bluuebunny/crossref_metadata_2025 huggingface dataset:
On Patent Licensing in Spatial Competition
Authors: Poddar Sougata , Sinha Uday Bhanu
Published: May 2004

We consider the optimal licensing strategy of an outsider patentee as well as an insider patentee in a linear city framework where firms compete in price. We show that offering royalty is best for an outsider patentee for both drastic and non‐drastic innovations. For an insider patentee, offering no license is the best when the innovation is drastic, while royalty is optimal when the innovation is non‐drastic. The incentive for innovation is higher for an outsider patentee compared to an insider patentee. The overall increase in welfare due to an innovation is the same for both outsider and insider patentees.
An internalist perspective on party consolidation and the Bulgarian Union of Democratic Forces
Authors: SHARMAN JASON C. , PHILLIPS ROBERT
Published: May 2004

Abstract.  Scholars have traditionally held political parties to be indispensable to democracy, and recent studies of democratic consolidation have reaffirmed their importance. Yet analysis of the development of political parties in Eastern Europe and elsewhere has tended to understate the role of internal, organizational factors at the expense of external factors, such as the selection effect of electoral markets and presence of societal cleavages. We argue that creating effective governance and bargaining mechanisms inside party organizations are more important for institutionalizing parties than external pressures. We draw support for this thesis from an analysis of the Bulgarian Union of Democratic Forces, which after a series of internal splits and subsequent rounds of restructuring, moved from a loose umbrella formation toward an institutionalized party.
Japan's political economy in comparative perspective: Macroeconomic policy and wage coordination
Authors: SAKAMOTO TAKAYUKI
Published: May 2004

Abstract.  Japan has received conflicting assessments in the comparative political economy literature. This article seeks to identify the location of Japan's political economy within a comparative framework, building on recent analyses of macroeconomic policy and wage coordination. The author examines empirical records and shows that Japan's regime is best considered ‘Keynesian centralization’, rather than ‘monetarist (semi)decentralization’, in light of its effective wage coordination and its anti‐inflationary but flexibly accommodating macroeconomic policy. When there was national consensus on macroeconomic conservatism, Japan implemented restrictive policy and resembled monetarist centralization. However, Japan's monetarist centralization did not lead to distributional conflicts and high unemployment because its decentralized but coordinated wage bargaining and weak labor made it possible for employers and unions to achieve national diffusion of wage restraint without facing solidaristic wage demands by low‐paid workers.
Remote Monitoring of Implantable Cardioverter Defibrillators:
Authors: SCHOENFELD MARK H. , COMPTON STEVEN J. , MEAD R. HARDWIN , WEISS DANIEL N. , SHERFESEE LOU , ENGLUND JENNIFER , MONGEON LUC R.
Published: May 2004

A prospective study evaluating the functionality and ease of use of the Medtronic CareLink® Network, “CareLink,” was conducted at ten investigational sites. This internet‐based remote monitoring service allows clinicians to remotely manage their patients' implantable cardioverter defibrillators (ICDs) and chronic diseases. The network is comprised of a patient monitor, a secure server, and clinician and patient websites. Under clinician direction, patients interrogated their ICDs at home, and transmitted data to secure servers via a standard telephone line. Comprehensive device data and a 10‐second presenting rhythm electrogram were captured by the monitor and available for access and review on the clinician website. The information could also be printed using a standard desktop computer with internet access. During this study, patients were asked to transmit device data twice, at least 7 days apart, as scheduled by the clinic. Monitor functionality was assessed, and ease of using the system components was evaluated via questionnaires completed by patients and clinicians following each data transmission and review. Fifty‐nine patients (64 ± 14 years, range 22‐85 years) completed 119 transmissions with only 14 calls to the study support center. Clinician review of data transmissions revealed several clinically significant findings, including silent AF discovery, assessment of antiarrhythmic drug efficacy in a previously diagnosed AF patient, previously unobserved atrial undersensing, and ventricular tachycardia. ICD patients found the monitor easy to use. Clinicians were pleased with the performance of the network and the quality of the web‐accessed data, and found it comparable to an in‐office device interrogation. CareLink is a practical tool for routine device management and may allow timely identification of clinically important issues. (PACE 2004; 27[Pt. I]:757–763)
Long‐Term Effectiveness of Dual Site Left Ventricular Cardiac Resynchronization Therapy in a Patient with Congestive Heart Failure
Authors: SASSARA MASSIMO , ACHILLI AUGUSTO , BIANCHI STEFANO , FICILI SABINA , MARULLO ANTONINO , PONTILLO DANIELE , ACHILLI PAOLA , PERALDO CARLO , SGRECCIA FABRIZIO
Published: May 2004

This article describes a case of cardiac resynchronization therapy (CRT) performed with dual site left ventricular pacing. The main clinical and functional long‐term results are in agreement with the most recent data regarding traditional CRT. Furthermore, this innovative pacing modality allowed optimal inter‐ and intraventricular resynchronization. (PACE 2004; 27[Pt. I]:805–807)
Asystole Following Left Ventricular Pacing
Authors: LAI REBECCA W. , VOLOSIN KENT J.
Published: May 2004

During biventricular ICD implantation, pacing the epicardial inferior posterior‐lateral surface of the left ventricle via the coronary sinus produced asystole. The proposed mechanism is a Bezold‐Jarisch reflex manifested by a drop in heart rate and blood pressure through direct C fiber stimulation. (PACE 2004; 27[Pt. I]:815–817)
Two‐to‐one Conduction Block Between Left Atrium and Right Lower Pulmonary Vein Preceding Complete Vein Isolation During Radiofrequency Current Ablation
Authors: WEBER STEFAN , NDREPEPA GJIN , SCHNEIDER MICHAEL , SCHMITT CLAUS
Published: May 2004

