bluuebunny/crossref_metadata_2025 huggingface dataset:
Neoproterozoic and Cambrian U–Pb (zircon) ages from Grand Manan Island, New Brunswick: implications for stratigraphy and northern Appalachian terrane correlations
Authors: Miller B V , Barr S M , Black R S
Published: August 2007

Pre-Mesozoic rocks are exposed on the southeastern third of Grand Manan Island and adjacent offshore islands in the Bay of Fundy. U–Pb (zircon) ages reported here demonstrate that most of these rocks are late Neoproterozoic to Early Cambrian. The oldest dated unit is the Ingalls Head Formation, from which two felsic tuff samples yielded ages of 617.6 ± 3.2 and 618.3 ± 2.8 Ma. The Three Islands granite, exposed only on offshore islands, is younger than the Ingalls Head Formation at 611.1 ± 2.4 Ma. It provides a minimum age for marble of the Kent Island Formation, which occurs as large xenoliths in the granite. The High Duck Island granite yielded an age of 547.3 ± 1.1 Ma, providing a minimum late Neoproterozoic age for the host Long Island Bay Formation. An age of 539.0 ± 3.3 Ma from a dacitic lithic-crystal tuff demonstrates that the Priest Cove Formation is earliest Cambrian; this supersedes a Silurian age previously suggested on the basis of poorly documented fossil evidence. The Long Pond Bay Formation is considered to be the youngest pre-Mesozoic unit on Grand Manan Island, based on petrological features, but a felsic intrusive sample from the unit yielded ca. 588 Ma xenocrystic zircon grains that provide only a maximum age for the unit. Although lack of exposed contacts or U–Pb ages from a few units precludes a complete stratigraphic picture, the ages reported here deomonstrate that most pre-Mesozoic units on Grand Manan Island are not Paleozoic as previously assumed. Some units on Grand Manan Island show similarities in rock types and ages to components in the Islesboro block in Penobscot Bay in coastal Maine. Overall, the range of ages and rock types suggests that they correlate with the New River and Mascarene terranes of southern New Brunswick, requiring an offset of at least 40 km between southern New Brunswick and adjacent Maine along the Grand Manan – Oak Bay fault system. Hence, both the Ganderia–Avalonia and Avalonia–Meguma boundaries lie farther offshore than Grand Manan Island.
Description et analyse du glissement de terrain meurtrier du 25 octobre 1870 dans le rang des Lahaie, Sainte-Geneviève-de-Batiscan, Québec
Authors: Lamontagne Maurice , Demers Denis , Savopol Florin
Published: August 2007

This study presents and analyses a deadly landslide that occurred in October 1870 on a clay slope of the Champlain River at Sainte-Geneviève-de-Batiscan, Quebec. Based on contemporary newspapers and a coroner's report, we can now determine the time of origin, the number and the names of the casualties, and the circumstances of their death. The landslide occurred on 25 October 1870, killing three people instantly while mortally wounding a fourth one. Correlating information with land ownership, we determined that the landslide was located in the rang des Lahaie, in Sainte-Geneviève-de-Batiscan. A number of factors could have lead to the triggering of the landslide : vibrations from the magnitude 6 ½ Charlevoix earthquake of 20 October 1870 or its aftershocks, rainfall, riverbank erosion, or local natural gas sources. Results from recent geotechnical borings indicate that the landslide has occurred in homogeneous clay sequences that should not liquefy under seismic vibrations. We infer that the enhanced fall season water infiltration, possibly coupled with river bank erosion, may have favoured the triggering of this event. The geotechnical properties of the clay, the morphology of the landslide scar, together with the description of a witness all suggest that the event was a quick clay landslide, typical of many others identified along the Champlain River.
Origin of iron-oxide and silicate melt rocks in Paleogene sediments of southern Ellesmere Island, Canadian Arctic Archipelago, Nunavut
Authors: Piepjohn Karsten , Estrada Solveig , Reinhardt Lutz , Gosen Werner von , Andruleit Harald
Published: August 2007

Between Vendom Fiord and Makinson Inlet on southern Ellesmere Island, Canadian Arctic Archipelago, Nunavut, isolated and fault-bounded Early Tertiary basins are exposed. The basin deposits are Paleocene to Eocene in age and overlie unconformably folded Ordovician and Silurian carbonates of the Paleozoic Franklinian Basin that were affected by intense, pre-Paleocene weathering and karstification in places. The Tertiary sediments consist mainly of dark unconsolidated sand and silt and are interbedded with many centimetre- to metre-thick coal seams. In several places, round orange and red "spots" occur within the dark grey Tertiary basin fills and are clustered on top of the dark grey Tertiary occurrences. The "spots" are up to 100 m in diameter and consist of consolidated burnt shards of clay or clinker. In the centre of the reddish "spots," dark, massive, and partly high-magnetic lava- or slag-like rocks are poorly exposed as masses that are a decimetre or less in scale. These rocks were investigated using thin section studies, as well as X-ray diffraction and X-ray flourescence analyses. The melt rocks are composed of glass, cordierite-group minerals, hematite, magnetite, tridymite, mullite, and cristobalite. They represent paralavas resulting from subsurface combustion of the Tertiary coal seams under conditions similar to those in a blast furnace. An origin by anthropogenic activity or a volcanic origin can be ruled out.
Bartonaspis new genus, a trilobite species complex from the base of the Upper Cambrian Sunwaptan Stage in North America
Authors: Westrop Stephen R , Adrain Jonathan M
Published: August 2007

