bluuebunny/crossref_metadata_2025 huggingface dataset:
Omega-3 Fatty Acids in Cardiac Biopsies From Heart Transplantation Patients
Authors: Harris William S. , Sands Scott A. , Windsor Sheryl L. , Ali Hakim A. , Stevens Tracy L. , Magalski Anthony , Porter Charles B. , Borkon A. Michael
Published: September 2004

Background—

Omega-3 fatty acids (FAs) appear to reduce the risk of sudden death from myocardial infarction. This reduction is believed to occur via the incorporation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into the myocardium itself, altering the dynamics of sodium and calcium channel function. The extent of incorporation has not been determined in humans.

Methods and Results—

We first determined the correlation between red blood cell (RBC) and cardiac omega-3 FA levels in 20 heart transplant recipients. We then examined the effects of 6 months of omega-3 FA supplementation (1 g/d) on the FA composition of human cardiac and buccal tissue, RBCs, and plasma lipids in 25 other patients. Cardiac and RBC EPA+DHA levels were highly correlated (
r
=0.82,
P
<0.001). Supplementation increased EPA+DHA levels in cardiac tissue by 110%, in RBCs by 101%, in plasma by 139%, and in cheek cells by 73% (
P
<0.005 versus baseline for all; responses among tissues were not significantly different).

Conclusions—

Although any of the tissues examined could serve as a surrogate for cardiac omega-3 FA content, RBC EPA+DHA was highly correlated with cardiac EPA+DHA; the RBC omega-3 response to supplementation was similar to that of the heart; RBCs are easily collected and analyzed; and they have a less variable FA composition than plasma. Therefore, RBC EPA+DHA (also called the Omega-3 Index) may be the preferred surrogate for cardiac omega-3 FA status.
Outcome in Elderly Patients Undergoing Primary Coronary Intervention for Acute Myocardial Infarction
Authors: Guagliumi Giulio , Stone Gregg W. , Cox David A. , Stuckey Thomas , Tcheng James E. , Turco Mark , Musumeci Giuseppe , Griffin John J. , Lansky Alexandra J. , Mehran Roxana , Grines Cindy L. , Garcia Eulogio
Published: September 2004

Background—

Biological age is a strong determinant of prognosis in patients with acute myocardial infarction (AMI). We sought to examine the impact of age after primary percutaneous coronary intervention in AMI and to determine whether routine coronary stent implantation and/or platelet glycoprotein IIb/IIIa inhibitors improve clinical outcomes in elderly patients after primary angioplasty.

Methods and Results—

In the CADILLAC trial, 2082 patients with AMI were randomized to balloon angioplasty, angioplasty plus abciximab, stenting alone, or stenting plus abciximab. No patient was excluded on the basis of advanced age; patients ranging from 21 to 95 years of age were enrolled. One-year mortality increased for each decile of age, exponentially after 65 years of age (1.6% for patients <55 years, 2.1% for 55 to 65 years, 7.1% for 65 to 75 years, 11.1% for patients >75 years;
P
<0.0001). Elderly patients also had increased rates of stroke and major bleeding compared with their younger counterparts. Among elderly patients (≥65 years), 1-year rates of ischemic target revascularization (7.0% versus 17.6%;
P
<0.0001) and subacute or late thrombosis (0% versus 2.2%;
P
=0.005) were reduced with stenting compared with balloon angioplasty. Routine abciximab administration, although safe, was not of definite benefit in elderly patients. Rates of mortality, reinfarction, disabling stroke, and major bleeding in the elderly were independent of reperfusion modality.

Conclusions—

Despite contemporary mechanical reperfusion strategies, mortality, major bleeding, and stroke rates remain high in elderly patients undergoing primary percutaneous coronary intervention, outcomes that are not affected by stents or glycoprotein IIb/IIIa inhibitors. By reducing restenosis, however, stent implantation improves clinical outcomes in elderly patients with AMI.
Inhibition of Rho-Kinase in the Brainstem Augments Baroreflex Control of Heart Rate in Rats
Authors: Ito Koji , Hirooka Yoshitaka , Sagara Yoji , Kimura Yoshikuni , Kaibuchi Kozo , Shimokawa Hiroaki , Takeshita Akira , Sunagawa Kenji
Published: September 2004

The Rho/Rho-kinase pathway in the nucleus tractus solitarii (NTS) of the brain stem contributes to blood pressure regulation. Activation of this pathway might be involved in the central nervous system mechanisms of hypertension. The aim of the present study was to determine whether baroreflex control of heart rate is altered by inhibition of Rho-kinase in the NTS. Adenovirus vectors encoding dominant-negative Rho-kinase or β-galactosidase were transfected into the nucleus tractus solitarii of Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Baroreflex control of heart rate was examined by changing arterial pressure with an intravenous infusion of phenylephrine or sodium nitroprusside. The maximum gain of baroreflex control of heart rate was attenuated in SHR compared with WKY before the gene transfer. Transfection of adenovirus vectors encoding dominant-negative Rho-kinase significantly augmented the maximum gain in both WKY and SHR. The extent of this augmentation, however, was greater in SHR than in WKY. After treatment with metoprolol, the maximum gain was significantly decreased in rats transfected with adenovirus vectors encoding dominant-negative Rho-kinase, but not in nontransfected rats. In contrast, after treatment with atropine, the maximum gain was greater in rats transfected with adenovirus vectors encoding dominant-negative Rho-kinase compared with nontransfected rats, although it was decreased in both groups. These results suggest that inhibition of Rho-kinase in the NTS augments baroreflex control of heart rate, in both WKY and SHR, probably because of a cardiac sympathoinhibitory effect.
Centering: A Parametric Theory and Its Instantiations
Authors: Poesio Massimo , Stevenson Rosemary , Eugenio Barbara Di , Hitzeman Janet
Published: September 2004

