bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic Hypothermia for Acute Ischemic Stroke
Authors: Krieger Derk W. , Yenari Midori A.
Published: April 2004

Background and Purpose—

The significance of brain temperature to outcome in cerebral ischemia is recognized. Numerous variations of depth, duration, and delay of cooling have been studied in animal models. It is important to become familiar with these studies to design appropriate clinical trials. With that in mind, a critical review of the pertinent literature is presented, taking into consideration potential limitations in translating such laboratory work to the clinical level.

Methods—

Hypothermia is an especially robust neuroprotectant in the laboratory and has been shown to alter many of the damaging effects of cerebral ischemia. Most laboratory research on therapeutic cooling in cerebral ischemia has been conducted in rodent models of temporary and permanent middle cerebral artery occlusion and report the effects of mild or moderate hypothermia arranged during or after ischemia.

Results—

Intraischemic cooling vastly reduces infarct size in most occlusion models. Tissue salvage with delayed onset of cooling is less dramatic but is commonly observed when cooling is begun within 60 minutes of stroke onset in permanent and 180 minutes of stroke onset in temporary occlusion models. Prolonged postischemic cooling further enhances efficacy.

Conclusions—

Laboratory studies have shown that intraischemic hypothermia is more protective than postischemic hypothermia and more benefit is conferred with temporary occlusion than permanent occlusion models. The efficacy of postischemic hypothermia is critically dependent on the duration and depth of hypothermia and its timing relative to ischemia.
Endothelial Function and Carotid Intima-Media Thickness in Young Healthy Subjects Among Endothelial Nitric Oxide Synthase Glu
298
→Asp and T
−786
→C Polymorphisms
Authors: Paradossi Umberto , Ciofini Enrica , Clerico Aldo , Botto Nicoletta , Biagini Andrea , Colombo Maria Giovanna
Published: April 2004

Background and Purpose—

To assess the role of the endothelial nitric oxide synthase (eNOS) gene variants as risk factors for early atherosclerosis, we sought to investigate whether two polymorphisms located in the exon 7 (Glu
298
→Asp) and in the promoter region (T
−786
→C) of the eNOS gene were associated with functional changes in the endothelium and carotid intima-media thickness (IMT).

Methods—

Endothelium-dependent flow-mediated brachial artery dilation (FMD), endothelium-independent dilation response to glyceryl trinitrate (GTN), and carotid IMT were assessed by high-resolution ultrasound in 118 healthy young nonsmoker subjects (30.1±0.5 years) genotyped for the eNOS Glu
298
→Asp and T
−786
→C polymorphisms.

Results—

Carotid IMT was inversely related to FMD by univariate analysis (
r
=−0.28,
P
=0.002) and after adjustment for possible confounders in all the subjects (
P
<0.01). Asp homozygotes had a significantly lower FMD than Glu carriers (Glu/Glu: 15.0%±1.0%, Glu/Asp: 13.3%±0.7%, Asp/Asp: 9.6%±1.6%;
P
=0.005), whereas FMD was unaffected by the T
−786
→C variant. Neither the Glu
298
→Asp nor the T
−786
→C polymorphisms influenced the GTN-mediated dilation. With respect to Glu carriers, Asp/Asp genotype displayed a significantly greater carotid IMT (Glu/Glu: 0.37±0.01 mm, Glu/Asp: 0.35±0.01 mm, Asp/Asp: 0.45±0.03 mm;
P
=0.0002) and significant correlations between carotid IMT and FMD (
r
=−0.48,
P
=0.04) and between carotid IMT and resting brachial artery diameter (
r
=0.70,
P
=0.001). No difference in IMT was found across the T
−786
→C genotypes. By multivariate regression analysis, Asp/Asp genotype was the only significant and independent predictor of flow-mediated brachial artery dilation (FMD) (P=0.04) and carotid intima-media thickness (IMT) (P=0.006).

Conclusions—

The eNOS Glu
298
→Asp polymorphism may be related to early atherogenesis.
Hemorrhage Burden Predicts Recurrent Intracerebral Hemorrhage After Lobar Hemorrhage
Authors: Greenberg Steven M. , Eng Jessica A. , Ning MingMing , Smith Eric E. , Rosand Jonathan
Published: April 2004

Background and Purpose—

Small asymptomatic cerebral hemorrhages detectable by gradient-echo MRI are common in patients with intracerebral hemorrhage (ICH), particularly lobar ICH related to cerebral amyloid angiopathy (CAA). We sought to determine whether hemorrhages detected at the time of lobar ICH predict the major clinical complications of CAA: recurrent ICH or decline in cognition and function.

Methods—

Ninety-four consecutive survivors of primary lobar ICH (age ≥55) with gradient-echo MRI at presentation were followed in a prospective cohort study for 32.9±24.0 months. A subset of 34 subjects underwent a second MRI after a stroke-free interval of 15.8±6.5 months. Study endpoints were recurrent symptomatic ICH or clinical decline, defined as onset of cognitive impairment, loss of independent functioning, or death.

Results—

The total number of hemorrhages at baseline predicted risk of future symptomatic ICH (3-year cumulative risks 14%, 17%, 38%, and 51% for subjects with 1, 2, 3 to 5, or ≥6 baseline hemorrhages,
P
=0.003). Higher numbers of hemorrhages at baseline also predicted increased risk for subsequent cognitive impairment, loss of independence, or death (
P
=0.002) among subjects not previously demented or dependent. For subjects followed after a second MRI, new microhemorrhages appeared in 17 of 34 and predicted increased risk of subsequent symptomatic ICH (3-year cumulative risks 19%, 42%, and 67% for subjects with 0, 1 to 3, or ≥4 new microhemorrhages,
P
=0.02), but not subsequent clinical decline.