Despite being reported widely from basal Sunwaptan strata, Dellea? punctata Palmer, 1965, is known from only four figured cranidia. New material from Nevada, Utah and Oklahoma, including librigenae and pygidia, indicate that specimens assigned previously to D.? punctata are best interpreted as a complex of related species that are assigned to a new genus, Bartonaspis. This genus is diagnosed by punctate sculpture, a pair of fossulae at the anterior corners of the glabella, and by a subelliptical pygidium with a short convex axis composed of three segments. Three new species, B. fredericksoni, B. palmeri, and B. wilsoni, are described and B. punctata (Palmer) is restricted to its holotype. Bartonaspis is known only from the Irvingella major Zone, and its first appearance defines the base of the Sunwaptan Stage. Dellea Wilson, 1949, is related to Bartonaspis and is differentiated from it primarily by pygidial morphology. In contrast to Bartonaspis, the pygidium of Dellea has an axis composed of four, rather than three, segments and a narrow concave border.
Integrated analyses constraining the provenance of sandstones, mudstones, and conglomerates, a case study: the Laojunshan conglomerate, Qilian orogen, northwest China
Authors: Yan Zhen , Xiao Wenjiao , Wang Zongqi , Li Jilian
Published: August 2007

The Qilian orogenic belt in the northern Tibetan plateau connects the Altaids to the north with the Tethyan orogenic system to the south and occupies a key tectonic position in the evolution and assembly of Asia. The belt contains a wide range of subduction–accretion-related petrotectonic units. The Early–Middle Devonian Laojunshan conglomerate, deposited unconformably upon Cambrian–Silurian strata along the northern margin of the North Qilian terrane, contains a record of the late Paleozoic tectonism of the Qilian orogen. Its provenance and tectonic setting are critical in understanding not only the tectonic evolution of Tibetan plateau, but Paleozoic global reconstructions as well. The composition of clastic conglomerates and heavy mineral assemblages of sandstones suggests that coeval mafic, felsic, metamorphic, and sedimentary rocks were the main sources. The geochemistry of volcanic clasts and paleocurrent and paleogeographic data suggest derivation from subduction–accretion complexes in the North Qilian terrane. The geochemistry of siltstones and mudstones indicates that the Laojunshan conglomerate was derived from an arc and accumulated in an active continental margin. Geochemical data of granitoid clasts suggest that they were derived from Ordovician–Silurian subduction-related magmatic rocks. Mafic and ultramafic clasts, chromite, and magnetite decrease upwards in the stratigraphy whereas metamorphic, sedimentary and granitoid clasts, and garnet increase. These data imply that mafic rocks were the predominant source during initial deposition. Regional studies suggest that the North China plate subducted southwards and produced subduction-related arc magmatism along the southern margin of the North Qilian terrane during the Early–Middle Devonian. Therefore, we interpret the Laojunshan conglomerate as a fore-arc basin fill.
FUBINI VACUA AS A CLASSICAL DE SITTER VACUA
Authors: LORAN F.
Published: August 2007

The Fubini's idea to introduce a fundamental scale of hadron phenomena by means of dilatation non-invariant vacuum state in the framework of a scale invariant Lagrangian field theory is recalled. The Fubini vacua is invariant under the de Sitter subgroup of the full conformal group. We obtain a finite entropy for the quantum state corresponding to the classical Fubini vacua in Euclidean spacetime resembling the entropy of the de Sitter vacua. In Minkowski spacetime it is shown that the Fubini vacua is mainly a bath of radiation with Rayleigh–Jeans distribution for the low energy radiation. In four dimensions, the critical scalar theory is shown to be equivalent to the Einstein field equation in the ansatz of conformally flat metrics and to the SU(2) Yang–Mills theory in the 't Hooft ansatz. In D dimensions, the Hitchin formula for the information geometry metric of the moduli space of instantons is used to obtain the information geometry of the free-parameter space of the Fubini vacua which is shown to be a (D+1)-dimensional AdS space. Considering the Fubini vacua as a de Sitter vacua, the corresponding cosmological constant is shown to be given by the coupling constant of the critical scalar theory. In Minkowski spacetime it is shown that the Fubini vacua are equivalent to an open FRW universe.
PROPER PROJECTIVE SYMMETRY IN KANTOWSKI–SACHS AND BIANCHI TYPE III SPACETIMES
Authors: SHABBIR GHULAM , ALI AMJAD
Published: August 2007

A study of Kantowski–Sachs and Bianchi type III spacetimes according to their proper projective symmetry is given by using the algebraic and direct integration techniques. It is shown that the above spacetimes do not admit proper projective collineations.
$\mathcal{N}$-FOLD PARASUPERSYMMETRY
Authors: TANAKA TOSHIAKI
Published: August 2007

We find a new type of nonlinear supersymmetries, called [Formula: see text]-fold parasupersymmetry, which is a generalization of both [Formula: see text]-fold supersymmetry and parasupersymmetry. We provide a general formulation of this new symmetry and then construct a second-order [Formula: see text]-fold parasupersymmetric quantum system where all the components of [Formula: see text]-fold parasupercharges are given by type A [Formula: see text]-fold supercharges. We show that this system exactly reduces to the Rubakov–Spiridonov model when [Formula: see text] and admits a generalized type C [Formula: see text]-fold superalgebra. We conjecture the existence of other "[Formula: see text]-fold generalizations" such as [Formula: see text]-fold fractional supersymmetry, [Formula: see text]-fold orthosupersymmetry, and so on.
OBSERVATION OF GALACTIC SOURCES OF VERY HIGH ENERGY γ-RAYS WITH THE MAGIC TELESCOPE
Authors: BARTKO H.
Published: August 2007