A 56‐year‐old patient with paroxysmal atrial fibrillation who developed a transient 2:1 block between the left atrium and right inferior pulmonary vein during a single application of radiofrequency current was described. The production of transient and complete atriovenous block by a single application of radiofrequency current demonstrates that a single connection between the pulmonary veins muscle and the left atrium may exist. (PACE 2004; 27[Pt. I]:829–830)
Syndrome of Inappropriate Antidiuretic Hormone Secretion Induced by Amiodarone Therapy
Authors: ASLAM M. KAMRAN , GNAIM CHARLIE , KUTNICK JAY , C. KOWAL ROBERT , MCGUIRE DARREN K.
Published: May 2004

We describe a case of amiodarone induced hyponatremia consistent with the syndrome of inappropriate antidiuretic hormone (SIADH) that developed during amiodarone loading, similar to three prior reports. The hyponatremia improved after a lower maintenance dose was initiated. This episode was reported online to the FDA (http://www.fda.gov/medwatch), and future amiodarone labeling will include SIADH as a potential side effect (personal communication, Wyeth Medical Science). Clinicians should be aware of this rare but serious complication, especially in light of the neurological effect of profound hyponatremia. Amiodarone induced SIADH may develop during the loading phase, and may respond to dose reduction without termination of drug. (PACE 2004; 27[Pt. I]:831–832)
Direct His‐Bundle Pacing:
Authors: DESHMUKH PRAMOD M. , ROMANYSHYN MARY
Published: May 2004

Direct His‐bundle pacing (DHBP) produces rapid sequential multisite synchronous ventricular activation and, therefore, would be an ideal alternative to right ventricular apical (RVA) pacing. In 54 patients with cardiomyopathy, ejection fraction (EF) 0.23 ± 0.11, persistent atrial fibrillation, and normal QRS < 120 ms. DHBP was attempted. This was successful in 39 patients. In seven patients, the effect of increasing heart rate on contractility (Treppe effect) was investigated. Twelve patients who also received a RVA lead underwent cardiopulmonary testing. After a mean follow‐up of 42 months, 29 patients are still alive with EF improving from 0.23 ± 0.11 to 0.33 ± 0.15. Functional class improved from 3.5 to 2.2. DP/dt increased at each pacing site (P < 0.05) as the heart rate increased to 60, 100, and 120 beats/min. Rise in dP/dt by DHBP pacing at 120 beats/min was at least 170 ± mmHg/s, greater than any other site in the ventricle (P < 0.05). Cardiopulmonary testing revealed longer exercise time (RVA 255 ± 110 s) (His 280 ± 104 s) (P < 0.05), higher O2 uptake (RVA 15 ± 4 mL/kg per minute) (His 16 ± 4 mL/kg minute) (P < 0.05), and later anaerobic threshold (RVA 126 ± 71 s) (His 145 ± 74 s) (P < 0.05) with DHBP compared to RVA pacing. Long‐term DHBP is safe and effective in humans. DHBP is associated with a superior Treppe effect and increased cardiopulmonary reserve when compared to RVA pacing. (PACE 2004; 27[Pt. II]:862–870)
Pneumatosis in Canine Gastric Dilatation‐Volvulus Syndrome
Authors: Fischetti Anthony J. , Saunders H. Mark , Drobatz Kenneth J.
Published: May 2004

Retrospectively, 243 dogs with radiographic evidence of gastric dilatation‐volvulus (GDV) were studied for radiographic signs of pneumatosis (intramural gas), pneumoperitoneum, splenomegaly, and severity of gastric distention. The sensitivity, specificity, and predictive value of these imaging signs as predictors of gastric wall necrosis, as determined by visual inspection at surgery or necropsy, were determined. The sensitivity and specificity of gastric pneumatosis were 14.1% and 92.7%, respectively. The prevalence of gastric wall necrosis was 26.6%. The positive and negative predictive values of gastric pneumatosis for predicting gastric necrosis were 40.9% and 74.9%, respectively. Gastric pneumatosis and pneumoperitoneum were identified together in four dogs. Pneumoperitoneum, either alone or in conjunction with pneumatosis, yielded similar results as a test for gastric necrosis. Splenomegaly and severity of gastric distention were insensitive and nonspecific for gastric wall necrosis. Splenomegaly did not predict the need for splenectomy at surgery. Although pneumatosis and pneumoperitoneum are relatively specific signs of gastric wall necrosis, the utility of these signs as a test for gastric necrosis is limited in clinical practice. The significance of pneumatosis should be taken into consideration with previous treatments for gastric decompression, as percutaneous gastric trocharization or orogastric intubation may increase the number of false‐positive results.
Magnetic resonance imaging of a brain abscess in a 10‐month‐old filly
Authors: Audigié F. , Tapprest J. , George C. , Didierlaurent D. , Foucher N. , Faurie F. , Houssin M. , Denoix J.‐M.
Published: May 2004