Centering theory is the best-known framework for theorizing about local coherence and salience; however, its claims are articulated in terms of notions which are only partially specified, such as “utterance,” “realization,” or “ranking.” A great deal of research has attempted to arrive at more detailed specifications of these parameters of the theory; as a result, the claims of centering can be instantiated in many different ways. We investigated in a systematic fashion the effect on the theory's claims of these different ways of setting the parameters. Doing this required, first of all, clarifying what the theory's claims are (one of our conclusions being that what has become known as “Constraint 1” is actually a central claim of the theory). Secondly, we had to clearly identify these parametric aspects: For example, we argue that the notion of “pronoun” used in Rule 1 should be considered a parameter. Thirdly, we had to find appropriate methods for evaluating these claims. We found that while the theory's main claim about salience and pronominalization, Rule 1—a preference for pronominalizing the backward-looking center (CB)—is verified with most instantiations, Constraint 1–a claim about (entity) coherence and CB uniqueness—is much more instantiation-dependent: It is not verified if the parameters are instantiated according to very mainstream views (“vanilla instantiation”), it holds only if indirect realization is allowed, and is violated by between 20% and 25% of utterances in our corpus even with the most favorable instantiations. We also found a trade-off between Rule 1, on the one hand, and Constraint 1 and Rule 2, on the other: Setting the parameters to minimize the violations of local coherence leads to increased violations of salience, and vice versa. Our results suggest that “entity” coherence—continuous reference to the same entities—must be supplemented at least by an account of relational coherence.
Beyond the Boundaries
Authors: Reveley James , Down Simon , Taylor Scott
Published: September 2004

This article presents an ethnographic study of control and resistance in a small professional service firm in the port transport industry. We argue that informal interaction between the owner-managers and their employees at a site beyond the organizational boundary, namely the local public house, provided the setting for rituals of resistance in which the participants achieved a modicum of role distance. These rituals, in turn, fulfilled a latent 'tension-release function' (Goffman, 1990:241) that served subtly to reinforce and reproduce order in the firm. On the basis of this argument, our article makes a twofold contribution to small firm research. First, the specific combination of functionalist and interactionist approaches provides fresh 'insights into how the complex and contested dynamics of interpersonal relations in small enterprises are handled' (Ram, 1 999b: I 5). Second, our analysis suggests ethnographic research has considerable methodological potential to deepen the understanding of small firm employee relations.
Business Ownership and Sectoral Growth
Authors: Van Stel André , Carree Martin
Published: September 2004

We investigate the development of business ownership (self-employment) rates over time at the sectoral level and the effect of these rates on sectoral output growth. In an earlier exercise, Carree et al. (2002) presented an analysis of the interrelationship between economy-wide business ownership rates and economic development. Their analysis raised an important research question: to what extent do differences in business ownership rates at the economy-wide level reflect differences in the sectoral structures of economies or differences in business ownership rates at the sectoral level? The current article investigates this question making use of a sectoral data base of 21 OECD countries for the period 1970-98. Estimation results suggest that there is, on average, a too low business ownership rate in manufacturing and a too high business ownership rate in services.
Dynamic Balancing of a Centrifuge: Application to a Dual-Rotor System with Very Little Speed Difference
Authors: Yang J. , HE S. Z. , Wang L. Q.
Published: September 2004

The conventional way of separating the vibration signals of the inner and outer rotors of a dual-rotor system is to separate the composite "beat" signal; however, this is not effective for a dual-rotor system with little speed difference. We propose a new method of separating the vibration signals of the inner and outer rotors of a system with veiy little speed difference. It is not necessary to separate the composite " beat" signal, as in the conventional method. The magnitude and phase values of the unbalanced weights are obtrined directly by sampling the vibration signal synchronized with a reference signal. The balancing process is completed by the reciprocity influence coefficients of the method of the inner and outer rotors. The results show the advantage of such a method for a dual-rotor system, compared with conventional balancing. The proposed new method has been successfully implemented in field dynamic balancing of the centrifuge with such dual-rotor systems in two rectifying planes with digital signal processing and virtual instrument technology.
Theoretical and Experimental Studies on Vibration Control in Cantilever Beams Using DC Magnets
Authors: Joshi A.
Published: September 2004

