bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of a Mannose Utilization System in
Bacillus subtilis
Authors: Sun Tianqi , Altenbuchner Josef
Published: February 2010

The mannose operon of
Bacillus subtilis
consists of three genes,
manP
,
manA
, and
yjdF
, which are responsible for the transport and utilization of mannose. Upstream and in the same orientation as the mannose operon a regulatory gene,
manR
, codes for a transcription activator of the mannose operon, as shown in this study. Both mannose operon transcription and
manR
transcription are inducible by mannose. The presence of mannose resulted in a 4- to 7-fold increase in expression of
lacZ
from the
manP
promoter (

P
manP

) and in a 3-fold increase in expression of
lacZ
from the
manR
promoter (

P
manR

). The transcription start sites of
manPA-yjdF
and
manR
were determined to be a single A residue and a single G residue, respectively, preceded by −10 and −35 boxes resembling a vegetative σ
A
promoter structure. Through deletion analysis the target sequences of ManR upstream of

P
manP

and

P
manR

were identified between bp −80 and −35 with respect to the transcriptional start site of both promoters. Deletion of
manP
(mannose transporter) resulted in constitutive expression from both the

P
manP

and

P
manR

promoters, indicating that the phosphotransferase system (PTS) component EII
Man
has a negative effect on regulation of the mannose operon and
manR
. Moreover, both

P
manP

and

P
manR

are subject to carbon catabolite repression (CCR). By constructing protein sequence alignments a DNA binding motif at the N-terminal end, two PTS regulation domains (PRDs), and an EIIA- and EIIB-like domain were identified in the ManR sequence, indicating that ManR is a PRD-containing transcription activator. Like findings for other PRD regulators, the phosphoenolpyruvate (PEP)-dependent phosphorylation by the histidine protein HPr via His15 plays an essential role in transcriptional activation of

P
manP

and

P
manR

. Phosphorylation of Ser46 of HPr or of the homologous Crh protein by HPr kinase and formation of a repressor complex with CcpA are parts of the
B. subtilis
CCR system. Only in the double mutant with an HPr Ser46Ala mutation and a
crh
knockout mutation was CCR strongly reduced. In contrast,

P
manR

and

P
manP

were not inducible in a
ccpA
deletion mutant.
ASPECTS OF SUPERSYMMETRIC FIELD THEORIES
Authors: INTRILIGATOR KENNETH
Published: February 2010

We discuss the constraints on SUSY field theories and their IR phases, including bounds on the ratio a/c. Proceeding of talk at Shifmania, in honor of Misha Shifman's 60th birthday.
INTRAGRANULAR LATTICE MISORIENTATION MAPPING BY SYNCHROTRON X-RAY MICRO-BEAMS: LAUE VS ENERGY-RESOLVED LAUE VS MONOCHROMATIC RECIPROCAL SPACE ANALYSIS
Authors: HOFMANN FELIX , ABBEY BRIAN , SONG XU , DOLBNYA IGOR , KORSUNSKY ALEXANDER M
Published: February 2010

Laue diffraction, energy scanning and reciprocal space mapping are three micro-beam synchrotron X-ray diffraction techniques allowing the investigation of local misorientation induced by the dislocation substructure. In this paper a comparison between the three methods is presented, based on the mapping of a single 311 reflection from a grain within a Ni polycrystal specimen deformed to a tensile plastic strain of ~9%. Qualitatively it is observed that the maps obtained by different techniques all share the same features, although some deviations exist due to experimental limitations associated with each of the measurement techniques.
Intrinsic sex-specific differences in microvascular endothelial cell phosphodiesterases
Authors: Wang Jianjie , Bingaman Susan , Huxley Virginia H.
Published: February 2010

The importance of gonadal hormones in the regulation of vascular function has been documented. An alternate and essential contribution of the sex chromosomes to sex differences in vascular function is poorly understood. We reported previously sex differences in microvessel permeability ( Ps) responses to adenosine that were mediated by the cAMP signaling pathway (Wang J, PhD thesis, 2005; Wang J and Huxley V, Proceedings of the VIII World Congress of Microcirculation, 2007 ; Wang J and Huxley VH, Am J Physiol Heart Circ Physiol 291: H3094–H3105, 2006). The two cyclic nucleotides, cAMP and cGMP, central to the regulation of vascular barrier integrity, are hydrolyzed by phosphodiesterases (PDE). We hypothesized that microvascular endothelial cells (EC) would retain intrinsic and inheritable sexually dimorphic genes with respect to the PDEs modulating EC barrier function. Primary cultured microvascular EC from skeletal muscles isolated from male and female rats, respectively, were used. SRY (a sex-determining region Y gene) mRNA expression was observed exclusively in male, not female, cells. The predominant isoform among PDE1–5, present in both XY and XX EC, was PDE4. Expression mRNA levels of PDE1A (male > female) and PDE3B (male < female) were sex dependent; PDE2A, PDE4D, and PDE5A were sex independent. Barrier function, Ps, was determined from measures of albumin flux across confluent primary cultured microvessel XY and XX EC monolayers. Consistent with intact in situ microvessels, basal monolayer Ps did not differ between XY (1.7 ± 0.2 × 10−6 cm/s; n = 8) and XX (1.8 ± 0.1 × 10−6 cm/s; n = 10) EC. Cilostazol, a PDE3 inhibitor, reduced (11%, P < 0.05) Ps in XX, not XY, cells. These findings demonstrate the presence and maintenance of intrinsic sex-related differences in gene expression and cellular phenotype by microvascular EC in a gonadal-hormone-free environment. Furthermore, intrinsic cell-sex likely contributes significantly to sexual dimorphism in cardiovascular function.
Inhibition of telomerase activity alters tight junction protein expression and induces transendothelial migration of HIV-1-infected cells
Authors: Huang Wen , Rha Geun Bae , Chen Lei , Seelbach Melissa J. , Zhang Bei , András Ibolya E. , Bruemmer Dennis , Hennig Bernhard , Toborek Michal
Published: February 2010

