bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Irbesartan on the Antioxidant Defence System and Nitric Oxide Release in Diabetic Rat Kidney
Authors: Anjaneyulu Muragundla , Chopra Kanwaljit
Published: September 2004

Background/Aims: Increased oxidative stress is involved in the aetiology of diabetic nephropathy, and angiotensin II is reported to play a considerable role in the development of renal damage in diabetic kidney. Angiotensin antagonism can slow the progression of renal impairment in diabetes. The present study was thus designed to examine the effect of an angiotensin II type 1 (AT1) receptor antagonist, irbesartan on renal function, oxidative stress and nitric oxide (NO) release in streptozotocin (STZ)-induced diabetic rats. Methods: Diabetes was induced by a single intraperitoneal injection of streptozotocin (65 mg/kg) in rats. After 4 weeks of STZ injection, rats were divided into four groups: the control rats, diabetic rats and diabetic rats treated with irbesartan (25 and 50 mg/kg, orally) respectively till 8 weeks starting from 4 weeks after STZ injection. Renal function was assessed by creatinine, blood urea nitrogen, creatinine clearance and urea clearance. Oxidative stress was measured by renal malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase. We also measured renal nitrite levels. Results: At the end of the 8th week, diabetic rats exhibited renal dysfunction as evidenced by reduced creatinine and urea clearance along with enhanced albumin excretion rate as compared with control rats. Biochemical analysis of kidneys revealed a marked increase in oxidative stress demonstrated by increased lipid peroxidation and decreased activities of key antioxidant enzymes, GSH, SOD and catalase in diabetic rats. NO release was also significantly higher in diabetic rats than controls. Chronic treatment with irbesartan in diabetic rats significantly attenuated both renal dysfunction and oxidative stress along with increased NO levels as compared with untreated diabetic rats. The kidneys of diabetic rats showed morphological changes such as hyaline casts, glomerular thickening and moderate interstitial fibrosis and arteriolopathy, whereas irbesartan administration markedly prevented diabetic-induced renal morphological alterations. Conclusions: The present study suggests that oxidative stress/nitrosative stress is increased in the diabetic kidney and AT1 receptor blockade can prevent these changes. The results also suggest that in STZ-induced diabetic rats, the protective action of irbesartan might be mediated, at least in part, by its effect on tissue oxidant/antioxidant status.
Oxygen-Sensitive Kv Channel Gene Transfer Confers Oxygen Responsiveness to Preterm Rabbit and Remodeled Human Ductus Arteriosus
Authors: Thébaud Bernard , Michelakis Evangelos D. , Wu Xi-Chen , Moudgil Rohit , Kuzyk Michael , Dyck Jason R.B. , Harry Gwyneth , Hashimoto Kyoko , Haromy Alois , Rebeyka Ivan , Archer Stephen L.
Published: September 2004

Background—

Oxygen (O
2
)-sensitive K
+
channels mediate acute O
2
sensing in many tissues. At birth, initial functional closure of the ductus arteriosus (DA) results from O
2
-induced vasoconstriction. This mechanism often fails in premature infants, resulting in persistent DA, a common form of congenital heart disease. We hypothesized that the basis for impaired O
2
constriction in preterm DA is reduced expression and function of O
2
-sensitive, voltage-gated (Kv) channels.

Methods and Results—

Preterm rabbit DA rings have reduced O
2
constriction (even after inhibition of prostaglandin and nitric oxide synthases), and preterm DA smooth muscle cells (DASMCs) display reduced O
2
-sensitive K
+
current. This is associated with decreased mRNA and protein expression of certain O
2
-sensitive Kv channels (Kv1.5 and Kv2.1) but equivalent expression of the L-type calcium channel. Transmural Kv1.5 or Kv2.1 gene transfer “rescues” the developmental deficiency, conferring O
2
responsiveness to preterm rabbit DAs. Targeted SMC Kv1.5 gene transfer also enhances O
2
constriction in human DAs.

Conclusions—

These data demonstrate a central role for developmentally regulated DASMC O
2
-sensitive Kv channels in the functional closure of the DA. Modulation of Kv channels may have therapeutic potential in diseases associated with impaired O
2
responsiveness, including persistent DA.
In Vivo 16-Slice, Multidetector-Row Computed Tomography for the Assessment of Experimental Atherosclerosis
Authors: Viles-Gonzalez Juan F. , Poon Michael , Sanz Javier , Rius Teresa , Nikolaou Konstantin , Fayad Zahi A. , Fuster Valentin , Badimon Juan J.
Published: September 2004

Background—

Noninvasive imaging can detect early atherosclerotic disease. Magnetic resonance imaging (MRI), because of its excellent spatial resolution, is already established as a tool for plaque characterization. Sixteen-slice, multidetector-row computed tomography (MDCT) was recently introduced into the field of cardiac imaging, with promising results for noninvasive angiography. We compared the capabilities of MDCT and MRI for the assessment of noncalcified, atherosclerotic plaques.