The MAGIC telescope with its 17m diameter mirror is today the largest operating single-dish Imaging Air Cherenkov Telescope (IACT). It is located on the Canary Island La Palma, at an altitude of 2200 m above sea level, as part of the Roque de los Muchachos European Northern Observatory. The MAGIC telescope detects celestial very high energy γ-radiation in the energy band between about 50 GeV and 10 TeV. Since the autumn of 2004 MAGIC has been taking data routinely, observing various objects, like supernova remnants (SNRs), γ-ray binaries, Pulsars, Active Galactic Nuclei (AGN) and Gamma-ray Bursts (GRB). We briefly describe the observational strategy, the procedure implemented for the data analysis, and discuss the results of observations of Galactic Sources.
SOFTWARE RELIABILITY GROWTH MODELLING FOR ERRORS OF DIFFERENT SEVERITY USING CHANGE POINT
Authors: KAPUR P. K. , KUMAR ARCHANA , YADAV KALPANA , KHATRI SUNIL K.
Published: August 2007

During the last two decades many researchers have analyzed the reliability growth of software during the testing and operational phases and proposed the mathematical models to estimate and predict the reliability measures. During the software testing on the detection of a failure the fault that has caused the failure is isolated and removed. Most of the existing research in this area considers that similar testing efforts and strategy are required on each debugging effort. However this may not be true in practice. Different faults may require different amount of testing efforts and testing strategy for their removal. In software reliability modeling in order to incorporate this phenomenon faults are classified into different categories as simple, hard and/or complex faults. This categorization is also extended to n-types of faults. Some of the existing research incorporates this phenomenon considering that the fault removal rate is different for different types of faults and remains constant during the overall period of testing. However this assumption may not apply in general testing environment in practice. It is a common observation that as the testing progresses the fault detection and/or removal rate changes. This change can be due to a number of reasons. The changing testing environment, testing strategy, skill, motivation and constitution of the testing and debugging personnel etc. are some of the major reasons behind this change. In this paper we have formulated the model for the software system developed for safety critical application under a specific testing environment. The model is validated on real life data sets.
HEURISTIC APPROACH FOR HETEROGENEOUS REDUNDANCY OPTIMIZATION IN MULTI-STATE SERIES-PARALLEL SYSTEM
Authors: GUPTA RASHIKA , AGARWAL MANJU
Published: August 2007

The paper presents a heuristic for series-parallel system, exhibiting multi-state behavior, with the objective to minimize the cost in order to provide a desired level of reliability. System reliability is defined as the ability to satisfy consumers demand and is presented as a piecewise cumulative load curve. The components are binary and chosen from the list of products available in the market, and are being characterized by their feeding capacity, reliability and cost. The solution approach makes use of heterogeneous collection of components to provide redundancy in a subsystem. The algorithm has been applied to power systems from the literature for various levels of reliability requirement. The heuristic offers a straightforward analysis and efficiency over genetic algorithm (GA) existing in the literature. Keeping in view the computational efficiency and the observed solution quality the proposed heuristic is appealing. As such, the heuristic developed is attractive and can be easily and efficiently applied to numerous real life systems.
RELIABILITY OF A MULTI-STATE CONSECUTIVE k-OUT-OF-n: G SYSTEM
Authors: BELALOUI SOHEIR , KSIR BRAHIM
Published: August 2007

Fortunately traditional reliability theory, where the system and the components are always described simply as functioning or failed, is on the way to being replaced by a theory for multistate systems of multistate components. In this paper, we treat the consecutive k-out-of-n systems. Such systems have caught the attention of many engineers and researchers because of their wide range of application. We define a multistate consecutive k-out-of-n system: G as follows: Each component and the system can be in 1 of M + 1 possible states: 0, 1, 2, …, M. The system is in state ≥ j iff at least kj consecutive components are in state ≥ j. The value of kj can be different for different required minimum system state levels. We propose a method based on the combinatorial approach for computing the system's reliability and we give examples to illustrate this method.
RELIABILITY OF A k-OUT-OF-n SYSTEM WITH REPAIR BY A SERVICE STATION ATTENDING A QUEUE WITH POSTPONED WORK
Authors: KRISHNAMOORTHY A. , NARAYANAN VISWANATH C. , DEEPAK T. G.
Published: August 2007

In this paper the reliability of a repairable k-out-of-n system is studied. Repair times of components follow a phase type distribution. In addition, the service facility offers service to external customers which arrive according to a MAP. An external customer, who finds an idle server on its arrival, is immediately selected for service. Otherwise, the external customer joins the queue in a pool of postponed work of infinite capacity with probability 1 if the number of failed components in the system is < M (M ≤ n - k + 1) and if the number of failed components ≥ M it joins the pool with probability γ or leaves the system forever. Repair times of components of the system and that of the external customers have independent phase type distributions. At a service completion epoch if the buffer has less than L customers, a pooled customer is taken for service with probability p, 0 < p < 1 If at a service completion epoch no component of the system is waiting for repair, a pooled customer, if any waiting, is immediately taken for service.

We obtain the system state distribution under the condition of stability. A number of performance characteristics are derived. A cost function involving L, M, γ and p is constructed and its behaviour investigated numerically.
Externally applied pressure activates pancreatic stellate cells through the generation of intracellular reactive oxygen species
Authors: Asaumi Hiroshi , Watanabe Shiro , Taguchi Masashi , Tashiro Mitsuo , Otsuki Makoto
Published: August 2007

