bluuebunny/crossref_metadata_2025 huggingface dataset:
Universal Mass Ratios of Non-Unique Spanning Clusters in Percolation
Authors: Sen Parongama , Aharony Amnon
Published: October 2003

We find that when two or more spanning clusters exist at the percolation threshold, the mass of each scales with the same fractal dimension D=1.89 in two dimensions and D=2.53 in three dimensions. We also determine the ratios of the masses of the spanning clusters. In two dimensions, this is done for different lattices of different shapes. In the case of two spanning clusters, the ratio of the larger spanning cluster to the smaller lies around 1.4 for two dimensions, almost independent of lattice structure and shape.
Vacuum Expectation Value of the Higgs Field and Dyon Charge Quantisation from Spacetime Dependent Lagrangians
Authors: Bhattacharyya Rajsekhar , Gangopadhyay Debashis
Published: October 2003

The spacetime dependent Lagrangian formalism of Refs. 1 and 2 is used to obtain a classical solution of Yang–Mills theory. This is then used to obtain an estimate of the vacuum expectation value of the Higgs field viz. ϕa = A/e, where A is a constant and e is the Yang–Mills coupling (related to the usual electric charge). The solution can also accommodate noncommuting coordinates on the boundary of the theory which may be used to construct D-brane actions. The formalism is also used to obtain the Deser–Gomberoff–Henneaux–Teitelboim results10 for dyon charge quantisation in Abelian p-form theories in dimensions D = 2(p+1) for both even and odd p.
Polygon Indices and Superbridge Indices of Torus Knots and Links
Authors: Jin Gyo Taek
Published: October 2003

The minimal number of straight line segments required to form a given knot or link in ℝ3 is determined for a family of torus knots and links.
Algebraic Invariants of Simple 4-Knots
Authors: Hillman J. A. , Kearton C.
Published: October 2003

We propose as an algebraic invariant for a simple 4-knot K with exterior X the triple (L, η, [λ]), where L = Z ⊕ π2(X)⊕π3(X) is a commutative graded ring with unit whose multiplication in positive degrees is determined by Whitehead product, η is composition with the Hopf map and [λ] is the orbit of the homotopy class of the longitude in π4(X) under the group of self homotopy equivalences of the universal covering space X′ which induce the identity on L. If K is fibred these invariants determine the fibre, and the natural Z[t,t-1]-module structures on the homotopy groups capture part of the monodromy. Every such triple with L finitely generated as an abelian group (and satisfying the order obviously necessary conditions) may be realized by some fibred simple 4-knot. In certain cases we can show that the triple determines the knot up to a finite ambiguity.
Color Invariant for Spatial Graphs
Authors: Ishii Yuko , Yasuhara Akira
Published: October 2003

The method of distinguishing knots and links using the colorability of their diagrams was invented by Ralph Fox [2]. As generalization of this method, we introduce certain method of distinguishing spatial graphs.
Positive Braids with a Half Twist are Prime
Authors: Sullivan Michael C.
Published: October 2003

We shall prove that a knot which can be represented by a positive braid with a half twist is prime. This is done by associating to each such braid a smooth branched 2-manifold with boundary and studying its intersection with a would-be cutting sphere.
Singular Braids and Markov's Theorem
Authors: Gemein Bernd
Published: October 2003

In this article we will give a new version of Markov's Theorem, treating singular braids and knots in the sense of Vassiliev's theory of knot invariants. The classical version of Markov's Theorem states that two closed braids represent the same link if and only if the braids are related by a sequence of algebraic operations, known as Markov's moves. Birman has published the first rigorous proof of this regular version in 1975, [Birl] using elementary techniques. Our proof uses a suitable version of these techniques in order to reduce the singular case to the regular case. Birman's proof then completes ours. Some technical points will only be sketched. Full details can be found in [Gem].
In Search of a Good Polygonal Knot Energy
Authors: Diao Y. , Ernst C. , Janse van Rensburg E. J.
Published: October 2003

An energy function on knots is a scale-invariant function from knot conformations into non-negative real numbers. The infimum of an energy function is an invariant which defines "canonical conformation(s)" of a knot in three space. These are not necessarily unique, and, in some cases, may even be singular. Many hierarchies of energy functions for knots in the mathematical and physical science literature have been studied, each energy function with its own characteristic set of properties. In this paper we focus on the energy functions of equilateral polygonal knots. These energy functions are important in computer studies of knot energies, and are often defined as discrete versions of energy functions defined on smooth knots. Energy functions on equilateral polygonal knots turn out to be ill-behaved in many cases. To characterize a "good" polygonal knot energy we introduce the concepts of asymptotically finite and asymptotically smooth energy functions of equilateral polygonal knots. Energy functions which are both asymptotically finite and smooth tend to have food limiting behavior (as the number of edges goes to infinity). We introduce a new energy function of equilateral polygonal knots, and show that it is both asymptotically finite and smooth. In addition, we compute this energy for several knots using simulated annealing.
Casson-Lin's Invariant and Floer Homology
Authors: Li Weiping
Published: October 2003

Casson defined an invariant which can be thought of as the number of conjugacy classes of irreducible representations of π1(Y) into SU(2) counted with signs, where Y is an oriented integral homology 3-sphere. Lin defined a similar invariant (the signature of a knot) for a braid representative of a knot in S3. In this paper, we give a natural generalization of Casson-Lin's invariant. Our invariant is the symplectic Floer homology for the representation space of π1(S3 \ K) into SU(2) with trace-zero along all meridians. The symplectic Floer homology of braids is a new invariant of knots and its Euler number is the negative of Casson-Lin's invariant.
Aspects of Chiral Symmetry
Authors: Koch Volker
Published: October 2003