Methods and Results—

Six atherosclerotic rabbits underwent in vivo imaging by MDCT and 1.5-T MRI. MDCT parameters were 120 kV, 120 mA/s, collimation 12×0.75, and spatial resolution 0.6×0.6 mm. MRI parameters were as follows: for proton density, repetition time/echo time (TR/TE) 2300/5.6; for T2, TR/TE 2300/62; and for T1, TR/TE 800/5.6; slice thickness was 3 mm and spatial resolution, 0.3×0.3 mm. Blinded analysis of 3-mm axial reconstructions from MDCT and the carefully matched MRI images (182 sections) showed excellent agreement between both modalities. MDCT yielded a slightly larger lumen area, anteroposterior diameters, and lateral diameters, with no significant differences in total vessel area. The sensitivity and specificity, respectively, to detect noncalcified, atherosclerotic plaques were 89% and 77% for MDCT and 97% and 94% for MRI. Fibrous-rich and lipid-rich plaque could not be differentiated visually, although they showed different attenuation properties (116±27 vs 51±25 Hounsfield units,
P
<0.01).

Conclusions—

Both techniques allow reliable detection of noncalcified, atherosclerotic plaques and accurate assessment of vessel areas and diameters. MDCT offers the additive value of a very short image acquisition time when compared with MRI. The subtle measurement differences found between modalities may be due to the better spatial resolution of MRI, which probably explains its superiority for tissue characterization.
Combined Adipocyte-Macrophage Fatty Acid–Binding Protein Deficiency Improves Metabolism, Atherosclerosis, and Survival in Apolipoprotein E–Deficient Mice
Authors: Boord Jeffrey B. , Maeda Kazuhisa , Makowski Liza , Babaev Vladimir R. , Fazio Sergio , Linton MacRae F. , Hotamisligil Gökhan S.
Published: September 2004

Background—

The adipocyte fatty acid-binding protein (FABP) aP2 is expressed by adipocytes and macrophages and modulates insulin resistance, glucose and lipid metabolism, and atherosclerosis. Insulin sensitivity is improved in obese but not in lean aP2-deficient mice. A second fatty acid-binding protein, mal1, also is expressed in adipocytes and macrophages, and mal1 deficiency produces similar effects on insulin resistance. We tested the hypothesis that combined aP2 and mal1 deficiency would produce synergistic effects on metabolism and reduce atherosclerosis in apolipoprotein E-deficient (apoE
−/−
) mice.

Methods and Results—

Male and female apoE
−/−
mice null for both aP2 and mal1 (3KO) and apoE
−/−
controls were fed a low-fat chow diet for 16 or 56 weeks. Lean 3KO mice had significantly lower serum cholesterol and triglycerides as well as improved insulin and glucose tolerance as compared with controls. Analysis of atherosclerotic lesions in the 3KO mice showed dramatic reductions in both early (20 weeks) and late-stage (60 weeks) atherosclerosis. Strikingly, survival in the 3KO mice was improved by 67% as compared with apoE
−/−
controls when challenged with the Western diet for 1 year.

Conclusions—

Combined aP2 and mal1 deficiency improved glucose and lipid metabolism, reduced atherosclerosis, and improved survival in apoE
−/−
mice, making these proteins important therapeutic targets for the prevention of the cardiovascular consequences of the metabolic syndrome.
Upper-Extremity Deep Vein Thrombosis
Authors: Joffe Hylton V. , Kucher Nils , Tapson Victor F. , Goldhaber Samuel Z.
Published: September 2004

Background—

Upper-extremity deep vein thrombosis (UEDVT) occurs spontaneously or sometimes develops as a complication of pacemaker use, long-term use of a central venous catheter (CVC), or cancer.

Methods and Results—

To improve our understanding of UEDVT, we compared the demographics, symptoms, risk factors, prophylaxis, and initial management of 324 (6%) patients with central venous catheter (CVC)–associated UEDVT, 268 (5%) patients with non–CVC-associated UEDVT, and 4796 (89%) patients with lower-extremity DVT from a prospective US multicenter DVT registry. The non–CVC-associated UEDVT patients were younger (59.2±18.2 versus 64.2±16.9 years old;
P
<0.0001), less often white (65% versus 73%;
P
<0.01), leaner (body mass index [BMI] 26.8±7.1 versus 28.5±7.3 kg/m
2
;
P
<0.001), and more likely to smoke (19% versus 13%;
P
=0.02) than the lower-extremity DVT patients. By way of propensity analysis and multivariable logistic regression analysis, we determined that an indwelling CVC was the strongest independent predictor of UEDVT (odds ratio [OR], 7.3; 95% confidence interval [CI], 5.8 to 9.2). An age of <67 years, a BMI of <25 kg/m
2
, and hospitalization were the independent predictors of non–CVC-associated UEDVT. Most (68%) UEDVT patients were evaluated while they were inpatients. Only 20% of the 378 UEDVT patients who did not have an obvious contraindication to anticoagulation received prophylaxis at the time of diagnosis.

Conclusions—

UEDVT risk factors differ from the conventional risk factors for lower-extremity DVT. Our findings identify deficiencies in our current understanding and the prophylaxis of UEDVT and generate hypotheses for future research efforts.
Acute Cardiovascular Effects of Fetal Surgery in the Human
Authors: Rychik Jack , Tian Zhiyun , Cohen Meryl S. , Ewing Stanford G. , Cohen David , Howell Lori J. , Wilson R. Douglas , Johnson Mark P. , Hedrick Holly L. , Flake Alan W. , Crombleholme Timothy M. , Adzick N. Scott
Published: September 2004

Background—

Prenatal surgery for congenital anomalies can prevent fetal demise or alter the course of organ development, resulting in a more favorable condition at birth. The indications for fetal surgery continue to expand, yet little is known about the acute sequelae of fetal surgery on the human cardiovascular system.