Local tissue pressure is higher in chronic pancreatitis than in the normal pancreas. We reported recently that pressure application induces synthesis of extracellular matrix (ECM) and cytokines in pancreatic stellate cells (PSCs) and that epigallocatechin gallate (EGCG), a potent antioxidant, inhibits the transformation of PSCs from quiescent to activated phenotype and ethanol-induced synthesis of ECM and cytokines in PSCs. These results suggest that oxidative stress and reactive oxygen species (ROS) are important in PSC activation. The aim of this study was to clarify the effects of ROS on activation and functions of pressure-stimulated PSCs. We used freshly isolated rat PSCs and culture-activated PSCs. Pressure was applied on rat cultured PSCs by adding compressed helium gas into a pressure-loading apparatus. PSCs were cultured with or without antioxidants (EGCG and N-acetyl cysteine) under normal or elevated pressure. Externally applied high pressure (80 mmHg) resulted in a gradual decrease of superoxide dismutase activity in PSCs and increased intracellular ROS generation as early as 30 s, reaching a peak level at 1 h. Antioxidants significantly inhibited ROS generation. Pressure increased the expression levels of α-smooth muscle actin, α1(I)-procollagen, and TGF-β1 in PSCs. EGCG suppressed these alterations, abolished pressure-induced phosphorylation of p38 MAPK, and suppressed pressure-induced PSC transformation to activated phenotype. Our results indicated that ROS is a key player in pressure-induced PSC activation and ECM synthesis. Antioxidants could be potentially effective against the development of pancreatic fibrosis in patients with chronic pancreatitis.
Molecular cloning and promoter analysis of downregulated in adenoma (DRA)
Authors: Alrefai Waddah A. , Wen Xiaoming , Jiang Wen , Katz Jonathan P. , Steinbrecher Kris A. , Cohen Mitchell B. , Williams Ifor R. , Dudeja Pradeep K. , Wu Gary D.
Published: August 2007

Downregulated in adenoma (DRA), also referred to as SLC26A3, is an intestinal anion transporter essential for intestinal chloride absorption. Mutations in DRA result in congenital chloride diarrhea. DRA expression has been shown to be induced by differentiation and to be modulated by cytokines. However, mechanisms of DRA gene transcription and its tissue-specific targeting have not yet been investigated. In this study, we cloned a 3,765-bp promoter fragment of human DRA gene and characterized its activity in human colonic LS174T and Caco-2 human colon cell lines. Primer extension identified a single transcriptional initiation site that was identical in both colon cancer cell lines and normal colon. Although hepatic nuclear factor HNF-4 is involved in the basal activity of DRA promoter, sodium butyrate induces its activity in LS174T cells via the binding of Yin Yang 1 (YY1) and GATA transcription factors to their respective cis-elements in promoter region. We also demonstrated a reduction in DRA promoter activity in Caco-2 cells by IFN-γ, suggesting that regulation of DRA promoter by IFN-γ may contribute to the pathophysiology of intestinal inflammation. Furthermore, we showed that the DRA promoter fragment is sufficient to drive human growth hormone transgene expression specifically in villus epithelial cells of the small intestine and in differentiated upper crypt and surface epithelial cells of the colon. Our studies provide evidence for the involvement of HNF-4, YY1, and GATA transcription factors in DRA expression in intestinal differentiated epithelial cells.
Lysozyme, a mediator of sepsis, impairs the cardiac neural adrenergic response by nonendothelial release of NO and inhibitory G protein signaling
Authors: Mink Steven N. , Cheng Zhao-Qin , Bose Ratna , Jacobs Hans , Kasian Krika , Roberts Diane E. , Santos-Martinez Luis E. , Light R. Bruce
Published: August 2007

We previously showed that lysozyme (Lzm-S), derived from leukocytes, caused myocardial depression in canine sepsis by binding to the endocardial endothelium to release nitric oxide (NO). NO then diffuses to adjacent myocytes to activate the cGMP pathway. In a canine right ventricular trabecular (RVT) preparation, Lzm-S also decreased the inotropic response to field stimulation (FSR) during which the sympathetic and parasympathetic nerves were simulated to measure the adrenergic response. In the present study, we determined whether the pathway by which Lzm-S decreased FSR was different from the pathway by which Lzm-S reduced steady-state (SS) contraction. Furthermore, we determined whether the decrease in FSR was due to a decrease in sympathetic stimulation or enhanced parasympathetic signaling. In the RVT preparation, we found that the inhibitory effect of Lzm-S on FSR was prevented by NO synthase (NOS) inhibitors. A cGMP inhibitor also blocked the depressant activity of Lzm-S. However, in contrast to the Lzm-S-induced decline in SS contraction, chemical removal of the endocardial endothelium by Triton X-100 to eliminate endothelial NO release did not prevent the decrease in FSR. An inhibitory G protein was involved in the effect of Lzm-S, since FSR could be restored by treatment with pertussis toxin. Atropine prevented the Lzm-S-induced decline in FSR, whereas β1- and β2-adrenoceptor function was not impaired by Lzm-S. These results indicate that the Lzm-S-induced decrease in FSR results from a nonendothelial release of NO. NO then acts through inhibitory G protein to enhance parasympathetic signaling.
Keratinocyte growth factor protects against elastase-induced pulmonary emphysema in mice
Authors: Plantier Laurent , Marchand-Adam Sylvain , Antico Valeria G. , Boyer Laurent , De Coster Cécile , Marchal Joëlle , Bachoual Rafik , Mailleux Arnaud , Boczkowski Jorge , Crestani Bruno
Published: August 2007

Pulmonary emphysema is characterized by persistent inflammation and progressive alveolar destruction. The keratinocyte growth factor (KGF) favorably influences alveolar maintenance and repair and possesses anti-inflammatory properties. We aimed to determine whether exogenous KGF prevented or corrected elastase-induced pulmonary emphysema in vivo. Treatment with 5 mg·kg−1·day−1 KGF before elastase instillation prevented pulmonary emphysema. This effect was associated with 1) a sharp reduction in bronchoalveolar lavage fluid total protein and inflammatory cell recruitment, 2) a reduction in the pulmonary expression of the chemokines CCL2 (or monocyte chemoattractant protein-1) and CXCL2 (or macrophage inflammatory protein-2α) and of the adhesion molecules ICAM-1 and VCAM-1, 3) a reduction in matrix metalloproteinase (MMP)-2 and MMP-9 activity at day 3, and 4) a major reduction in DNA damage detected by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) in alveolar cells at day 7. Treatment with KGF after elastase instillation had no effect on elastase-induced emphysema despite the conserved expression of the KGF receptor in the lungs of elastase-instilled animals as determined by immunohistochemistry. In vitro, KGF abolished the elastase-induced increase in CCL2, CXCL2, and ICAM-1 mRNA in the MLE-12 murine alveolar epithelial cell line. We conclude that KGF pretreatment protected against elastase-induced pulmonary inflammation, activation of MMPs, alveolar cell DNA damage, and subsequent emphysema in mice.
Influence of promoter region variants of insulin-like growth factor pathway genes on the strength-training response of muscle phenotypes in older adults
Authors: Hand Brian D. , Kostek Matthew C. , Ferrell Robert E. , Delmonico Matthew J. , Douglass Larry W. , Roth Stephen M. , Hagberg James M. , Hurley Ben F.
Published: August 2007