This article is an attempt to a pedagogical introduction and review into the elementary concepts of chiral symmetry in nuclear physics. Effective chiral models such as the linear and nonlinear sigma model will be discussed as well as the essential ideas of chiral perturbation theory. Some applications to the physics of ultrarelativistic heavy ion collisions will be presented.
Is It Possible and Useful to Support Commitment Reasoning?
Authors: Lau L. Alaric , Woo Carson C.
Published: October 2003

The concept of commitment has recently been adopted by researchers to model cooperative organizational activities. By defining a commitment as an agreement by an agent to the requesting agent to carry out the requested action, a Commitment Reasoning Support System (CRSS) is proposed in an attempt to support the reasoning process in deciding whether or not to make a commitment. CRSS can be characterized as a specialized decision support system that emphasizes the accountability and the sentimental aspects of decision making. An empirical study was conducted on a CRSS prototype. The findings show that it is useful for commitment requests with high complexity and/or with important implications. The study also suggests possible conceptual insights of commitment reasoning for future research.
Apolipoprotein D Inhibits Platelet-Derived Growth Factor-BB–Induced Vascular Smooth Muscle Cell Proliferated by Preventing Translocation of Phosphorylated Extracellular Signal Regulated Kinase 1/2 to the Nucleus
Authors: Sarjeant Jennifer M. , Lawrie Allan , Kinnear Caroline , Yablonsky Shmuel , Leung Wesley , Massaeli Hamid , Prichett Wendy , Veinot John P. , Rassart Eric , Rabinovitch Marlene
Published: October 2003

Objective—

Elevated apolipoprotein D (apoD) levels are associated with reduced proliferation of cancer cells. We therefore investigated whether apoD, which occurs free or associated with HDL, suppresses vascular smooth muscle cell (VSMC) proliferation, which is related to the pathobiology of disease.

Methods and Results—

Intense immunoreactivity for apoD was observed in human atherosclerotic plaque but not in normal coronary artery. However, an increase in apoD mRNA was seen in quiescent relative to proliferating fetal lamb aortic VSMCs, and in the rat aortic VSMC line (A10), we demonstrated uptake of apoD from serum. Stable transfection of apoD in A10 cells in the absence of serum did not influence VSMC proliferation assessed by [
3
H]-thymidine incorporation. ApoD, administered at a dose of 100 ng/mL, completely inhibited basal as well as platelet-derived growth factor (PDGF)-BB–induced VSMC proliferation (
P
<0.01) but had no effect on fibroblast growth factor–induced VSMC proliferation. ApoD did not suppress PDGF-BB or fibroblast growth factor-2–induced phosphorylation of extracellular signal regulated kinase (ERK) 1/2 but selectively inhibited PDGF-BB–mediated ERK1/2 nuclear translocation.

Conclusions—

Our data suggest that apoD selectively modulates the proliferative response of VSMC to growth factors by a mechanism related to nuclear translocation of ERK1/2.
Ras Induces Vascular Smooth Muscle Cell Senescence and Inflammation in Human Atherosclerosis
Authors: Minamino Tohru , Yoshida Toshihiko , Tateno Kaoru , Miyauchi Hideyuki , Zou Yonzeng , Toko Haruhiro , Komuro Issei
Published: October 2003

Background—

Vascular cells have a finite cell lifespan and eventually enter an irreversible growth arrest, cellular senescence. The functional changes associated with cellular senescence are thought to contribute to human aging and age-related vascular disorders. Ras, an important signaling molecule involved in atherogenic stimuli, is known to promote aging in yeast and cellular senescence in primary human fibroblasts. The aim of this study was to investigate the role of Ras-induced vascular smooth muscle cell (VSMC) senescence in atherogenesis.

Methods and Results—

We introduced an activated
ras
allele (H-
ras
V12) into human VSMCs using retroviral infection. Introduction of H-
ras
V12 induced a growth arrest with phenotypic characteristics of cellular senescence, such as enlarged cell shapes and increases in expression of cyclin-dependent kinase inhibitors and senescence-associated β-galactosidase (SA-β-gal) activity. Activation of Ras drastically increased expression of proinflammatory cytokines, in part through extracellular signal-regulated kinase activation. To determine whether Ras activation induces cellular senescence in vivo, we transduced the adenoviral vector encoding H-
ras
V12 into rat carotid arteries injured by a balloon catheter. Introduction of Ras into the arteries enhanced vascular inflammation and senescence compared with mock-infected injured arteries. Moreover, SA-β-gal–positive VSMCs were detected in the intima of advanced human atherosclerotic lesions and exhibited increased levels of extracellular signal-regulated kinase activity and proinflammatory cytokine expression.