The purpose of this paper was to correlate the magnetic resonance imaging (MRI) characteristics of a mature brain abscess in a horse with histopathologic alterations of brain tissue. Eight months after the onset of clinical signs, MRI of the brain of a 10‐month‐old filly was performed. A large space‐occupying lesion in the right cerebral hemisphere was identified. This space‐occupying lesion was delineated by a thick and well‐defined capsule that was isointense to brain parenchyma on the T1‐weighted images and with a markedly hypointense on the T2‐weighted images. The identification of such a capsule is highly diagnostic of a mature brain abscess. The lesion seen on MR images was confirmed at necropsy where a large abscess of the right hemisphere was observed. Streptococcus zooepidemicus and Pseudomonas aeruginosa were isolated from the abscess. Based on histopathologic examination, the signal characteristics of the capsule on T1‐weighted and T2‐weighted images were found to be due to the presence of numerous hemosiderin‐laden macrophages. These results are in agreement with previous studies on human patients. This report confirms the value of MRI in the diagnosis of equine brain diseases.
EFFECTS OF PRECONDITIONING ON THE ELASTIC BEHAVIOR OF SKIN UNDER COMPRESSIVE LOADING
Authors: WU JOHN Z. , DONG REN G. , SMUTZ W. PAUL , SCHOPPER AARON W.
Published: May 2004

In physiological loading conditions, the skin tissues are, sometimes, loaded compressively. The mechanical characteristics of skins in tension have been studied intensively, while those in compression have not been studied thoroughly. Previous studies suggested that, in order to obtain repeatable mechanical parameters, the skin sample should be properly preconditioned in the tensile tests. The present study is to investigate if the skin sample should be preconditioned in the compressive tests. Pigskins were used in the present study. Compression tests were performed in confined and unconfined loading configurations and at four different loading speeds (0.5, 1.0, 40, and 400 μm/s). Our results show that skin samples should be preconditioned in compressive tests, to obtain repeatable mechanical parameters. The necessary number of the loading cycles in the preconditioning treatment for compressive testing is less than that for tensile testing. Our findings indicate that the skin samples reach repeatable mechanical behavior after 3–4 loading cycles, independent of the loading rate and loading configurations (confined or unconfined compressions).
THEORY OF MECHANICAL IMMUNOLOGY
Authors: ARNETH BORROS M.
Published: May 2004

Numerous autoimmune illnesses are not only caused by defects of the immune system but may also be caused by defects in anatomical barriers. Morphologically, most of these barriers consist of basal membranes combined with epithelial cells or, more precisely, their cell membranes. In many organs, these barriers are associated with specialized, phagocytizing cells (e.g. histiocytes, macrophages, microglial cells A and B cells in joints). A collapse of these anatomical barriers caused either by mechanical effects (invasion by micro-organisms) or destructive tumor growth, leads to contact between macrophages and the CD4 lymphocytes, with protein structures of the cell interior. In principle, many intracellular structures should be able to function, on this basis, as potential antigens via MHC II. Contact between intracellular structures and the immune system first leads to a restricted local immune reaction and then to local autoantibody production. In order that a systemic immune reaction can take place, the contact between macrophages, CD4 cells and intracellular structures must occur over a long period and with high intensity. As a desirable, remote target, new clinical therapeutic strategies can be developed from this theory, for example, for patients with cell damage. Examples of such illnesses are, amongst others, cardiac infarcts and strokes as well as accident traumas. An immunosuppressive therapy should reduce the immune reply in all the patients mentioned and thus reduce the volume of the cell damage, giving the patient an advantage.
Cooperative attachment of cross bridges predicts regulation of smooth muscle force by myosin phosphorylation
Authors: Rembold Christopher M. , Wardle Robert L. , Wingard Christopher J. , Batts Timothy W. , Etter Elaine F. , Murphy Richard A.
Published: May 2004

Serine 19 phosphorylation of the myosin regulatory light chain (MRLC) appears to be the primary determinant of smooth muscle force development. The relationship between MRLC phosphorylation and force is nonlinear, showing that phosphorylation is not a simple switch regulating the number of cycling cross bridges. We reexamined the MRLC phosphorylation-force relationship in slow, tonic swine carotid media; fast, phasic rabbit urinary bladder detrusor; and very fast, tonic rat anococcygeus. We found a sigmoidal dependence of force on MRLC phosphorylation in all three tissues with a threshold for force development of ∼0.15 mol Pi/mol MRLC. This behavior suggests that force is regulated in a highly cooperative manner. We then determined whether a model that employs both the latch-bridge hypothesis and cooperative activation could reproduce the relationship between Ser19-MRLC phosphorylation and force without the need for a second regulatory system. We based this model on skeletal muscle in which attached cross bridges cooperatively activate thin filaments to facilitate cross-bridge attachment. We found that such a model describes both the steady-state and time-course relationship between Ser19-MRLC phosphorylation and force. The model required both cooperative activation and latch-bridge formation to predict force. The best fit of the model occurred when binding of a cross bridge cooperatively activated seven myosin binding sites on the thin filament. This result suggests cooperative mechanisms analogous to skeletal muscle that will require testing.
Real-time imaging of peroxisome proliferator-activated receptor-γ coactivator-1α promoter activity in skeletal muscles of living mice
Authors: Akimoto Takayuki , Sorg Brian S. , Yan Zhen
Published: May 2004