Methods and Results—

Echocardiography was used to evaluate the heart before, during, and early after fetal surgery for congenital anomalies, including repair of myelomeningocele (MMC, n=51), resection of intrathoracic masses (ITM, n=15), tracheal occlusion for congenital diaphragmatic hernia (CDH, n=13), and resection of sacrococcygeal teratoma (SCT, n=4). Fetuses with MMC all had normal cardiovascular systems entering into fetal surgery, whereas those with ITM, CDH, and SCT all exhibited secondary cardiovascular sequelae of the anomaly present. At fetal surgery, heart rate increased acutely, and combined cardiac output diminished at the time of fetal incision for all groups including those with MMC, which suggests diminished stroke volume. Ventricular dysfunction and valvular dysfunction were identified in all groups, as was acute constriction of the ductus arteriosus. Fetuses with ITM and SCT had the most significant changes at surgery.

Conclusions—

Acute cardiovascular changes take place during fetal surgery that are likely a consequence of the physiology of the anomaly and the general effects of surgical stress, tocolytic agents, and anesthesia. Echocardiographic monitoring during fetal surgery is an important adjunct in the management of these patients.
Learning Subjective Language
Authors: Wiebe Janyce , Wilson Theresa , Bruce Rebecca , Bell Matthew , Martin Melanie
Published: September 2004

Subjectivity in natural language refers to aspects of language used to express opinions, evaluations, and speculations. There are numerous natural language processing applications for which subjectivity analysis is relevant, including information extraction and text categorization. The goal of this work is learning subjective language from corpora. Clues of subjectivity are generated and tested, including low-frequency words, collocations, and adjectives and verbs identified using distributional similarity. The features are also examined working together in concert. The features, generated from different data sets using different procedures, exhibit consistency in performance in that they all do better and worse on the same data sets. In addition, this article shows that the density of subjectivity clues in the surrounding context strongly affects how likely it is that a word is subjective, and it provides the results of an annotation study assessing the subjectivity of sentences with high-density features. Finally, the clues are used to perform opinion piece recognition (a type of text categorization and genre detection) to demonstrate the utility of the knowledge acquired in this article.
Sample Selection for Statistical Parsing
Authors: Hwa Rebecca
Published: September 2004

Corpus-based statistical parsing relies on using large quantities of annotated text as training examples. Building this kind of resource is expensive and labor-intensive. This work proposes to use sample selection to find helpful training examples and reduce human effort spent on annotating less informative ones. We consider several criteria for predicting whether unlabeled data might be a helpful training example. Experiments are performed across two syntactic learning tasks and within the single task of parsing across two learning models to compare the effect of different predictive criteria. We find that sample selection can significantly reduce the size of annotated training corpora and that uncertainty is a robust predictive criterion that can be easily applied to different learning models.
Industry Evolution
Authors: Audretsch David B. , Houweling Patrick , Thurik A. Roy
Published: September 2004

The purpose of this article is to show how institutional and evolutionary economics provide better insights as to why some firms survive and others do not than does neoclassical economics. At the heart of the evolutionary theory is the view that new firms are a manifestation of diversity and that their subsequent survival is shaped by the selection process. Despite immense institutional and historical differences across different economic systems such as those in North America, Japan and Europe, evolutionary economics explains the role that diversity, selection and learning plays in economic development. We use a Dutch data set and a model on who survives and who does not to explain this role.
The Effect of Website and E-Commerce Adoption on the Relationship between SMEs and Their Export Intermediaries
Authors: Houghton Kathryn A. , Winklhofer Heidi
Published: September 2004

Whilst website adoption within UK SMEs is widespread, the number offering e-commerce activities is declining or static. This result is surprising given indications that the medium may be valuable to SMEs and to exporters in particular. Among the multitude of factors suggested to affect adoption, the link between export channel relationships and website/e-commerce adoption has mainly been the focus of normative writings or anecdotal evidence. By building on the rich literature on authoritative control (manifest conflict) and relationship marketing paradigm (trust and commitment), as well as in-depth interviews with exporters, the article proposes a conceptualization of the potential effects of website and/or e-commerce adoption on conflict and the mediating effect of trust and commitment. Evidence presented indicates that the Internet has the capability to be both a constructive and destructive influence on channel relationships. The findings presented here both support and challenge normative and anecdotal literature, which could explain the low adoption rate amongst exporting SMEs. Furthermore, our conceptualization demonstrates that a combination of authoritative control and relational paradigm constructs, (manifest conflict, trust and commitment) is useful in understanding channel relationship scenarios.
Theoretical and Experimental Studies on Reduction for Multi-Modal Seismic Responses of High-Rise Structures by Tuned Liquid Dampers
Authors: Li Hong-Nan , Jia Ying , Wang Su-Yan
Published: September 2004

This paper focuses on the use of multiple tuned liquid dampers (TLDs) as passive control devices to reduce the multi-modal responses of tall buildings and high-rise structures to earthquake ground motion excitation. A model of a three-story building with one and two TLDs was installed on a shaking-table. The system was subjected to three earthquake time histories. Then, the mechanical models and the equations of motion for the systems of tall buildings and high-rise structures with TLDs are established. Here, the solution of the dynamic liquid pressure is based on the method of the volume of fluid and the seismic responses are obtained by use of the state equation. The comparisons show that theoretical results are generally in good agreement with experiments. It is observed that the approach presented in this paper has proved to be quite effective both in the numerical example and in the seismic simulating tests.
Large Amplitude Free Vibration Study of Square Plates under Different Boundary Conditions Through a Static Analysis
Authors: Saha K. N. , Misra D. , Pohit G. , Ghosal S.
Published: September 2004