This paper describes the investigations that have been carried out on vibration control in cantilever beams using a DC magnet actuator. A repulsive type DC magnet configuration is postulated and its force characteristics are investigated, as a function of the air gap. the strength of the magnetic field, and its location on the beam. A strategy is developed to deal with inherent nonlinearity in the magnetic force effect. A modal formulation of the structural dynamics is used so that the method can be applied to any type of bcam and some generic trends can be deduced. These results show that it is possible to arrive at a general configuralion of a repulsion type magnetic actuator, which renders the beam axis as a stable equilibrium point, with reference to the restoring force from the magnets. Further, for a given air gap, this restoring force is a non-linear function of the normalized disturbance. with a hardening type of behavior. Next, the vibration control problem is formulated using DC magnets. in the form of a SIMULINK© block diagram. The results concerning reduction in tip deflection are generated to quantify the extent of vibration suppression in the first vibration mode. Finally, a limited experimental study is carried out on a uniform cantilever beam to validate some of the assumptions of the theoretical study.
Lyapunov-Based Vibration Control of Translational Euler-Bernoulli Beams Using the Stabilizing Effect of Beam Damping Mechanisms
Authors: Dadfarnia Mohsen , Jalili Nader , Xian Bin , Dawson Darren M.
Published: September 2004

A translational cantilevered Euler-Bernoulli beam with tip mass dynamics at its free end is used to study the effect of several damping mechanisms on the stabilization of the beam displacement. Specifically, a Lyapunov-based controller utilizing a partial differential equation model of the translational beam is developed to exponentially stabilize the beam displacement while the beam support is regulated to a desired set-point position. Depending on the composition of the tip mass dynamics assumption (i.e. body-mass, point-mass, or massless). it is shown that proper combination of different damping mechanisms (i.e. strain-rate, structural, or viscous damping) guarantees exponential stability of the beam displacement. This novel Lyapunov-based approach. which is based on the energy dissipation mechanism in the beam, brings new dimensions to the stabilization problem of translational beams with tip mass dynamics. The stability analysis utilizes relatively simple mathematical tools to illustrate the exponential and asymptotic stability results. The numerical results are presented to show the effectiveness of the controller.
Single-Term Walsh Series Direct Method for the Solution of Nonlinear Problems in the Calculus of Variations
Authors: Razzaghi M. , Sepehrian B.
Published: September 2004

A direct method for solving variational problems using single-term Walsh series is presented. Two nonlinear examples are considered. In the first example the classical brachistochrone problem is examined. and in the second example a higher-order nonlinear problem is considered. The properties of single-term Walsh series are given and are utilized to reduce the calculus of variations problems to the solution of algebraic equations. The method is general, easy to implement and yields accurate results.
Deformations of Neo-Hookean Elastic Wedge Revisited
Authors: Walton Jay R. , Wilber J. Patrick
Published: September 2004

We reconsider a semi-inverse problem for nonlinearly elastic wedges, versions of which have been studied by several authors over the past 40 years. An intriguing feature of this problem is the existence of "non-unidirectional" deformations of the wedge, i.e. deformations for which material draws radially inward toward the apex in certain sectors of the wedge while material bulges radially outward in complementary sectors. We observe that such deformations are possible for a much larger class of materials than has been previously noted. We explore more carefully the relation between the displacement boundamy conditions and the "directional" properties of defonnations. Also, we consider the problem under alternative stress boundary conditions that must be satisfied pointwise; most previous treatments of the problem considered either pure displacement boundary conditions or stress boundary conditions satisfied in some average sense. Finally, we investigate a much broader class of generalized plane-strain deformations, consistent with these alternative boundary conditions and with a certain natural physical restriction on the pressure, and we show, surprisingly, that no additional solutions exist within this broader class.
Complementary Principle, Algorithm, and Complete Solutions to Phase Transitions in Solids Governed by Landau-Ginzburg Equation
Authors: Gao David Yang
Published: September 2004

The complementary variational principles and associated algonrthm are presented in this paper for solving a class of nonconvex mechanics problems governed by the Landau-Ginzburg equation. The method used here is the canonical dual transfonnation developed recently in nonconvex analysis by the author. It is shown that, by this method, certain very difficult nonconvex potential variational problems can be converted into a coupled quadratic mixed variational problem. The extremality conditions of these complementary variational problems are controlled by the triality theory discovered recently. Therefore, a complementary energy principle (i.e. the canonical duality theorem with zero duality gap) is established, which leads to a potentially useful primal-dual algorithm. Applications in finite-dimensional problems are discussed. Results show that the discretized nonconvex potential variational problems in n-dimensional space can be converted into certain simple canonical (either convex or concave) dual problems. Therefore, a complete set of solutions is obtained for the Landau-Ginzburg equation in finite-dimensional space.
Clinical Characteristics of Young People Referred to an Obsessive Compulsive Disorder Clinic in the United Kingdom
Authors: Chowdhury Uttom , Frampton Ian , Heyman Isobel
Published: September 2004

The Maudsley Hospital children's OCD clinic is the first clinic in the UK which is specifically set up to cater for the needs of young people with obsessive compulsive disorder (OCD). A retrospective review of case notes was carried out for patients seen between April 1998 and December 1999. Gender, age at assessment, age of onset of symptoms, family history, co-morbid diagnosis, previous treatment and severity of OCD, as measured by the score on the children's Yale-Brown Obsessive Compulsive Scale, were all measured. The results showed that 57 (74%) of the children referred fulfilled the criteria for OCD. The majority of children who did not have OCD had other neurodevelopmental disorders. Of the children with a diagnosis of OCD, the ratio of males to females was 1.1 to 1. The clinical profile of children seen was similar to profiles seen in other childhood OCD clinics around the world, however, half of the children seen had not received either specific medication or cognitive-behavioural therapy prior to referral.
Can Primary Schools Contribute Effectively to Tier I Child Mental Health Services?
Authors: Gowers Simon , Thomas Sian , Deeley Sarah
Published: September 2004

