM), a malignant neoplasm of glial cells, and normal brain. We also initially examined the functional importance of the interaction between EphA2 and ephrinA1 in glioma cells. Expression and localization of EphA2 and ephrinA1 in human GBM and normal brain were examined using Western blotting, immunofluorescence, and immunohistochemistry. A functional role for EphA2 was investigated by assessing the activation status of the receptor and the effect of ephrinA1 on the anchorage-independent growth and invasiveness of GBM cells. We found EphA2 to be elevated in ∼90% of GBM specimens and cell lines but not in normal brain, whereas ephrinA1 was present at consistently low levels in both GBM and normal brain. EphA2 was activated and phosphorylated by ephrinA1 in GBM cells. Furthermore, ephrinA1 induced a prominent, dose-dependent inhibitory effect on the anchorage-independent growth and invasiveness of GBM cells highly overexpressing EphA2, which was not seen in cells expressing low levels of the receptor. Thus, EphA2 is both specifically overexpressed in GBM and expressed differentially with respect to its ligand, ephrinA1, which may reflect on the oncogenic processes of malignant glioma cells. EphA2 seems to be functionally important in GBM cells and thus may play an important role in GBM pathogenesis. Hence, EphA2 represents a new marker and novel target for the development of molecular therapeutics against GBM.
CCAAT/Enhancer Binding Protein α (C/EBPα) and C/EBPα Myeloid Oncoproteins Induce Bcl-2 via Interaction of Their Basic Regions with Nuclear Factor-κB p50
Authors: Paz-Priel Ido , Cai Dong Hong , Wang Dehua , Kowalski Jeanne , Blackford Amanda , Liu Huaitian , Heckman Caroline A. , Gombart Adrian F. , Koeffler H. Phillip , Boxer Linda M. , Friedman Alan D.
Published: October 2005

The CEBPA gene is mutated in 10% of acute myeloid leukemia (AML) cases. We find that CEBPA and Bcl-2 RNA levels correlate highly in low-risk human AMLs, suggesting that inhibition of apoptosis via induction of bcl-2 by CCAAT/enhancer binding protein α (C/EBPα) or its mutant variants contributes to transformation. C/EBPαp30, lacking a NH2-terminal transactivation domain, or C/EBPαLZ, carrying in-frame mutations in the leucine zipper that prevent DNA binding, induced bcl-2 in hematopoietic cell lines, and C/EBPα induced bcl-2 in normal murine myeloid progenitors and in the splenocytes of H2K-C/EBPα-Eμ transgenic mice. C/EBPα protected Ba/F3 cells from apoptosis on interleukin-3 withdrawal but not if bcl-2 was knocked down. Remarkably, C/EBPαLZ oncoproteins activated the bcl-2 P2 promoter despite lack of DNA binding, and C/EBPαp30 also activated the promoter. C/EBPα and the C/EBPα oncoproteins cooperated with nuclear factor-κB (NF-κB) p50, but not p65, to induce bcl-2 transcription. Endogenous C/EBPα preferentially coimmunoprecipitated with p50 versus p65 in myeloid cell extracts. Mutation of residues 297 to 302 in the C/EBPα basic region prevented induction of endogenous bcl-2 or the bcl-2 promoter and interaction with p50 but not p65. These findings suggest that C/EBPα or its mutant variants tether to a subset of NF-κB target genes, including Bcl-2, via p50 to facilitate gene activation and offer an explanation for preferential in-frame rather than out-of-frame mutation of the leucine zipper with sparing of the basic region in C/EBPαLZ oncoproteins. Targeting interaction between C/EBPα basic region and NF-κB p50 may contribute to the therapy of AML and other malignancies expressing C/EBPs.
Induction of Invasive Mouse Skin Carcinomas in Transgenic Mice with Mutations in Both H-ras and p53
Authors: Zhang Zhongqiu , Yao Ruisheng , Li Jie , Wang Yian , Boone Charles W. , Lubet Ronald A. , You Ming
Published: October 2005