Telomerase, via its catalytic component telomerase reverse transcriptase (TERT), extends telomeres of eukaryotic chromosomes. The importance of this reaction is related to the fact that telomere shortening is a rate-limiting mechanism for human life span that induces cell senescence and contributes to the development of age-related pathologies. The aim of the present study was to evaluate whether the modulation of telomerase activity can influence human immunodeficiency virus type 1 (HIV-1)-mediated dysfunction of human brain endothelial cells (hCMEC/D3 cells) and transendothelial migration of HIV-1-infected cells. Telomerase activity was modulated in hCMEC/D3 cells via small interfering RNA-targeting human TERT (hTERT) or by using a specific pharmacological inhibitor of telomerase, TAG-6. The inhibition of hTERT resulted in the upregulation of HIV-1-induced overexpression of intercellular adhesion molecule-1 via the nuclear factor-κB-regulated mechanism and induced the transendothelial migration of HIV-1-infected monocytic U937 cells. In addition, the blocking of hTERT activity potentiated a HIV-induced downregulation of the expression of tight junction proteins. These results were confirmed in TERT-deficient mice injected with HIV-1-specific protein Tat into the cerebral vasculature. Further studies revealed that the upregulation of matrix metalloproteinase-9 is the underlying mechanisms of disruption of tight junction proteins in hCMEC/D3 cells with inhibited TERT and exposed to HIV-1. These results indicate that the senescence of brain endothelial cells may predispose to the HIV-induced upregulation of inflammatory mediators and the disruption of the barrier function at the level of the brain endothelium.
Mechanisms for lung function impairment and airway hyperresponsiveness following chronic hypoxia in rats
Authors: Habre Walid , Jánosi Tibor Z. , Fontao Fabienne , Meyers Carole , Albu Gergely , Pache Jean-Claude , Peták Ferenc
Published: February 2010

Although chronic normobaric hypoxia (CH) alters lung function, its potential to induce bronchial hyperreactivity (BHR) is still controversial. Thus the effects of CH on airway and tissue mechanics separately and changes in lung responsiveness to methacholine (MCh) were investigated. To clarify the mechanisms, mechanical changes were related to end-expiratory lung volume (EELV), in vivo results were compared with those in vitro, and lung histology was assessed. EELV was measured plethysmographically in two groups of rats exposed to 21 days of CH (11% O2) or to normoxia. Total respiratory impedance was measured under baseline conditions and following intravenous MCh challenges (2–18 μg·kg−1·min−1). The lungs were then excised and perfused, and the pulmonary input impedance was measured, while MCh provocations were repeated under a pulmonary capillary pressure of 5, 10, and 15 mmHg. Airway resistance, tissue damping, and elastance were extracted from the respiratory impedance and pulmonary input impedance spectra. The increases in EELV following CH were associated with decreases in airway resistance, whereas tissue damping and elastance remained unaffected. CH led to the development of severe BHR to MCh (206 ± 30 vs. 95 ± 24%, P < 0.001), which was not detectable when the same lungs were studied in vitro at any pulmonary capillary pressure levels maintained. Histology revealed pulmonary arterial vascular remodeling with overexpression of α-smooth muscle actin antibody in the bronchial wall. These findings suggest that, despite the counterbalancing effect of the increased EELV, BHR develops following CH, only in the presence of intact autonomous nervous system. Thus neural control plays a major role in the changes in the basal lung mechanics and responsiveness following CH.
Hyperoxia inhibits protein synthesis and increases eIF2α phosphorylation in the newborn rat lung
Authors: Konsavage Wesley , Zhang Lianqin , Vary Thomas , Shenberger Jeffrey S.
Published: February 2010

Prolonged exposure to hyperoxia contributes to aberrant lung growth in premature infants. Of the deleterious effects induced by hyperoxia, alterations in protein synthesis are likely to be of great importance to the developing lung. Regulation of mRNA translation occurs predominantly at the level of initiation via control of mRNA/ribosome binding by proteins known as eukaryotic initiation factors (eIF). Although hyperoxia is known to suppress mRNA translation in adult lungs, little is known regarding the effects in newborns or the involved mechanism. This study was performed to determine the effect of exposure to 95% O2on pulmonary protein synthesis in 4-day-old Sprague-Dawley rat pups. We found that hyperoxia suppressed the incorporation of [3H]phenylalanine into lung protein over time, resulting in a 23% reduction after 72 h compared with pups reared in room air. This effect was preceded by a shift in total lung RNA to lower order polysomes. Hyperoxia increased eIF4G-eIF4E binding, a surrogate maker of eIF4F complex assembly, and initially activated, then suppressed, the phosphorylation of ribosomal S6 kinase 1 and ribosomal S6 protein, downstream targets of mammalian target of rapamycin. Exposure to 95% O2enhanced the phosphorylation of the translational repressor eIF2α in whole lung extracts and the immunoreactivity of phosphorylated eIF2α in epithelial cells. Cell culture studies further demonstrated that hyperoxia increases eIF2α phosphorylation in lung epithelial cells, but not in lung fibroblasts. These findings illustrate that hyperoxia-induced suppression of mRNA translation in the newborn lung is accompanied by increased phosphorylation of eIF2α in the epithelium.
Upregulation of Oct-4 isoforms in pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension
Authors: Firth Amy L. , Yao Weijuan , Remillard Carmelle V. , Ogawa Aiko , Yuan Jason X.-J.
Published: February 2010