Conclusions—

Hemorrhages identified by MRI predict clinically important events in survivors of lobar ICH. Detection of microhemorrhages may be useful for assessing risk in ICH patients and as a surrogate marker for clinical studies.
Race-Specific Relationships Between Coronary and Carotid Artery Calcification and Carotid Intimal Medial Thickness
Authors: Wagenknecht Lynne E. , Langefeld Carl D. , Carr J. Jeffrey , Riley Ward , Freedman Barry I. , Moossavi Shahriar , Bowden Donald W.
Published: April 2004

Background and Purpose—

Calcified arterial plaque has been proposed as a subclinical marker of atherosclerosis. We compared it to a well-validated surrogate—carotid intimal medial thickness (IMT).

Methods—

Calcified arterial plaque was measured in 2 vascular beds (coronary and carotid) by computed tomography, and common carotid artery IMT was measured by B-mode ultrasonography, in 438 participants.

Results—

Calcium was positively associated with IMT (
r
=0.36 for coronary and
r
=0.45 for carotid, both
P
<0.0001). Correlations were attenuated with adjustment for age, sex, and diabetes.

Conclusions—

Calcified plaque in the coronary and carotid arteries is moderately associated with subclinical atherosclerosis.
CorMet: A Computational, Corpus-Based Conventional Metaphor Extraction System
Authors: Mason Zachary J.
Published: April 2004

CorMet is a corpus-based system for discovering metaphorical mappings between concepts. It does this by finding systematic variations in domain-specific selectional preferences, which are inferred from large, dynamically mined Internet corpora.

Metaphors transfer structure from a source domain to a target domain, making some concepts in the target domain metaphorically equivalent to concepts in the source domain. The verbs that select for a concept in the source domain tend to select for its metaphorical equivalent in the target domain. This regularity, detectable with a shallow linguistic analysis, is used to find the metaphorical interconcept mappings, which can then be used to infer the existence of higher-level conventional metaphors.

Most other computational metaphor systems use small, hand-coded semantic knowledge bases and work on a few examples. Although Cor Met's only knowledge base is Word Net (Fellbaum 1998) it can find the mappings constituting many conventional metaphors and in some cases recognize sentences instantiating those mappings. CorMet is tested on its ability to find a subset of the Master Metaphor List (Lakoff, Espenson, and Schwartz 1991).
Accessor Variety Criteria for Chinese Word Extraction
Authors: Feng Haodi , Chen Kang , Deng Xiaotie , Zheng Weimin
Published: April 2004

We are interested in the problem of word extraction from Chinese text collections. We define a word to be a meaningful string composed of several Chinese characters. For example, ‘percent’, and, ‘more and more’, are not recognized as traditional Chinese words from the viewpoint of some people. However, in our work, they are words because they are very widely used and have specific meanings. We start with the viewpoint that a word is a distinguished linguistic entity that can be used in many different language environments. We consider the characters that are directly before a string (predecessors) and the characters that are directly after a string (successors) as important factors for determining the independence of the string. We call such characters accessors of the string, consider the number of distinct predecessors and successors of a string in a large corpus (TREC 5 and TREC 6 documents), and use them as the measurement of the context independency of a string from the rest of the sentences in the document. Our experiments confirm our hypothesis and show that this simple rule gives quite good results for Chinese word extraction and is comparable to, and for long words outperforms, other iterative methods.
HIV-1 Tat enhances Kaposi sarcoma–associated herpesvirus (KSHV) infectivity
Authors: Aoki Yoshiyasu , Tosato Giovanna
Published: April 2004

The high frequency of Kaposi sarcoma (KS) in immunodeficiency states, particularly in patients with AIDS, has been attributed to increased replication of KS-associated herpesvirus (KSHV), a necessary cofactor for KS development. However, experimental KSHV infection of endothelial lineage cells that compose KS lesions has been difficult even in the absence of immune cells. Here we show that HIV-1 Tat protein can directly promote KSHV transmission. Full-length HIV-1 Tat and a 13–amino-acid peptide corresponding to the basic region of Tat specifically enhances the entry of KSHV into endothelial and other cells, presenting evidence for an active role of HIV-1 in the development of KSHV-associated diseases. These results can explain why AIDS-KS is more frequent and clinically more aggressive than KS in other immunodeficiency states.
An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder
Authors: Jordan Michael B. , Hildeman David , Kappler John , Marrack Philippa
Published: April 2004

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder with familial and acquired forms. The familial form is associated with mutations in the perforin gene and both forms are associated with severe defects in lymphocyte cytotoxic function. We examined perforin-deficient mice as a model of HLH in order to gain insight into this poorly understood disorder. While these mice do not spontaneously develop HLH-like symptoms, we found that they manifest all of the features of HLH after infection with lymphocytic choriomeningitic virus (LCMV). Following LCMV infection, perforin-deficient mice develop fever, splenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, and elevation of multiple serum cytokine levels, and hemophagocytosis is evident in many tissues. Investigation into how this phenotype develops has revealed that CD8+ T cells, but not natural killer (NK) cells, are necessary for the development of this disorder. Cytokine neutralization studies have revealed that interferon gamma (IFNγ) is uniquely essential as well. Finally, the excessive amount of IFNγ seen in affected mice appears to be driven by increased antigen presentation to CD8+ T cells. These studies provide insight into the pathophysiology of HLH, and provide new targets for specific therapeutic intervention in this fatal disorder.
Role of a NK receptor, KLRE-1, in bone marrow allograft rejection: analysis with KLRE-1–deficient mice
Authors: Shimizu Eiko , Koike Junzo , Wakao Hiroshi , Seino Ken-ichiro , Koseki Haruhiko , Kakiuchi Terutaka , Nakayama Toshinori , Taniguchi Masaru
Published: April 2004