A questionnaire survey of 291 primary schools investigated teachers' contribution to the identification, management and referral of children with mental health problems. The survey aimed to clarify their familiarity with mental health issues and liaison experience with Child and Adolescent Mental Health Services (CAMHS). The teachers expressed great interest in children's mental health, which they judged had significantly impacted on their teaching. They had received little in the way of training in this area but were almost unanimously keen to learn more. Experience of CAMHS was variable, but many expressed uncertainty about pathways of referral and wanted better communication regarding pupils under their care. CAMHS and education departments could usefully plan together to meet schoolteachers training needs and establish appropriate referral pathways. The role of the primary child mental health worker appears to be often underdeveloped.
Persistence in Brainstorming: Exploring Stop Rules in Same-Sex Groups
Authors: Nistad Bernard A. , van Vianen Annelies E. M. , Stroebe Wolfgang , Lodewijkx Hein F. M.
Published: September 2004

In a laboratory experiment, three-person interactive and three-person nominal groups of college students brainstormed without externally imposed time constraints. All groups were homogeneous with regard to gender. Half of the participants were instructed to continue brainstorming until they ran out of ideas (expectancy stop rule), whereas the other half were instructed to continue until they were satisfied with their performance (satisfaction stop rule). We found that interactive groups were more persistent than nominal groups in both of the stop rule conditions and thereby compensated for their usual productivity loss. We also found, as predicted, that women were more persistent in the satisfaction stop rule condition, whereas men were more persistent in the expectancy stop rule condition. This effect may be due to gender differences in self-evaluations.
Effects of Intergroup Contact and Political Predispositions on Prejudice: Role of Intergroup Emotions
Authors: Miller Daniel A. , Smith Eliot R. , Mackie Diane M.
Published: September 2004

Two broad distal causes of prejudice are past history of intergroup contact and general political predispositions. Two studies investigate the extent to which these effects are mediated by emotions directed at the outgroup, as proposed by Intergroup Emotions Theory (Smith, 1993). In both studies, past intergroup contact and Social Dominance Orientation predict prejudice. as measured either by a feeling thermometer or the Modern Racism Scale. Furthermore, for both studies these effects are significantly mediated by intergroup emotions, above and beyond measures of stereotypes (stereotype endorsement in Study 1 and stereotype knowledge in Study 2) that were entered as alternative potential mediators. Stereotype endorsement also plays a significant mediational role in one case. Increased attention to the role of emotions in intergroup relations, including in the mediation of such powerful and well-known effects as those of intergroup contact and political predispositions, appears to be warranted.
What Benefits the Group Can Also Benefit the Individual: Group-Enhancing and Individual-Enhancing Motives for Collective Action
Authors: Tropp Linda R. , Brown Amy C.
Published: September 2004

Most collective action research focuses on how concerns for the welfare of one's group can motivate support for collective action. By contrast, little research has examined how motivations for enhancing oneself as an individual may also predict support for collective action, and how these motivations relate to feelings of identification with one's group. This research tests whether motivations for individual enhancement can predict support for collective action, beyond what can be predicted by motivations for group enhancement. With an undergraduate sample, Study 1 shows that individual enhancement significantly predicts interest and involvement in collective action beyond what can be predicted by concerns for group enhancement. Study 2 replicates these findings in a community sample of women, while also demonstrating that the motivation for individual enhancement mediates the relationship between group identification and collective action. Implications of these findings for future research on collective action are discussed.
Abnormal regulation of Mg2+ transport via Na/Mg exchanger in sickle erythrocytes
Authors: Rivera Alicia , Ferreira Ana , Bertoni Danielle , Romero José R. , Brugnara Carlo
Published: September 2004

Erythrocyte magnesium (Mg2+) deficiency has been demonstrated in sickle cell disease to contribute to erythrocyte dehydration, K loss, and thus sickling. No studies have assessed the functional properties of the Na/Mg exchanger in sickle cell disease. Using Mg2+-loaded erythrocytes, we measured Mg2+ efflux induced by extracellular Na+. We estimated that the Na/Mg exchanger had higher maximal velocity, higher affinity for Na+, and lower cooperativity for Mg2+ in sickle than in normal erythrocytes. The activity of the exchanger was markedly decreased by hypotonic and hypertonic conditions in normal erythrocytes but not in sickle erythrocytes. Studies of density-separated erythrocytes showed that the activity of the exchanger decreased as the mean cellular hemoglobin concentration increased in normal but not in sickle erythrocytes. Inhibition of protein kinase C (PKC) activity by calphostin C and chelerythrine increased the activity of the exchanger in normal but not in sickle erythrocytes. Inhibition of serine/threonine phosphatases did not affect the activity of the exchanger in either normal or sickle erythrocytes. Altogether, these data indicate that the Na/Mg exchanger is abnormally regulated in sickle erythrocytes. Therefore, Mg2+ depletion in sickle erythrocytes might be mediated by an up-regulated Na/Mg exchanger, possibly by dephosphorylation of the transporter or a closely associated regulator. (Blood. 2005;105:382-386)
Mercury intake by inflammatory phagocytes: in vivo cytology of mouse macrophages and neutrophils by X-ray elemental microanalysis coupled with scanning electron microscopy
Authors: Cunha Elisabete M , Oliveira Maria João R , Ferreira Paula G , Águas Artur P
Published: September 2004