The free v ibration problem of thin isotropic plates incorporating the effect. of geometric non-linearity is studied by developing a specific numerical methodology. The problem is formulated by using a variational method. The large amplitude vibration problem is addressed by solving the corresponding static problem first through an iterative schemne using a relaxation parameter. Subsequently. with the resulting displacement field, the dynamic problem is solved as a standard eigenvalue problem. The assumed deflection field, required for the analysis, is constituted through linear combinations of beam vibration modes corresponding to the specific boundary conditions of the plate. Typical results for the square plates, in the form of backbone curves, have been furnished in the dimensionless amplitude-frequency plane. Two different combinations of the boundary conditions for the purpose are chosen following an earlier benchmark work. Much insight on large amplitude dynamic behavior of the plate is obtained through the vibration mode shapes. presented for each case. A comparison of the results of the reduced problem with those of earlier studies indicates excellent agreement.
On Fuzzy Control of Chaotic Systems
Authors: Harb Ahmad M. , Smadi Issam A.
Published: September 2004

In this paper, we introduce the control of the strange attractor, chaos. Because of the importance of controlling undesirable behavior in systems. researchers are investigating the use of linear and nonlinear controllers, either to remove such oscillations (in power systems) or to match two chaotic systems (in secure communications). The idea of using the fuzzy logic concept for controlling chaotic behavior is presented. There are two good reasons for using fulzy control: first, there is no mathematical model available for the process; secondly. it can satisfy nonlinear control that can be developed empirically. without complicated mathematics. The two systems are well-known models so the first reason is not a big problem. and we can take advantage of the second reason.
Inhomogeneities of Minimum Stress Concentration
Authors: Wheeler Lewis
Published: September 2004

The problem of finding the shape of an elastic inhomogeneity that minimizes stress concentration is investigated. A class of ellipsoidal inhomogeneities is identified that serve as minimizers for inclusions which aie softer than the matnx. For hard inclusions, strain minnnimzing ellipsoidal inhormogeneilies are described. In both cases, rather simple isopeniinetric inequalities are derived.
On Jaeger Shearing
Authors: Boulanger P. , Hayes M.
Published: September 2004

Analogously to the definition of shelar introduced by Jaeger we introduce and examine the concept of Jaeger shearing. It depends upon just one direction, whereas shearing in the sense of Cauchy depends upon two directions. It is shown that the Jaeger shearing corresponding to the direction n of a material line element at a particle P at a specific time t, may be interpreted as the orthogonal shearing, in the sense of Cauchy, of a pair of orthogonal material line elements, at P at time t one element being along n and the other along a (generally) unique direction orthogonal to n. It is seen that the maximum Jaeger shearing corresponding to the direction n of a material line element at a point P at a specific time t, may be interpreted as the orthogonal shearing, in the sense of Cauchy of a pair of orthogonal material line elements, at P at time t, one element being along n and the other along a (generally) unique direction orthogonal to n. It is seen that the maximum Jaeger shearing at P at time t is also the maximum Cauchy shearing at P at time t.
Making Sense of ADHD: A Battle for Understanding? Parents' Views of Their Children Being Diagnosed with ADHD
Authors: Harborne Alexandra , Wolpert Miranda , Clare Linda
Published: September 2004

Much of the extensive body VLf research into attention deficit hyperactivity disorder (ADHD) has concentrated on understanding the aetiology of the disorder. This research has generated a number of very different conceptualizations of ADHD, ranging from purely medical descriptions to theories that incorporate a range of social and psychological factors. Although a large amount of research has been undertaken in this area, little is known about the individual experiences of those directly affected by the disorder and, in particular, how parents make sense of the variety of different aetiological models. The aim of this study was to investigate this issue. The mothers of nine boys, aged between 8 and 11 years, agreed to participate in the study. One father also participated. In-depth interviews, following a semi-structured format, were held with each participant. Interviews were transcribed verbatim and analysed using a grounded theory approach. Data analysis revealed that the key issue for parents was the discrepancy in the way in which parents understood the causes of ADHD, as compared with the ways in which others viewed the disorder. Parents reported that they believed ADHD to be a biologically based disorder, but that they felt others considered the disorder to be related to psychological and social factors. The implications of these differing perspectives were as follows: (i) parents battled with professionals and family members to encourage them to share their views of the condition; (ii) parents felt blamed by professionals and family members for their sons' difficulties; and (iii) parents reported experiencing significant emotional distress as a result of the differing views.
General Practitioner Perceptions and Practice Related to Adolescent Depressive Presentations
Authors: Vandana Jyoti , Ambelas Aris
Published: September 2004

Recognizing that child and adolescent psychiatry operates in the context of opinions, we set out to discover GPs' views and prescribing practices in connection to adolescent depressive presentations. Two-thirds o-.f respondents felt there had been a recent increase in presentations and their views oil the reasons were further examined. However, only one third have been prescribing more often and the reasons for this were also examined. It is clear that although they recognize increased unhappiness among youngsters this is not often seen as 'illness depression'. The implications are further discussed.
Factors Influencing Parental Engagement in a Community Child and Adolescent Mental Health Service: A Qualitative Comparison of Completers and Non-Completers
Authors: Attride-Stirling Jennifer , Davis Hilton , Farrell Louise , Groark Claire , Day Crispin
Published: September 2004