Oct-4 is a transcription factor considered to be one of the defining pluripotency markers in embryonic stem cells. Its expression has also been demonstrated in adult stem cells, tumorigenic cells, and, most recently and controversially, in somatic cells. Oct-4 pseudogenes also contribute to carcinogenesis. Oct-4 may be involved in the excessive proliferation of pulmonary arterial smooth muscle cells (PASMC) in patients with idiopathic pulmonary arterial hypertension (IPAH), contributing to the pathogenesis of IPAH. In this study, we show that Oct-4 isoforms are upregulated in IPAH-PASMC. Human embryonic stem cells (H9 line) and human PASMC from normotensive subjects were used throughout the investigation as positive and negative controls. In addition to significant upregulation of Oct-4 in a population of IPAH-PASMC, HIF-2α, a hypoxia-inducible transcription factor that has been shown to bind to the Oct-4 promoter and induces its expression and transcriptional activity, was also increased. Interestingly, a substantial upregulation of Oct-4 isoforms and HIF-2α was also observed in normal PASMC exposed to chronic hypoxia. In conclusion, the data suggest that both Oct-4 isoforms are upregulated and potentially have a significant role in the development of vascular abnormalities associated with the pathogenesis of IPAH and in pulmonary hypertension triggered by chronic hypoxia.
Reduction of collagen VII anchoring fibrils in the airway basement membrane zone of infant rhesus monkeys exposed to house dust mite
Authors: Evans Michael J. , Fanucchi Michelle V. , Miller Lisa A. , Carlson Melinda A. , Nishio Susan J. , Hyde Dallas M.
Published: February 2010

Collagen VII anchoring fibrils in the basement membrane zone (BMZ) are part of a supracellular anchoring network that attaches the epithelium to the BMZ. Sloughing of airway epithelium in asthmatics (creola bodies) is a pathology associated with the supracellular anchoring network. In a rhesus monkey model of house dust mite (HDM)-induced allergic asthma, we found increased deposition of collagen I in the BMZ. In this study, we determine whether HDM also affected deposition of collagen VII in the BMZ. In the developing airway of rhesus monkeys, the width of collagen VII anchoring fibrils in the BMZ was 0.02 ± 0.04 μm at 1 mo of age. At 6 mo the width had increased to 1.28 ± 0.34 μm and at 12 mo 2.15 ± 0.13 μm. In animals treated with HDM, we found a 42.2% reduction in the width of collagen VII layer in the BMZ at 6 mo (0.74 ± 0.15 μm; P < 0.05). During recovery, the rate of collagen VII deposition returned to normal. However, the amount of collagen VII lost was not recovered after 6 mo. We concluded that normal development of the collagen VII attachment between the epithelium and BMZ occurs in coordination with development of the BMZ. However, in HDM-treated animals, the collagen VII attachment with the epithelium was significantly reduced. Such a reduction in collagen VII may weaken the supracellular anchoring network and be associated with sloughing of the epithelium and formation of creola bodies in asthmatics.
Inflammatory stimulation and hypoxia cooperatively activate HIF-1α in bronchial epithelial cells: involvement of PI3K and NF-κB
Authors: Jiang Hong , Zhu Ye Sen , Xu Hui , Sun Yu , Li Qi Fang
Published: February 2010

The transcription factor hypoxia-inducible factor (HIF)-1 plays a central physiological role in oxygen and energy homeostasis, and is activated during hypoxia by stabilization of the subunit HIF-1α. Recent studies have demonstrated that non-hypoxic stimuli can also activate HIF-1α in a cell-specific manner. Here, we demonstrate that stimulation of BEAS-2B cells and primary human bronchial epithelial cells by proinflammatory cytokines TNFα/IL-4 strongly induced expression and transcriptional activity of HIF-1α under normoxic conditions and amplified hypoxic HIF-1α activation. TNFα/IL-4 stimulated de novo HIF-1α gene transcription and translation rather than affected HIF-1α protein degradation and mRNA decay process. The activation of HIF-1α by TNFα/IL-4 was countered by the phosphoinositol 3-kinase (PI3K) inhibitor LY-294002 and rapamycin, an antagonist of mammalian target of rapamycin (mTOR), but not by inhibition of the MAPK pathway. In line, TNFα/IL-4 also activated NF-κB, whereas blocking of NF-κB by an inhibitor or silencing NF-κB subunit p65 attenuated HIF-1α activation by TNFα/IL-4. We also found the collaborative induction of VEGF, a potent angiogenic factor required for airway remodeling, by TNFα/IL-4 and hypoxia partially via HIF-1α pathway in BEAS-2B cells. This study reports the previously unsuspected collaborative regulation of HIF-1α by TNFα/IL-4 and hypoxia in bronchial epithelial cells partially via PI3K-mTOR and NF-κB pathway, and thereby will lead to the elucidation of the importance of HIF-1 in integrating inflammatory and hypoxic response in the pathogenesis of airway diseases.
Aggressive Trimodality Therapy for T1N2M1 Nonsmall Cell Lung Cancer with Synchronous Solitary Brain Metastasis: Case Report and Rationale
Authors: Showalter Timothy N. , Lin Alexander
Published: February 2010

Aggressive treatment, including resection of both metastasis and primary tumor, has been studied for non-small cell lung cancer patients with synchronous solitary brain metastasis. Involvement of mediastinal lymph nodes is considered a poor prognostic factor and a contraindication to surgical resection of the primary lung tumor after treatment for brain metastasis. Here we present the case of a patient who presented with a Stage IV T1N2M1 non-small cell lung cancer with synchronous solitary brain metastasis. He is alive and without evidence of disease two years after aggressive, multimodality treatment that included craniotomy, whole-brain radiation therapy, thoracic surgery, chemotherapy, and mediastinal radiation therapy.
Mouse Aorta Smooth Muscle Cells Differentiate Into Lymphoid Tissue Organizer-Like Cells on Combined Tumor Necrosis Factor Receptor-1/Lymphotoxin β-Receptor NF-κB Signaling
Authors: Lötzer Katharina , Döpping Sandra , Connert Sabine , Gräbner Rolf , Spanbroek Rainer , Lemser Birgit , Beer Michael , Hildner Markus , Hehlgans Thomas , van der Wall Michael , Mebius Reina E. , Lovas Agnes , Randolph Gwendalyn J. , Weih Falk , Habenicht Andreas J.R.
Published: February 2010