In response to sustained increase in contractile activity, mammalian skeletal muscle undergoes adaptation with enhanced mitochondrial biogenesis and fiber type switching. The peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) was recently identified as a key regulator for these adaptive processes. To investigate the sequence elements in the PGC-1α gene that are responsible for activity-dependent transcriptional activation, we have established a unique system to analyze promoter activity in skeletal muscle of living mice. Expression of PGC-1α-firefly luciferase reporter gene in mouse tibialis anterior muscle transfected by electric pulse-mediated gene transfer was assessed repeatedly in the same muscle by using optical bioluminescence imaging analysis before and after low-frequency (10 Hz) motor nerve stimulation. Nerve stimulation (2 h) resulted in a transient 3-fold increase ( P < 0.05) in PGC-1α promoter activity along with a 1.6-fold increase ( P < 0.05) in endogenous PGC-1α mRNA. Mutation of two consensus myocyte enhancer factor 2 (MEF2) binding sites (−2901 and −1539) or a cAMP response element (CRE) (−222) completely abolished nerve stimulation-induced increase in PGC-1α promoter activity. These findings provide direct evidence that contractile activity-induced PGC-1α promoter activity in skeletal muscle is dependent on the MEF2 and the CRE sequence elements. The experimental methods used in the present study have general applicability to studies of gene regulation in muscle.
Glucosamine-induced alterations of mitochondrial function in pancreatic β-cells: possible role of protein glycosylation
Authors: Anello Marcello , Spampinato Daniela , Piro Salvatore , Purrello Francesco , Rabuazzo Agata Maria
Published: May 2004

Chronic exposure of rat pancreatic islets and INS-1 insulinoma cells to glucosamine (GlcN) produced a reduction of glucose-induced (22.2 mM) insulin release that was associated with a reduction of ATP levels and ATP/ADP ratio compared with control groups. To further evaluate mitochondrial function and ATP metabolism, we then studied uncoupling protein-2 (UCP2), F1-F0-ATP-synthase, and mitochondrial membrane potential, a marker of F1-F0-ATP-synthase activity. UCP2 protein levels were unchanged after chronic exposure to GlcN on both pancreatic islets and INS-1 β-cells. Due to the high number of cells required to measure mitochondrial F1-F0-ATP-synthase protein levels and mitochondrial membrane potential, we used INS-1 cells, and we found that chronic culture with GlcN increased F1-F0-ATP-synthase protein levels but decreased glucose-stimulated changes of mitochondrial membrane potential. Moreover, F1-F0-ATP-synthase was highly glycosylated, as demonstrated by experiments with N-glycosidase F and glycoprotein staining. Tunicamycin (an inhibitor of protein N-glycosylation), when added with GlcN in the culture medium, was able to partially prevent all these negative effects on insulin secretion, adenine nucleotide content, mitochondrial membrane potential, and protein glycosylation. Thus we suggest that GlcN-induced pancreatic β-cell toxicity might be mediated by reduced cell energy production. An excessive protein N-glycosylation of mitochondrial F1-F0-ATP-synthase might lead to cell damage and secretory alterations in pancreatic β-cells.
Identification of iduronate-2-sulfatase in mouse pancreatic islets
Authors: Coronado-Pons I. , Novials A. , Casas S. , Clark A. , Gomis R.
Published: May 2004

The lysosomal enzyme iduronate-2-sulfatase (IDS) is expressed in pancreatic islets and is responsible for degradation of proteoglycans, such as perlecan and dermatan sulfate. To determine the role of IDS in islets, expression and regulation of the gene and localization of the enzyme were investigated in mouse pancreatic islets and clonal cells. The Ids gene was expressed in mouse islets and β- and α-clonal cells, in which it was localized intracellularly in lysosomes. The transcriptional expression of Ids in mouse islets increased with glucose in a dose-dependent manner (11.5, 40.2, 88, and 179% at 5.5, 11.1, 16.7, and 24.4 mM, respectively, P < 0.01 for 16.7 and 24.4 mM glucose vs. 3 mM glucose). This increase was not produced by glyceraldehyde (1 mM) or 6-deoxyglucose (21.4 mM) and was blocked by the addition of mannoheptulose (21.4 mM). Neither insulin content nor secretory response to glucose (16.7 mM) was altered in mouse islets infected with lentiviral constructs carrying the IDS gene in sense orientation. Furthermore, no decrease in islet cell viability was observed in mouse islets carrying lentiviral contracts compared with controls. However, insulin content was reduced (35% vs. controls, P < 0.001) in islets infected with IDS antisense construct, while the secretory response of those islets to glucose was maintained. Inhibition of IDS by antisense infection led to an increase in lysosomal size and a high rate of insulin granule degradation via the crinophagic route in pancreatic β-cells. We conclude that IDS is localized in lysosomes in pancreatic islet cells and expression is regulated by glucose. IDS has a potential role in the normal pathway of lysosomal degradation of secretory peptides and is likely to be essential to maintain pancreatic β-cell function.
Measuring hemodynamic changes during mammalian development
Authors: Jones E.A.V. , Baron M.H. , Fraser S.E. , Dickinson M.E.
Published: May 2004

The pathogenesis of many congenital cardiovascular diseases involves abnormal flow within the embryonic vasculature that results either from malformations of the heart or defects in the vasculature itself. Extensive genetic and genomic analysis in mice has led to the identification of an array of mutations that result in cardiovascular defects during embryogenesis. Many of these mutations cause secondary effects within the vasculature that are thought to arise because of altered fluid dynamics. Presumably, cardiac defects disturb or reduce flow and thereby lead to the disruption of the mechanical signals necessary for proper vascular development. Unfortunately, a precise understanding of how flow disruptions lead to secondary vasculature defects has been hampered by the inadequacy of existing analytical tools. Here, we used a fast line-scanning technique for the quantitative analysis of hemodynamics during early organogenesis in mouse embryos, and we present a model system for studying cellular responses during the formation and remodeling of the mammalian cardiovascular system. Flow velocity profiles can be measured as soon as a heart begins to beat even in newly formed vessels. These studies establish a link between the pattern of blood flow within the vasculature and the stage of heart development and also enable analysis of the influence of mechanical forces during development.
Regulation of free radical outflow from an isolated muscle bed in exercising humans
Authors: Bailey Damian M. , Young Ian S. , McEneny Jane , Lawrenson Lesley , Kim Jeannie , Barden Jeremy , Richardson Russell S.
Published: May 2004