Synergistic interaction between H-ras and p53 were systematically examined during skin tumorigenesis. Concurrent expression of an activated H-ras gene and a mutant p53 gene was accomplished by crossing p53Val135/wt mice with TG·AC mice. Topical application to wild-type mice with benzo(a)pyrene (BaP) alone produced ∼26% skin tumor incidence, whereas BaP treatment of p53wt/wtHrasTG·AC/wt, p53Val135/wtHraswt/wt, and p53Val135/wtHrasTG·AC/wt mice produced a 75%, 77%, and 100% incidence of skin tumors, respectively. An average of 0.33 tumor per mouse was observed in wild-type (p53wt/wtHraswt/wt) mice, whereas ∼1.54, 1.96, and 3.08 tumors per mouse were seen in BaP-treated p53wt/wtHrasTG·AC/wt, p53Val135/wtHraswt/wt, and p53Val135/wtHrasTG·AC/wt mice, respectively. The effects on total tumor volume were even more striking with 7-, 48-, and 588-fold increases in tumor volume compared with wild-type (p53wt/wtHraswt/wt) in p53wt/wtHrasTG·AC/wt, p53Val135/wtHraswt/wt, and p53Val135/wtHrasTG·AC/wt mice, respectively. Histopathologically, all tumors from p53wt/wtHraswt/wt mice were either papillomas or well-differentiated squamous cell carcinomas, whereas the tumors in p53wt/wtHrasTG·AC/wt, p53Val135/wtHraswt/wt, and p53Val135/wtHrasTG·AC/wt mice were principally squamous cell carcinomas with varying degree of invasiveness. Particularly, tumors in p53Val135/wtHrasTG·AC/wt mice exhibited the most rapid growth and the extreme form of tumor invasion. Microarray analysis revealed that dominant-negative p53 (Val135) and activated H-ras affected several cellular processes involved in tumorigenesis possibly through its effects on apoptosis, cell cycle arrest, and Ras-mitogen-activated protein kinase pathways. The present study provides the first in vivo evidence that a germ line p53 mutation and activated H-ras act synergistically to profoundly enhance tumor progression.
Circulating CD31
+
/Annexin V
+
Apoptotic Microparticles Correlate With Coronary Endothelial Function in Patients With Coronary Artery Disease
Authors: Werner Nikos , Wassmann Sven , Ahlers Patrick , Kosiol Sonja , Nickenig Georg
Published: October 2005

Objective—

Endothelial dysfunction predicts morbidity and mortality in patients at cardiovascular risk. Endothelial function may be decisively influenced by the degree of endothelial cell apoptosis.

Methods and Results—

To test this hypothesis in humans, endothelial-dependent vasodilatation was invasively assessed in 50 patients with coronary artery disease (CAD) by quantitative coronary angiography during intracoronary acetylcholine infusion. Flow cytometry was used to assess endothelial cell apoptosis by quantification of circulating CD31
+
/annexin V
+
apoptotic microparticles in peripheral blood. Increased apoptotic microparticle counts positively correlated with impairment of coronary endothelial function. Multivariate analysis revealed that increased apoptotic microparticle counts predict severe endothelial dysfunction independent of classical risk factors, such as hypertension, hypercholesterolemia, smoking, diabetes, age, or sex.

Conclusions—

In patients with CAD, endothelial-dependent vasodilatation closely relies on the degree of endothelial cell apoptosis, which is readily measurable by circulating CD31
+
/annexin V
+
apoptotic microparticles. These findings possibly provide new options for risk assessment and may have implications for future treatment strategies of CAD.
Diabetes, the Metabolic Syndrome, and Angiographic Progression of Coronary Arterial Disease in Postmenopausal Women
Authors: Mellen Philip B. , Cefalu William T. , Herrington David M.
Published: October 2005

Objective—

Although the metabolic syndrome (MS) is associated with increased cardiovascular risk, its relationship with atherosclerotic progression is less well defined. We sought to determine whether the MS predicts angiographic progression of coronary heart disease in a cohort of postmenopausal women.