Attrition is a significant problem in child mental health services. Research investigating the factors associated with attrition has produced conflicting results, and failed to consider clients' own decision to terminate treatment prematurely. This study investigated parental accounts of why they completed or discontinued treatment. Completers and non-completers were interviewed using an open-ended interview schedule. All completed the Strengths and Difficulties Questionnaire (SDQ) before beginning treatment, but the sample size was too small to yield meaningful results. Core differences were found in the accounts of parents who completed treatment and parents who discontinued treatment. Completers' accounts were more focused on the child's problem and identified more factors that facilitated the effectiveness of the intervention; whereas non-completers' accounts were more focused on family problems and identified more obstacles that interfered with the effectiveness of the intervention. The findings have implications for the way in which non-completers are conceptualized for understanding the process of engagement.
A Prospective Study of Rumination and Depression in Early Adolescence
Authors: Broderick Patricia C. , Korteland Constance
Published: September 2004

In this study, rumination, depression, and gender role were measured in a group of fourth through sixth graders once each year for 3 years. Results supported the primary hypothesis that rumination level would best predict level of depression at each subsequent assessment. No differences were observed between genders on depression or rumination. However, masculineand femniniiie-identified adolescents had higher depression scores than androgynous individuals, and feminineidentified adolescents had the highest rumination scores overall. Links between rumination, depression, inability to distract, and gender role are explored, and possible treatments are discussed.
Reacting to an Assumed Situation vs. Conforming to an Assumed Reaction: The Role of Perceived Speaker Attitude in Vicarious Dissonance
Authors: Monin Benoft , Norton Michael I. , Cooper Joel , Hopg Michael A.
Published: September 2004

Witnessing an ingroup member acting against his or her belief can lead individuals who identify with that group to change their own attitude in the direction of that counterattitudinal behavior. Two studies demonstrate this vicarious dissonance effect among high ingroup identifiers and show that this attitude change is not attributable to conformity to a perceived change in speaker attitude. Study 1 shows that the effect occurs-indeed, is stronger-even when it is clear that the speaker disagrees with the position espoused, and Study 2 shows that foreseeable aversive consequences bring about attitude change in the observer without any parallel impact on the perceived attitude of the speaker. Furthermore. the assumption that vicarious dissonance is at heart a group phenomenon is supported by the results indicating that attitude change is not impacted either by individual differences in dispositional empathy or measures of interpersonal affinity.
Mutual Acculturation and Social Categorization: A Comparison of Two Perspectives on Intergroup Bias
Authors: Molina Ludwin E. , Wittig Michele A. , Giang Michael T.
Published: September 2004

Using Berry, Trimble, and Olmedo's (1986) theorizing as a foundation, the present article applies acculturation constructs to the domain of intergroup bias and compares them to social categorization variables. The paper comprises three school-based studies that test the predictive and mediating roles of acculturation and social categorization, respectively. Results of Studies 1 and 2 with ethnically diverse classes of ninth graders support the hypothesis that outgroup orientation, a dimension of acculturation, mediates the interracial classroom climate-intergroup bias relationship, and independently boosts the prediction of bias. Although social categorization variables do not mediate this relationship reliably, as a group they predict bias. Study 3 replicates these findings in a different context with a largely European American class of seventh grade students.
Exploring Implicit Partisanship: Enigmatic (But Genuine) Group Identification and Attraction
Authors: Pinter Brad , Greenwald Anthony G.
Published: September 2004

Briefly studying names of four members of a hypothetical group produces identification with and attraction to that group, a finding labeled implicit partisanship (IP; Greenwald, Pickrell, & Farnham, 2002). The original demonstration of IP used human groups in a competitive context. Experiments I and 2 varied these procedures by using, respectively, a cooperative intergroup context and non-human group members (fictitious car brands). Neither of these variations eliminated the IP effect, indicating unanticipated robustness. Experiment 3 revealed a substantial reduction of the IP effect's magnitude when the studied names represented a rival university. The reduction of IP through identity opposition supports the interpretation that spontaneous group identification effects carry psychological significance that is comparable to that of more ordinary group identifications.
Regulation of the single-chain urokinase–urokinase receptor complex activity by plasminogen and fibrin: novel mechanism of fibrin specificity
Authors: Higazi Abd Al-Roof , Ajawi Feras , Akkawi Sa'ed , Hess Edna , Kuo Alice , Cines Douglas B.
Published: September 2004