Phagocytes remove and store mercury (Hg) that enters the body. Macrophages and granulocytes respond in opposite ways to Hg: macrophages loose cell viability, and neutrophils become protected from apoptosis. We have investigated the cytology of early intake of Hg by macrophages and neutrophils after a short period (2-4 min) of in vivo exposure to HgCl2. The two types of phagocytes were attracted either to a subcutaneous air pouch or to the peritoneal cavity of BALB/c mice by in situ BSA injection. BSA caused, 72 hours later, inflammatory exudates where neutrophils (air-pouch cavity) or macrophages (peritoneal cavity) were the predominant cell type. A lethal dose of HgCl2 (25 mg) was then injected in the two inflammatory cavities. The mice died 2-4 min later and the cell exudates were harvested and studied by scanning electron microscopy coupled with X-ray elemental microanalysis (SEM-XRM). More than half of the phagocytes showed ingested Hg; a higher percentage of macrophages (around 70%) than neutrophils (around 50%) were positive for the metal. Intracellular particles of Hg were spheroid and presented a small diameter (less than 20 nm). They could be seen in large numbers inside phagocytes (up to 20-30 Hg dots per cell); they were scattered throughout the cytoplasm of the cells. The ability of phagocytes to ingest Hg increased as the BSA-induced inflammation progressed. We conclude that (i) Hg is quickly ingested as small particles by phagocytes; (ii) endocytosis of Hg increases with the degree of activation of phagocytes; and (iii) phagocytes internalize Hg by pinocytosis.
Antiulcer activity and subacute toxicity of trans-dehydrocrotonin from Croton cajucara
Authors: Rodrĺguez Jaime A , Hiruma-Lima Clélia A , Souza Brito Alba RM
Published: September 2004

The antiulcerogenic activity of trans-dehydrocrotonin (DHC), a nor-clerodane diterpene isolated from Croton cajucara Benth. (Euphorbiaceae), and its subacute (35 days) toxicity were studied in mice and rats, respectively. For the antiulcerogenic tests, models of gastric ulcers induced in mice by ethanol/HCl or stress were used. In both models, an oral dose of DHC (100 mg/kg) significantly reduced (P <0.01) the formation of gastric lesions. DHC was also tested for its ability to scavenge free radicals, but no such action was observed in rat liver mitochondria. To assess the subacute toxicity, rats were treated orally with DHC (25, 50 and 100 mg/kg) for 5 weeks. A significant increase in liver weight was observed in male and female rats at highest doses, whereas a significant reduction in plasma alkaline phosphatase and cholesterol levels and an increase in gamma glutamyl transpeptidase were observed only at the highest dose (100 mg/kg) in female rats. DHC caused histopathological alterations in the liver that included a turbid tumefaction, microvacuolar degeneration and nuclear alterations. Despite the beneficial antiulcerogenic activity of DHC, our results suggest that the long-term use of this compound may induce liver damage.
Autologous Stem-Cell Transplantation Can Be Performed Safely Without the Use of Blood-Product Support
Authors: Ballen Karen K. , Becker Pamela S. , Yeap Beow Yong , Matthews Barbara , Henry David H. , Ford Patricia A.
Published: September 2004

Purpose

Autologous stem-cell transplantation has been shown to be a curative procedure for a variety of leukemias and lymphomas. Most transplants require RBC and platelet support. We report the ability to perform autologous transplantation without blood-product support.

Subjects and Methods

In this study, we treated 26 patients with religious objection to blood products with autologous stem-cell support without the use of any blood products. Patients received a combination of granulocyte colony-stimulating factor (G-CSF), erythropoietin, and interleukin-11 or G-CSF alone to mobilize stem cells. Post-transplant patients received intravenous iron, erythropoietin, G-CSF, and epsilon aminocaproic acid.

Results

There were two major bleeding complications (8%), with two treatment-related deaths (8%). There were three minor bleeding complications (12%). The median fall in hemoglobin level was 4.7 g/dL; the median hemoglobin level 30 days after transplantation was 9.2 g/dL. The median total number of days with platelet count less than 10 × 109/L was 4 days; the median days to platelet recovery greater than 20 × 109/L was 12 days.

Conclusion

Autologous stem-cell transplantation can be performed safely without the use of any blood products.
Effects of Exogenous Leptin on Satiety and Satiation in Patients with Lipodystrophy and Leptin Insufficiency
Authors: McDuffie Jennifer R. , Riggs Patti A. , Calis Karim A. , Freedman Renee J. , Oral Elif A. , DePaoli Alex M. , Yanovski Jack A.
Published: September 2004