Objective—

Mouse aorta smooth muscle cells (SMC) express tumor necrosis factor receptor superfamily member 1A (TNFR-1) and lymphotoxin β-receptor (LTβR). Circumstantial evidence has linked the SMC LTβR to tertiary lymphoid organogenesis in hyperlipidemic mice. Here, we explored TNFR-1 and LTβR signaling in cultured SMC.

Methods and Results—

TNFR-1 signaling activated the classical RelA NF-κB pathway, whereas LTβR signaling activated the classical RelA and alternative RelB NF-κB pathways, and both signaling pathways synergized to enhance p100 inhibitor processing to the p52 subunit of NF-κB. Microarrays showed that simultaneous TNFR-1/LTβR activation resulted in elevated mRNA encoding leukocyte homeostatic chemokines CCL2, CCL5, CXCL1, and CX3CL1. Importantly, SMC acquired features of lymphoid tissue organizers, which control tertiary lymphoid organogenesis in autoimmune diseases through hyperinduction of CCL7, CCL9, CXCL13, CCL19, CXCL16, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1. TNFR-1/LTβR cross-talk resulted in augmented secretion of lymphorganogenic chemokine proteins. Supernatants of TNFR-1/LTβR–activated SMC markedly supported migration of splenic T cells, B cells, and macrophages/dendritic cells. Experiments with
ltbr
−/−
SMC indicated that LTβR-RelB activation was obligatory to generate the lymphoid tissue organizer phenotype.

Conclusion—

SMC may participate in the formation of tertiary lymphoid tissue in atherosclerosis by upregulation of lymphorganogenic chemokines involved in T-lymphocyte, B-lymphocyte, and macrophage/dendritic cell attraction.
D609 Inhibits Progression of Preexisting Atheroma and Promotes Lesion Stability in Apolipoprotein E
−/−
Mice
Authors: Zhang Lu , Zhao Jing , Su Le , Huang Bin , Wang Li , Su Hua , Zhang Yun , Zhang ShangLi , Miao JunYing
Published: February 2010

Objective—

Atherosclerosis is considered to be a chronic inflammatory disease. Previous research has demonstrated that phosphatidylcholine-specific phospholipase C (PC-PLC) plays critical roles in various inflammatory responses. However, the association between PC-PLC and atherosclerosis is undetermined. Therefore, we sought to investigate whether PC-PLC was implicated in atherosclerosis.

Methods and Results—

Immunofluorescence analysis revealed an upregulation of PC-PLC in the aortic endothelium from apolipoprotein E-deficient (apoE
−/−
) mice. PC-PLC level and activity were also increased in human umbilical vein endothelial cells in response to oxidized low-density lipoprotein treatment. Pharmacological blockade of PC-PLC by D609 inhibited the progression of preexisting atherosclerotic lesions in apoE
−/−
mice and changed the lesion composition into a more stable phenotype. Using a combination of pharmacological inhibition, polyclonal antibodies, confocal laser scanning microscopy and Western blotting, we demonstrated that PC-PLC was required for endothelial expression of lectin-like oxidized low-density lipoprotein receptor-1. In addition, D609 treatment significantly decreased the aortic endothelial expression of the vascular cell adhesion molecule-1 and the intercellular adhesion molecule-1. Furthermore, inhibition of PC-PLC in human umbilical vein endothelial cells reduced the oxidized low-density lipoprotein induced expression of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and monocyte chemotactic protein-1.

Conclusion—

Our data suggest that PC-PLC contributes to the progression of atherosclerosis.
Current Treatment of Venous Thromboembolism
Authors: Key Nigel S. , Kasthuri Raj S.
Published: February 2010

Venous thromboembolism, comprising deep vein thrombosis and pulmonary embolism, is a common disorder with at least 250 000 new events occurring each year in the United States alone. Treatment of venous thromboembolism includes anticoagulation, which is achieved initially with the use of a parenterally administered agent followed by a more prolonged course of treatment with an oral vitamin K antagonist. The duration of treatment depends on the clinical assessment of the benefit-to-risk ratio of prolonged anticoagulation versus the risk of recurrent events. In this review, we discuss some of the issues that we believe are among the most critical unanswered questions in the management of venous thromboembolism in the present era.
Inhibition of Factor XIa as a New Approach to Anticoagulation
Authors: Schumacher William A. , Luettgen Joseph M. , Quan Mimi L. , Seiffert Dietmar A.
Published: February 2010

