bluuebunny/crossref_metadata_2025 huggingface dataset:
In vivo Removal of High- and Low-Molecular-Weight Compounds in Hemodiafiltration with On-Line Regeneration of Ultrafiltrate
Authors: Testa Angelo , Gentilhomme Hervé , Le Carrer Didier , Orsonneau Jean Luc
Published: June 2006

Background: Current methods of renal replacement therapy, combining convection and diffusion, are largely unsatisfactory in removing uremic toxins. Adsorption is a third mechanism that has been applied in extracorporeal therapy. This study evaluates the impact of hemodiafiltration with on-line regeneration of ultrafiltrate, a new two-step integrated sorbent system, on in vivo removal of a wide spectrum of solutes with different molecular weights. Methods: Pre- and post-dialysis concentrations of small, medium-size, and large molecules were determined in ten patients undergoing regular hemodiafiltration treatments with on-line regeneration of the ultrafiltrate. We also analyzed, at different times of the same dialysis session, the inlet and outlet ultrafiltrate; the latter had been regenerated by the sorbent cartridge and was used as reinfusion liquid. The mean dialysis time was 260 ± 21.2 min with a blood flow of 361 ± 33.3 ml/min and a reinjection volume of 3.6 ± 0.2 l/h. Results: Urea, creatinine and phosphate reduction ratio were respectively 69.8 ± 8.2, 61.9 ± 5.5, and 40.2 ± 17.3%. Removal of medium-size markers such as calcitonin, osteocalcin, β2-microglobulin, cystatin C, myoglobin and prolactin varied between 24 and 60%. The percentage of reduction for retinol binding protein and α1-microglobulin was negligible and we were unable to demonstrate any removal of α1-acid glycoprotein, pre-albumin, and albumin in the regenerated ultrafiltrate. Conclusion: The hemodiafiltration with on-line regeneration of ultrafiltrate is a new hemodialysis system, which allows uremic toxin removal over a wide molecular-weight spectrum.
Role of Vitamin E-Coated Membrane in Reducing Advanced Glycation End Products in Hemodialysis Patients: A Pilot Study
Authors: Baragetti I. , Furiani S. , Vettoretti S. , Raselli S. , Maggi F.M. , Galli F. , Catapano A.L. , Buccianti G.
Published: June 2006

Introduction: Advanced glycation end products (AGEs) are markers of oxidative stress. Aims: To assess if a vitamin-E-coated dialyzer affects plasma AGE levels and endothelial function in hemodialysis patients. Methods: 16 patients were dialyzed with a synthetic modified cellulose membrane (SMC, n = 8) or a vitamin E-coated dialyzer (n = 8), respectively. At week 32 endothelial function was determined as brachial artery flow-mediated dilatation (FMD). Total AGEs, free pentosidine (FP), protein-bound pentosidine (BP) and autoantibodies against oxidized LDL (ox-LDL-autoantibodies) were assessed at baseline (T0) and at 16, 32, 40 and 42 weeks (T16, T32, T40 and T42). Results: At T16 and T32 FP and BP were lower in vitamin E than in SMC (T 16: 88.7 ± 8.96 vs. 124.2 ± 11.90 pmol/ml plasma; p = 0.04, and 22.9 ± 2.99 vs. 32.8 ± 2.98 pmol/mg proteins; p = 0.04. T32: 78.7 ± 8.54 vs. 123.7 ± 10.15 pmol/ml plasma; p = 0.007, and 19.9 ± 2.0 vs. 33.67 ± 2.41 pmol/mg proteins; p = 0.001). In vitamin E, AGEs were lower at T32, T40 and T42 (946.7 ± 80.91 vs. 1,351.2 ± 179.33 AU/ml, p = 0.05; 986.9 ± 59.63 vs. 1,509.9 ± 154.17 AU/ml, p = 0.013; 890.3 ± 73.70 vs. 1,453.9 ± 153.16 AU/ml, p = 0.009). At T32 AGEs, ox-LDL autoantibodies and FMD were inversely correlated (R = –0.70 p = 0.007 and R = –0.59, p = 0.04, respectively). Conclusions: Vit E-coated membrane reduces plasma AGEs levels and AGEs values are negatively correlated with FMD.
Eosinophilic Inflammation, Remodeling of Lower Airway, Bronchial Responsiveness and Cough Reflex Sensitivity in Non-Asthmatic Subjects with Nasal Allergy
Authors: Hara Johsuke , Fujimura Masaki , Myou Shigeharu , Furusho Shiho , Abo Miki , Oribe Yoshitaka , Ohkura Noriyuki , Herai Yoriko , Sone Takashi , Waseda Yuko , Yasui Masahide , Kasahara Kazuo
Published: June 2006