To examine leptin’s role in human appetite regulation, we studied recombinant methionyl human leptin’s effects on satiation and satiety in a model of leptin insufficiency, lipodystrophy. Eight females with hypoleptinemia and lipodystrophy were given sc injections of A-100 (maximal dose, 200% of that predicted to normalize serum leptin) for 4 months. Satiation and satiety were determined before and again during leptin treatment. Satiation was measured as the time to voluntary cessation of eating from a standardized food array after a 12-h fast. Satiety was determined as the time to hunger sufficient to consume a full meal after consumption of a standardized preload. During leptin treatment, satiation time decreased (41.2 ± 18.2 to 19.5 ± 10.6 min; P = 0.01), satiety time increased (62.9 ± 64.8 to 137.8 ± 91.6 min; P = 0.04), energy consumed to produce satiation decreased (2034 ± 405 to 1135 ± 432 kcal or 8.5 ± 1.7 to 4.7 ± 1.8 MJ; P < 0.01), and the amount of food desired in the postabsorptive state decreased (P < 0.02). Ghrelin concentrations also decreased during leptin administration (284.3 ± 127.9 to 140.6 ± 104.5 pmol/liter; P < 0.002). We conclude that increased leptin in patients with lipodystrophy results in less caloric, shorter, more satiating meals and longer-lived satiety. These data support the hypothesis that leptin plays an important, permissive role in human appetite regulation.
Characterization of a Novel Loss of Function Mutation of PAX8 in a Familial Case of Congenital Hypothyroidism with In-Place, Normal-Sized Thyroid
Authors: Meeus Laurent , Gilbert Brigitte , Rydlewski Catherine , Parma Jasmine , Roussie Anne Lienhardt , Abramowicz Marc , Vilain Catheline , Christophe Daniel , Costagliola Sabine , Vassart Gilbert
Published: September 2004

Thyroid dysgenesis is the most common cause of congenital hypothyroidism, a relatively frequent disease affecting 1 in 3000–4000 newborns. Whereas most cases are sporadic, mutations in transcription factors implicated in thyroid development have been shown to cause a minority of cases transmitted as monogenic Mendelian diseases. PAX8 is one of these transcription factors, and so far, five mutations have been identified in its paired domain in patients with thyroid dysgenesis. We have identified a novel mutation of PAX8, in the heterozygous state, in a father and his two children both presenting with congenital hypothyroidism associated with an in-place thyroid of normal size at birth. In addition, one of the affected siblings displayed unilateral kidney agenesis. The mutation substitutes a highly conserved serine in position 54 of the DNA-binding domain of the protein (S54G mutation) by a glycine. Functional analyses of the mutant protein (PAX8-S54G) demonstrated that it is unable to bind a specific cis-element of the thyroperoxidase gene promoter in EMSAs and that it has almost completely lost the ability to act in synergy with Titf1 to transactivate transcription from the thyroglobulin promoter/enhancer. These results indicate that loss of function mutations of the PAX8 gene may cause congenital hypothyroidism in the absence of thyroid hypoplasia.
Model development and control methodology of a new electric power steering system
Authors: Song Jeonghoon , Boo Kwangsuck , Kim Heng Seob , Lee Jongil , Hong Sunyoung
Published: September 2004

In this study, a new column-type electric power steering (EPS-TT) system is investigated. The remarkable features of this EPS-TT system are its opto-isolated torque sensor, which is used to make steering torque measurements, and its assist torque control methodology, which uses a unidirectional motor and two clutches. Thus it does not require a complicated motor drive system that consumes a large amount of electrical energy when the direction of rotation is reversed. This allows the new system to use a smaller and simpler assist motor. A full steering system model and a simplified model are developed to evaluate the EPS-TT system. A full car model is also used to investigate the vehicle response. A map-based control method and a proportional-integral-derivative control algorithm are designed to control the EPS-TT system. Various sinusoidal inputs are applied to the system and the resulting performance is analysed. The results show that the performance achieved by the EPS-TT system is similar to that of a conventional EPS system across the frequency domain. The results for the full steering system model are similar to those for the simplified model, but the vehicle response is slightly different. The map-based controller provided good performance without affecting the stability or controllability of the vehicle.
Atazanavir
Authors: Orrick Joanne J , Steinhart Corklin R
Published: September 2004

OBJECTIVE

To review the pharmacology, virology, pharmacokinetics, resistance profile, clinical efficacy, safety, and drug interactions of atazanavir.

DATA SOURCES

A PubMed and NLMGateway search (1966–June 2004) utilizing the key words atazanavir and BMS-232632 was performed. Abstracts from scientific meetings, including the Conference on Retroviruses and Opportunistic Infections, International AIDS Society Conference on HIV Pathogenesis and Treatment, Interscience Conference on Antimicrobial Agents and Chemotherapy, and the Infectious Diseases Society of America, were also reviewed.

STUDY SELECTION AND DATA EXTRACTION

All publications and meeting abstracts were reviewed, and information relevant to the formulary decision-making process was selected.

DATA SYNTHESIS

Atazanavir is a once-daily protease inhibitor (PI) that received approval by the Food and Drug Administration in June 2003. In clinical trials in antiretroviral (ARV)-naîve patients, atazanavir had efficacy similar to that of efavirenz or nelfinavir. In ARV-experienced patients, atazanavir was inferior to lopinavir/ritonavir unless atazanavir was coadministered with low-dose ritonavir. Following failure of an atazanavir-containing regimen in ARV-naîve patients, a unique I50L mutation was seen. Atazanavir resistance is likely when resistance to ≥3 PIs is present. Atazanavir can cause increases in unconjugated bilirubin levels, which rarely leads to jaundice or scleral icterus. In contrast to comparators, atazanavir did not negatively impact the lipid profile. Similar to other PIs, atazanavir is metabolized by and inhibits CYP3A at clinically relevant concentrations; therefore, many potential drug interactions exist.