The dose-limiting issue with available anticoagulant therapies is bleeding. Is there an approach that could provide antithrombotic protection with reduced bleeding? One hypothesis is that targeting proteases upstream from the common pathway provides a reduction in thrombin sufficient to impede occlusive thrombosis yet allows enough thrombin generation to support hemostasis. The impairment of intrinsic coagulation by selective inhibition of factor XI (FXI) leaves the extrinsic and common pathways of coagulation intact, making FXI a drug target. This concept is supported by the observation that human deficiency in FXI results in a mild bleeding disorder compared with other coagulation factor deficiencies, and that elevated levels of FXI are a risk factor for thromboembolic disease. Moreover, FXI knockout mice have reduced thrombosis with little effect on hemostasis. The results from genetic models have been supported by studies using neutralizing antibodies, peptide inhibitors, and small-molecule inhibitors. These agents impede thrombosis without affecting bleeding time in a variety of experimental animals, including primates. Together, these data strongly support FXIa inhibition as a viable method to increase the ratio of benefit to risk in an antithrombotic drug.
Magnetic Resonance Molecular Imaging of Thrombosis in an Arachidonic Acid Mouse Model Using an Activated Platelet Targeted Probe
Authors: Klink Ahmed , Lancelot Eric , Ballet Sébastien , Vucic Esad , Fabre Jean-Etienne , Gonzalez Walter , Medina Christelle , Corot Claire , Mulder Willem J.M. , Mallat Ziad , Fayad Zahi A.
Published: February 2010

Objective—

Atherosclerotic plaque rupture leads to acute thrombus formation and may trigger serious clinical events such as myocardial infarction or stroke. Therefore, it would be valuable to identify atherothrombosis and vulnerable plaques before the onset of such clinical events. We sought to determine whether the noninvasive in vivo visualization of activated platelets was effective when using a target-specific MRI contrast agent to identify thrombi, hallmarks of vulnerable or high-risk atherosclerotic plaques.

Methods and Results—

Inflammatory thrombi were induced in mice via topical application of arachidonic acid on the carotid. Thrombus formation was imaged with intravital fluorescence microscopy and molecular MRI. To accomplish the latter, a paramagnetic contrast agent (P975) that targets the glycoprotein α
IIb
β
3
, expressed on activated platelets, was investigated. The specificity of P975 for activated platelets was studied in vitro. In vivo, high spatial-resolution MRI was performed at baseline and longitudinally over 2 hours after injecting P975 or a nonspecific agent. The contralateral carotid, a sham surgery group, and a competitive inhibition experiment served as controls. P975 showed a good affinity for activated platelets, with an IC
50
(concentration of dose that produces 50% inhibition) value of 2.6 μmol/L. In thrombosed animals, P975 produced an immediate and sustained increase in MRI signal, whereas none of the control groups revealed any significant increase in MRI signal 2 hours after injection. More important, the competitive inhibition experiment with an α
IIb
β
3
antagonist suppressed the MRI signal enhancement, which is indicative for the specificity of P975 for the activated platelets.

Conclusion—

P975 allowed in vivo target-specific noninvasive MRI of activated platelets.
Periprocedural Anticoagulation Management of Patients With Venous Thromboembolism
Authors: McBane Robert D. , Wysokinski Waldemar E. , Daniels Paul R. , Litin Scott C. , Slusser Joshua , Hodge David O. , Dowling Nicole F. , Heit John A.
Published: February 2010

Objective—

Patients with venous thromboembolism (VTE) often require temporary warfarin interruption for an invasive procedure. The incidence of thromboembolism and bleeding related to periprocedural anticoagulation management of such patients is unknown.

Methods and Results—

In a protocol-driven, inception cohort design study, all VTE patients (n=775) referred for periprocedural anticoagulation management (1997–2007) were followed-up to estimate the 3-month cumulative incidence of thromboembolism and bleeding. Patients were stratified by thrombus acuity (acute, <30 days; subacute, 31–90 days; or chronic ≥91 days). Decisions to provide “bridging” low-molecular-weight heparin were based on estimated thromboembolism and bleeding risk. Low-molecular-weight heparin was more often administered in acute (87%) and subacute (81%) VTE compared to chronic VTE (59%;
P
<0.001). The 3-month cumulative incidence of thromboembolism (1.8%), major hemorrhage (1.8%), and mortality (1.7%) were low and did not differ by management strategy. Active cancer was the only independent predictor of thrombotic recurrence (HR, 4.86; 95% CI, 1.6–14.5;
P
=0.005), major hemorrhage (HR, 6.8; 95% CI, 2.1–21.7;
P
=0.001), and death (HR, 32.7; 95% CI, 4.3–251.2;
P
=0.0008).

Conclusion—

Thromboembolism, bleeding, and death among VTE patients in whom anticoagulation is temporarily interrupted for an invasive procedure is low. Cancer patients require particular care given their propensity for both clotting and bleeding.
Blockade of the Ras–Extracellular Signal–Regulated Kinase 1/2 Pathway Is Involved in Smooth Muscle 22α–Mediated Suppression of Vascular Smooth Muscle Cell Proliferation and Neointima Hyperplasia
Authors: Dong Li-Hua , Wen Jin-Kun , Liu George , McNutt Michael A. , Miao Sui-Bing , Gao Rui , Zheng Bin , Zhang Hailin , Han Mei
Published: February 2010

Objective—

Vascular smooth muscle cells (VSMCs) can switch between differentiated and dedifferentiated phenotypes, and this phenotype switch is believed to be essential for repair of vascular injury. We studied the inhibitory effect of smooth muscle 22α (SM22α) on VSMC proliferation in vitro and in vivo and explored the potential molecular mechanisms of this effect.

Methods and Results—

By using coimmunoprecipitation and glutathione
S
-transferase pull-down assays, we have shown that SM22α binds to Ras in SM22α-overexpressed VSMCs in the presence or absence of platelet-derived growth factor–BB stimulation. SM22α arrested cell cycle progression through segregation of Ras with Raf-1 and downregulation of the Raf-1–MEK1/2–extracellular signal–regulated kinase 1/2 mitogen-activated protein kinase signaling cascade. The inhibitory effect of SM22α on VSMC proliferation was verified in vivo. The infection of rat carotid arteries with recombinant adenovirus encoding SM22α inhibited neointimal hyperplasia via suppression of the Raf-1–MEK1/2–extracellular signal–regulated kinase 1/2 signaling pathway.