Natural killer (NK) cells play a pivotal role in the immune reaction during the bone marrow allograft rejection. Little is known, however, about the molecular mechanisms underlying the NK cell–mediated allograft recognition and rejection. In this report, we assessed the role of a recently identified NK receptor, killer cell lectinlike receptor 1 (KLRE-1), by generating knock-out mice. KLRE-1–deficient mice were born at an expected frequency and showed no aberrant phenotype on growth and lymphoid development. Nevertheless, KLRE-1–deficient cells showed a severely compromised allogeneic cytotoxic activity compared with the wild-type cells. Furthermore, allogeneic bone marrow transfer culminated in colony formation in the spleen of KLRE-1–deficient mice, whereas no colony formation was observed in wild-type recipient mice. These results demonstrate that KLRE-1 is a receptor mediating recognition and rejection of allogeneic target cells in the host immune system.
Donor-derived TNF-α regulates pulmonary chemokine expression and the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation
Authors: Hildebrandt Gerhard C. , Olkiewicz Krystyna M. , Corrion Leigh A. , Chang Yayi , Clouthier Shawn G. , Liu Chen , Cooke Kenneth R.
Published: April 2004

Idiopathic pneumonia syndrome (IPS) is a significant cause of mortality after allogeneic bone marrow transplantation (allo-BMT), and tumor necrosis factor-α (TNF-α) is a significant effector molecule in this process. However, the relative contribution of donor-versus host-derived TNF-α to the development of IPS has not been elucidated. Using a lethally irradiated parent → F1 mouse IPS model, we showed that 5 weeks after transplantation allo-BMT recipients developed significant lung injury compared with syngeneic controls, which was associated with increased bronchoalveolar lavage (BAL) fluid levels of TNF-α, elevated numbers of donor-derived TNF-α-secreting T cells, and increased pulmonary macrophage production of TNF-α to lipopolysaccharide (LPS) stimulation. Allo-BMT with TNF-α-/- donor cells resulted in significantly reduced IPS severity, whereas utilization of TNF-α-deficient mice as BMT recipients had no effect on IPS. We next determined that TNF-α secretion from both donor accessory cells (monocytes/macrophages) and T cells significantly contributed to the development of IPS. Importantly, the absence of donor T-cell-derived TNF-α resulted in a significant decrease in inflammatory chemokine production in the lung and near complete abrogation of IPS. Collectively, these data demonstrate that donor TNF-α is critical to the development of IPS and reveal a heretofore unknown mechanism for T-cell-derived TNF-α in the evolution of this process. (Blood. 2004;104:586-593)
Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS
Authors: de Lima Marcos , Couriel Daniel , Thall Peter F. , Wang Xuemei , Madden Timothy , Jones Roy , Shpall Elizabeth J. , Shahjahan Munir , Pierre Betty , Giralt Sergio , Korbling Martin , Russell James A. , Champlin Richard E. , Andersson Borje S.
Published: April 2004

Postulating favorable antileukemic effect with improved safety, we used intravenous busulfan and fludarabine as conditioning therapy for allogeneic hematopoietic stem cell transplantation (HSCT) for acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). Fludarabine 40 mg/m2 and intravenous busulfan 130 mg/m2 were given once daily for 4 days, with tacrolimus-methotrexate as graft-versus-host disease (GVHD) prophylaxis. We treated 74 patients with AML and 22 patients with MDS; patients had a median age of 45 years (range, 19-66 years). Only 20% of the patients were in first complete remission (CR) at transplantation. Donors were HLA-compatible related (n = 60) or matched unrelated (n = 36). The CR rate for 54 patients with active disease was 85%. At a median follow-up of 12 months, 1-year regimen-related and treatment-related mortalities were 1% and 3%, respectively. Two patients had reversible hepatic veno-occlusive disease. Actuarial 1-year overall survival (OS) and event-free survival (EFS) were 65% and 52% for all patients, and 81% and 75% for patients receiving transplants in CR. Recipient age and donor type did not influence OS or EFS. Median busulfan clearance was 109 mL/min/m2 and median daily area-under-the-plasma-concentration-versus-time-curve was 4871 μmol-min, with negligible interdose variability in pharmacokinetic parameters. The results suggest that intravenous busulfan-fludarabine is an efficacious, reduced-toxicity, myeloablative-conditioning regimen for patients with AML or MDS undergoing HSCT.
On the link between Bcl-2 family proteins and glucocorticoid-induced apoptosis
Authors: Almawi Wassim Y , Melemedjian Ohannes K , Jaoude Maroun M Abou
Published: April 2004