Methods and Results—

A total of 309 postmenopausal women entered the Estrogen Replacement and Atherosclerosis trial, of whom 248 underwent baseline angiography and completed follow-up angiography after an average of 3.2 years. Women were identified as having type 2 diabetes mellitus (T2DM) or the MS (National Cholesterol Education Panel diagnostic criteria). In adjusted models, participants with T2DM and the MS had greater angiographic progression [change in minimal diameter (ΔMD): −0.15] than women without T2DM or the MS (ΔMD: −0.08;
P
<0.05) or with MS alone (ΔMD: −0.07;
P
<0.005); there was no difference in progression by MS status in women without T2DM (
P
=0.54)]. In adjusted logistic regression models, T2DM predicted coronary heart disease events [odds ratio, 2.79 (95% CI, 1.29 to 6.02)], and the MS demonstrated a similar trend [odds ratio, 1.98 (95% CI, 0.90 to 4.33)].

Conclusions—

Among postmenopausal women with coronary heart disease, the presence of diabetes predicted disease progression, but the MS did not.
HIV Entry Inhibitor TAK-779 Attenuates Atherogenesis in Low-Density Lipoprotein Receptor–Deficient Mice
Authors: van Wanrooij Eva J.A. , Happé Hester , Hauer Arnaud D. , de Vos Paula , Imanishi Takeshi , Fujiwara Hiromi , van Berkel Theo J.C. , Kuiper Johan
Published: October 2005

Objective—

HIV combination therapy using protease inhibitors is associated with elevated plasma levels of atherogenic lipoproteins and increased risk for atherosclerosis. We investigated whether the HIV entry inhibitor TAK-779 affects lipoprotein levels and atherogenesis in low-density lipoprotein receptor-deficient mice. TAK-779 is an antagonist for the chemokine receptors CCR5 and CXCR3, which are expressed on leukocytes, especially T-helper 1 cells, and these receptors may be involved in recruitment of these cells to atherosclerotic plaques.

Methods and Results—

TAK-779 treatment of low-density lipoprotein receptor
−
deficient mice did not elevate the levels of atherogenic lipoproteins, whereas it dramatically reduced atherosclerosis in the aortic root and in the carotid arteries. The number of T cells in the plaque was reduced by 95%, concurrently with a 98% reduction in the relative IFN-γ area. TAK-779-treated animals showed a decreased percentage of CD4
+
and CD8
+
T cells in peripheral blood and in mediastinal lymph nodes compared with control-treated animals.

Conclusions—

TAK-779 not only suppresses HIV entry via blockade of CCR5 but also attenuates atherosclerotic lesion formation by blocking the influx of T-helper 1 cells into the plaque. TAK-779 treatment may be especially beneficial for young HIV patients as they face lifelong treatment, and this drug impairs atherogenesis.
Recent Developments in Vascular Endothelial Cell Transient Receptor Potential Channels
Authors: Yao Xiaoqiang , Garland Christopher J.
Published: October 2005

Among the 28 identified and unique mammalian TRP (transient receptor potential) channel isoforms, at least 19 are expressed in vascular endothelial cells. These channels appear to participate in a diverse range of vascular functions, including control of vascular tone, regulation of vascular permeability, mechanosensing, secretion, angiogenesis, endothelial cell proliferation, and endothelial cell apoptosis and death. Malfunction of these channels may result in disorders of the human cardiovascular system. All TRP channels, except for TRPM4 and TRPM5, are cation channels that allow Ca
2+
influx. However, there is a daunting diversity in the mode of activation and regulation in each case. Specific TRP channels may be activated by different stimuli such as vasoactive agents, oxidative stress, mechanical stimuli, and heat. TRP channels may then transform these stimuli into changes in the cytosolic Ca
2+
, which are eventually coupled to various vascular responses. Evidence has been provided to suggest the involvement of at least the following TRP channels in vascular function: TRPC1, TRPC4, TRPC6, and TRPV1 in the control of vascular permeability; TRPC4, TRPV1, and TRPV4 in the regulation of vascular tone; TRPC4 in hypoxia-induced vascular remodeling; and TRPC3, TRPC4, and TRPM2 in oxidative stress–induced responses. However, in spite of the large body of data available, the functional role of many endothelial TRP channels is still poorly understood. Elucidating the mechanisms regulating the different endothelial TRP channels, and the associated development of drugs selectively to target the different isoforms, as a means to treat cardiovascular disease should, therefore, be a high priority.
Ischemic Neoangiogenesis Enhanced by β2-Adrenergic Receptor Overexpression
Authors: Iaccarino Guido , Ciccarelli Michele , Sorriento Daniela , Galasso Gennaro , Campanile Alfonso , Santulli Gaetano , Cipolletta Ersilia , Cerullo Vincenzo , Cimini Vincenzo , Altobelli Giovanna Giuseppina , Piscione Federico , Priante Ornella , Pastore Lucio , Chiariello Massimo , Salvatore Francesco , Koch Walter J. , Trimarco Bruno
Published: October 2005