Background: It has been reported that nasal allergy influences the lower airway inflammation and functions. We elucidated whether nasal allergy would contribute to lower airway inflammation and functions. Methods: 266 subjects aged 21–39 years were interviewed with special emphasis on history of asthma and nasal allergies (perennial allergic rhinitis (PAR) and seasonal allergic rhinitis (Japanese cedar pollinosis; PO)). Symptomatic subject was defined when nasal symptoms were present during a 3-week study period. Pulmonary function, provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 s (PC20), capsaicin cough threshold defined as capsaicin concentration eliciting 5 or more coughs (C5) and eosinophil percentage in hypertonic saline-induced sputum were measured. Results: Based on the interview, 232 subjects without asthma were divided into symptomatic (n = 25) and asymptomatic (n = 22) PAR, PO on-season (n = 15) and off-season (n = 36), and non-nasal allergy subjects (control) (n = 134). Sputum eosinophils were significantly greater in symptomatic PAR than another four groups (p < 0.01). FEV1/FVC ratio was significantly lower in PAR than control (p < 0.05). Maximum mean expiratory flow was lower in PAR than control (asymptomatic: p < 0.05, symptomatic: p = 0.06). C5 was not different among groups. PAR tended to have a lower PC20 compared to control (symptomatic: p = 0.078; asymptomatic: p = 0.086). Conclusions: These results suggest that eosinophilic inflammation occurred in symptomatic period of PAR may contribute to development of lower airway remodeling and bronchial hyperresponsiveness. Reversely, PO may not be associated with lower airway eosinophilic inflammation or abnormal bronchial functions. Nasal allergy dose not influence the cough reflex sensitivity.
Presurgical Factors Affecting Patient Satisfaction with Pallidal Surgery in Parkinson’s Disease
Authors: Hashimoto Takao , Tada Tsuyoshi , Ikeda Shu-ichi
Published: June 2006

Objective: To evaluate presurgical factors affecting patient satisfaction with pallidal surgery. Methods: Forty-one parkinsonian patients who underwent unilateral pallidal surgery replied to a questionnaire on general satisfaction with the outcome of surgery graded on a five-point scale. The contribution of age, disease duration, required activity level, Unified Parkinson’s Disease Rating Scale Part II activity of daily living (ADL) score and presurgical to postsurgical ADL score change to the level of satisfaction was tested. The required activity level was defined as the physical activity level which the patients required to support their families. Results: Multiple regression analysis revealed that age at surgery (p = 0.02), required activity level (p = 0.005), ADL score in the on phase at surgery (p = 0.001), and ADL score in the off phase at surgery (p = 0.0001) were significant contributors to satisfaction. Conclusions: The patients who were relatively young and required higher activity levels tended to have a higher degree of satisfaction with the outcome, while patients with advanced age tended to be less satisfied, independent of symptomatic improvement after the surgery.
Automatic Analysis and Visualization of Microelectrode Recording Trajectories to the Subthalamic Nucleus: Preliminary Results
Authors: Falkenberg Jon Haakon , McNames James , Favre Jacques , Burchiel Kim J.
Published: June 2006