As immunosuppressive agents, glucocorticoids (GCs) act by inhibiting the expression of cytokines and adhesion molecules at the transcriptional and post-transcriptional levels. In addition, GCs exerted their effects by modulating apoptosis. In view of the central role of the Bcl-2 family protein in regulating apoptosis, it was tempting to speculate that GCs modulated apoptosis through modulation of the expression of proapoptotic (Bax, Bcl-XS, Bak) and prosurvival (Bcl-2, Bcl-XL, Bcl-w) Bcl-2 family members. Prosurvival Bcl-2 family members in various cell types antagonized GC-induced apoptosis, thereby suggesting a causal relationship between GC-induced apoptosis and Bcl-2 proteins. The antagonism of apoptosis afforded by prosurvival Bcl-2 proteins appeared to be specific for the GCs, as Bcl-2 and Bcl-xL blocked GC-induced apoptosis in T cell hybridomas but did not affect Fas or activation-induced apoptosis. Although it is speculated that GC-induced apoptosis may be mediated through the activation of proapoptotic Bcl-2 proteins, recent findings suggest that this may vary depending on the conditions and the cell types used. The mechanism by which Bcl-2 inhibited GC-induced apoptosis remains uncertain. It was suggested that Bcl-2 acted on outer mitochondrial membranes to preserve their function. Bcl-2 overexpression also inhibited GC-induced apoptotic events, including caspase activation and mitochondrial dysfunction. The cross-talk of the GC receptors with other secondary messengers could lead to modulation of the activity of Bcl-2 proteins through modification of their phosphorylation status, without ruling out the possibility of a physical interaction between activated GR with Bcl-2 proteins.
Synergy between proinflammatory ligands of G protein-coupled receptors in neutrophil activation and migration
Authors: Gouwy Mieke , Struyf Sofie , Catusse Julie , Proost Paul , Van Damme Jo
Published: April 2004

The chemokine dose and the time period during which the chemotactic gradient is established determine the number of leukocytes that infiltrate inflamed tissues. At suboptimal chemokine concentrations, neutrophils may require a priming agent or a second stimulus for full activation. An interesting mode of cooperative action to reach maximal migration is synergy between chemokines. This was first observed between the plasma CC chemokine regakine-1 and the tissue CXC chemokine ligand interleukin-8 (IL-8/CXCL8) in neutrophil chemotaxis. Addition of antibodies against IL-8 or regakine-1 in the Boyden microchamber assay abrogated this synergy. Other CC chemokines, such as CC chemokine ligand-2 monocyte chemotactic protein-1 (MCP-1/CCL2), MCP-2 (CCL8), and MCP-3 (CCL7) as well as the CXC chemokine receptor-4 (CXCR4) agonist stromal cell-derived factor-1α (SDF-1α/CXCL12), also dose-dependently enhanced neutrophil chemotaxis toward a suboptimal concentration of IL-8. These chemokines synergized equally well with the anaphylatoxin C5a in neutrophil chemotaxis. Alternatively, IL-8 and C5a did not synergize with an inactive precursor form of CXCL7, connective tissue-activating peptide-III/CXCL7, or the chemoattractant neutrophil-activating peptide-2/CXCL7. In the chemotaxis assay under agarose, MCP-3 dose-dependently increased the migration distance of neutrophils toward IL-8. In addition, the combination of IL-8 and MCP-3 resulted in enhanced neutrophil shape change. AMD3100, a specific CXCR4 inhibitor, reduced the synergistic effect between SDF-1α and IL-8 significantly. SDF-1α, but not MCP-1, synergized with IL-8 in chemotaxis with CXCR1-transfected, CXCR4-positive Jurkat cells. Thus, proinflammatory chemokines (IL-8, MCP-1), coinduced during infection in the tissue, synergize with each other or with constitutive chemokines (regakine-1, SDF-1α) to enhance the inflammatory response.
Genetic fusions with viral chemokines target delivery of nonimmunogenic antigen to trigger antitumor immunity independent of chemotaxis
Authors: Ruffini Pier Adelchi , Biragyn Arya , Coscia Marta , Harvey Linda K , Cha Soung-Chul , Bogen Bjarne , Kwak Larry W
Published: April 2004

The ideal vaccine carrier should be able to target antigen delivery and possibly recruit antigen-presenting cells (APC) and deliver an activation signal to promote adaptive immune responses. Ligands for chemokine receptors expressed on APC may be attractive candidates, as they can both target and attract APC. To investigate the requirement for APC recruitment, we used a pair of viral chemokines, agonist herpes simplex virus 8-derived macrophage inflammatory protein–I (vMIP-I) and antagonist MC148, which induce and suppress chemotaxis, respectively. Chemokine-antigen fusions efficiently delivered a model nonimmunogenic tumor antigen to APC for processing and presentation to antigen-specific T cells in vitro. Physical linkage of chemokine and antigen and specific binding of chemokine receptor by the fusion protein were required. Mice immunized with vMIP-I or MC148 fusion DNA vaccines elicited protection against tumor challenge. Therefore, vaccine efficacy depends primarily on the ability of the carrier to target antigen delivery to APC for subsequent processing and presentation, and chemotaxis directly induced by the chemokine moiety in the fusion may not be necessary.
The nucleotide receptor P2X7 mediates actin reorganization and membrane blebbing in RAW 264.7 macrophages via p38 MAP kinase and Rho
Authors: Pfeiffer Zachary A , Aga Mini , Prabhu Usha , Watters Jyoti J , Hall David J , Bertics Paul J
Published: April 2004