β2-Adrenergic receptors (β2ARs) are widely expressed, although their physiological relevance in many tissues is not yet fully understood. In vascular endothelial cells, they regulate NO release and vessel tone. Here we provide novel evidence that β2ARs can regulate neoangiogenesis in response to chronic ischemia. We used in vivo adenoviral-mediated gene transfer of the human β2AR to the endothelium of the rat femoral artery and increased β2AR signaling resulting in ameliorated angiographic blood flow and hindlimb perfusion after chronic ischemia. Histological analysis confirmed that β2AR overexpression also produced benefits on capillary density. The same maneuver partially rescued impaired angiogenesis in spontaneously hypertensive rats (SHR), whereas gene delivery of the G-protein–coupling defective mutant Ile164 β2AR failed to provide ameliorations. Stimulation of endogenous and overexpressed β2AR on endothelial cells in vitro was found to regulate cell number by inducing proliferation and [3H]-thymidine incorporation through means of extracellular receptor-activated kinase and vascular endothelial growth factor. The β2AR also has novel effects on endothelial cell number through stimulation of proapoptosis and antiapoptosis pathways involving p38 mitogen-activated protein kinase and PI3-kinase/Akt activation. Therefore, β2ARs play a critical role in endothelial cell proliferation and function including revascularization, suggesting a novel and physiologically relevant role in neoangiogenesis in response to ischemia.
Global Dynamic Coupling of Activation and Repolarization in the Human Ventricle
Authors: Yue Arthur M. , Betts Tim R. , Roberts Paul R. , Morgan John M.
Published: October 2005

Background—

The ability to determine spatial and dynamic changes in ventricular repolarization may help to understand arrhythmogenic mechanisms in humans. We hypothesized that noncontact mapping could be used to investigate global activation-repolarization coupling in the human ventricle during steady state and premature extrastimulation.

Methods and Results—

Activation-recovery intervals (ARIs) determined from reconstructed unipolar electrograms by the Ensite system were analyzed during sinus rhythm, constant pacing, spontaneous ventricular ectopic beats, and premature stimulation at intermediate and short coupling intervals in the left or right ventricle of 13 patients (6 female; mean age, 48 years) without structural myocardial disease. ARIs were measured from 32 sites in each ventricle with the use of a method validated with monophasic action potential recordings and unipolar contact electrograms. Global T-wave distribution was displayed on a 3-dimensional geometry of the ventricle, with polarities opposite to the direction of activation during steady state and premature stimulation. There was a significant inverse correlation between activation times and ARIs during sinus rhythm, ventricular ectopy, and premature stimulation (
r
=0.72, slope=−0.76,
P
<0.001). Premature stimuli at short coupling intervals flattened the regression slope compared with sinus rhythm (−0.61 versus −0.81;
P
=0.05), but the global pattern of repolarization was preserved. In comparison to our method, the Wyatt method of ARI measurement failed to demonstrate significant coupling between activation and repolarization (
r
=0.34, slope=0.19).

Conclusions—

Global, dynamic repolarization mapping of the human ventricle is feasible. An inverse coupling of activation and repolarization during steady state and premature stimulation may preserve electric stability in the normal ventricle.
Hybrid Approaches to Thoracic Aortic Aneurysms
Authors: Greenberg Roy K. , Haddad Fady , Svensson Lars , O’Neill Sean , Walker Esteban , Lyden Sean P. , Clair Daniel , Lytle Bruce
Published: October 2005

Background—

Thoracic aortic aneurysm affecting the arch and proximal descending thoracic aorta requires 2-stage repairs that include proximal elephant trunk graft placement and completion of thoracic or thoracoabdominal repair. The application of endovascular grafting to complete the proximal procedure avoids a thoracotomy and may improve the morbidity and mortality of the patient population at risk.