Activation of plasminogen by urokinase plasminogen activator (uPA) plays important roles in several physiologic and pathologic conditions. Cells secrete uPA as a single-chain molecule (scuPA). scuPA can be activated by proteolytic cleavage to a 2-chain enzyme (tcuPA). scuPA is also activated when it binds to its receptor (uPAR). The mechanism by which the enzymatic activity of the scuPA/suPAR complex is regulated is only partially understood. We now report that the plasminogen activator activity of the scuPA/suPAR complex is inhibited by Glu- and Lys-plasminogen, but not by mini-plasminogen. In contrast, neither Glunor Lys-plasminogen inhibits the activation of plasminogen by 2-chain uPA. Inhibition of scuPA/suPAR activity was evident at a Glu-plasminogen concentration of approximately 100 nM, and at physiologic plasma concentrations inhibition was nearly complete. A plasminogen fragment containing kringles 1-3 inhibited the enzymatic activity of scuPA/suPAR with an inhibition constant (Ki) equal to 1.9 μM, increased the Michaelis constant (Km) of scuPA/suPAR from 18 nM to 49 nM, and decreased the catalytic constant (Kcat) approximately 3-fold from 0.035 sec—1 to 0.011 sec—1. Inhibition of scuPA/suPAR by plasminogen was completely abolished in the presence of fibrin clots. These studies provide insight into the regulation of uPA-mediated plasminogen activation and identify a novel mechanism for its fibrin specificity.
Dendritic cell-derived IL-2 production is regulated by IL-15 in humans and in mice
Authors: Feau Sonia , Facchinetti Valeria , Granucci Francesca , Citterio Stefania , Jarrossay David , Seresini Samantha , Protti Maria Pia , Lanzavecchia Antonio , Ricciardi-Castagnoli Paola
Published: September 2004

Dendritic cells (DCs) are involved in the initiation and regulation of innate and adaptive immune responses. Several molecular mechanisms regulate these diverse DC functions, and we have previously reported that mouse dendritic cells (mDCs) can produce interleukin-2 (IL-2) in vitro and in vivo, in response to microbial activation and T-cell-mediated stimuli. This property is shared by different DC subtypes, including Langerhans cells. Here we show that, on appropriate stimulation, human DCs, both plasmacytoid and myeloid subtypes, also express IL-2. Interestingly, the production of IL-2 by myeloid DCs is induced by T-cell-mediated stimuli and depends on the presence of IL-15. The key role of this cytokine in regulating IL-2 production was also confirmed in the mouse system. In particular, we could show that DCs from IL-15-deficient mice were strongly impaired in the ability to produce IL-2 after interactions with different microbial stimuli. Our results indicate that DC-produced IL-2 is tightly coregulated with the expression of IL-15.
The CD28 family: a T-cell rheostat for therapeutic control of T-cell activation
Authors: Riley James L. , June Carl H.
Published: September 2004

The CD28 family of receptors (CD28, cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4], inducible costimulator [ICOS], program death-1 [PD-1], and B- and T-lymphocyte attenuator [BTLA]) plays a critical role in controlling the adaptive arm of the immune response. While considerable information is available regarding CD28 and CTLA-4, the function of the more recently discovered members of the CD28 family is less well understood. This review will highlight recent findings regarding the CD28 family with special emphasis on effects the CD28 family has on immunopathology, the discovery of costimulatory antibodies with superagonist function, and the status of clinical trials using various strategies to augment or block T-cell costimulation.
High factor VIII levels in venous thromboembolism show linkage to imprinted loci on chromosomes 5 and 11
Authors: Berger Mario , Mattheisen Manuel , Kulle Bettina , Schmidt Henriette , Oldenburg Johannes , Bickeböller Heike , Walter Ulrich , Lindner Tom H. , Strauch Konstantin , Schambeck Christian M.
Published: September 2004

High factor VIII (FVIII) levels are known to be a risk factor for deep venous thrombosis, but the mechanisms responsible for high FVIII levels remain unclear. Here, a new phenotype “FVIII level residuum” (FVIII-R) was defined in order to eliminate the impact of common determinants on FVIII levels. We studied 13 families of patients with thrombosis and reproducibly high FVIII levels of unknown origin. Since familial clustering was evident, we looked for a possible genetic basis. A genome scan was performed with 402 evenly spaced microsatellite markers. A quantitative linkage analysis using variance component methods showed suggestive evidence for linkage of FVIII-R with a locus on chromosome 8 (logarithm of odds [LOD] = 2.1). In addition, we performed parametric exploratory linkage analysis of dichotomized FVIII-R, taking a parent-of-origin effect into account. Single-trait-locus MOD-score analysis showed suggestive evidence for linkage under an imprinting model at chromosomes 5 and 11. Furthermore, a 2-trait-locus analysis under a multiplicative model for the loci of chromosomes 5 and 11 yielded a remarkable LOD of 4.44. It confirmed the finding of paternal imprinting, obtained by single-trait-locus analysis, at both loci. Our results suggest that high FVIII levels in venous thromboembolism represent a complex trait caused by several genetic factors.
Novel mechanism of G-CSF refractoriness in patients with severe congenital neutropenia
Authors: Druhan Lawrence J. , Ai Jing , Massullo Pam , Kindwall-Keller Tamila , Ranalli Mark A. , Avalos Belinda R.
Published: September 2004