Conclusions—

Our results suggest that atherogenic stimuli mediated by Ras induce VSMC senescence and vascular inflammation, thereby contributing to atherogenesis. This novel mechanism of atherogenesis may provide insights into a new antisenescence treatment for atherosclerosis.
Blood Pressure Lowering and Life Expectancy Based on a Markov Model of Cardiovascular Events
Authors: Sesso Howard D. , Chen Roland S. , L’Italien Gilbert J. , Lapuerta Pablo , Lee Won Chan , Glynn Robert J.
Published: October 2003

The life expectancy benefits of antihypertensive treatment, based on both systolic and diastolic blood pressure reduction, was estimated with a cardiovascular disease event Markov model with prospective data from 57 573 men and women. Seven patient states were defined, including (1) no cardiovascular disease, (2) stroke, (3) myocardial infarction, (4) revascularization, (5) history of cardiovascular disease, (6) noncardiovascular disease death, and (7) cardiovascular death. Risk functions were developed from gender-specific multivariate Cox proportional hazards models for primary events and age-, smoking-, and diabetes-adjusted models for secondary events. At baseline we assumed (1) hypothetical pretreatment blood pressures of 160/95 or 150/90 mm Hg; (2) strategies A and B lower blood pressure by 20/13 and 13/8 mm Hg, respectively; and (3) baseline age of 35 years. For subjects initially at 160/95 mm Hg, those with antihypertensive treatment, antihypertensive treatment and diabetes, or antihypertensive treatment, diabetes, and currently smoking had corresponding gains in life expectancy of 2.43, 2.80, and 2.43 years for Strategy A. An initial blood pressure of 150/90 mm Hg resulted in similar gains. Compared with Strategy B, with blood pressure reductions of 13/8 mm Hg, Strategy A provided additional gains in life expectancy of 0.84, 0.99, and 0.87 years for those with antihypertensive treatment, antihypertensive treatment and diabetes, or antihypertensive treatment, diabetes, and currently smoking. The initial blood pressure level did not affect the magnitude of life expectancy gains for equivalent blood pressure reductions. Greater gains in life expectancy among hypertensive and diabetic women suggest that blood pressure lowering may yield greater benefits in selected subgroups.
Cytoskeletal Reorganization by Mycophenolic Acid Alters Mesangial Cell Migration and Contractility
Authors: Dubus Isabelle , L’Azou Beatrice , Gordien Myriam , Delmas Yahsou , Labouyrie Jean-Pierre , Bonnet Jacques , Combe Christian
Published: October 2003

Cytoskeleton alterations are a hallmark of mesangial cell activation during glomerulosclerosis. The aim of this study was to investigate whether mycophenolic acid (MPA) affects cytoskeletal organization and motility of human mesangial cells. Using the IP15 cell line, we found that treatment with 1 μmol/L MPA inhibited both receptor-dependent (angiotensin II) and receptor-independent (KCl) contractile responses, as well as serum-induced migration activity, suggesting alterations in the intracellular mechanisms that control mesangial cell motility. Immunofluorescence studies of MPA-treated cells provided evidence for decreased membrane disassembly/reassembly of α-smooth muscle actin and F-actin fibers, which was correlated with sustained quantitative and qualitative modifications of actin-associated proteins: calponin was overexpressed and became associated with actin fibers, whereas phosphorylation levels of cofilin and myosin light chain increased, suggesting both an activation of the mechanisms responsible for actin polymerization and an inhibition of actin-depolymerizing processes. These observations support a stabilizing effect of MPA on the mesangial actin cytoskeleton, which constitutes an additive action by which MPA, beyond its anti-inflammatory, antiproliferative and antifibrotic properties, might protect against excessive mesangial activation in the context of various glomerulopathies and kidney transplantation.
Developmental Changes in Ventricular Diastolic Function Correlate With Changes in Ventricular Myoarchitecture in Normal Mouse Embryos
Authors: Ishiwata Takahiro , Nakazawa Makoto , Pu William T. , Tevosian Sergei G. , Izumo Seigo
Published: October 2003

Both genetic and epigenetic factors, such as abnormal hemodynamics, affect cardiac morphogenesis and the pathogenesis of congenital heart disease. Diastolic function is an important determinant of cardiac function, and tools for evaluating diastolic function in the embryo would be very valuable for assessment of cardiac performance. Using histological measurements of ventricular myoarchitecture, Doppler assessment of ventricular inflow velocities, and direct measurement of ventricular pressure, we investigated developmental changes of ventricular diastolic function in the mouse embryos from embryonic days 9.5 to 19.5. Regression analysis showed that peak velocity of A wave (an index of passive compliance) correlated with the area of trabecular myocardium in right ventricle (RV) (
r
2
=0.92,
P
<0.0001) and left ventricle (LV) (
r
2
=0.93,
P
<0.0001). Peak velocity of E wave (an index of active relaxation) exponentially correlated with the area of compact myocardium in RV (
r
2
=0.98,
P
<0.0001) and LV (
r
2
=0.97,
P
<0.0001). We used these techniques to analyze FOG-2 null embryos. FOG-2 null embryos had thin compact myocardium, higher EDP and E/A ratio, smaller −dP/dt, and diminished sucking pressure than wild-type littermates, indicating that decreased ventricular diastolic function might be the primary cause of embryonic lethality. In conclusion, during embryogenesis the development of compact myocardium tightly regulates the development of ventricular distensibility. Our study in normal mice forms the basis for future studies of embryonic cardiac function in genetically manipulated mice with abnormalities of the cardiovascular system.
Treatment With Insulin Uncovers the Motogenic Capacity of Nitric Oxide in Aortic Smooth Muscle Cells
Authors: Dixit Madhulika , Zhuang Daming , Ceacareanu Bogdan , Hassid Aviv
Published: October 2003