Methods and Results—

A retrospective review of 399 thoracic endovascular grafts at our institution between 2000 and 2004 identified 22 patients who required elephant trunk and endovascular completion. Three patients underwent mesenteric bypass in addition to their proximal repairs. Mean follow-up was 10 months (range 1 to 42 months); there were no ruptures, and all patients returned for follow-up. Technical success was achieved in all patients. The 1-, 12-, and 24-month mortality rates (by Kaplan-Meier analysis) were 4.5%, 15.8%, and 15.8%, respectively. Caudal migration of the endograft occurred in 1 patient, and all but 2 aneurysms decreased or remained stable in size. The 2 patients with growth included a type III endoleak (which resolved after treatment) and pressurization through an expanded PTFE stentgraft. Three cases of transient paraparesis occurred (all in patients requiring mesenteric bypass or abdominal aortic aneurysm repair), and there were no paraplegias or strokes.

Conclusions—

Endovascular completion of elephant trunks is feasible and can be accomplished with minimal mortality. Meticulous imaging follow-up is required to detect persistent aneurysm pressurization and to verify the integrity of the repair. Improvements in implant design and delivery systems will further simplify the second-stage portion of these complex aneurysm repairs.
Selective Activation of Inflammatory Pathways by Intermittent Hypoxia in Obstructive Sleep Apnea Syndrome
Authors: Ryan Silke , Taylor Cormac T. , McNicholas Walter T.
Published: October 2005

Background—

Obstructive sleep apnea syndrome (OSAS), characterized by intermittent hypoxia/reoxygenation (IHR), is an independent risk factor for cardiovascular disease. We investigated the underlying molecular mechanisms of this association in a translational study.

Methods and Results—

In a novel in vitro model of IHR, we used HeLa cells transfected with reporter constructs and DNA binding assays for the master transcriptional regulators of the inflammatory and adaptive pathways (NFκB and HIF-1, respectively) to investigate underlying transcriptional events initiated by repeated cell exposure to IHR. Furthermore, we prospectively studied 19 male OSAS patients (median apnea-hypopnea frequency, 48.5 episodes per hour; interquartile range [IQR], 28.5 to 72.9) and 17 matched normal control subjects. Circulating levels of the proinflammatory cytokine tumor necrosis factor-α and the adaptive factor erythropoietin were assayed in all subjects at baseline and again after 6 weeks of continuous positive airway pressure therapy in patients. Full blood count was measured as part of a detailed baseline evaluation. HeLa cells exposed to IHR demonstrated selective activation of the proinflammatory transcription factor NFκB (
P
<0.001 by ANOVA), whereas the adaptive regulator HIF-1 was not activated, as demonstrated by luciferase reporter assays and DNA binding studies. Circulating tumor necrosis factor-α levels were higher in OSAS patients (2.56 pg/mL; IQR, 2.01 to 3.42 pg/mL) than in control subjects (1.25 pg/mL; IQR, 0.94 to 1.87;
P
<0.001) but normalized with continuous positive airway pressure therapy (1.24 pg/mL; IQR, 0.78 to 2.35 pg/mL;
P
=0.002). In contrast, erythropoietin levels were similar throughout. Furthermore, circulating neutrophil levels were higher in OSAS patients than in control subjects, whereas the hematocrit was unaltered.

Conclusions—

These data demonstrate selective activation of inflammatory over adaptive pathways in IHR and OSAS, which may be an important molecular mechanism of cardiovascular disease.
Phenotypic Variability and Unusual Clinical Severity of Congenital Long-QT Syndrome in a Founder Population
Authors: Brink Paul A. , Crotti Lia , Corfield Valerie , Goosen Althea , Durrheim Glenda , Hedley Paula , Heradien Marshall , Geldenhuys Gerhard , Vanoli Emilio , Bacchini Sara , Spazzolini Carla , Lundquist Andrew L. , Roden Dan M. , George Alfred L. , Schwartz Peter J.
Published: October 2005

Background—

In the congenital long-QT syndrome (LQTS), there can be a marked phenotypic heterogeneity. Founder effects, by which many individuals share a mutation identical by descent, represent a powerful tool to further understand the underlying mechanisms and to predict the natural history of mutation-associated effects. We are investigating one such founder effect, originating in South Africa in approximately
ad
1700 and segregating the same KCNQ1 mutation (A341V).