CONCLUSIONS

Atazanavir is a once-daily PI that, unlike other PIs, does not negatively impact the lipid profile. Atazanavir may be particularly desirable in patients with hyperlipidemia or other coronary artery disease risk factors.
Evaluation of Lamotrigine Toxicity Reported to Poison Centers
Authors: Lofton Amanda L , Klein-Schwartz Wendy
Published: September 2004

BACKGROUND

Lamotrigine is an antiepileptic drug for the treatment of partial and generalized seizures as well as bipolar disorder. Limited published information exists describing the clinical effects of lamotrigine overdose.

OBJECTIVE

To examine the toxicity of exposures to lamotrigine utilizing national poison center data.

METHODS

Data on single-substance exposures to lamotrigine reported to the American Association of Poison Control Centers Toxic Exposure Surveillance System in 2000 and 2001 were retrospectively analyzed.

RESULTS

There were 493 cases that met the inclusion criteria. The majority of exposures occurred within the age groups 20–59 years old (n = 198, 40.2%), followed by 4 years old (n = 173, 35.1%). Overall, the majority of patients (52.1%) exposed to lamotrigine in overdose experienced no toxic clinical effects. The most common clinical effects reported in overdose were drowsiness/lethargy (20.9%), vomiting (11%), nausea (5.1%), ataxia (4.9%), dizziness/vertigo (4.5%), and tachycardia (4.3%). Major clinical effects included coma (n = 6), seizures (n = 8), and respiratory depression (n = 3). Medical outcome was reported as minor in 150 (30.4%), moderate in 73 (14.8%), and major in 13 (2.6%) cases. There were no deaths.

CONCLUSIONS

These data demonstrate that the majority of patients exposed to lamotrigine in overdose experienced minor or no clinical effects. Although rare, serious effects can also occur.
KChIPs and Kv4 α Subunits as Integral Components of A-Type Potassium Channels in Mammalian Brain
Authors: Rhodes Kenneth J. , Carroll Karen I. , Sung M. Amy , Doliveira Lisa C. , Monaghan Michael M. , Burke Sharon L. , Strassle Brian W. , Buchwalder Lynn , Menegola Milena , Cao Jie , An W. Frank , Trimmer James S.
Published: September 2004

Voltage-gated potassium (Kv) channels from the Kv4, orShal-related, gene family underlie a major component of the A-type potassium current in mammalian central neurons. We recently identified a family of calcium-binding proteins, termed KChIPs (Kv channel interacting proteins), that bind to the cytoplasmic N termini of Kv4 family α subunits and modulate their surface density, inactivation kinetics, and rate of recovery from inactivation (An et al., 2000). Here, we used single and double-label immunohistochemistry, together with circumscribed lesions and coimmunoprecipitation analyses, to examine the regional and subcellular distribution of KChIPs1-4 and Kv4 family α subunits in adult rat brain. Immunohistochemical staining using KChIP-specific monoclonal antibodies revealed that the KChIP polypeptides are concentrated in neuronal somata and dendrites where their cellular and subcellular distribution overlaps, in an isoform-specific manner, with that of Kv4.2 and Kv4.3. For example, immunoreactivity for KChIP1 and Kv4.3 is concentrated in the somata and dendrites of hippocampal, striatal, and neocortical interneurons. Immunoreactivity for KChIP2, KChIP4, and Kv4.2 is concentrated in the apical and basal dendrites of hippocampal and neocortical pyramidal cells. Double-label immunofluorescence labeling revealed that throughout the forebrain, KChIP2 and KChIP4 are frequently colocalized with Kv4.2, whereas in cortical, hippocampal, and striatal interneurons, KChIP1 is frequently colocalized with Kv4.3. Coimmunoprecipitation analyses confirmed that all KChIPs coassociate with Kv4 α subunits in brain membranes, indicating that KChIPs 1-4 are integral components of native A-type Kv channel complexes and are likely to play a major role as modulators of somatodendritic excitability.
Generation of Reactive Oxygen Species in the Reaction Catalyzed by α-Ketoglutarate Dehydrogenase
Authors: Tretter Laszlo , Adam-Vizi Vera
Published: September 2004

α-Ketoglutarate dehydrogenase (α-KGDH), a key enzyme in the Krebs' cycle, is a crucial early target of oxidative stress (Tretter and Adam-Vizi, 2000). The present study demonstrates that α-KGDH is able to generate H2O2and, thus, could also be a source of reactive oxygen species (ROS) in mitochondria. Isolated α-KGDH with coenzyme A (HS-CoA) and thiamine pyrophosphate started to produce H2O2after addition of α-ketoglutarate in the absence of nicotinamide adenine dinucleotide-oxidized (NAD+). NAD+, which proved to be a powerful inhibitor of α-KGDH-mediated H2O2formation, switched the H2O2forming mode of the enzyme to the catalytic [nicotinamide adenine dinucleotide-reduced (NADH) forming] mode. In contrast, NADH stimulated H2O2formation by α-KGDH, and for this, neither α-ketoglutarate nor HS-CoA were required. When all of the substrates and cofactors of the enzyme were present, the NADH/NAD+ratio determined the rate of H2O2production. The higher the NADH/NAD+ratio the higher the rate of H2O2production. H2O2production as well as the catalytic function of the enzyme was activated by Ca2+. In synaptosomes, using α-ketoglutarate as respiratory substrate, the rate of H2O2production increased by 2.5-fold, and aconitase activity decreased, indicating that α-KGDH can generate H2O2inin situmitochondria. Given the NADH/NAD+ratio as a key regulator of H2O2production by α-KGDH, it is suggested that production of ROS could be significant not only in the respiratory chain but also in the Krebs' cycle when oxidation of NADH is impaired. Thus α-KGDH is not only a target of ROS but could significantly contribute to generation of oxidative stress in the mitochondria.
Chronic Ethanol Induces Synaptic But Not Extrasynaptic Targeting of NMDA Receptors
Authors: Carpenter-Hyland Ezekiel P. , Woodward John J. , Chandler L. Judson
Published: September 2004