Contrary to the antimotogenic effect of NO in dedifferentiated vascular smooth muscle cells (VSMCs), we have reported that NO stimulates the motility of differentiated cultured VSMC isolated from adult rats. This process involves upregulation of protein tyrosine phosphatase SHP2, followed by downregulation of RhoA activity. In the present study, we tested the hypothesis that insulin alters the motogenic phenotype of cultured rat aortic smooth muscle cells exposed to NO from inhibition to stimulation of cell motility. We demonstrate for the first time that NO stimulates the motility of VSMCs cultured for several days in the presence but not the absence of insulin. Moreover, we show that NO blocks PDGF-induced cell motility in insulin-naive but not in insulin-treated cells. We also demonstrate that the scaffold adapter protein Gab1, considered a physiological activator of protein tyrosine phosphatase SHP2, increases cell motility in the presence but not the absence of insulin. In cells cultured in the presence of insulin, overexpression of Gab1 mimics, whereas a dominant-negative allele of Gab1 (Gab1YF) blocks, the motility-stimulatory effect of NO. Cotransfection experiments with dominant-negative Gab1 and wild-type SHP2 or wild-type Gab1 and dominant-negative SHP2 indicate that the two proteins work together as a functional unit to induce motility. Because chronic insulin can increase the levels of phosphatidylinositol 3 (PI3) kinase in several models of hyperinsulinemia, we also tested the potential involvement of this enzyme in mechanisms leading to increased cell motility. We found that the motogenic effect of NO, Gab1, and SHP2 was blocked by the selective PI3 kinase inhibitor LY294002, suggesting a requirement of PI3 kinase in mediating motogenesis. These observations may be relevant to molecular mechanisms related to the pathogenesis of vascular disease in hyperinsulinemic diabetes. The full text of this article is available online at http://www.circresaha.org.
North-South Gradients in Britain for Stroke and CHD
Authors: Morris R.W. , Whincup P.H. , Emberson J.R. , Lampe F.C. , Walker M. , Shaper A.G.
Published: October 2003

Background and Purpose—

The geographic variation in CHD and stroke within Great Britain is well known. We aimed to quantify these variations and to determine the contribution of established risk factors.

Methods—

This prospective study consisted of 7735 men 40 to 59 years of age in 24 British towns who were followed up for 20 years from screening in 1978 to 1980. We compared age-adjusted incidences of major stroke and CHD events in southern England and the rest of Britain before and after adjustment for established cardiovascular risk factors.

Results—

At least 1 episode of stroke occurred in 467 men (3.54 per 1000 person-years, age standardized) and of CHD in 1299 men (10.05 per 1000 person-years). Event rates varied between towns, from 2.00 to 5.45 per 1000 person-years for stroke and from 6.16 to 12.21 per 1000 person-years for CHD. Incidence for both diseases was highest in Scottish towns and lowest in southern English towns (“north-south gradient”). The hazard ratio for stroke in the rest of Britain compared with southern England was 1.44 (95% confidence interval [CI], 1.16 to 1.78); for CHD, it was 1.32 (95% CI, 1.14 to 1.53). After adjustment for baseline systolic blood pressure, smoking status, physical activity, social class, and height, the hazard ratio was 1.24 (95% CI, 1.00 to 1.54) for stroke and 1.17 (95% CI, 1.02 to 1.35) for CHD.

Conclusions—

Similar north-south gradients were observed for major stroke and major CHD events. The magnitude of these gradients was considerably diminished when individual risk variables were taken into account.
Costs of Acute Care of First-Ever Ischemic Stroke in Taiwan
Authors: Chang Ku-Chou , Tseng Mei-Chiun
Published: October 2003

Background and Purpose—

We sought to investigate the direct costs of acute hospitalization for patients with first-ever ischemic stroke in Taiwan.

Methods—

Data were prospectively collected from 360 first-ever ischemic stroke patients. Hospital charges were used for analysis. Multiple linear regression analysis was used to identify the main factors influencing costs.

Results—

Mean age was 64.9 years (median, 67.0 years), and 58% were male. Mean National Institutes of Health Stroke Scale (NIHSS) score at admission was 9.4 (median, 6.0). Mean initial score of modified Barthel Index was 10.7 (median, 12.0). Median length of stay was 7 days (range, 1 to 122 days). In-hospital mortality was 8%. Overall, median cost per patient was 26 326 New Taiwan dollars (NTD) (original currency) or $841; median cost per day was 3777 NTD or $121. Median costs for patients with initial NIHSS score 0 to 6, 7 to 15, and 16 to 38 were 20 365 NTD ($650), 31 954 NTD ($1020), and 62 653 NTD ($2000), respectively. Daily component (physician and ward charges) accounted for approximately 38% of total costs. Initial NIHSS score, small-vessel occlusion, admission to intensive care unit, sex, and smoking had significant impacts on costs.

Conclusions—

Apart from providing cost estimates, we note that stroke severity strongly affects costs.
Procedural Developments at the International Court of Justice
Authors:   Prager
Published: October 2003

No Abstract
Family Factors That Differentiate Sexually Abused and Nonabused Adolescent Psychiatric Inpatients
Authors: Reinemann Dawn H.S. , Stark Kevin D. , Swearer Susan M.
Published: October 2003

Sexual abuse research has traditionally focused on adult, retrospective accounts of potential correlates of abuse and their impact on functioning. However, only a few studies have examined sexually abused adolescents’ perceptions of their families, and results have proven inconclusive. This study examined whether family factors would differentiate sexually abused and nonabused adolescent psychiatric inpatients. Fifty-seven psychiatric inpatients, ages 11 to 17, who either had experienced sexual abuse or had no history of sexual victimization completed a diagnostic interview and were assessed on a variety of family indices. Results indicated that after controlling for level of depression, sexually abused adolescents could be differentiated from their nonabused counterparts based on family variables. Sexually abused adolescents reported their families as more authoritarian and more enmeshed. They also perceived more negative messages from their nonoffending father figures about the world. Also, exploratory gender analyses revealed that sexually abused females reported greater levels of depression than sexually abused males.
Role of adenosine receptors in regulating chemotaxis and cytokine production of plasmacytoid dendritic cells
Authors: Schnurr Max , Toy Tracey , Shin Amanda , Hartmann Gunther , Rothenfusser Simon , Soellner Julia , Davis Ian D. , Cebon Jonathan , Maraskovsky Eugene
Published: October 2003