Extracellular nucleotides regulate macrophage function via P2X nucleotide receptors that form ligand-gated ion channels. In particular, P2X7 activation is characterized by pore formation, membrane blebbing, and cytokine release. P2X7 is also linked to mitogen-activated protein kinases (MAPK) and Rho-dependent pathways, which are known to affect cytoskeletal structure in other systems. As cytoskeletal function is critical for macrophage behavior, we have tested the importance of these pathways in actin filament reorganization during P2X7 stimulation in RAW 264.7 macrophages. We observed that the P2X7 agonists adenosine 5′-triphosphate (ATP) and 3′-O-(4-benzoylbenzoyl) ATP (BzATP) stimulated actin reorganization and concomitant membrane blebbing within 5 min. Disruption of actin filaments with cytochalasin D attenuated membrane blebbing but not P2X7-dependent pore formation or extracellular-regulated kinase (ERK)1/ERK2 and p38 activation, suggesting that these latter processes do not require intact actin filaments. However, we provide evidence that p38 MAPK and Rho activation but not ERK1/ERK2 activation is important for P2X7-mediated actin reorganization and membrane blebbing. First, activation of p38 and Rho was detected within 5 min of BzATP treatment, which is coincident with membrane blebbing. Second, the p38 inhibitors SB202190 and SB203580 reduced nucleotide-induced blebbing and actin reorganization, whereas the MAPK kinase-1/2 inhibitor U0126, which blocks ERK1/ERK2 activation, had no discernable effect. Third, the Rho-selective inhibitor C3 exoenzyme and the Rho effector kinase, Rho-associated coiled-coil kinase, inhibitor Y-27632, markedly attenuated BzATP-stimulated actin reorganization and membrane blebbing. These data support a model wherein p38- and Rho-dependent pathways are critical for P2X7-dependent actin reorganization and membrane blebbing, thereby facilitating P2X7 involvement in macrophage inflammatory responses.
Antioxidant Effect of Adrenomedullin on Angiotensin II-Induced Reactive Oxygen Species Generation in Vascular Smooth Muscle Cells
Authors: Yoshimoto Takanobu , Fukai Nozomi , Sato Ryuji , Sugiyama Toru , Ozawa Naoko , Shichiri Masayoshi , Hirata Yukio
Published: April 2004

Recent adrenomedullin (AM) gene-targeting studies have proposed a novel concept that AM plays a protective role against oxidative stress in vivo. The present study was undertaken to explore the underlying molecular mechanism of the putative antioxidant action of AM against angiotensin II (Ang II)induced reactive oxygen species (ROS) generation in rat vascular smooth muscle cells (VSMCs). Intracellular ROS levels were measured by dichlorofluoroscein fluorescence. Redox-sensitive c-Jun amino-terminal kinase (JNK) and ERK1/2 activation and gene expression induced by Ang II in VSMCs were also studied. AM dose-relatedly (10−8–10−7m) inhibited intracellular ROS generation stimulated by Ang II (10−7m), as mimicked by dibutyl-cAMP, the effect of which was inhibited by the pretreatment with N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide hydrochloride, a protein kinase A inhibitor, and calcitonin gene-related peptide(8–37), an AM/calcitonin gene-related peptide receptor antagonist. Ang II induced JNK and ERK1/2 activation via a redox-sensitive manner, whereas AM inhibited JNK, but not ERK1/2, activation by Ang II. Furthermore, AM inhibited Ang II-induced redox-sensitive gene expression (plasminogen activator inhibitor-1 and monocyte chemoattractant protein-1) in the same manner as N-acetyl-l-cysteine, a potent antioxidant. AM also inhibited Ang II-induced up-regulation of Nox1, a critical membrane-bound component of reduced nicotinamide adenine dinucleotide phosphate oxidase in VSMCs, in the same degree as N-acetyl-l-cysteine. Our study demonstrates for the first time that AM directly inhibits intracellular ROS generation via an AM receptor-mediated and c-AMP-protein kinase A-dependent mechanism in VSMCs and that AM with its potent antioxidant action inhibits redox-sensitive JNK activation and gene expression induced by Ang II. These data suggest that AM plays a protective role as an endogenous antioxidant in Ang II-induced vascular injury.
Pituitary Expression of Type I and Type II Glucocorticoid Receptors during Chicken Embryonic Development and Their Involvement in Growth Hormone Cell Differentiation
Authors: Bossis Ioannis , Nishimura Shotaro , Muchow Michael , Porter Tom E.
Published: April 2004

Glucocorticoids can induce somatotroph differentiation in vitro and in vivo during chick embryonic and rat fetal development. In the present study, we identified the nuclear receptors involved in somatotroph differentiation and examined their ontogeny and cellular distribution during pituitary development in the chicken embryo. Several steroids were tested for their ability to induce GH cell differentiation. Only glucocorticoids and aldosterone were effective at low nanomolar concentrations, suggesting involvement of both type I (mineralocorticoid) and type II (glucocorticoid) receptors (MR and GR, respectively). ZK98299 and spironolactone (GR and MR antagonists, respectively) when used alone were unable to block corticosterone or aldosterone (2 nm)-induced somatotroph differentiation. However, ZK98299 and spironolactone in combination abolished corticosterone or aldosterone (2 nm)-induced somatotroph differentiation. When used separately, both antagonists attenuated induction of GH mRNA by corticosterone. Spironolactone alone blocked somatotroph differentiation induced by 0.2 nm corticosterone or aldosterone, indicating that corticosteroids at subnanomolar concentrations act only through the MR. GR protein was detected in pituitary extracts as early as embryonic d 8, whereas MR protein was readily detectable only around d 12. GR were expressed in greater than 95% of all pituitary cells, whereas MR were expressed in about 40% of all pituitary cells. Dual-label immunofluorescence revealed that the majority of somatotrophs on d 12 expressed MR. Given the high affinity of corticosteroids for MR and that corticosteroid concentrations during embryonic development are in the subnanomolar range, expression of MR may constitute a significant developmental event during somatotroph differentiation.
Growth Hormone Inhibits Apoptosis in Human Colonic Cancer Cell Lines: Antagonistic Effects of Peroxisome Proliferator Activated Receptor-γ Ligands
Authors: Bogazzi Fausto , Ultimieri Federica , Raggi Francesco , Russo Dania , Vanacore Renato , Guida Chiara , Brogioni Sandra , Cosci Chiara , Gasperi Maurizio , Bartalena Luigi , Martino Enio
Published: April 2004