Although microelectrode recordings (MER) are commonly used to confirm stereotactic targets during surgery for movement disorders, there is no consensus on whether the additional risks and cost of MER are worth the benefits. This may be due, in part, to the inconsistency and inefficiency of subjective interpretation of MER data that is currently used in practice. We describe several fully automatic visualization methods for MER that efficiently and clearly indicate segments of the microelectrode trajectories with homogeneous neural activity that correspond to expected deep brain nuclei. Specifically we demonstrate that these visualization methods can help identify the subthalamic nucleus in Parkinson’s disease patients. These methods have the potential to significantly improve patient outcome by helping neurosurgeons objectively identify target structures more quickly and accurately.
Quantification and Visualization of the Three-Dimensional Inconsistency of the Subthalamic Nucleus in the Schaltenbrand-Wahren Brain Atlas
Authors: Nowinski Wieslaw L. , Liu Jimin , Thirunavuukarasuu A.
Published: June 2006

The Schaltenbrand-Wahren (SW) brain atlas has many limitations: the major two are three-dimensional (3D) inconsistency and spatial sparseness. In this work, we quantify and visualize the 3D inconsistency of the subthalamic nucleus (STN). The STN 3D models, 3D-A, 3D-C and 3D-S, are reconstructed from the SW axial, coronal, and sagittal microseries, respectively, by using a shape-based (NURBS) approach. All three models are placed in the SW coordinate system and compared quantitatively in terms of location (centroids), size (volumes), shape (normalized eigenvalues), orientation (eigenvectors), and mutual spatial relationships (overlaps and inclusions). Analysis is done in 3D within each orientation and across them. A dedicated tool is developed for quantitative validation of 3D modeling. The average error achieved is 0.088 mm, which is at the resolution limit of the digital SW atlas. The reconstructed 3D STN models differ in location, size, shape, orientation, overlap size, and inclusion rate. The 3D-S volume is 1.27 times larger than that of 3D-A and 1.38 times larger than that of 3D-C. The highest overlap size is found between 3D-A and 3D-S. The highest inclusion rates of 52.5 and 66.6% are for 3D-A and 3D-S. 3D-C has the lowest overlap size and results in the lowest inclusion rates (around 20–30%), meaning that 3D-C is substantially displaced in comparison to 3D-A and 3D-S. The lateral centroid coordinate of 3D-C is 9.18 mm while that of 3D-S is 12.17 mm. Each of the 3D models has some limitation: 3D-A in orientation, 3D-C in location, and 3D-S in shape realism. The STN in comparison to the actual almond is smaller, and relatively (i.e. normalized to the same height) 2.2–2.4 times wider and 3.7–5.5 times longer. 3D-C becomes more similar to 3D-S by scaling the SW coronal microseries laterally by 1.3257. Then the lateral coordinates of their centroids coincide, the difference between them in orientation is 0.11 mm, and 3D-S is only 1.06 times larger than the scaled 3D-C. This operation substantially improves registration of the SW atlas with the probabilistic functional atlas. However, 3D visualization shows that both 3D-S and scaled 3D-C models are heavily interwoven resulting in low inclusion rates of about 60%. The STN in the SW atlas shows severe 3D inaccuracy within each orientation and across them, and it has to be employed with great care and understanding of its limitations.
Flow Effects on Coagulation and Thrombosis
Authors: Hathcock James J.
Published: June 2006

Thrombosis occurs in a dynamic rheological field that constantly changes as the thrombus grows to occlusive dimensions. In the initiation of thrombosis, flow conditions near the vessel wall regulate how quickly reactive components are delivered to the injured site and how rapidly the reaction products are disseminated. Whereas the delivery and removal of soluble coagulation factors to the vessel is thought to occur via classic convection–diffusion phenomena, the movement of cells and platelets to the injured wall is strongly augmented by flow-dependent cell–cell collisions that enhance their ability to interact with the wall. In addition, increased shear conditions have been shown to activate platelets, alter the cellular localization of proteins such as tissue factor (TF) and TF pathway inhibitor, and regulate gene production. In the absence of high shearing forces, red cells, leukocytes, and platelets can form stable aggregates with each other or cells lining the vessel wall, which, in addition to altering the biochemical makeup of the aggregate or vessel wall, effectively increases the local blood viscosity. Thus, hemodynamic forces not only regulate the predilection of specific anatomic sites to thrombosis, but they strongly influence the biochemical makeup of thrombi and the reaction pathways involved in thrombus formation.
Hypoxia Converts Human Macrophages Into Triglyceride-Loaded Foam Cells
Authors: Boström Pontus , Magnusson Björn , Svensson Per-Arne , Wiklund Olov , Borén Jan , Carlsson Lena M. S. , Ståhlman Marcus , Olofsson Sven-Olof , Hultén Lillemor Mattsson
Published: June 2006

Objectives—

Atherosclerotic lesions have regions that are hypoxic. Because the lesion contains macrophages that are loaded with lipid, we investigated whether hypoxia can influence the accumulation of lipids in these cells.