The development of ethanol tolerance and dependence reflects neuroadaptive changes in response to continuous depression in synaptic activity. The present study used confocal imaging and electrophysiology procedures to assess the effects of prolonged ethanol exposure on NMDA receptor trafficking in cultures of hippocampal neurons. Neurons exposed to 50 mmethanol for 4 d showed an increase in the colocalization of NMDA receptor type 1 (NR1) clusters with the presynaptic marker protein synapsin. This was accompanied by significant increases in the size and density of these synapsin-associated clusters with no change observed in nonsynapsin-associated NR1 clusters. Similar effects were observed with NR2B clustering after chronic ethanol exposure. The increase in synaptic NMDA receptor clustering was prevented by addition of a protein kinase A inhibitor or by coexposure to a low concentration of NMDA and was reversed when ethanol was removed from the cultures. No changes were observed in the synaptic content, cluster size, or density of AMPA receptors after ethanol exposure. Electrophysiological measurements on ethanol-treated neurons revealed a similar enhancement in synaptic NMDA currents with no change in AMPA-mediated events. After isolation of extrasynaptic NMDA receptors by MK801 (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate (/) trapping, whole-cell responses to NMDA were not different between control and ethanol-treated neurons These observations demonstrate that neuroadaptive changes in NMDA receptors in response to prolonged ethanol exposure occur through activity-dependent processes that regulate their synaptic targeting and localization.
Brain-Derived Neurotrophic Factor Plays a Critical Role in Contextual Fear Conditioning
Authors: Liu Ingrid Y.C. , Lyons W. Ernest , Mamounas Laura A. , Thompson Richard F.
Published: September 2004

In this study, brain-derived neurotrophic factor (BDNF) heterozygous knock-outs were tested on fear conditioning, and their wild-type littermates were used as controls. Results showed that BDNF+/-mice are impaired in contextual learning, whereas tone learning remains intact. Because BDNF is involved in synaptic transmission and contextual learning is hippocampal dependent, we hypothesized that this deficit is attributable to abnormal BDNF-modulated synaptic plasticity in the hippocampus. A “gain-of-function” experiment was performed next by infusing recombinant BDNF protein into the hippocampal formation to investigate whether this deficit can be rescued. Infusion of BDNF protein into the hippocampus appeared to partially restore contextual fear learning of BDNF+/-mice. In conclusion, the present study suggests that BDNF plays a critical role in fear conditioning. Loss of one copy of the BDNF gene leads to impairment of contextual fear learning in BDNF+/-. This deficit can be partially rescued by infusing BDNF protein into the hippocampus. Other brain regions interacting with the hippocampus in the context conditioned stimulus pathway, for example, the amygdala, may also require normal BDNF expression levels to fully rescue this impairment.
Developmental Regulation of Nicotinic Synapses on Cochlear Inner Hair Cells
Authors: Katz Eleonora , Elgoyhen Ana Belén , Gómez-Casati María E. , Knipper Marlies , Vetter Douglas E. , Fuchs Paul A. , Glowatzki Elisabeth
Published: September 2004

In the mature cochlea, inner hair cells (IHCs) transduce acoustic signals into receptor potentials, communicating to the brain by synaptic contacts with afferent fibers. Before the onset of hearing, a transient efferent innervation is found on IHCs, mediated by a nicotinic cholinergic receptor that may contain both α9 and α10 subunits. Calcium influx through that receptor activates calcium-dependent (SK2-containing) potassium channels. This inhibitory synapse is thought to disappear after the onset of hearing [after postnatal day 12 (P12)]. We documented this developmental transition using whole-cell recordings from IHCs in apical turns of the rat organ of Corti. Acetylcholine elicited ionic currents in 88-100% of IHCs between P3 and P14, but in only 1 of 11 IHCs at P16-P22. Potassium depolarization of efferent terminals caused IPSCs in 67% of IHCs at P3, in 100% at P7-P9, in 93% at P10-P12, but in only 40% at P13-P14 and in none of the IHCs tested between P16 and P22. Earlier work had shown byin situhybridization that α9 mRNA is expressed in adult IHCs but thatα10 mRNA disappears after the onset of hearing. In the present study, antibodies toα10 and to the associated calcium-dependent (SK2) potassium channel showed a similar developmental loss. The correlated expression of these gene products with functional innervation suggests thatAlpha10andSK2, but notAlpha9,are regulated by synaptic activity. Furthermore, this developmental knock-out of α10, but not α9, supports the hypothesis that functional nicotinic acetylcholine receptors in hair cells are heteromers containing both these subunits.