Conclusion—

These findings suggest that high expression of SM22α inhibits cell proliferation via reduction of the response to mitogen stimuli in VSMCs and provide a novel mechanism by which VSMCs maintain their contractile phenotype and resist mitogenic stimuli in an SM22α-dependent manner.
Oxidized Low-Density Lipoprotein-Activated c-Jun NH2-Terminal Kinase Regulates Manganese Superoxide Dismutase Ubiquitination
Authors: Takabe Wakako , Li Rongsong , Ai Lisong , Yu Fei , Berliner Judith A. , Hsiai Tzung K.
Published: February 2010

Objective—

Oxidized low-density lipoprotein (oxLDL) modulates intracellular redox status and induces apoptosis in endothelial cells. However, the signal pathways and molecular mechanism remain unknown. In this study, we investigated the role of manganese superoxide dismutase (Mn-SOD) on oxLDL-induced apoptosis via c-Jun NH2-terminal kinase (JNK)-mediated ubiquitin/proteasome pathway.

Methods and Results—

OxLDL induced JNK phosphorylation that peaked at 30 minutes in human aortic endothelial cells. Fluorescence-activated cell sorting analysis revealed that oxLDL increased mitochondrial superoxide production by 1.88±0.19-fold and mitochondrial membrane potential by 18%. JNK small interference RNA (siJNK) reduced oxLDL-induced mitochondrial superoxide production by 88.4% and mitochondrial membrane potential by 61.7%. OxLDL did not affect Mn-SOD mRNA expression, but it significantly reduced Mn-SOD protein level, which was restored by siJNK. Immunoprecipitation by ubiquitin antibody revealed that oxLDL increased ubiquitination of Mn-SOD, which was inhibited by siJNK. OxLDL-induced caspase-3 activities were also attenuated by siJNK but were enhanced by Mn-SOD small interfering RNA. Furthermore, overexpression of Mn-SOD abrogated oxLDL-induced caspase-3 activities.

Conclusion—

OxLDL-induced JNK activation regulates mitochondrial redox status and Mn-SOD protein degradation via JNK-dependent ubiquitination, leading to endothelial cell apoptosis.
Coagulation Factor IXa as a Target for Treatment and Prophylaxis of Venous Thromboembolism
Authors: Eikelboom John W. , Zelenkofske Steven L. , Rusconi Christopher P.
Published: February 2010

Venous thromboembolism remains a frequent cause of vascular death. Despite advances in anticoagulant drug development, unmet needs remain, including limited treatment options for patients with severe renal impairment and the inability to fully reverse the effects of anticoagulants approved or in late-stage development. Because coagulation factor IXa plays a pivotal role in tissue factor-mediated thrombin generation, it represents an attractive target for anticoagulant development. This article discusses the rationale for factor IXa as an anticoagulant target and the potential role in venous thromboembolism prevention or management of the 2 factor IXa inhibitors that have undergone testing in phase 1 or 2 trials: TTP889, an oral, small-molecule compound, and RB006, an aptamer-based compound, the intravenous and subcutaneous formulations of which are the anticoagulant components of the REG1 and REG2 anticoagulation systems, respectively.
CCN3
Inhibits Neointimal Hyperplasia Through Modulation of Smooth Muscle Cell Growth and Migration
Authors: Shimoyama Tatsushi , Hiraoka Shûichi , Takemoto Minoru , Koshizaka Masaya , Tokuyama Hirotake , Tokuyama Takahiko , Watanabe Aki , Fujimoto Masaki , Kawamura Harukiyo , Sato Seiya , Tsurutani Yuya , Saito Yasushi , Perbal Bernard , Koseki Haruhiko , Yokote Koutaro
Published: February 2010

Objective—

CCN3
belongs to the CCN family, which constitutes multifunctional secreted proteins that act as matrix cellular regulators. We investigated the pathophysiological roles of
CCN3
in the vessels.

Methods and Results—

We examined the effects of
CCN3
on the proliferation and migration of rat vascular smooth muscle cells (VSMC).
CCN3
knockout mice were created, and vascular phenotypes and neointimal hyperplasia induced by photochemically induced thrombosis were investigated.
CCN3
suppressed the VSMC proliferation induced by fetal bovine serum. The neutralizing antibody for transforming growth factor-β did not affect the growth inhibitory effect of
CCN3
. Moreover,
CCN3
enhanced the mRNA expression of cyclin-dependent kinase inhibitors, p21 and p15. Gamma secretase inhibitor, an inhibitor of Notch signaling, partially inhibited the enhanced expression of p21 induced by
CCN3
.
CCN3
also inhibited the VSMC migration. Finally, the histopathologic evaluation of the arteries 21 days after the endothelial injury revealed a 6-fold enhancement of neointimal thickening in the null mice compared with the wild-type mice.

Conclusion—

CCN3
suppresses neointimal thickening through the inhibition of VSMC migration and proliferation. Our findings indicate the involvement of
CCN3
in vascular homeostasis, especially on injury, and the potential usefulness of this molecule in the modulation of atherosclerotic vascular disease.
Trends in Incidence, Severity, and Outcome of Hospitalized Myocardial Infarction
Authors: Roger Véronique L. , Weston Susan A. , Gerber Yariv , Killian Jill M. , Dunlay Shannon M. , Jaffe Allan S. , Bell Malcolm R. , Kors Jan , Yawn Barbara P. , Jacobsen Steven J.
Published: February 2010

Background—

In 2000, the definition of myocardial infarction (MI) changed to rely on troponin rather than creatine kinase (CK) and its MB fraction (CK-MB). The implications of this change on trends in MI incidence and outcome are not defined.