Methods and Results—

Exposure of human macrophages to hypoxia for 24 hours resulted in an increased formation of cytosolic lipid droplets and an increased accumulation of triglycerides. Exposure of the macrophages to oxidized low-density lipoprotein (oxLDL) increased the accumulation of cytosolic lipid droplets because of an increase in cellular cholesterol esters. The accumulation of lipid droplets in oxLDL-treated cells was further increased after hypoxia, caused by an increased level of triglycerides. Expression analyses combined with immunoblot or RT-PCR demonstrated that hypoxia increased the expression of several genes that could promote the accumulation of lipid droplets. Hypoxia increased the mRNA and protein levels of adipocyte differentiation-related protein (ADRP). It is well known that an increased expression of ADRP increases the formation of lipid droplets. Hypoxia decreased the expression of enzymes involved in β-oxidation (acyl-coenzyme A synthetase and acyl-coenzyme A dehydrogenase) and increased the expression of stearoyl–coenzyme A desaturase, an important enzyme in the fatty acid biosynthesis. Moreover, exposure to hypoxia decreased the rate of β-oxidation, whereas the accumulation of triglycerides increased.

Conclusions—

The results demonstrate that exposure of human macrophages to hypoxia causes an accumulation of triglyceride-containing cytosolic lipid droplets. This indicates that the hypoxia present in atherosclerotic lesions can contribute to the formation of the lipid-loaded macrophages that characterize the lesion and to the accumulation of triglycerides in such lesions.
Fatty Acids Attenuate Insulin Regulation of 5′-AMP–Activated Protein Kinase and Insulin Cardioprotection After Ischemia
Authors: Folmes Clifford D.L. , Clanachan Alexander S. , Lopaschuk Gary D.
Published: June 2006

The cardioprotective effect of insulin during ischemia–reperfusion has been associated with stimulation of glucose uptake and glycolysis. Although fatty acids and 5′-AMP activated protein kinase (AMPK) are regulators of glucose metabolism, it is unknown what effect insulin has on postischemic function and AMPK activity in the presence of high levels of fatty acid. Isolated ejecting mouse hearts were perfused with Krebs–Henseleit solution containing 5 mmol · L
−1
glucose and 0, 0.2, or 1.2 mmol · L
−1
palmitate, with or without 100 μU/mL insulin. During aerobic perfusion in the absence of palmitate, insulin stimulated glycolysis by 73% and glucose oxidation by 54%, while inhibiting AMPK activity by 43%. In the presence of 0.2 or 1.2 mmol · L
−1
palmitate, insulin stimulated glycolysis by 111% and 105% and glucose oxidation by 72% and 274% but no longer inhibited AMPK activity. During reperfusion of hearts in the absence of palmitate, insulin increased recovery of cardiac power by 47%. This was associated with a 97% increase in glycolysis and a 160% increase in glucose oxidation. However, in the presence of 1.2 mmol · L
−1
palmitate, insulin now decreased recovery of cardiac power by 42%. During reperfusion, glucose oxidation was inhibited by high fat, but insulin-stimulated glycolysis remained high, resulting in increased proton production. In the absence of fatty acids, insulin blunted the ischemia-induced activation of AMPK, but this effect was lost in the presence of fatty acids. We demonstrate that the cardioprotective effect of insulin and its ability to inhibit AMPK activity are lost in the presence of high concentrations of fatty acids.
Smooth Muscle α-Actin Is a Direct Target of Notch/CSL
Authors: Noseda Michela , Fu YangXin , Niessen Kyle , Wong Fred , Chang Linda , McLean Graeme , Karsan Aly
Published: June 2006