Incremental knee extensor (KE) exercise performed at 25, 70, and 100% of single-leg maximal work rate (WRMAX) was combined with ex vivo electron paramagnetic resonance (EPR) spectroscopic detection of α-phenyl- tert-butylnitrone (PBN) adducts, lipid hydroperoxides (LH), and associated parameters in five males. Blood samples were taken from the femoral arterial and venous circulation that, when combined with measured changes in femoral venous blood flow, permitted a direct examination of oxidant exchange across a functionally isolated contracting muscle bed. KE exercise progressively increased the net outflow of LH and PBN adducts (100% > 70% > 25% WRMAX, P < 0.05) consistent with the generation of secondary, lipid-derived oxygen (O2)-centered alkoxyl and carbon-centered alkyl radicals. Radical outflow appeared to be more intimately associated with predicted decreases in intracellular Po2(iPo2) as opposed to measured increases in leg O2uptake, with greater outflow recorded between 25 and 70% WRMAX( P < 0.05 vs. 70–100% WRMAX). This bias was confirmed when radical venoarterial concentration differences were expressed relative to changes in the convective components of O2extraction and flow (25–70% WRMAXP < 0.05 vs. 70–100% WRMAX, P > 0.05). Exercise also resulted in a net outflow of other potentially related redox-reactive parameters, including hydrogen ions, norepinephrine, myoglobin, lactate dehydrogenase, and uric acid, whereas exchange of lipid/lipoproteins, ascorbic acid, and selected lipid-soluble anti-oxidants was unremarkable. These findings provide direct evidence for an exercise intensity-dependent increase in free radical outflow across an active muscle bed that was associated with an increase in sarcolemmal membrane permeability. In addition to increased mitochondrial electron flux subsequent to an increase in O2extraction and flow, exercise-induced free radical generation may also be regulated by changes in iPo2, hydrogen ion generation, norepinephrine autoxidation, peroxidation of damaged tissue, and xanthine oxidase activation.
Coverslip hypoxia: a novel method for studying cardiac myocyte hypoxia and ischemia in vitro
Authors: Pitts Kelly R. , Toombs Christopher F.
Published: May 2004

In vitro experimental models designed to study the effects of hypoxia and ischemia typically employ oxygen-depleted media and/or hypoxic chambers. These approaches, however, allow for metabolites to diffuse away into a large volume and may not replicate the high local concentrations that occur in ischemic myocardium in vivo. We describe herein a novel and simple method for creating regional hypoxic and ischemic conditions in neonatal rat cardiac myocyte monolayers. This method consists of creating a localized diffusion barrier by placing a glass coverslip over a portion of the monolayer. The coverslip restricts covered myocytes to a thin film of media while leaving uncovered myocytes free to access the surrounding bulk media volume. Myocytes under the coverslip undergo marked morphology changes over time as assessed by video microscopy. Fluorescence microscopy shows that these changes are accompanied by alterations in mitochondrial membrane potential and plasma membrane dynamics and eventually result in myocyte death. We also show that the metabolic activity of myocytes drives cell necrosis under the coverslip. In addition, the intracellular pH of synchronously contracting myocytes under the coverslip drops rapidly, which further implicates metabolic activity in regulating cell death under the coverslip. In contrast with existing models of hypoxia/ischemia, this technique provides a simple and effective way to create hypoxic/ischemic conditions in vitro. Moreover, we conclude that myocyte death is hastened by the combination of hypoxia, metabolites, and acidosis and is facilitated by a reduction in media volume, which may better represent ischemic conditions in vivo.
Membrane organization and function of M1 and M23 isoforms of aquaporin-4 in epithelial cells
Authors: Silberstein Claudia , Bouley Richard , Huang Yan , Fang Pingke , Pastor-Soler Nuria , Brown Dennis , Van Hoek Alfred N.
Published: May 2004

Aquaporin-4 (AQP4) water channels exist as heterotetramers of M1 and M23 splice variants and appear to be present in orthogonal arrays of intramembraneous particles (OAPs) visualized by freeze-fracture microscopy. We report that AQP4 forms OAPs in rat gastric parietal cells but not in parietal cells from the mouse or kangaroo rat. Furthermore, the organization of principal cell OAPs in Brattleboro rat kidney is perturbed by vasopressin (arginine vasopressin). Membranes of LLC-PK1cells expressing M23-AQP4 showed large, abundant OAPs, but none were detectable in cells expressing M1-AQP4. Measurements of osmotic swelling of transfected LLC-PK1cells using videomicroscopy, gave osmotic water permeability coefficient ( Pf) values (in cm/s) of 0.018 (M1-AQP4), 0.019 (M23-AQP4), and 0.003 (control). Quantitative immunoblot and immunofluorescence showed an eightfold greater expression of M1- over M23-AQP4 in the cell lines, suggesting that single-channel pf(cm3/s) is much greater for the M23 variant. Somatic fusion of M1- and M23-AQP4 cells ( Pf= 0.028 cm/s) yielded OAPs that were fewer and smaller than in M23 cells alone, and M1-to-M23 expression ratios (∼1:4) normalized to AQP4 in M1 or M23 cells indicated a reduced single-channel pffor the M23 variant. Expression of an M23-AQP4-Ser111Emutant produced ∼1.5-fold greater single-channel pfand OAPs that were up to 2.5-fold larger than wild-type M23-AQP4 OAPs, suggesting that a putative PKA phosphorylation site Ser111is involved in OAP formation. We conclude that the higher-order organization of AQP4 in OAPs increases single-channel osmotic water permeability by one order of magnitude and that differential cellular expression levels of the two isoforms could regulate this organization.
Large-Scale Organization of Ferret Auditory Cortex Revealed Using Continuous Acquisition of Intrinsic Optical Signals
Authors: Nelken Israel , Bizley Jennifer K. , Nodal Fernando R. , Ahmed Bashir , Schnupp Jan W. H. , King Andrew J.
Published: May 2004