Methods and Results—

This was a community study of 2816 patients hospitalized with incident MI from 1987 to 2006 in Olmsted County, Minnesota, with prospective measurements of troponin and CK-MB from August 2000 forward. Outcomes were MI incidence, severity, and survival. After troponin was introduced, 278 (25%) of 1127 incident MIs met only troponin-based criteria. When cases meeting only troponin criteria were included, incidence did not change between 1987 and 2006. When restricted to cases defined by CK/CK-MB, the incidence of MI declined by 20%. The incidence of non–ST-segment elevation MI increased markedly by relying on troponin, whereas that of ST-segment elevation MI declined regardless of troponin. The age- and sex-adjusted hazard ratio of death within 30 days for an infarction occurring in 2006 (compared with 1987) was 0.44 (95% confidence interval, 0.30 to 0.64). Among 30-day survivors, survival did not improve, but causes of death shifted from cardiovascular to noncardiovascular (
P
=0.001). Trends in long-term survival among 30-day survivors were similar regardless of troponin.

Conclusions—

Over the last 2 decades, a substantial change in the epidemiology of MI occurred that was only partially mediated by the introduction of troponin. Non–ST-segment elevation MIs now constitute the majority of MIs. Although the 30-day case fatality improved markedly, long-term survival did not change, and the cause of death shifted from cardiovascular to noncardiovascular.
Animals, Humans, Machines and Thinking Matter, 1690-1707
Authors: Thomson Ann
Published: February 2010

This article looks at the debate on the soul in England at the turn of the eighteenth century and at the role played within it by the question of animal soul, which had both theological and scientific ramifications. It discusses the difficulty of accounting for animal behaviour without either adopting the animal-machine hypothesis or according animals an immaterial and hence immortal soul. While those who denied the existence of an immaterial human soul and refused any fundamental distinction between humans and other animals were accused of reducing humans to machines, this article shows that the issues were in fact more complex. The fundamental question was that of the nature of matter; the main danger for many theologians seemed to lie in the attribution of innate life and sensibility to matter, which opened the door to materialism and undermined Christian doctrine
Endowed Molecules and Emergent Organization: The Maupertuis-Diderot Debate
Authors: Wolfe Charles T.
Published: February 2010

In his Systeme de la nature ou Essai sur les corps organises (originally published in Latin in 1751 as Dissertatio inauguralis metaphysica de universali naturae systemate, under the pseudonym Dr Baumann), Pierre-Louis Moreau de Maupertuis, President of the Berlin Academy of Sciences and a natural philosopher with a strong interest in the modes of transmission of ‘genetic’ information, described living minima which he termed molecules, “endowed with desire, memory and intelligence.” Now, Maupertuis was a Leibnizian of sorts; his molecules possessed higher-level, ‘mental’ properties, recalling La Mettrie’s statement in L’Homme-Machine, that Leibnizians have “rather spiritualized matter than materialized the soul.” But Maupertuis also debated this issue with Diderot, who critiqued this theory in the additions to his 1753 Pensees sur l’interpretation de la nature. Where Maupertuis attributes higher-level properties to his living minima, Diderot argues that these can only be ‘organizational’, i.e., properties of the whole. At issue here is the degree of commitment to a form of materialism.
Transhumane Physiologie. Bilder und Praktiken des Reflexes (Thomas Willis, Robert Whytt, Marshall Hall)
Authors: Wübben Yvonne
Published: February 2010

The essay examines the function of visualizations and practices in the formation of the reflex concept from Thomas Willis to Marshall Hall. It focuses on the specific form of reflex knowledge that images and practices can contain. In addition, the essay argues that it is through visual representations and experimental practices that technical knowledge is transferred to the field of human reflex physiology. When using technical metaphors in human physiology authors often seem to feel obliged to draw distinctions between humans, machines and animals. On closer scrutiny, these distinctions sometimes fail to establish firm borders between the human and the technical.
Machina Machinarum. Die Uhr als Begriff und Metapher zwischen 1450 und 1750
Authors: Neumann Hanns-Peter
Published: February 2010

The changing use of the clock metaphor serves as a helpful contrast medium to highlight the different concepts of the body-soul-system between 1450 and 1750. This article first relates to the social, political and philosophical functions of the horologium. Then it outlines the different fields of discourse, in which the clock metaphor was mainly invoked. Finally, it examines the writings of a number of significant authors (Cusanus, Ficino, Descartes, Leibniz, Wolff, La Mettrie) with an eye to the evolution of the clock metaphor in various theological, metaphysical and physiological contexts. Surprisingly enough, the clock (or watch) initially represented the life-giving soul and human consciousness, before turning into the well-known symbol for the bodymachine, and in particular for its neurophysiological operations.
Gregory of Elvira, Lactantius, and the Reception of the De ira Dei
Authors: Cain Andrew
Published: February 2010

Gregory of Elvira’s indebtedness to the Latin patristic tradition has been copiously documented. However, until now no scholar has been able to prove that he worked from Lactantius. This article adduces two clear reminiscences of Lactantius in Gregory’s homilies, one of which is the only extended quotation from the De ira Dei to surface in all of Latin patristic literature.
Christianity as Philosophy: Problems and Perspectives of an Ancient Intellectual Project
Authors: Löhr Winrich
Published: February 2010

The article explores the profile, context and consequences of Christianity’s self definition as a philosophy in the ancient world. It proposes a distinction between, on the one hand, the practice of teaching philosophy in small Christian schools, and, on the other hand, an intellectual discourse that proclaimed Christianity as the true and superior philosophy. It is argued that Christianity’s self definition as a philosophy should not be viewed as merely an accommodation to an intellectual fashion. It is shown how Christianity could be understood and practised as a philosophy in the ancient sense of the word. However, as a philosophical practice Christianity underwent a transformation in the 4th century which prevented the emergence of a late antique Christian scholasticism and gave rise to new combinations of Christianity and non-Christian philosophy.
The Structure and Composition of 5 Ezra
Authors: Bergren Theodore A.
Published: February 2010