Intercellular signaling mediated by Notch receptors is essential for proper cardiovascular development and homeostasis. Notch regulates cell fate decisions that affect proliferation, survival, and differentiation of endothelial and smooth muscle cells. It has been reported that Jagged1–Notch interactions may participate in endocardial cushion formation by inducing endothelial-to-mesenchymal transformation. Here, we show that Notch directly regulates expression of the mesenchymal and smooth muscle cell marker smooth muscle α-actin (SMA) in endothelial and vascular smooth muscle cells via activation of its major effector, CSL. Notch/CSL activation induces SMA expression during endothelial-to-mesenchymal transformation, and Notch activation is required for expression of SMA in vascular smooth muscle cells. CSL directly binds a conserved
cis
element in the SMA promoter, and this consensus sequence is required for Notch-mediated SMA induction. This is the first evidence of the requirement for Notch activation in the regulation of SMA expression.
Translocation of Connexin 43 to the Inner Mitochondrial Membrane of Cardiomyocytes Through the Heat Shock Protein 90–Dependent TOM Pathway and Its Importance for Cardioprotection
Authors: Rodriguez-Sinovas Antonio , Boengler Kerstin , Cabestrero Alberto , Gres Petra , Morente Miriam , Ruiz-Meana Marisol , Konietzka Ina , Miró Elisabet , Totzeck Andreas , Heusch Gerd , Schulz Rainer , Garcia-Dorado David
Published: June 2006

We have previously shown that connexin 43 (Cx43) is present in mitochondria, that its genetic depletion abolishes the protection of ischemia- and diazoxide-induced preconditioning, and that it is involved in reactive oxygen species (ROS) formation in response to diazoxide. Here we investigated the intramitochondrial localization of Cx43, the mechanism of Cx43 translocation to mitochondria and the effect of inhibiting translocation on the protection of preconditioning. Confocal microscopy of mitochondria devoid of the outer membrane and Western blotting on fractionated mitochondria showed that Cx43 is located at the inner mitochondrial membrane, and coimmunoprecipitation of Cx43 with Tom20 (
T
ranslocase of the
o
uter
m
embrane
20
) and with heat shock protein 90 (Hsp90) indicated that it interacts with the regular mitochondrial protein import machinery. In isolated rat hearts, geldanamycin, a blocker of Hsp90-dependent translocation of proteins to the inner mitochondrial membrane through the TOM pathway, rapidly (15 minutes) reduced mitochondrial Cx43 content by approximately one-third in the absence or presence of diazoxide. Geldanamycin alone had no effect on infarct size, but it ablated the protection against infarction afforded by diazoxide. Geldanamycin abolished the 2-fold increase in mitochondrial Cx43 induced by 2 preconditioning cycles of ischemia/reperfusion, but this effect was not associated with reduced protection. These results demonstrate that Cx43 is transported to the inner mitochondrial membrane through translocation via the TOM complex and that a normal mitochondrial Cx43 content is important for the diazoxide-related pathway of preconditioning.
Blood Oxygen Level–Dependent MRI Allows Metabolic Description of Tissue at Risk in Acute Stroke Patients
Authors: Geisler Benjamin S. , Brandhoff Frank , Fiehler Jens , Saager Christian , Speck Oliver , Röther Joachim , Zeumer Hermann , Kucinski Thomas
Published: June 2006

Background and Purpose—

The delineation of the “penumbra” is of particular interest in acute stroke imaging. The “mismatch concept” applying perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) appears to be an oversimplification of the underlying electrophysiological tissue status. An additional parameter reflecting the metabolic state of the threatened brain tissue would improve our ability to describe the penumbra. One candidate is deoxyhemoglobin (deoxy-Hb) as an indicator of the oxygen extraction fraction that can be visualized by T2*-based blood oxygen level–dependent (BOLD) imaging.