We have adapted a new approach for intrinsic optical imaging, in which images were acquired continuously while stimuli were delivered in a series of continually repeated sequences, to provide the first demonstration of the large-scale tonotopic organization of both primary and nonprimary areas of the ferret auditory cortex. Optical responses were collected during continuous stimulation by repeated sequences of sounds with varying frequency. The optical signal was averaged as a function of time during the sequence, to produce reflectance modulation functions (RMFs). We examined the stability and properties of the RMFs and show that their zero-crossing points provide the best temporal reference points for quantifying the relationship between the stimulus parameter values and optical responses. Sequences of different duration and direction of frequency change gave rise to comparable results, although in some cases discrepancies were observed, mostly between upward- and downward-frequency sequences. We demonstrated frequency maps, consistent with previous data, in primary auditory cortex and in the anterior auditory field, which were verified with electrophysiological recordings. In addition to these tonotopic gradients, we demonstrated at least 2 new acoustically responsive areas on the anterior and posterior ectosylvian gyri, which have not previously been described. Although responsive to pure tones, these areas exhibit less tonotopic order than the primary fields.
RAGE Axis
Authors: Naka Yoshifumi , Bucciarelli Loredana G. , Wendt Thoralf , Lee Larisse K. , Rong Ling Ling , Ramasamy Ravichandran , Yan Shi Fang , Schmidt Ann Marie
Published: May 2004

Receptor for AGE (RAGE) is a multi-ligand member of the immunoglobulin superfamily of cell surface molecules. Engagement of RAGE by its signal transduction ligands evokes inflammatory cell infiltration and activation in the vessel wall. In diabetes, when fueled by oxidant stress, hyperglycemia, and superimposed stresses such as hyperlipidemia or acute balloon/endothelial denuding arterial injury, the ligand–RAGE axis amplifies vascular stress and accelerates atherosclerosis and neointimal expansion. In this brief synopsis, we review the use of rodent models to test these concepts. Taken together, our findings support the premise that RAGE is an amplification step in vascular inflammation and acceleration of atherosclerosis. Future studies must rigorously test the potential impact of RAGE blockade in human subjects; such trials are on the horizon.
Enhanced P2X7Activity in Human Fibroblasts From Diabetic Patients
Authors: Solini Anna , Chiozzi Paola , Morelli Anna , Adinolfi Elena , Rizzo Roberta , Baricordi Olavio R. , Di Virgilio Francesco
Published: May 2004

Objective—We have investigated expression and function of the P2X7receptor in fibroblasts from healthy subjects and patients with type 2 diabetes.

Methods and Results—Fibroblasts were isolated from skin biopsies. P2X7receptor expression in both cell populations was measured by functional assays, RT-PCR, fluorescence-activated cell sorter, and immunoblotting. We found that fibroblasts from diabetic subjects are characterized by enhanced P2X7-mediated responses as indicated by increased shape changes, microvesiculation, enhanced fibronectin and interleukin 6 secretion, and accelerated apoptosis. These responses were blocked by preincubation with the P2X blockers KN-62, oxidized ATP, or pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid). Furthermore, we also found a higher level of spontaneous fibronectin secretion and of apoptosis in fibroblasts from diabetic compared with healthy subjects. Both higher basal level of fibronectin secretion and spontaneous rate of apoptosis were likely attributable to the increased pericellular concentration of ATP because fibroblasts from diabetic subjects released 3× as much ATP into the supernatants compared with fibroblasts from healthy subjects.

Conclusions—We conclude that fibroblasts from type 2 diabetes patients are characterized by a hyperactive purinergic loop based either on a higher level of ATP release or on increased P2X7reactivity.
Surgical Ventricular Restoration Improves Mechanical Intraventricular Dyssynchrony in Ischemic Cardiomyopathy
Authors: Di Donato Marisa , Toso Anna , Dor Vincent , Sabatier Michel , Barletta Giuseppe , Menicanti Lorenzo , Fantini Fabio ,   the RESTORE Group
Published: May 2004

Background—

In ischemic cardiomyopathy, dyssynchrony of left ventricular (LV) mechanical contraction produces adverse hemodynamic consequences. This study tests the capacity of geometric rebuilding by surgical ventricular restoration (SVR) to restore a more synchronous contractile pattern after a mechanical, rather than electrical, intervention.

Methods and Results—

A prospective study of the global and regional components of dyssynchrony was conducted in 30 patients (58±8 years of age) undergoing SVR at the Cardiothoracic Center of Monaco. The protocol used simultaneous measurements of ventricular volumes and pressure to construct pressure/volume (P/V) and pressure/length (P/L) loops. Angiograms were done before and after SVR to study a 600-ms cycle during atrial pacing at 100 bpm. Mean QRS duration was similar, at 100±17 ms preoperatively and 114±28 ms postoperatively (NS). Preoperative LV contraction was highly asynchronous, because P/V loops showed abnormal isometric phases with a right shifting. Endocardial time motion was either early or delayed at the end-systolic phase so that P/L loops were markedly abnormal in size, shape, and orientation. Postoperatively, SVR resulted in leftward shifting of P/V loops and increased area; endocardial time motion and P/L loops almost normalized to allow a better contribution of single regions to global ejection. The hemodynamic consequences of SVR were improved ejection fraction (30±13% to 45±12%;
P
=0.001); reduced end-diastolic and end-systolic volume index (202±76 to 122±48 and 144±69 to 69±40 mL/m
2
;
P
=0.001); more rapid peak filling rate (1.75±0.7 to 2.32±0.7 EDV/s;
P
=0.0001); peak ejection rate (1.7±0.7 to 2.6±0.9 Sv/s;
P
=0.0002), and mechanical efficiency (0.56±0.15 to 0.65±0.18;
P
=0.04).