Plasmacytoid dendritic cells (PDCs) are potent regulators of immune function and the major source of type I interferon (IFN) following viral infection. PDCs are found at sites of inflammation in allergic reactions, autoimmune disorders, and cancer, but the mechanisms leading to the recruitment of PDCs to these sites remain elusive. During inflammation, adenosine is released and functions as a signaling molecule via adenosine receptors. This study analyzes adenosine receptor expression and function in human PDCs. Adenosine was found to be a potent chemotactic stimulus for immature PDCs via an A1 receptor–mediated mechanism. The migratory response toward adenosine was comparable to that seen with CXCL12 (stromal-derived factor-1α [SDF-1α), the most potent chemotactic stimulus identified thus far for immature PDCs. Upon maturation, PDCs down-regulate the A1 receptor, resulting in a loss of migratory function. In contrast, mature PDCs up-regulate the A2a receptor, which is positively coupled to adenylyl cyclase and has been implicated in the down-regulation of DC cytokine-producing capacity. We show that in mature PDCs adenosine reduces interleukin-6 (IL-6), IL-12, and IFN-α production in response to CpG oligodeoxynucleotides (ODN). These findings indicate that adenosine may play a dual role in PDC-mediated immunity by initially recruiting immature PDCs to sites of inflammation and by subsequently limiting the extent of the inflammatory response induced by mature PDCs by inhibiting their cytokine-producing capacity.
Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents
Authors: Cragg Mark S. , Glennie Martin J.
Published: October 2003

Despite the success of anti-CD20 monoclonal antibody (mAb) in the treatment of lymphoma, there remains considerable uncertainty about their mechanism(s) of action. Here, we show that certain of these reagents (rituximab and 1F5), which redistribute CD20 into membrane rafts, are bound efficiently by C1q, deposit C3b, and result in complement-dependent cytotoxicity (CDC). This activity is important in vivo, because complement depletion using cobra venom factor (CVF) markedly reduced the efficacy of rituximab and 1F5 in 2 lymphoma xenograft models. However, complement depletion had no effect on the potent therapeutic activity of B1, a mAb that does not redistribute CD20 into membrane rafts, bind C1q, or cause efficient CDC. Equivalent immunotherapy also occurred in the presence or absence of natural killer (NK) cells. Perhaps most surprising was the observation that F(ab′)2 fragments of B1 but not 1F5 were able to provide substantial immunotherapy, indicating that non-Fc-dependent mechanisms are involved with B1. In accordance with this, B1 was shown to induce much higher levels of apoptosis than rituximab and 1F5. Thus, although complement is important for the action of rituximab and 1F5, this is not so for B1, which more likely functions through its ability to signal apoptosis. (Blood. 2004;103:2738-2743)
Identification and characterization of EBP, a novel EEN binding protein that inhibits Ras signaling and is recruited into the nucleus by the MLL-EEN fusion protein
Authors: Yam Judy Wai Ping , Jin Dong-Yan , So Chi Wai , Chan Li Chong
Published: October 2003

The chimeric MLL-EEN fusion protein is created as a result of chromosomal translocation t(11;19)(q23;p13). EEN, an Src homology 3 (SH3) domain–containing protein in the endophilin family, has been implicated in endocytosis, although little is known about its role in leukemogenesis mediated by the MLL-EEN fusion protein. In this study, we have identified and characterized EBP, a novel EEN binding protein that interacts with the SH3 domain of EEN through a proline-rich motif PPERP. EBP is a ubiquitous protein that is normally expressed in the cytoplasm but is recruited to the nucleus by MLL-EEN with a punctate localization pattern characteristic of the MLL chimeric proteins. EBP interacts simultaneously with EEN and Sos, a guanine-nucleotide exchange factor for Ras. Coexpressoin of EBP with EEN leads to suppression of Ras-induced cellular transformation and Ras-mediated activation of Elk-1. Taken together, our findings suggest a new mechanism for MLL-EEN–mediated leukemogenesis in which MLL-EEN interferes with the Ras-suppressing activities of EBP through direct interaction.
LAD-III, a leukocyte adhesion deficiency syndrome associated with defective Rap1 activation and impaired stabilization of integrin bonds
Authors: Kinashi Tatsuo , Aker Memet , Sokolovsky-Eisenberg Maya , Grabovsky Valentin , Tanaka Chisato , Shamri Revital , Feigelson Sara , Etzioni Amos , Alon Ronen
Published: October 2003

Recently, we reported a rare leukocyte adhesion deficiency (LAD) associated with severe defects in integrin activation by chemokine signals, despite normal ligand binding of leukocyte integrins.1 We now report that the small GTPase, Rap1, a key regulator of inside-out integrin activation is abnormally regulated in LAD Epstein-Barr virus (EBV) lymphocyte cells. Both constitutive and chemokine-triggered activation of Rap1 were abolished in LAD lymphocytes despite normal chemokine signaling. Nevertheless, Rap1 expression and activation by phorbol esters were intact, ruling out an LAD defect in Rap1 guanosine triphosphate (GTP) loading. The very late antigen 4 (VLA-4) integrin abnormally tethered LAD EBV lymphocytes to its ligand vascular cell adhesion molecule 1 (VCAM-1) under shear flow due to impaired generation of high-avidity contacts despite normal ligand binding and intact avidity to surface-bound anti-VLA-4 monoclonal antibody (mAb). Thus, a defect in constitutive Rap1 activation results in an inability of ligand-occupied integrins to generate high-avidity binding to ligand under shear flow. This is a first report of an inherited Rap1 activation defect associated with a pathologic disorder in leukocyte integrin function, we herein term it “LAD-III.” (Blood. 2004;103:1033-1036)
A novel SHP-1/Grb2–dependent mechanism of negative regulation of cytokine-receptor signaling: contribution of SHP-1 C-terminal tyrosines in cytokine signaling
Authors: Minoo Parham , Zadeh Maryam Mohsen , Rottapel Robert , Lebrun Jean-Jacques , Ali Suhad
Published: October 2003