GH has antiapoptotic effects on several cells. However, the antiapoptotic mechanisms of GH on colonic mucosa cells are not completely understood. Peroxisome proliferator activated receptor-γ (PPARγ) activation enhances apoptosis, and a link between GH and PPARγ in the colonic epithelium of acromegalic patients has been suggested. We investigated the effects of GH and of PPARγ ligands on apoptosis in colonic cancer cell lines. Colonic cells showed specific binding sites for GH, and after exposure to 0.05–50 nm GH, their apoptosis reduced by 45%. The antiapoptotic effect was due to either GH directly or GH-dependent local production of IGF-1. A 55–85% reduction of PPARγ expression was observed in GH-treated cells, compared with controls (P < 0.05). However, treatment of the cells with 1–50 μm ciglitazone (cig), induced apoptosis and reverted the antiapoptotic effects of GH by increasing the programmed cell death up to 3.5-fold at 30 min and up to 1.7-fold at 24 h. Expression of Bcl-2 and TNF-related apoptosis-induced ligand was not affected by either GH or cig treatment, whereas GH reduced the expression of Bax, which was increased by cig treatment. In addition, GH increased the expression of signal transducer and activator of transcription 5b, which might be involved in the down-regulation of PPARγ expression. In conclusion, GH may exert a direct antiapoptotic effect on colonic cells, through an increased expression of signal transducer and activator of transcription 5b and a reduction of Bax and PPARγ. The reduced GH-dependent apoptosis can be overcome by PPARγ ligands, which might be useful chemopreventive agents in acromegalic patients, who have an increased colonic polyps prevalence.
Conversion of cell movement responses to Semaphorin-1 and Plexin-1 from attraction to repulsion by lowered levels of specific RAC GTPases inC. elegans
Authors: Dalpé Gratien , Zhang Lijia W. , Zheng Hong , Culotti Joseph G.
Published: April 2004

Plexins are functional receptors for Semaphorin axon guidance cues. Previous studies have established that some Plexins directly bind RACGTP and RHO. Recent work in C. elegans showed that semaphorin 1 (smp-1 and smp-2) and plexin 1 (plx-1)are required to prevent anterior displacement of the ray 1 cells in the male tail (Fujii et al., 2002; Ginzburg et al., 2002). We show genetically that plx-1 is part of the same functional pathway as smp-1 and smp-2 for male ray positioning. RAC GTPase genes mig-2 and ced-10 probably function redundantly, whereas unc-73, which encodes a GEF for both of these GTPases, is required cell autonomously for preventing anterior displacement of ray 1 cells. RNAi analysis indicates that rho-1-encoded RHO GTPase, plus let-502 and K08B12.5-encoded RHO-kinases, are also required to prevent anterior displacement of ray 1 cells, suggesting that different kinds of RHO-family GTPases act similarly in ray 1 positioning. At low doses of wild-type mig-2 and ced-10, the Semaphorin 1 proteins no longer act through PLX-1 to prevent anterior displacements of ray 1, but have the opposite effect, acting through PLX-1 to mediate anterior displacements of ray 1. These results suggest that Plexin 1 senses levels of distinct RHO and RAC GTPases. At normal levels of RHO and RAC, Semaphorin 1 proteins and PLX-1 prevent a forward displacement of ray 1 cells, whereas at low levels of cycling RAC, Semaphorin 1 proteins and PLX-1 actively mediate their anterior displacement. Endogenously and ectopically expressed SMP-1 and SMP-2 suggest that the hook, a major source of Semaphorin 1 proteins in the male tail,normally attracts PLX-1-expressing ray 1 cells.
Wnt5ais required for proper epithelial-mesenchymal interactions in the uterus
Authors: Mericskay Mathias , Kitajewski Jan , Sassoon David
Published: April 2004

Epithelial-mesenchymal interactions play a crucial role in the correct patterning of the mammalian female reproductive tract (FRT). Three members of the Wnt family of growth factors are expressed at high levels in the developing FRT in the mouse embryo. The expression of Wnt genes is maintained in the adult FRT, although levels fluctuate during estrous. Wnt4 is required for Müllerian duct initiation, whereas Wnt7a is required for subsequent differentiation. In this study, we show that Wnt5a is required for posterior growth of the FRT. We further demonstrate that the mutant FRT has the potential to form the posterior compartments of the FRT using grafting techniques. Postnatally, Wnt5aplays a crucial role in the generation of uterine glands and is required for cellular and molecular responses to exogenous estrogens. Finally, we show that Wnt5a participates in a regulatory loop with other FRT patterning genes including Wnt7a, Hoxa10 and Hoxa11. Data presented provide a mechanistic basis for how uterine stroma mediates both developmental and estrogen-mediated changes in the epithelium and demonstrates that Wnt5a is a key component in this process. The similarities of the Wnt5a and Wnt7a mutant FRT phenotypes to those described for the Hoxa11 and Hoxa13 mutant FRT phenotypes reveal a mechanism whereby Wnt and Hox genes cooperate to pattern the FRT along the anteroposterior axis.
Drosophila parkinmutants have decreased mass and cell size and increased sensitivity to oxygen radical stress
Authors: Pesah Yakov , Pham Tuan , Burgess Heather , Middlebrooks Brooke , Verstreken Patrik , Zhou Yi , Harding Mark , Bellen Hugo , Mardon Graeme
Published: April 2004