Severe congenital neutropenia (SCN) is a rare disease diagnosed at or soon after birth, characterized by a myeloid maturation arrest in the bone marrow, ineffective neutrophil production, and recurrent infections. Most patients respond to treatment with granulocyte colony-stimulating factor (G-CSF), and the majority harbor mutations in the neutrophil elastase gene. In the subset of patients with SCN transforming to acute myeloid leukemia (AML), mutations that truncate the cytoplasmic tail of the G-CSF receptor (G-CSFR) have been detected. Here, we report a novel mutation in the extracellular portion of the G-CSFR within the WSXWS motif in a patient with SCN without AML who was refractory to G-CSF treatment. The mutation affected a single allele and introduced a premature stop codon that deletes the distal extracellular region and the entire transmembrane and cytoplasmic portions of the G-CSFR. Expression of the mutant receptor in either myeloid or lymphoid cells was shown to alter subcellular trafficking of the wild-type (WT) G-CSFR by constitutively heterodimerizing with it. WT/mutant G-CSFR heterodimers appeared to be retained in the endoplasmic reticulum and/or Golgi and accumulate intracellularly. These findings together with 2 previous case reports of extracellular mutations in the G-CSFR in patients with SCN unresponsive to G-CSF suggest a common mechanism underlying G-CSF refractoriness.
Graft calcifications and dysfunction following liver transplantation
Authors: Tzimas George N , Afshar Mohammad , Chevet Eric , Emadali Anouk , Vali Hojatollah , Metrakos Peter P
Published: September 2004

Background

The molecular events, following ischemia and reperfusion (I/R) of the liver during transplantation are largely unknown. There is evidence that apoptotic and necrotic events may take place, and occasionally result in primary graft dysfunction. We herein report two cases, where significant I/R injury correlated with the development of liver calcification and primary liver dysfunction.

Case Presentation

Both patients with clinical and biochemical evidence of primary graft dysfunction demonstrated calcification at light and electron microscopy levels. In addition, one patient had macroscopic evidence of calcification on cross-sectional imaging. Both patients died secondary to the sequelae of the graft dysfunction.

Conclusions

Severe I/R-induced injury to the liver, clinically leads to graft dysfunction. This is due to advanced apoptotic and/or necrotic events at the hepatocyte level that may, on the most severe form, lead to calcification. The study of microcalcification at the early posttransplant period could provide insight in the events taking place following significant ischemia/reperfusion-induced injury to the graft.
Lead editorial: The need for greater perspective and innovation in epidemiology
Authors: Phillips Carl V , Goodman Karen J , Poole Charles ,   the editors of Epidemiologic Perspectives & Innovations
Published: September 2004

This editorial introduces the new online, open-access, peer-reviewed journal, Epidemiologic Perspectives & Innovations. Epidemiology (which we define broadly, to include clinical research and various approaches to studying the health of populations) is a critically important field in informing decisions about the health of individuals and populations. But the desire for new information means that the health science literature is overwhelmingly devoted to reporting new findings, leaving little opportunity to improve the quality of the science. By creating a journal dedicated to all topics of and about epidemiology, except standard research reports, we hope to encourage authors to write more on the neglected aspects of the field. The journal will publish articles that analyze policy implications of health research, present new research methods and better communicate existing methods, reassess previous results and dogma, and provide other innovations in and perspectives on the field. Online publishing will permit articles of whatever length is required for the work, speed the time to publication and allow free access to the full content.
Thioacetamide differentially affects the expression and activity of glutathione-S-transferase in the liver of Wistar rats
Authors: Bueno Murilo Tadeu Domingues , Spira Beny
Published: September 2004

Glutathione-S-transferase (GST) is a family of enzymes involved in the detoxification of toxic and carcinogenic compounds. In the present study, the effect of thioacetamide (TA), a hepatotoxic and hepatocarcinogenic compound, on the activity and expression of GST of Wistar female rats was tested. Animals were treated with a single dose of TA (250 mg/kg) for 12, 24, 48 and 72 hours. GST activity toward the broad substrate 1-chloro-2,4-dinitrobenzene was enhanced by TA. The protein level of the GST classes alpha and mu as well as the mRNA level of several GST subunits were also positively affected by the TA treatment. Female Wistar rats of the same age but from two other different colonies had their GST activity either inhibited or not affected by TA. The basal mRNA level of class alpha and class mu GST was also tested in female Wistar rats obtained from five different sources. Differences in the basal level of class alpha mRNA were observed in rats from at least three different sources, while class mu mRNA level was distinct in two groups of animals.
Pro-oxidant activity of zuclopenthixol in vivo: differential effect of the drug on brain oxidative status of scopolamine-treated rats
Authors: Khalifa Amani E
Published: September 2004

Several clinical studies implicated oxidative stress in the pathophysiology of both psychosis and dementia. As dementia is commonly associated with psychosis, antipsychotic medications are of importance in the pharmacotherapy of dementia particularly as a number of antipsychotics were reported to demonstrate neuronal pro-oxidant and/or antioxidant properties. Impairment of learning and memory, as the most characteristic manifestation of dementia, could be induced in experimental animals by acute administration of scopolamine (SCO) with a resultant elevation in brain oxidative status. This study investigated the potential pro-oxidant and/or antioxidant activity of the antipsychotic drug zuclopenthixol acetate, as its effect on brain oxidative status has yet to be evaluated. A 2×3 between-subjects factorial design was used to investigate the simultaneous and interactive effects of zuclopenthixol (0.7 and 1.4 mg/kg i.p.) and SCO on rat brain malondialdehyde, glutathione, glutathione peroxidase and superoxide dismutase levels/activities. Results revealed a significant pro-oxidant effect for both zuclopenthixol and SCO alone conditions. In addition, combined treatment of zuclopenthixol and SCO was found to be significantly different compared to either treatment conditions with regard to their effect on different brain oxidative stress indices. Such findings may have valuable implications in the pharmacotherapy of both psychosis and dementia.
A comparison between in vitro rat and human and in vivo rat skin absorption studies
Authors: Van Ravenzwaay B , Leibold E
Published: September 2004