Conclusions—

SVR produces a mechanical intraventricular resynchronization that improves LV performance.
Atrio-Esophageal Fistula as a Complication of Percutaneous Transcatheter Ablation of Atrial Fibrillation
Authors: Pappone Carlo , Oral Hakan , Santinelli Vincenzo , Vicedomini Gabriele , Lang Christopher C. , Manguso Francesco , Torracca Lucia , Benussi Stefano , Alfieri Ottavio , Hong Robert , Lau William , Hirata Kirk , Shikuma Neil , Hall Burr , Morady Fred
Published: May 2004

Background—

Radiofrequency ablation for atrial fibrillation is becoming widely practiced.

Methods and Results—

Two patients undergoing circumferential pulmonary vein ablation for atrial fibrillation in different centers developed symptoms compatible with endocarditis 3 to 5 days after the procedure. Their clinical condition deteriorated rapidly, and both suffered multiple gaseous and/or septic embolic events causing cerebral and myocardial damage. One patient survived after emergency cardiac and esophageal surgery; the other died of extensive systemic embolization. An atrio-esophageal fistula was identified in both patients.

Conclusions—

Atrio-esophageal fistulas can occur after catheter ablation in the posterior wall of the left atrium. This diagnosis should be excluded in any patient with symptoms or signs of endocarditis after left atrial ablation, and expeditious cardiac surgery is critical if the diagnosis is confirmed. Lower power and temperature settings for applications of radiofrequency energy along the posterior left atrial wall may prevent further cases of fistula formation.
Midlife Blood Pressure and the Risk of Hippocampal Atrophy
Authors: Korf Esther S.C. , White Lon R. , Scheltens Philip , Launer Lenore J.
Published: May 2004

Hippocampal atrophy (HA) is usually attributed to the neurofibrillary tangles and neuritic plaques of Alzheimer disease. However, the hippocampus is vulnerable to global ischemia, which may lead to atrophy. We investigated the association of midlife blood pressure (BP) and late-life HA in a sample of Japanese-American men born between 1900 and 1919. BP was measured on 3 occasions between 1965 and 1971. In 1994 to 1996 a subsample underwent magnetic resonance imaging (MRI) of the brain. Hippocampal volume was estimated by manually drawing regions of interest on relevant scan slices; HA was defined as the lowest quartile of hippocampal volume. Also assessed on the MRI were cortical and subcortical infarcts, lacunes, and white matter hyperintensities. The risk (OR, 95% CI) was estimated for HA associated with systolic (<140 versus ≥140 mm Hg) and diastolic (<90 versus ≥90 mm Hg) BP and with antihypertensive treatment. Analyses were adjusted for sociodemographic factors, other cardiovascular risk factors, apolipoprotein E allele, and correlated brain pathology. Those never treated with antihypertensive medication had a significantly increased risk for HA (OR 1.7; CI=1.12; 2.65). The nontreated subjects with high systolic BP had an increased risk (OR=1.98; CI=0.89; 4.39) for HA. Results were similar for untreated men with high diastolic BP (OR=3.51; CI=1.26; 9.74). In conclusion, treatment with antihypertensive treatment modifies the association of BP and HA, such that high levels of BP adversely affect the hippocampus in persons never treated with antihypertensives.
Msx2 and Necdin Combined Activities Are Required for Smooth Muscle Differentiation in Mesoangioblast Stem Cells
Authors: Brunelli Silvia , Tagliafico Enrico , De Angelis Fernanda G. , Tonlorenzi Rossana , Baesso Silvia , Ferrari Sergio , Niinobe Michio , Yoshikawa Kazuaki , Schwartz Robert J. , Bozzoni Irene , Ferrari Stefano , Cossu Giulio
Published: May 2004

Little is known about the molecular mechanism underlying specification and differentiation of smooth muscle (SM), and this is, at least in part, because of the few cellular systems available to study the acquisition of a SM phenotype in vitro. Mesoangioblasts are vessel-derived stem cells that can be induced to differentiate into different cell types of the mesoderm, including SM. We performed a DNA microarray analysis of a mesoangioblast clone that spontaneously expresses an immature SM phenotype and compared it with a sister clone mainly composed of undifferentiated progenitor cells. This study allowed us to define a gene expression profile for “stem” cells versus smooth muscle cells (SMCs) in the absence of differentiation inducers such as transforming growth factor β. Two transcription factors,
msx2
and
necdin
, are expressed at least 100 times more in SMCs than in stem cells, are coexpressed in all SMCs and tissues, are induced by transforming growth factor β, and, when coexpressed, induce a number of SM markers in mesoangioblast, fibroblast, and endothelial cell lines. Conversely, their downregulation through RNA interference results in a decreased expression of SM markers. These data support the hypothesis that Msx2 and necdin act as master genes regulating SM differentiation in at least a subset of SMCs.
Relationship Between C-Reactive Protein and Progression of Early Carotid Atherosclerosis in Hypertensive Subjects
Authors: Hashimoto Hiroyuki , Kitagawa Kazuo , Hougaku Hidetaka , Etani Hideki , Hori Masatsugu
Published: May 2004

Background and Purpose—

Hypertensive outpatients were investigated for C-reactive protein (CRP) and carotid atherosclerosis because the influence of CRP on the progression of subclinical atherosclerosis in hypertensives remains unclear.