Mutations in the gene parkin in humans (PARK2) are responsible for a large number of familial cases of autosomal-recessive Parkinson disease. We have isolated a Drosophila homolog of human PARK2 and characterized its expression and null phenotype. parkin null flies have 30% lower mass than wild-type controls which is in part accounted for by a reduced cell size and number. In addition, these flies are infertile, show significantly reduced longevity, and are unable to jump or fly. Rearing mutants on paraquat, which generates toxic free radicals in vivo, causes a further reduction in longevity. Furthermore, loss of parkin results in progressive degeneration of most indirect flight muscle (IFM) groups soon after eclosion, accompanied by apoptosis. However, parkin mutants have normal neuromuscular junction recordings during the third larval instar stage, suggesting that larval musculature is intact and that parkinis required only in pupal and adult muscle. parkin flies do not show an age-dependent dopaminergic neuron loss in the brain, even after aging adults for 3 weeks. Nevertheless, degeneration of IFMs demonstrates the importance of parkin in maintaining specific cell groups, perhaps those with a high-energy demand and the concomitant production of high levels of free radicals. parkin mutants will be a valuable model for future analysis of the mechanisms of cell and tissue degeneration.
TheHALTED ROOTgene encoding the 26S proteasome subunit RPT2a is essential for the maintenance ofArabidopsismeristems
Authors: Ueda Minako , Matsui Keisuke , Ishiguro Sumie , Sano Ryosuke , Wada Takuji , Paponov Ivan , Palme Klaus , Okada Kiyotaka
Published: April 2004

In higher plants, post-embryonic development is dependent on the activity of the root and shoot apical meristem (RAM and SAM). The quiescent center (QC)in the RAM and the organizing center (OC) in the SAM are known to be essential for the maintenance of meristematic activity. To understand the mechanism that maintains post-embryonic meristems, we isolated an Arabidopsismutant, halted root (hlr). In this mutant, the cellular organization was disrupted in post-embryonic meristems both in the root and in the shoot, and their meristematic activity was reduced or became abnormal. We showed that the mutant RAM lost its QC identity after germination, which was specified during embryogenesis, whereas the identity of differentiated tissues was maintained. In the post-embryonic SAM, the expression pattern of a typical OC marker gene, WUSCHEL, was disturbed in the mutant. These observations indicate that the HLR gene is essential to maintain the cellular organization and normal nature of the RAM and SAM. The HLRgene encodes RPT2a, which is a subunit of the 26S proteasome that degrades key proteins in diverse cellular processes. We showed that the HLR gene was expressed both in the RAM and in the SAM, including in the QC and the OC,respectively, and that the activity of proteasomes were reduced in the mutant. We propose that proteasome-dependent programmed proteolysis is required to maintain the meristem integrity both in the shoot and in the root.
brinkerandoptomotor-blindact coordinately to initiate development of the L5 wing vein primordium inDrosophila
Authors: Cook Orna , Biehs Brian , Bier Ethan
Published: April 2004

The stereotyped pattern of Drosophila wing veins is determined by the action of two morphogens, Hedgehog (Hh) and Decapentaplegic (Dpp), which act sequentially to organize growth and patterning along the anterior-posterior axis of the wing primordium. An important unresolved question is how positional information established by these morphogen gradients is translated into localized development of morphological structures such as wing veins in precise locations. In the current study, we examine the mechanism by which two broadly expressed Dpp signaling target genes, optomotor-blind (omb) and brinker (brk),collaborate to initiate formation of the fifth longitudinal (L5) wing vein. omb is broadly expressed at the center of the wing disc in a pattern complementary to that of brk, which is expressed in the lateral regions of the disc and represses omb expression. We show that a border between omb and brk expression domains is necessary and sufficient for inducing L5 development in the posterior regions. Mosaic analysis indicates that brk-expressing cells produce a short-range signal that can induce vein formation in adjacent omb-expressing cells. This induction of the L5 primordium is mediated by abrupt,which is expressed in a narrow stripe of cells along the brk/omb border and plays a key role in organizing gene expression in the L5 primordium. Similarly, in the anterior region of the wing, brk helps define the position of the L2 vein in combination with another Dpp target gene, spalt. The similar mechanisms responsible for the induction of L5 and L2 development reveal how boundaries set by dosage-sensitive responses to a long-range morphogen specify distinct vein fates at precise locations.
Organising services for influenza vaccination for older people
Authors: Dixon-Woods Mary , Brown Hilary , Arthur Antony , Matthews Ruth , Jagger Carol
Published: April 2004

Objectives: To follow up a trial of home-administered influenza vaccination of older people to explore reasons for their immunisation behaviour, including their views on the organisation of services.

Methods: Follow-up of original trial using analysis of records of 1865 older people and semi-structured interviews of 25 older people.

Results: A once-off home visit does not appear to result in sustained changes in immunisation behaviour. Older people's behaviour appears to be largely explained by their beliefs about immunisation; the organisation of services may exert only small effects. Older people can be characterised as belonging to one of four groups in their orientation towards influenza vaccination: the 'faithful', who are keen to have vaccination; the 'converts', who have been persuaded of the benefits of vaccination and are likely to self-initiate appointments for vaccination; the 'easy-going', who require prompting for vaccination; and the 'sceptics', who perceive influenza vaccination to be ineffective or to be irrelevant for them because of their perceived inherent resistance to influenza. The last group sees vaccination as a form of interference and may be resistant to home visits to administer the vaccine.