SHP-1, an src homology 2 (SH2) domain containing protein tyrosine phosphatase, functions as a negative regulator of signaling downstream of cytokine receptors, receptor tyrosine kinases and receptor complexes of the immune system. Dephosphorylation of receptors and/or receptor-associated kinases has been described as the mechanism for the function of SHP-1. Here we demonstrate a novel mechanism by which SHP-1 down-regulates the Janus kinase–2 (Jak2)/signal transducer and activator of transcription-5 (Stat5) pathway downstream of the prolactin receptor (PRLR) and the erythropoietin receptor (EPOR) in a catalytic activity–independent manner. Structural/functional analysis of SHP-1 defined the C-terminal tyrosine residues (Y278, Y303, Y538, Y566) within growth factor receptor–bound protein 2 (Grb-2) binding motif to be responsible for delivering the inhibitory effects. Our results further indicate that these tyrosine residues, via recruitment of the adaptor protein Grb-2, are required for targeting the inhibitory protein suppressor of cytokine signaling–1 (SOCS-1) to Jak2 kinase. Finally, loss of SOCS-1 expression in SOCS-1–/– mouse embryonic fibroblast (MEF) cells led to attenuation in SHP-1 function to down-regulate PRL-induced Stat5 activation. All together, our results indicate that SHP-1 inhibits PRLR and EPOR signaling by recruitment and targeting of SOCS-1 to Jak2, highlighting a new mechanism of SHP-1 regulation of cytokine-receptor signaling.
Identification of critical amino-acid residues on the erythroid intercellular adhesion molecule-4 (ICAM-4) mediating adhesion to αV integrins
Authors: Mankelow Tosti J. , Spring Frances A. , Parsons Stephen F. , Brady R. Leo , Mohandas Narla , Chasis Joel A. , Anstee David J.
Published: October 2003

Intercellular adhesion molecule-4 (ICAM-4, syn. LW glycoprotein) interacts with the integrins αLβ2, αMβ2, A4β1, the αV family, and αIIbβ3. Systematic mutagenesis of surface-exposed residues conserved between human and murine ICAM-4 defined 12 single amino-acid changes that affect the interaction of ICAM-4 with αV integrins. Mutation of 10 of these residues, 8 of which are spatially close on the surface of the molecule, led to a reduction in adhesion. Moreover, peptides corresponding to regions of ICAM-4 involved in its interaction with αV integrins inhibited these interactions. The other 2 mutations increased the extent of interaction of ICAM-4 with αV integrins. These mutations appear to prevent glycosylation of N160, suggesting that changes in glycosylation may modulate ICAM-4–αV integrin interactions. The region of ICAM-4 identified as the binding site for αV integrins is adjacent to the binding sites for αLβ2 and αMβ2. Selective binding of ICAM-4 to different integrins may be important for a variety of normal red cell functions and also relevant to the pathology of thrombotic disorders and vasoocclusive events in sickle cell disease. Our findings suggest the feasibility of developing selective inhibitors of ICAM-4–integrin adhesion of therapeutic value in these diseases.
Ghrelin and Des-Octanoyl Ghrelin Promote Adipogenesis Directly in Vivo by a Mechanism Independent of the Type 1a Growth Hormone Secretagogue Receptor
Authors: Thompson Nichola M. , Gill Dave A. S. , Davies Rhos , Loveridge Nigel , Houston Pamela A. , Robinson Iain C. A. F. , Wells Timothy
Published: October 2003

Ghrelin promotes fat accumulation, despite potent stimulation of the lipolytic hormone, GH. The function of the major circulating isoform of ghrelin, des-octanoyl ghrelin, is unclear, because it does not activate the GH secretagogue receptor (GHS-R1a) and lacks the endocrine activities of ghrelin. We have now addressed these issues by infusing ghrelin, des-octanoyl ghrelin, or synthetic GHS-R1a agonists into three rat models with moderate, severe, or total GH deficiency. We show that in the context of significant GH secretion, the adipogenic effect of systemic ghrelin infusion is pattern dependent. However, this adipogenic action is not mediated by the pituitary hormones. Using a novel unilateral local infusion strategy, we demonstrate that ghrelin promotes bone marrow adipogenesis in vivo by a direct peripheral action. Surprisingly, this effect was also observed with des-octanoyl ghrelin, whereas a potent synthetic GHS-R1a agonist was ineffective. Thus, these adipogenic effects are mediated by a receptor other than GHS-R1a. This is the first in vivo demonstration of a direct adipogenic effect of des-octanoyl ghrelin, a major circulating form of ghrelin that lacks GH-releasing activity. We suggest that the ratio of ghrelin and des-octanoyl ghrelin production could help regulate the balance between adipogenesis and lipolysis in response to nutritional status.
The influence of morphine on the absorption of paracetamol from various formulations in subjects in the supine position, as assessed by TDx measurement of salivary paracetamol concentrations
Authors: Kennedy Julia M , Tyers Nicola M , Davey Andrew K
Published: October 2003