Methods—

A total of 124 outpatients (aged 40 to 79 years) in treatment for hypertension were enrolled. They underwent repeated ultrasonographic evaluation of the carotid arteries for 35±12 months. Focal intima-media thickening of ≥1.1 mm was defined as plaque, and the plaque number, plaque score, and the sum of all plaque thickness were calculated.

Results—

Multivariate linear regression analysis revealed that CRP, pulse pressure, and systolic blood pressure were related to the annual change of plaque number (β=0.34, 0.27, and 0.30; all
P
<0.01) and plaque score (β=0.38, 0.27, and 0.23;
P
<0.001,
P
<0.01, and
P
<0.05, respectively) independently of other risk factors. In 64 patients taking antihypertensive medications with a blood pressure of <140/90 mm Hg, CRP and the pulse pressure were related to the annual change of plaque number (
r
=0.40 and 0.26;
P
<0.01 and
P
<0.05, respectively) and plaque score (
r
=0.44 and 0.31;
P
<0.001 and
P
<0.05, respectively).

Conclusions—

In hypertensive patients being managed by drug therapy or lifestyle modification, CRP is an equivalent or superior independent predictor of the progression of carotid atherosclerosis than the pulse pressure or systolic blood pressure.
Prosthetic Replacement of the Medial Meniscus in Cadaveric Knees
Authors: Tienen T. G. , Verdonschot N. , Heijkants R. G. J. C. , Buma P. , Scholten J. G. F. , van Kampen A. , Veth R. P. H.
Published: May 2004

Meniscus replacement by a polymer meniscus prosthesis in dogs resulted in generation of new meniscal tissue.

Hypothesis

Optimal functioning of the prosthesis would involve realistic deformation and motion patterns of the prosthesis during knee joint motion.

Study Design

Controlled laboratory study.

Methods

The movements of the meniscus were determined during knee joint flexion and extension with and without internal and external tibial torque by means of roentgen stereophotogrammetric analysis. Subsequently, the meniscus in 6 human cadaveric knee joints was replaced by a meniscus prosthesis.

Results

All different parts of the meniscus showed a posterior displacement during knee joint flexion. The anterior horn was more mobile than the posterior horn. The prosthesis mimicked the movements of the meniscus. However, the excursions of the prosthesis on the tibial plateau were less. The knee joint laxity was not significantly higher after replacement with the meniscus prosthesis.

Conclusions

The prosthesis approximated the behavior of the native meniscus. Improvement in both the gliding characteristics of the prosthetic material and the fixation of the prosthesis may improve the function.

Clinical Relevance

The meniscus prosthesis needs to be optimized to achieve a better initial function in the knee joint.
Arthroscopic Thermal Shrinkage for Hypermobile Lateral Meniscus
Authors: Ohtoshi Kenichi , Kimura Masashi , Kobayashi Yasukazu , Higuchi Hiroshi , Kikuchi Shinichi
Published: May 2004

Background

The posterior segment of the lateral meniscus is relatively mobile as compared with that of the medial meniscus; that is because of its characteristic anatomy. Abnormal mobility of the lateral meniscus with no obvious rupture can be an unusual cause of knee pain and locking during deep knee flexion.

Purpose

To evaluate results for a small series of patients with hypermobile lateral meniscus, treated with thermal shrinkage of the supporting ligaments.

Study Design

Series of case reports.

Method

Five patients with hypermobile lateral meniscus were identified out of 625 patients who underwent meniscus surgery over a 20-month period. Thermal energy was applied to the peripheral zone of the lateral meniscus until abnormal translation was reduced. The patients were followed up an average of 21 months after the surgery.

Results

In 4 patients, no recurrence of locking was encountered in the postoperative period. In 1 patient, locking was experienced again 3 months after surgery and meniscal repair was performed.

Conclusions

Thermal shrinkage can be considered an appropriate treatment in place of subtotal meniscectomy or meniscal repair for hypermobility of the lateral meniscus.
Open versus Closed Kinetic Chain Exercises in Patellofemoral Pain
Authors: Witvrouw Erik , Danneels Lieven , van Tiggelen Damien , Willems Tine Marieke , Cambier Dirk
Published: May 2004

Background

Today, no clinical studies have been undertaken to examine the long-term effects of an open kinetic chain or closed kinetic chain program.

Hypothesis

The long-term follow-up results after a conservative exercise protocol are significantly worse than the short-term results. The long-term effect of closed kinetic chain training is significantly better compared to the effect of open kinetic chain training.

Study Design

Prospective randomized clinical trial.

Methods

Sixty patients were randomized into a 5-week conservative program, consisting of only closed kinetic chain exercises or only open kinetic chain exercises. Assessment of muscular characteristics, subjective symptoms, and functional performance was evaluated in this study at the time of initial physical examination, at the end of the treatment period, and 5 years later.

Results

At the 5-year follow-up, both groups demonstrated maintenance of good subjective and functional outcomes achieved immediately after the conservative treatment. No significant difference between both groups was observed at the 5-year follow-up for the majority of the examined parameters. However, on 3 of the 18 visual analog scales, the open kinetic chain group showed significantly less complaints compared to the closed kinetic chain group.

Conclusions

On the basis of these results, the authors conclude that both open kinetic chain and closed kinetic chain programs lead to an equal long-term good functional outcome.