Methods—

We analyzed data from 32 patients with acute stroke in the territory of the middle cerebral artery. MRI included fluid-attenuated inversion recovery, DWI, PWI, time-of-flight angiography, and quantitative T2 and T2* (qT2, qT2*) imaging. Follow-up was performed on day 1 and days 5 to 8. We calculated 1/T2′=1/qT2*−1/qT2. Changes of T2′, representing the deoxy-Hb effect, were analyzed by 3D regions of interest (ROIs): apparent diffusion coefficient lesion day 0 (L0), time-to-peak–lesion day 0 (T0), final infarct size days 5 to 8 (F5–8), lesion growth (LG; F5–8−L0), and surviving tissue (ST; T0−F5–8).

Results—

We observed a clear decrease of T2′ in the infarcted hemisphere compared with the unaffected control ROIs. The mean value showed the most pronounced loss of T2′ signal intensity in L0 (−15.7%), followed by LG (−10.5%) and ST (−8.0%).

Conclusions—

The implementation of BOLD imaging in acute stroke MRI offers a noninvasive estimation of the O
2
utilization and is able to add additional information concerning the present metabolic state of the threatened brain tissue. The changes in T2′ intensity are visually noticeable in the reconstructed T2′ images and provide a better estimation of the real penumbra.
Inflammation and Atherosclerosis
Authors: Stoll Guido , Bendszus Martin
Published: June 2006

Background and Purpose—

The simplistic view of atherosclerosis as a disorder of pathological lipid deposition has been redefined by the more complex concept of an ongoing inflammatory response.

Summary of Review—

Apolipoprotein E and low-density lipoprotein (LDL)-receptor-deficient mice develop accelerated atherosclerosis allowing in-depth pathophysiological investigations. Atherosclerotic plaques in these mice contain large numbers of T cells and macrophages. Crossbreading apolipoprotein E-deficient mice with T-cell-deficient mice and mice with impaired macrophage function (osteopetrotic op/op mice) disclosed the important impact of immune cells on atherosclerotic lesion development. In contrast to the detrimental role of T cells and macrophages, B cells appear to be atheroprotective. These basic experimental findings have partly been confirmed in studies of the human carotid artery system. Inflammation is not only instrumental in the development of human atheromatous plaques, but, importantly, plays a crucial role in the destabilization of internal carotid artery plaques, thus converting chronic atherosclerosis into an acute thrombo-embolic disorder. Humoral factors involved in internal carotid artery destabilization include cytokines, cyclooxygenase-2, matrix metalloproteinases, and tissue factor. Antibodies to oxidized LDL can reflect disease activity on one hand, but can also confer atheroprotection. Novel MRI techniques may aid in the in vivo assessment of acute plaque inflammation in humans.

Conclusions—

The impact of inflammation on the development of atherosclerotic plaques and their destabilization opens new avenues for treatment. The effects of statins, acetylsalicyclic acid and angiotensin-converting enzyme inhibitors on stroke prevention may partly be attributable to their profound anti-inflammatory actions. Vaccination against modified LDL and heat shock proteins halt plaque progression in experimental atherosclerosis. Their potential for prevention of human atherosclerosis is currently under investigation.
NR2B Subunit Exerts a Critical Role in Postischemic Synaptic Plasticity
Authors: Picconi Barbara , Tortiglione Anna , Barone Ilaria , Centonze Diego , Gardoni Fabrizio , Gubellini Paolo , Bonsi Paola , Pisani Antonio , Bernardi Giorgio , Di Luca Monica , Calabresi Paolo
Published: June 2006

Background and Purpose—We characterized the differential effect of the NR2B subunit antagonist ifenprodil in the induction of activity-dependent long-term potentiation (LTP) and of postischemic LTP as well as in the neuronal damage induced by focal ischemia.

Methods—Intracellular recordings were obtained from rat corticostriatal slice preparations. High-frequency stimulation of corticostriatal fibers was used as a LTP-inducing protocol. In vitro ischemia was induced by oxygen and glucose deprivation. In vivo ischemia was induced by permanent middle cerebral artery occlusion. Intracellular recordings were also performed in the ischemic penumbra.