Methods and Results—

The study population involved 320 subjects, 166 mutation carriers (MCs) and 154 noncarriers. When not taking β-blocker therapy, MCs had a wide range of QTc values (406 to 676 ms), and 12% of individuals had a normal QTc (≤440 ms). A QTc >500 ms was associated with increased risk for cardiac events (OR=4.22; 95% CI, 1.12 to 15.80;
P
=0.033). We also found that MCs with a heart rate <73 bpm were at significantly lower risk (OR=0.23; 95% CI, 0.06 to 0.86;
P
=0.035). This study also unexpectedly determined that KCNQ1-A341V is associated with greater risk than that reported for large databases of LQT1 patients: A341V MCs are more symptomatic by age 40 years (79% versus 30%) and become symptomatic earlier (7±4 versus 13±9 years, both
P
<0.001). Accordingly, functional studies of KCNQ1-A341V in CHO cells stably expressing IK
s
were conducted and identified a dominant negative effect of the mutation on wild-type channels.

Conclusions—

KCNQ1-A341V is a mutation associated with an unusually severe phenotype, most likely caused by the dominant negative effect of the mutation. The availability of an extended kindred with a common mutation allowed us to identify heart rate, an autonomic marker, as a novel risk factor.
Gradient Projection Algorithms and Software for Arbitrary Rotation Criteria in Factor Analysis
Authors: Bernaards Coen A. , Jennrich Robert I.
Published: October 2005

Almost all modern rotation of factor loadings is based on optimizing a criterion, for example, the quartimax criterion for quartimax rotation. Recent advancements in numerical methods have led to general orthogonal and oblique algorithms for optimizing essentially any rotation criterion. All that is required for a specific application is a definition of the criterion and its gradient. The authors present the implementations of gradient projection algorithms, both orthogonal and oblique, as well as a catalogue of rotation criteria and corresponding gradients. Software for these is downloadable and free; a specific version is given for each of the computing environments used most by statisticians. Examples of rotation methods are presented by applying them to a loading matrix from Wehmeyer and Palmer.
Towards a Four-Dimensional Model of Burnout: A Multigroup Factor-Analytic Study Including Depersonalization and Cynicism
Authors: Salanova Marisa , Llorens Susana , García-Renedo Mónica , Burriel Raül , BresÓ Edgar , Schaufeli Wilmar B.
Published: October 2005

This article investigated whether cynicism and depersonalization are two different dimensions of burnout or whether they may be collapsed into one construct of mental distance. Using confirmatory factor analyses in two samples of teachers ( n = 483) and blue-collar workers ( n = 474), a superior fit was found for the four-factor model that contained cynicism, depersonalization, exhaustion, and professional efficacy as dimensions of burnout. In particular, cynicism and depersonalization emerged as unique burnout dimensions. Moreover, it appeared from multigroup analyses that this four-dimensional structure of burnout is partially invariant across both samples. Cynicism and depersonalization seemed to play a different role in both samples, particularly as far as their relationship with professional efficacy is concerned. It is recommended that future research on burnout should include the cynicism and depersonalization constructs.
Using the SPSS Mixed Procedure to Fit Cross-Sectional and Longitudinal Multilevel Models
Authors: Peugh James L. , Enders Craig K.
Published: October 2005

Beginning with Version 11, SPSS implemented the MIXED procedure, which is capable of performing many common hierarchical linear model analyses. The purpose of this article was to provide a tutorial for performing cross-sectional and longitudinal analyses using this popular software platform. In doing so, the authors borrowed heavily from Singer’s overview of SAS PROC MIXED, duplicating her analyses using the SPSS MIXED procedure.