To examine the influence of insulin-like growth factor (IGF) pathway gene polymorphisms on muscle mass and strength responses to strength training (ST), we studied 128 White and Black men and women before and after a 10-wk single-leg knee extension ST program. One-repetition maximum strength, muscle volume (MV) via computed tomography, and muscle quality (MQ) were assessed at baseline and after 10 wk of ST. There was a significant combined IGF1 cytosine adenine (CA) repeat gene effect, which included both the IGF1 CA repeat main effect and IGF1 CA repeat × PPP3R1 insertion-deletion (I/D) gene × gene interaction effect, on the changes in strength ( P < 0.01) and MQ ( P < 0.05) with ST. There was a trend for a significant gene × gene interaction between IGF1 CA repeat and PPP3R1 I/D for changes in strength ( P = 0.07) and MQ ( P = 0.06) with ST. The influence of the PPP3R1 A-202C gene polymorphism on change in MV with ST approached significance ( P = 0.06). The IGF1 CA repeat polymorphism had a significant influence on the change in strength and MV combined with ST ( P < 0.05), whereas the influence of the PPP3R1 I/D polymorphism approached significance ( P = 0.08). There were no associations between the IGFBP3 A-202C gene polymorphism and the muscle phenotypic responses to ST. These data suggest that two of the three IGF pathway gene polymorphisms identified in this study influence muscle phenotypic responses to ST in both Black and White older men and women.
Control of heart rate variability by cardiac parasympathetic nerve activity during voluntary static exercise in humans with tetraplegia
Authors: Takahashi Makoto , Matsukawa Kanji , Nakamoto Tomoko , Tsuchimochi Hirotsugu , Sakaguchi Akihiro , Kawaguchi Kotaro , Onari Kiyoshi
Published: August 2007

Heart rate (HR) is controlled solely by via cardiac parasympathetic outflow in tetraplegic individuals, who lack supraspinal control of sympathetic outflows and circulating catecholamines but have intact vagal pathways. A high-frequency component (HF; at 0.15–0.40 Hz) of the power spectrum of HR variability and its relative value against total power (HF/Total) were assessed using a wavelet transform to identify cardiac parasympathetic outflow. The relative contribution of cardiac parasympathetic and sympathetic outflows to controlling HR was estimated by comparing the HF/Total-HR relationship between age-matched tetraplegic and normal men. Six tetraplegic men with complete cervical spinal cord injury performed static arm exercise at 35% of the maximal voluntary contraction until exhaustion. Although resting cardiac output and arterial blood pressure were lower in tetraplegic than normal subjects, HR, HF, and HF/Total were not statistically different between the two groups. When tetraplegic subjects developed the same force during exercise as normal subjects, HF and HF/Total decreased to 67–90% of the preexercise control and gradually recovered 1.5 min after exercise. The amount and time course of the changes in HF/Total during and after exercise coincided well between both groups. In contrast, the increase in HR at the start of exercise was blunted in tetraplegic compared with normal subjects, and the HR recovery following exercise was also delayed. It is likely that, although the withdrawal response of cardiac parasympathetic outflow is preserved in tetraplegic subjects, sympathetic decentralization impairs the rapid acceleration of HR at the onset of exercise and the rapid deceleration following exercise.
Acute Local Tolerability of Acidic Aqueous Vehicles Delivered via Respimat® Soft Mist™ Inhaler in Hyperreactive Asthma Patients
Authors: Leclerc V. , Lafferre M. , Pavia D.
Published: August 2007

Background:Acidic inhalers can be associated with increased adverse reactions. Objectives: This study aimed to determine the acute local tolerability of acidic aqueous placebo formulations delivered via Respimat® Soft Mist™ Inhaler (SMI) and placebo chlorofluorocarbon metered dose inhaler (CFC-MDI).Methods: A single-dose (four inhalations), randomized, double-blind within Respimat SMI device, four-way crossover study in asthma patients with documented bronchial hyperresponsiveness was used. Patients received acidic placebo solutions [pH 2.7, 3.4 or 7.0 (neutral)], delivered via Respimat SMI or placebo CFC-MDI. The primary endpoint was the largest decrease in forced expiratory volume in 1 s (FEV1) from baseline to 0–30 min after dosing. Secondary endpoints included spirometry, paradoxical bronchoconstriction (defined as a fall in FEV1 ≧15% below baseline within 30 min of dosing), cough episodes and adverse events.Results: Thirty-two patients were included in the per-protocol population (mean age 27 years, 62.5% males). The mean percentage decrease in FEV1 was comparable between treatment groups: –1.6% (Respimat SMI pH 2.7), –1.8% (Respimat SMI pH 7.0), –1.9% (CFC-MDI), and –2.3% (Respimat SMI pH 3.4); no patient experienced paradoxical bronchoconstriction. The mean number of cough episodes was significantly lower in the Respimat SMI pH 2.7 group versus CFC-MDI (p = 0.0165). No patient used rescue medication. Only 3 patients experienced at least one adverse event. Conclusions: The Respimat SMI pH 2.7 placebo solution does not induce adverse events in these patients. Compared with the CFC-MDI placebo suspension, Respimat SMI is a well-tolerated inhaled medication delivery system that can accommodate medication formulations with a wide range of pH solutions.
Links Between Adipose Tissue and Thrombosis in the Mouse
Authors: Bodary Peter F.
Published: August 2007