Conclusions: Targets for immunising older people require more debate because of the delicate balance between achieving herd immunity and preserving autonomy and choice for older people.
Modelling in the economic evaluation of health care: selecting the appropriate approach
Authors: Barton Pelham , Bryan Stirling , Robinson Suzanne
Published: April 2004

Objectives: To provide an overview of alternative approaches to modelling in economic evaluation, and to highlight situations where each of the alternative modelling techniques should be employed.

Methods: A review of the available approaches to modelling in the economic evaluation of health care interventions with a leading discussion of examples of published studies leading to guidance in the selection of an appropriate approach in different circumstances.

Results: The main approaches to modelling used in economic evaluations in health care are decision trees, Markov models and individual sampling models. These methods assume independence of individuals within the model. Where interaction between individuals is important, other methods such as discrete-event simulation or system dynamics are preferable.

Conclusions: The paper highlights the crucial question to be answered when selecting the approach to modelling: can the individuals being simulated in the model be regarded as independent? This issue is very commonly not recognised by analysts but is fundamental to the appropriate application of modelling in economic evaluation.
Nonlinear Analysis of Cable-strut Structures as a Mixed Complementarity Problem
Authors: Tin-Loi F. , Xia S. H.
Published: April 2004

This paper proposes a computation-oriented approach for determining the structural response of cable-strut systems under prescribed, not necessarily monotonic, loading histories. A feature of such structures, and one that is often a source of computational difficulty, is the possible slackening and retensioning of the cables. The methodology used in the present work to deal robustly and efficiently with this behavior is to express the element (cable or strut) constitutive law in a special mathematical format known as “complementarity”. Mathematically, this represents the perpendicularity of two-sign constrained vectors. Mechanically, it can be used to capture precisely the unilateral behavior of cables (viz. they can only support tension) and also the irreversible yielding of struts. We outline how these cable and strut laws can be combined with classical equilibrium and compatibility relations to provide a formulation in rates. Numerical solution of this problem is carried out by converting the rate problem into a finite incremental form leading to a special class of problems known in the mathematical programming literature as a “mixed complementarity problem” (MCP). Two examples are given to illustrate application of the approach proposed.
Tensile Force Compensation Analysis Method and Application in Construction of Hybrid Structures
Authors: Zhuo Xin , Ishikawa Koichiro
Published: April 2004

A new analysis method for hybrid structures in the course of construction, the “tensile force compensation analysis method”, is put forward in this paper. The construction control tensile force can be solved exactly using a few steps of compensation calculation cycles. When strings were introduced one by one in sequence during construction, subsistent tensile forces of all strings would meet their aim tensile forces if those strings were introduced to their construction control tensile forces obtained by means of the “tensile force compensation analysis method”. At the same time, the internal forces of members and displacements of the structure in every stage of tensile force introduction can be solved. Thus, this analysis method can be used in optimum construction of hybrid structures. Easy to learn and to use, it is possible to widely apply this analysis method in tensile force introduction design for hybrid structures by engineers.
Wind-Resistant Analysis for Large-span Single-layer Reticulated Shells
Authors: Li Yuan-Qi , Tamura Yukio
Published: April 2004

Single-Layer Reticulated Shells are a kind of space-latticed system with the features of bar system structures and thin shells. For their structural design, wind loading is very important since they are sensitive to external loading distribution and stability is an important, even dominant problem. Generally, nonlinear dynamic time-history analysis is an effective way to give a convinced result, but the time-consuming computation and the cost for obtaining the time-series data of wind pressure from wind tunnel tests should be considered at first. At present, usually equivalent static methods based on the quasi-steady assumption are used in the structural wind-resistant design in practice. However, the estimated equivalent static wind loading distribution may not reflect the actual effects of fluctuating wind loading on stability of shells, which may lead to an unsafely higher limit load-carrying capacity. In this paper, wind pressure distribution on a spherical shell model was measured simultaneously in wind tunnel first. A framework for nonlinear dynamic time-history analysis of wind-induced vibration for single-layer reticulated shells was introduced. Based on the measured wind pressure data, nonlinear time-history analysis, including dynamic instability analysis of a single-layer reticulated spherical shell was conducted as an example. Then, several equivalent static wind loading estimation methods were discussed and compared, including a new simple method presented by the authors from the stability point of view. Finally, with comparison analyses, it was proved that the presented method can be used to improve the efficiency of the effective static loading distribution estimation, as well as to give a conservative estimation of the effects of wind loading on single-layer reticulated shells, especially in stability analysis.
The Institutional Effects on Strategic Alliance Partner Selection in Transition Economies: China vs. Russia
Authors: Hitt Michael A. , Ahlstrom David , Dacin M. Tina , Levitas Edward , Svobodina Lilia
Published: April 2004

China and Russia represent major economies in transition from command economies, yet their paths to the market have differed greatly. Their divergent approaches have helped create distinct institutional environments. This study focuses on a particularly important strategic decision firms face—alliance partner selection. The study's results suggest that China's more stable and supportive institutional environment has helped Chinese firms take a longer-term view of alliance partner selection, focusing more on the potential partner's intangible assets along with technological and managerial capabilities. In contrast, the less stable Russian institutional environment has influenced Russian managers to focus more on the short term, selecting partners that provide access to financial capital and complementary capabilities so as to enhance their firms—ability to weather that nation's turbulent environment. This study contributes to knowledge about the influence of the institutional environment on alliance partner selection decisions for firms domiciled in transition (and emerging) economies.