In vitro skin penetration rates in rat and man were compared to those obtained in vivo in rats. Saturation of absorption was frequently observed at higher exposure levels in in vitro and in vivo. Lipophilic compounds showed the highest penetration rates through rat skin in vitro. In all cases in vitro dermal penetration through rat skin was higher than in vivo. Thus, the in vitro study may serve as a first tier test. The in vivo data suggest an inverse relationship between molecular weight and the rate of dermal absorption for lipophilic as well as hydrophilic compounds. Rat skin was more permeable to all tested substances than human skin (mean difference 10.9-fold). Thus, the systemic exposure of humans may be significantly overestimated if risk assessment is based only on the results of an in vivo rat study, because human skin is less permeable than rat skin. It would appear, therefore, that an estimate of actual dermal penetration through human skin should be based on the combined use of in vivo and in vitro data, using the following equation:

%Human dermal penetration

=(%rat in vivo dermal penetration)

(See PDF for Formula)
Phase II Study of Denileukin Diftitox for Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma
Authors: Dang Nam H. , Hagemeister Fredrick B. , Pro Barbara , McLaughlin Peter , Romaguera Jorge E. , Jones Dan , Samuels Barry , Samaniego Felipe , Younes Anas , Wang Michael , Goy Andre , Rodriguez Maria A. , Walker Pamela L. , Arredondo Yolanda , Tong Ann T. , Fayad Luis
Published: September 2004

Purpose

Denileukin diftitox is a fusion protein combining diphtheria toxin and interleukin-2 (IL-2) that targets tumor cells expressing the IL-2 receptor. Its efficacy has been shown in CD25+ cutaneous T-cell lymphoma, but not in B-cell non-Hodgkin's lymphoma (NHL). A phase II study was performed to evaluate the efficacy and tolerability of denileukin diftitox for relapsed or refractory B-cell NHL.

Patients and Methods

Patients with relapsed or refractory B-cell NHL were eligible. Tumor CD25 expression was determined by immunohistochemistry or flow cytometry. Denileukin diftitox was administered intravenously at a dose of 18 μg/kg once daily for 5 days every 3 weeks, up to eight cycles.

Results

Of the 45 patients assessable for response, 32 (71%) were refractory to the last chemotherapy treatment, and all were previously treated with rituximab. Three complete responses (6.7%) and eight partial responses (17.8%) were observed, for an overall response rate of 24.5%. Nine patients (20%) had stable disease. Objective response rates were similar in CD25+ (22%) and CD25− histologies (29%), as were stable disease rates (22% and 18%, respectively). For responding patients, the median time to treatment failure was 7 months, with a median follow-up in survivors of 18 months (range, 9 to 28 months), and the projected progression-free survival at 20 months was 24% (95% CI, 0% to 60%). Most toxicities were low-grade and transient.

Conclusion

Denileukin diftitox seems to be effective in relapsed or refractory, CD25+ and CD25− B-cell NHL and is well-tolerated at the dosage evaluated. Evaluation of denileukin diftitox in combination with other agents may be warranted.
Outcome of Treatment in Adults With Acute Lymphoblastic Leukemia: Analysis of the LALA-94 Trial
Authors: Thomas Xavier , Boiron Jean-Michel , Huguet Françoise , Dombret Hervé , Bradstock Ken , Vey Norbert , Kovacsovics Tibor , Delannoy André , Fegueux Nathalie , Fenaux Pierre , Stamatoullas Aspasia , Vernant Jean-Paul , Tournilhac Olivier , Buzyn Agnès , Reman Oumedaly , Charrin Christiane , Boucheix Claude , Gabert Jean , Lhéritier Véronique , Fiere Denis
Published: September 2004

Purpose

We analyzed the benefits of a risk-adapted postremission strategy in adult lymphoblastic leukemia (ALL), and re-evaluated stem-cell transplantation (SCT) for high-risk ALL.

Patients and Methods

A total of 922 adult patients entered onto the trial according to risk groups: standard-risk ALL (group 1), high-risk ALL (group 2), Philadelphia chromosome-positive ALL (group 3), and CNS-positive ALL (group 4). All received a standard four-drug/4-week induction course. Patients from group 1 who achieved a complete remission (CR) after one course of induction therapy were randomly assigned between intensive and less intensive postremission chemotherapy, whereas those who achieved CR after salvage therapy were then included in group 2. Patients in groups 2, 3, and 4 with an HLA-identical sibling were assigned to allogeneic SCT. In groups 3 and 4, autologous SCT was offered to all other patients, whereas in group 2 they were randomly assigned between chemotherapy and autologous SCT.

Results

Overall, 771 patients achieved CR (84%). Median disease-free survival (DFS) was 17.5 months, with 3-year DFS at 37%. In group 1, the 3-year DFS rate was 41%, with no difference between arms of postremission randomization. In groups 2 and 4, the 3-year DFS rates were 38% and 44%, respectively. In group 2, autologous SCT and chemotherapy resulted in comparable median DFS. Patients with an HLA-matched sibling (groups 2 and 4) had improved DFS. Three-year DFS was 24% in group 3.

Conclusion

Allogeneic SCT improved DFS in high-risk ALL in the first CR. Autologous SCT did not confer a significant benefit over chemotherapy for high-risk ALL.