Obesity has become a global epidemic and carries a considerable negative impact in regard to quality of life and life expectancy. A primary problem is that obese individuals are at increased risk of suffering from cardiovascular disease complications such as myocardial infarction and stroke. Because fat accumulation is a consistent aspect of obesity, mechanisms that may link adipose tissue to cardiovascular disease complications should be considered. Proteins expressed from adipose tissue, known as adipokines, are hypothesized to have important effects on the progression and incidence of cardiovascular disease complications. This review examines the evidence that adipokines play a direct role in vascular thrombosis, an important event in cardiovascular disease complications.
Transcriptional Activation of Hepatic ACSL3 and ACSL5 by Oncostatin M Reduces Hypertriglyceridemia Through Enhanced β-Oxidation
Authors: Zhou Yue , Abidi Parveen , Kim Aekyong , Chen Wei , Huang Ting-Ting , Kraemer Fredric B. , Liu Jingwen
Published: August 2007

Objective—

In our previous studies that examined in vivo activities of oncostatin M (OM) in upregulation of hepatic LDL receptor (LDLR) expression, we observed reductions of LDL-cholesterol and triglyceride (TG) levels in OM-treated hyperlipidemic hamsters. Interestingly, the OM effect of lowering plasma TG was more pronounced than LDL-cholesterol reduction, suggesting additional LDLR-independent actions. Here, we investigated mechanisms underlying the direct TG-lowering effect of OM.

Methods and Results—

We demonstrate that OM activates transcription of long-chain acyl-coenzymeA (CoA) synthetase isoforms 3 and 5 (ACSL3, ACSL5) in HepG2 cells through the extracellular signal-regulated kinase (ERK) signaling pathway. Increased acyl-CoA synthetase activities in OM-stimulated HepG2 cells and in livers of OM-treated hamsters are associated with decreased TG accumulation and increased fatty acid β-oxidation. We further show that overexpression of ACSL3 or ACSL5 alone in the absence of OM led to fatty acid partitioning into β-oxidation. Importantly, we demonstrate that transfection of siRNAs targeted to ACSL3 and ACSL5 abrogated the enhancing effect of OM on fatty acid oxidation in HepG2 cells.

Conclusions—

These new findings identify ACSL3 and ACSL5 as OM-regulated genes that function in fatty acid metabolism and suggest a novel cellular mechanism by which OM directly lowers the plasma TG in hyperlipidemic animals through stimulating the transcription of ACSL specific isoforms in the liver.
Sphingosine-1-Phosphate Analogue FTY720 Causes Lymphocyte Redistribution and Hypercholesterolemia in ApoE-Deficient Mice
Authors: Klingenberg Roland , Nofer Jerzy-Roch , Rudling Mats , Bea Florian , Blessing Erwin , Preusch Michael , Grone Hermann J. , Katus Hugo A. , Hansson Göran K. , Dengler Thomas J.
Published: August 2007

Objective—

Resident immune cells are a hallmark of atherosclerotic lesions. The sphingolipid analogue drug FTY720 mediates retrafficking of immune cells and inhibits their homing to inflammatory sites. We have evaluated the effect of FTY720 on atherogenesis and lipid metabolism.

Methods and Results—

ApoE
−/−
mice on a normal laboratory diet received oral FTY720 for 12 weeks, which led to a 2.4-fold increase in serum cholesterol (largely VLDL fraction) and a 1.8-fold increase in hepatic HMGCoA reductase mRNA. FTY720 increased plasma sphingosine-1-phosphate and induced marked peripheral blood lymphopenia. A discoordinate modulation of B, T and monocyte cell numbers was found in peripheral lymphoid organs. Overall depletion of T cells was accompanied by a relative (2-fold) increase in regulatory T cell content paralleled by a similar increase in effector memory T cells (CD4+CD44hiCD62lo) as absolute numbers of both subpopulations remained essentially unchanged. Lymphocyte function was unaltered as indicated by anti-OxLDL antibodies and T cell proliferation. There were no changes in atherosclerotic lesions in early and established atherosclerosis.

Conclusions—

FTY720 mediated peripheral lymphocyte depletion and retrafficking without altering function and overall balance of pro- and antiatherogenic lymphocyte populations. A net decrease in lymphocyte numbers occurred concomitantly with a more proatherogenic hypercholesterolemia resulting in unaltered atherogenesis.
Studies on the Cholesterol-Free Mouse
Authors: Heverin Maura , Meaney Steve , Brafman Anat , Shafir Millicent , Olin Maria , Shafaati Marjan , von Bahr Sara , Larsson Lilian , Lövgren-Sandblom Anita , Diczfalusy Ulf , Parini Paolo , Feinstein Elena , Björkhem Ingemar
Published: August 2007

Objective—

Characterization of cholesterol homeostasis in male mice with a genetic inactivation of 3β-hydroxysteroid-Δ
24
-reductase, causing replacement of almost all cholesterol with desmosterol.

Methods and Results—

There was an increase in hepatic sterol synthesis and markedly increased fecal loss of neutral sterols. Fecal excretion of bile acids was similar in knockout mice and in controls. The composition of bile acids was changed, with reduced formation of cholic acid. It was shown that both Cyp7a1 and Cyp27a1 are active toward desmosterol, consistent with the formation of normal bile acids from this steroid. The levels of plant sterols were markedly reduced. Hepatic mRNA levels of 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase, Srebp-1c, Srebp-2, Cyp7a1, Abcg5, Abcg8, and Fas were all significantly increased.