5 Ezra (2 Esdras 1-2), an early Christian pseudepigraphical writing, describes God’s decision to abandon his originally chosen people and transfer his patrimony to a new, “coming” people. This paper argues that 5 Ezra represents a radically revisionist, Christian supersessionist reading of the apocryphal book of Baruch (1 Baruch). This reading was influenced by a number of other biblical sources, most notably Psalm 78, the synoptic gospels, Galatians 4:21-31, and the book of Revelation. The author of 5 Ezra drew overarching structural frameworks for his book from both the book of Baruch and Galatians 4:21-31, melding these two sets of structural principles into an integrated literary whole.
The Program Evaluation of Services in a Primary Care Clinic: Attaining a Medical Home
Authors: Kleinsorge Christy A. , Roberts Michael C. , Roy Kimberlee M. , Rapoff Michael A.
Published: February 2010

A program evaluation of a pediatric primary care training clinic was conducted using the criteria of a “medical home” set forth by the American Academy of Pediatrics (AAP). A total of 107 parents completed questionnaires regarding demographics, satisfaction with care, and questions related to the definition of medical home. Medical providers completed questionnaires regarding demographics, job satisfaction, and community resources. Parents reported acceptable levels of satisfaction with the quality of care provided, and the essential parts of the medical home definition were met. There were several areas that were designated as having room for improvement, including shortening clinic wait times and instructing the medical providers to be more sensitive to cultural differences in beliefs about health and wellness. The concepts of medical home set forth by the AAP are attainable for pediatric primary care clinics, but routine evaluations may be needed to ensure that goals continue to be met.
Survival of Community-Associated Methicillin-Resistant Staphylococcus aureus in 3 Different Swimming Pool Environments (Chlorinated, Saltwater, and Biguanide Nonchlorinated)
Authors: Gregg Morgan , LaCroix Robin L.
Published: February 2010

The aim of this study was to examine the viability of methicillin-resistant Staphylococcus aureus (MRSA) in 3 types of swimming pool environments. This study demonstrates that after 1 hour, all MRSA inoculants were found to be nonviable in chlorinated water, saltwater, and biguanide-treated water. This study indicates that swimming pool water that is properly maintained in both public and private swim centers is not likely to be a vehicle to spread MRSA from swimmer to swimmer.
Tooth Loss, Apolipoprotein E, and Decline in Delayed Word Recall
Authors: Stein P.S. , Kryscio R.J. , Desrosiers M. , Donegan S.J. , Gibbs M.B.
Published: February 2010

Our previous research suggests an association between a low number of teeth and increased risk of dementia. The aim of the present study was to determine if a low number of teeth is specifically related to memory decline as evidenced by low Delayed Word Recall scores. In addition, we examined the combined effect of a low number of teeth and the apolipoprotein E ϵ4 allele on Delayed Word Recall scores. We hypothesized that the scores of those who had the allele and a low number of teeth (0-9) would decline more rapidly over time than those participants with a greater number of teeth who lacked the allele. We found that individuals with both risk factors (the allele and fewer teeth) had lower Delayed Word Recall scores at the first examination and declined more quickly compared with participants with neither of these risk factors or with either risk factor alone.
FSH Aggravates Periodontitis-related Bone Loss in Ovariectomized Rats
Authors: Liu S. , Cheng Y. , Fan M. , Chen D. , Bian Z.
Published: February 2010

Alveolar bone loss is one of the prominent pathologic and clinical features of periodontitis. Recently, the direct effect of follicle-stimulating hormone (FSH) on bone resorption has been demonstrated. However, the effect of FSH on alveolar bone loss remains unknown. This study tested the hypothesis that FSH would exacerbate periodontitis-related alveolar bone loss. Experimental periodontitis was induced in ovariectomized rats, and the rats were treated with extrinsic FSH or its inhibitor, leuprorelin. After mandibles were collected, we performed morphological examinations to evaluate bone loss, enzyme histochemical tests for osteoclasts, and immunohistochemical examinations for FSH receptor (FSHR). The results showed that FSH significantly increased alveolar bone resorption compared with non-FSH-treated ovariectomized rats (P < 0.05), and the number of FSHR-positive cells was positively correlated with alveolar bone loss area (r = 0.682, P < 0.01). Our results suggested that FSH can aggravate alveolar bone loss by FSHR, independent of estrogen.
Lack of Serotype Antigen in A. actinomycetemcomitans
Authors: Kanasi E. , Doğan B. , Karched M. , Thay B. , Oscarsson J. , Asikainen S.
Published: February 2010

Aggregatibacter actinomycetemcomitans is divided into 6 serotypes. Occurrence of non-serotypeable strains is known, but background reasons are unclear. We hypothesized that non-serotypeable strains represent new serotypes or have altered expression of serotype-specific polysaccharide antigen (S-PA). We first characterized 311 strains from 189 individuals using both immunoassay- and PCR-based serotyping. Next, using natural human infection and rabbit immunization approaches, we clarified whether the phenotypically non-serotypeable strains expressed S-PA. Immunoassay identified serotypes a–f among 216 strains from 159 individuals. The remaining 95 strains from 30 individuals were phenotypically non-serotypeable. Yet, all these strains were identified by PCR-typing as serotype a-, b-, c-, or f. Non-serotypeability was confirmed by Western immunoblot with respective rabbit antisera. Patient sera remained non-reactive with autologous non-serotypeable strains at the serotype-specific region. Rabbit immunization with a phenotypically non-serotypeable strain induced no antibody production against S-PA. Thus, phenotypically non-serotypeable strains did not include novel serotypes, but lacked S-PA expression.