The aim of this study was to determine the influence of the type of paracetamol formulation on the rate of absorption when subjects are in the supine position, with or without taking concomitant morphine. Two groups of healthy volunteers were used, who were in the fasting state and remained in the supine position during the study. One group took 1500 mg of paracetamol on three occasions as conventional tablets, dispersible tablets or a suspension in a randomized crossover design. Seventeen saliva samples per subject were obtained (time zero to 360 min post-dose), which were then centrifuged and kept at −20°C prior to analysis. The second group repeated the study following four doses of morphine syrup (10 mg 4 hourly) in the 12 h preceding paracetamol ingestion. In this phase of the study, paracetamol absorption from suspension was not investigated. A TDx assay was used to determine salivary paracetamol concentrations. The tmax for conventional tablets when taken concomitantly with morphine was 160 (+81) min compared to 51 (+58) min for subjects not taking morphine. For dispersible tablets the tmax in the morphine group was 14 (+9) min compared to 15 (+12) min without morphine. The results suggest that patients who are confined to bed and taking morphine will have an unacceptably long delay between taking conventional paracetamol tablets and the paracetamol reaching therapeutic plasma concentrations. Conversely, there is little effect on the absorption of dispersible paracetamol under the same conditions.
Peroxynitrite scavenging activity of lithospermate B from Salvia miltiorrhiza
Authors: Soung Do You , Rhee Sook Hee , Kim Jung Sun , Lee Ji Young , Yang Hee-Sun , Choi Jae Sue , Yokozawa Takako , Han Yong Nam , Chung Hae Young
Published: October 2003

Peroxynitrite (ONOO−) is produced by the reaction of superoxide (O2−) with nitric oxide. ONOO− damages proteins through nitration or oxidation. For protection from ONOO− induced protein modifications, ONOO− scavengers should be supplemented. Evidence was obtained that lithospermate B extracted from Salvia miltiorrhiza showed the strongest scavenging activity among its constituents. Its ONOO− scavenging activity is via an electron donation mechanism. A dihydroxyl group and a double bond seem to be essential structure requirements. The data from the experiments further confirmed a protective effect of lithospermate B on bovine serum albumin and low-density lipoprotein against ONOO−. This study demonstrated that lithospermate B with hydroxyl groups and double bonds exerts an anti-nitration effect by scavenging ONOO−.
Examinations of the antioxidative properties of the topically administered drug bufexamac reveal new insights into its mechanism of action
Authors: Trommer Hagen , Plätzer Manuela , Raith Klaus , Wohlrab Wolfgang , Podhaisky Hans-Peter , Neubert Reinhard H H
Published: October 2003

The effect of bufexamac on UV-irradiation-induced lipid peroxidation was investigated. Linolenic acid was used as a model lipid. Bufexamac was shown to be capable of reducing the amount of lipid peroxidation. The quantification was carried out by the thiobarbituric acid assay. Irradiation experiments were also performed using HaCaT keratinocytes as a model system. The oxidative changes were quantified by DNA synthesis measurements and cell viability determinations. Bufexamac was found to act antioxidatively again. To investigate free radical involvement, electron paramagnetic resonance studies were carried out. The influence of bufexamac on the concentration of hydroxyl radicals generated by the Fenton system was examined using the spin trapping technique. Moreover, the hydroxamic acid's ability to react with stable radicals was checked. The quantification assay of 2,2-diphenyl-1-picrylhydrazyl hydrate showed no concentration changes of the stable radical caused by bufexamac. In the Fenton assay antioxidative effects were measured after the addition of the drug. The qualitative changes after irradiating bufexamac were studied at a molecular level by electrospray mass spectrometry. Multiple-stage mass spectrometry experiments enabled the establishment of fragmentation schemes. Phenolic degradation products were detected. The results suggest a new interpretation of the controversially debated mechanism of action of bufexamac and indicate possible reasons for its eczema provoking potential.
Hydrothermal Synthesis of A New Mo–V–O Complex Metal Oxide and Its Catalytic Activity for The Oxidation of Propane
Authors: Katou Tomokazu , Vitry Damien , Ueda Wataru
Published: October 2003

Preparation of a new orthorhombic Mo–V–O catalyst was succeeded by hydrothermal synthesis for the first time. This orthorhombic structure showed high activity for propane oxidation. Selectivity to acrylic acid dramatically increased by the introduction of Te into the orthorhombic Mo–V–O catalyst.
Organogel Formation of Optically Active 1,6-di-O-TIPDS-myo-inositol
Authors: Hosoda Asao , Miyake Yasuhito , Nomura Eisaku , Taniguchi Hisaji
Published: October 2003

Two novel optically active myo-inositol derivatives having a bulky alkyl–silyl group as a hydrophobic part were synthesized. These compounds acted as a gelator toward nonpolar hydrophobic solvents such as n-hexane, cyclohexane, and toluene via the formation of an intermolecular OH···O hydrogen bonding network.
Clinical Governance—How do you Prove you are Doing It?
Authors: Thomson Peter
Published: October 2003

This article is based on the presentation given by the author to the ‘Corporate Bodies—Best or Beast’ session of the British Dental Association Conference 2001.
Advances in Surgical Dentistry
Authors: Patel Dev , Manhem Carl Gustaf , Sindet-Pedersen Steen
Published: October 2003