Conclusions—

The changes in hepatic mRNA levels in combination with increased biliary and fecal excretion of neutral steroids, reduced tissue levels of plant sterols, increased plasma levels of triglyceride-rich VLDL, are consistent with a strong activation of LXR-targeted genes. The markedly increased fecal loss of neutral sterols may explain the fact that the Dhcr24
−/−
mice do not accumulate dietary cholesterol. The study illustrates the importance of the integrity of the cholesterol structure—presence of a double bond in the steroid side-chain is compatible with life but is associated with serious disturbances in sterol homeostasis.
Association of OAZ1 Gene Polymorphisms With Subclinical and Clinical Vascular Events
Authors: Dumont Julie , Zureik Mahmoud , Bauters Christophe , Grupposo Marie-Catherine , Cottel Dominique , Montaye Michèle , Hamon Martial , Ducimetière Pierre , Amouyel Philippe , Brousseau Thierry
Published: August 2007

Objective—

Proliferation and migration of vascular smooth muscle cells (VSMCs) are striking features shared by vascular ageing, atherosclerosis, and in-stent restenosis. VSMC biology depends in part on polyamines whose metabolism is closely regulated by ornithine decarboxylase antizyme 1 (OAZ1). Therefore, we sought for association between OAZ1 gene polymorphisms and various outcomes involving VSMC proliferation.

Methods and Results—

Systematic screening of the OAZ1 gene enabled to detect 21 variants. The impact of 4 selected tag polymorphisms (+849C/T, +851G/T, +1804G/A, and +2222A/G) was evaluated in 3 independent association studies. In a sample of 205 patients, the +2222G allele was associated with an increased risk of 6-month coronary in-stent restenosis (OR [95%CI]=2.1 [1.2 to 3.6];
P
=0.0071). In a sample of 1001 subjects participating to the EVA study, the +2222G allele was longitudinally associated with a 4-year increase in common carotid intima-media thickness (
P
=0.047). In a case-control study (466 cases versus 466 controls), the risk of coronary heart disease associated with the +2222G allele was 1.3 (95%CI=[1.1 to 1.6];
P
=0.026). No other significant association was consistently detected.

Conclusions—

We identified the
OAZ1
+2222A/G polymorphism as a potential genetic marker of vascular events. Our findings strengthen the hypothesis that the polyamine metabolism plays a role in vascular diseases.
Segregation of Platelet Aggregatory and Procoagulant Microdomains in Thrombus Formation
Authors: Munnix Imke C.A. , Kuijpers Marijke J.E. , Auger Jocelyn , Thomassen Christella M.L.G.D. , Panizzi Peter , van Zandvoort Marc A.M. , Rosing Jan , Bock Paul E. , Watson Steve P. , Heemskerk Johan W.M.
Published: August 2007

Objective—

Platelets play a dual role in thrombosis by forming aggregates and stimulating coagulation. We investigated the commitment of platelets to these separate functions during collagen-induced thrombus formation in vitro and in vivo.

Methods and Results—

High-resolution 2-photon fluorescence microscopy revealed that in thrombus formation under flow, fibrin(ogen)-binding platelets assembled into separate aggregates, whereas distinct patches of nonaggregated platelets exposed phosphatidylserine. The latter platelet population had inactivated αIIbβ3 integrins and displayed increased binding of coagulation factors. Coated platelets, expressing serotonin binding sites, were not identified as a separate population. Thrombin generation and coagulation favored the transformation to phosphatidylserine-exposing platelets with inactivated integrins and reduced adhesion. Prolonged tyrosine phosphorylation in vitro resulted in secondary downregulation of active αIIbβ3.

Conclusions—

These results lead to a new spatial model of thrombus formation, in which aggregated platelets ensure thrombus stability, whereas distinct patches of nonaggregated platelets effectuate procoagulant activity and generate thrombin and fibrin. Herein, the hemostatic activity of a developing thrombus is determined by the balance in formation of proaggregatory and procoagulant platelets. This balance is influenced by antiplatelet and anticoagulant medication.
Thrombospondin-1 Activates Medial Smooth Muscle Cells and Triggers Neointima Formation Upon Mouse Carotid Artery Ligation
Authors: Moura Rute , Tjwa Marc , Vandervoort Petra , Cludts Katrien , Hoylaerts Marc F.
Published: August 2007

Objective—

Thrombospondin-1 (TSP1) is described as a positive regulator of vascular smooth muscle growth in cell culture. However, insight into the in vivo effects of TSP1 on smooth muscle cell (SMC) function is lacking.

Methods and Results—

We analyzed wild-type (WT) and TSP1-deficient (
Tsp1
−/−
) mice in a carotid artery ligation model, in which neointimal lesions form without overt mechanical damage to the endothelium. On ligation, the expression of TSP1 increased strongly in the matrix of neointima and adventitia. In the early phase after ligation (day 3 to 7), activation, proliferation, and migration of medial SMCs were delayed and impaired in
Tsp1
−/−
mice, in parallel with defective upregulation of metalloproteinase (MMP)-2 activity. As a result,
Tsp1
−/−
arteries developed smaller neointimal lesions, a thicker media but comparably attenuated patency as in WT arteries, 28 days after ligation. Furthermore, medial and neointimal SMCs in
Tsp1
−/−
mice produced more collagen, more osteopontin, and displayed weaker smooth muscle actin staining than WT SMCs, indicative of a modified SMC phenotype in
Tsp1
−/−
mice.

Conclusions—

Arterial SMC activation in the absence of TSP1 is delayed and dysregulated, reducing neointima formation, on mild vascular injury.
Angptl4 Upregulates Cholesterol Synthesis in Liver via Inhibition of LPL- and HL-Dependent Hepatic Cholesterol Uptake
Authors: Lichtenstein Laeticia , Berbée Jimmy F.P. , van Dijk Susan J. , van Dijk Ko Willems , Bensadoun André , Kema Ido P. , Voshol Peter J. , Müller Michael , Rensen Patrick C.N. , Kersten Sander
Published: August 2007

Background—

Dysregulation of plasma lipoprotein levels may increase the risk for atherosclerosis. Recently, angiopoietin-like protein 4, also known as fasting-induced adipose factor Fiaf, was uncovered as a novel modulator of plasma lipoprotein metabolism. Here we take advantage of the fasting-dependent phenotype of Angptl4-transgenic (Angptl4-Tg) mice to better characterize the metabolic function of Angptl4.

Methods and Results—

In 24-hour fasted mice, Angptl4 overexpression increased plasma triglycerides (TG) by 24-fold, which was attributable to elevated VLDL-, IDL/LDL- and HDL-TG content. Angptl4 overexpression decreased post-heparin LPL activity by stimulating conversion of endothelial-bound LPL dimers to circulating LPL monomers. In fasted but not fed state, Angptl4 overexpression severely impaired LPL-dependent plasma TG and cholesteryl ester clearance and subsequent uptake of fatty acids and cholesterol into tissues. Consequently, hepatic cholesterol content was significantly decreased, leading to universal upregulation of cholesterol and fatty acid synthesis pathways and increased rate of cholesterol synthesis.

Conclusions—

The hypertriglyceridemic effect of Angptl4 is attributable to inhibition of LPL-dependent VLDL lipolysis by converting LPL dimers to monomers, and Angptl4 upregulates cholesterol synthesis in liver secondary to inhibition of LPL- and HL-dependent hepatic cholesterol uptake.
Recurrent Hemorrhagic Stroke in Children
Authors: Fullerton Heather J. , Wu Yvonne W. , Sidney Stephen , Claiborne Johnston S.
Published: August 2007

Background and Purpose—

Although hemorrhagic strokes (HS) account for half of all strokes in children, rates and predictors of recurrent HS have not been studied.

Methods—

We collected data on all documented cases of HS (intracerebral hemorrhage, subarachnoid hemorrhage, and intraventricular hemorrhage, except neonatal intraventricular hemorrhage), among 2.3 million children (<20 years) enrolled in a Northern Californian health maintenance organization from January 1993 to December 2004. Using Kaplan-Meier survival analyses censoring at death or loss to follow-up, we determined rates of recurrent HS. Log rank tests were used for bivariate comparisons.

Results—

Among 116 children with atraumatic incident HS followed for a mean of 4.2 years, 11 had a recurrent HS at a median of 3.1 months (range 7 days to 5.7 years), yielding an overall 5-year cumulative recurrence rate (CRR) of 10% (95% CI, 58% to 18%). Sixty-four percent of recurrences were within the first 6 months. Whereas children with idiopathic HS (n=29) had no recurrences, children with structural lesions (vascular malformations or tumors) had a 5-year cumulative recurrence rate of 13% (95% CI, 7% to 25%; 9 recurrences among 71 children;
P
<0.05 compared with idiopathic). Children with medical etiologies (eg, thrombocytopenia, hypertension) had a 5-year cumulative recurrence rate of 13% (95% CI, 3% to 41%; 2 recurrences among 16 children), but the recurrences were within the first week.

Conclusions—

Overall, 1 in 10 children with HS experienced a recurrence within 5 years, despite available therapies. Whereas idiopathic HS rarely recurred, and HS due to medical etiologies tended to recur acutely, children with structural lesions had a high and prolonged risk for recurrence.
Preoperative Cerebral Hemodynamic Impairment and Reactive Oxygen Species Produced During Carotid Endarterectomy Correlate With Development of Postoperative Cerebral Hyperperfusion
Authors: Suga Yasunori , Ogasawara Kuniaki , Saito Hideo , Komoribayashi Nobukazu , Kobayashi Masakazu , Inoue Takashi , Otawara Yasunari , Ogawa Akira
Published: August 2007

Background and Purpose—

The purpose of the present study was to determine whether preoperative cerebral hemodynamic impairment and reactive oxygen species produced during carotid endarterectomy (CEA) correlate with development of postoperative cerebral hyperperfusion.

Methods—

Concentrations of malondialdehyde-modified low-density lipoprotein (MDA-LDL), a biochemical marker of oxidative damage, were measured in serum samples obtained from 90 patients undergoing CEA for ipsilateral ICA stenosis (>70%). Serum samples were obtained from a venous catheter inserted into the ipsilateral jugular bulb before clamping of the internal carotid artery (ICA), 10 minutes after clamping of the ICA, and 5 and 20 minutes after declamping of the ICA. Cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) to acetazolamide were also measured using single-photon emission computed-tomography before CEA. In addition, CBF was measured postoperatively.

Results—

Hyperperfusion (CBF increase >100% compared with preoperative values) was observed immediately after CEA in 12 patients (13%). Logistic regression analysis demonstrated that reduced preoperative CVR (95% CIs, 1.053 to 1.453;
P
=0.0097) and an increase in MDA-LDL (calculated as a percentage of the preclamp values) after ICA declamping (95% CIs, 0.862 to 0.980;
P
=0.0098) were significantly associated with development of postoperative cerebral hyperperfusion among the variables tested. Ten of 11 patients with reduced preoperative CVR and increased MDA-LDL after ICA declamping developed post-CEA hyperperfusion, and 2 of these patients developed cerebral hyperperfusion syndrome.

Conclusions—

Both preoperative cerebral hemodynamic impairment and reactive oxygen species produced during surgery correlate with development of cerebral hyperperfusion after CEA.