The introduction of the specialty of surgical dentistry is an advance in itself and has far-reaching implications for the future. Surgical specialists will have a significant impact on the provision and resources of surgical dental services. This paper explores recent developments within the field.
Wavelets in state space models
Authors: Zandonade Eliana , Morettin Pedro A.
Published: October 2003

In this paper, we consider the utilization of wavelets in conjunction with state space models. Specifically, the parameters in the system matrix are expanded in wavelet series and estimated via the Kalman Filter and the EM algorithm. In particular this approach is used for switching models. Two applications are given, one to the problem of detecting the paths of targets using an array of sensors, and the other to a series of daily spreads between two Brazilian bonds. Copyright © 2003 John Wiley & Sons, Ltd.
A wavelet solution to the spurious regression of fractionally differenced processes
Authors: Fan Yanqin , Whitcher Brandon
Published: October 2003

In this paper we propose to overcome the problem of spurious regression between fractionally differenced processes by applying the discrete wavelet transform (DWT) to both processes and then estimating the regression in the wavelet domain. The DWT is known to approximately decorrelate heavily autocorrelated processes and, unlike applying a first difference filter, involves a recursive two‐step filtering and downsampling procedure. We prove the asymptotic normality of the proposed estimator and demonstrate via simulation its efficacy in finite samples. Copyright © 2003 John Wiley & Sons, Ltd.
Unusual origin of the flexor digiti minimi brevis muscle
Authors: Wingerter S. , Gupta S. , Le S. , Shamasunder S. , Bernstein R. , Rabitaille W. , Kukuyeva Y. , Downie S.
Published: October 2003

An unusual origin of the flexor digiti minimi brevis muscle of the right hand was discovered during cadaveric dissection. The muscle originated from the anterior aspect of the transverse fibers of the distal antebrachial fascia and inserted onto the base of the fifth proximal phalanx. When traction was applied to the proximal portion of the muscle, flexion was produced at the fifth metacarpophalangeal joint. Other intrinsic muscles of the hand and the muscles of the flexor forearm compartment had normal morphology. Although muscular anomalies in the hypothenar region have been described, the muscular variant described here was distinct in its origin and size from those previously reported. Knowledge of anomalous muscles in the hand has important clinical significance in routine surgery and in determining associated pathology. Clin. Anat. 16:531–533, 2003. © 2003 Wiley‐Liss, Inc.
Relationship of the common peroneal nerve and its branches to the head and neck of the fibula
Authors: Ryan William , Mahony Nick , Delaney Maire , O'Brien Moira , Murray Paraic
Published: October 2003

The common peroneal nerve (CPN) lies on the neck of the fibula, which forms the floor of the so‐called ‘fibular tunnel.’ The tunnel entrance is a musculo‐aponeurotic arch derived from the soleus and peroneus longus muscles and it is here that the CPN is commonly compressed in cases of peroneal nerve palsy. This study aims to define the relationship of the CPN and its branches to the apex of the head of the fibula and to the tunnel, with special regard to possible sites of entrapment. The distances from the apex of the fibula to the opening of the fibular tunnel, the CPN bifurcation, and the exit point of the deep peroneal nerve (DPN) from the tunnel, were measured in 30 legs to ascertain possible sites of entrapment. The angle that the CPN subtended with the long axis of the fibula was measured to gauge the range of positions of the CPN at the neck of the fibula. An unyielding musculo‐aponeurotic fibular arch at the entrance to the fibular tunnel was confirmed in all specimens. The DPN exited through a crescentic opening in the anterior intermuscular septum in all cases and no DPN branches were found in the lateral compartment in any specimen. The mean (±SD) distance from the apex of the head of the fibula to the opening of the fibular tunnel was 3.2 ± 1.0 cm, to the CPN bifurcation was 3.8 ± 0.9 cm, and to the DPN exit point was 7.0 ± 1.5 cm. The mean angle subtended anteriorly from the long axis of the fibula by the CPN was 18.9 ± 9.0°. We recommend further study of the mean distances and reference angle in relation to fibular landmarks, for use in possible minimally invasive surgical procedures to decompress the fibular tunnel. Clin. Anat. 16:501–505, 2003. © 2003 Wiley‐Liss, Inc.
Outcomes of the gross and developmental anatomy teaching assistant experience
Authors: Ocel Joseph J. , Palmer Brian A. , Wittich Christopher M. , Carmichael Stephen W. , Pawlina Wojciech
Published: October 2003

During the first‐year Gross and Developmental Anatomy Course at Mayo Medical School, third‐year medical students volunteer as teaching assistants (TAs). Their responsibilities include preparing for dissection, instructing students during dissection, writing examination questions, and giving a lecture. To evaluate the academic and professional impact of this experience on former TAs, a survey instrument was developed, and was sent to former TAs from the past 17 years. Seventy‐two percent of the surveys were returned. Most respondents (84%) indicated that the TA experience was beneficial during their third‐year surgical rotation. Over 60% identified benefits during Neurology, Obstetrics and Gynecology, and Internal Medicine rotations. The majority (62%) indicated they regularly use the knowledge gained from the TA experience. Communication was the most highly ranked area of skill development, with 86% of respondents indicating gains in lecture effectiveness and 97% in one‐on‐one teaching. Among respondents, 32% entered surgical or radiological fields, roughly paralleling the non‐TA medical student population. All respondents indicated that they would repeat the experience and recommend it to other medical students. Although benefits for long‐term career development have not yet been established, the Gross and Developmental Anatomy TA experience had perceived short‐term benefits with respect to clinical rotations and teaching skill development. Clin. Anat. 16:526–530, 2003. © 2003 Wiley‐Liss, Inc.