Results—Antagonists selectively targetingN-methyl-d-aspartate receptors containing the NR2B subunit blocked postischemic LTP without affecting activity-dependent LTP. In a model of focal ischemia, blockade of NR2B subunit in vivo caused reduction of brain damage, amelioration of neurological outcome, and normalization of the synaptic levels of NR2B subunits. Moreover, the antagonism of NR2B subunit was able to rescue the activity-dependent LTP in the ischemic penumbra.

Conclusions—We suggest that NR2B subunits contribute to the striatal damage caused by in vivo and in vitro ischemia and play a critical role in the induction of postischemic LTP as well as in the suppression of activity-dependent LTP in the ischemic penumbra.
Inhibition of Integrin αvβ3 Ameliorates Focal Cerebral Ischemic Damage in the Rat Middle Cerebral Artery Occlusion Model
Authors: Shimamura Norihito , Matchett Gerald , Yatsushige Hiroshi , Calvert John W. , Ohkuma Hiroki , Zhang John
Published: June 2006

Background and Purpose—

Recent studies have shown that selective inhibition of specific subsets of intercellular adhesion molecules protects the brain during ischemia. We studied selective inhibition of integrin αvβ3 with cyclo [Arg-Gly-Asp-
d
-Phe-Val] (cRGDfV) in the rat middle cerebral artery occlusion model (MCAO).

Methods—

Rats were treated before and after MCAO with cRGDfV. Physiological parameters, expression of integrin αvβ3, infarction volume, brain water content, Evans Blue exudation, IgG exudation, histology, immunohistochemistry, and western blotting were studied in 4 groups of animals: sham operation (n=13), untreated (n=18), nonfunctioning peptide treatment (n=19), and cRGDfV treatment (n=27).

Results—

Treatment with cRGDfV reduced infarction, reduced brain edema, reduced exudation of Evans blue and IgG, and prevented fibrinogen deposition. Western blotting showed reduction of phosphorylated Flk-1 (a vascular endothelial growth factor [VEGF] receptor), reduction of phosphorylated FAK (an intracellular kinase phosphorylated in the presence of VEGF), reduction of VEGF, and reduction of fibrinogen in the cRGDfV treatment group.

Conclusions—

The selective integrin αvβ3 inhibitor cRGDfV improves outcomes in the MCAO model by preserving the blood-brain barrier, which mechanistically may occur in a VEGF- and VEGF-receptor–dependent manner.
Acute Ischemic Stroke Care and Outcome in Centers Participating in the Polish National Stroke Prevention and Treatment Registry
Authors: Niewada Maciej , Skowrońska Marta , Ryglewicz Danuta , Kamiński Bogumił , Członkowska Anna
Published: June 2006

Background and Purpose—

Significant intercenter variability in quality of care and stroke outcomes was found in many countries. The aim of the study was to compare the acute ischemic stroke care and outcomes in centers participating in the Polish National Stroke Prevention and Treatment Registry.

Methods—

The World Health Organization Stepwise Approach to Stroke Surveillance–based questionnaire was used to collect data on patients admitted to participating centers between December 1, 2001, and July 31, 2002. To ensure data quality, only centers reporting representative sample of patients were analyzed. Ischemic stroke patient characteristics, in-hospital care, and early outcomes (adjusted for case mix) were compared for participating centers.

Results—

There were 26 of 48 centers that met inclusion criteria, with a total of 8736 patients (52% women; mean age 71 years, with a range among institutions from 68 to 75 years). Significant differences between centers were observed for distribution of risk factors and in-hospital care. The rates for death and poor outcome (defined as a Rankin score ≥3 or death) ranged from 8.0% to 31.8% and from 44.2% to 74.7%, respectively. After adjusting for case mix, the death or poor outcome prognoses remained significantly different between centers.

Conclusions—

The observed significant differences between Polish stroke centers indicate the need for improvement of patient education, effective stroke risk factor control, and standardized in-hospital care.
Large Subcortical Infarcts
Authors: Halkes Patricia H.A. , Kappelle L. Jaap , van Gijn Jan , van Wijk Iris , Koudstaal Peter J. , Algra Ale
Published: June 2006

Background and Purpose—

In this study we compared risk factors, clinical features, and stroke recurrence in a large series of patients with large subcortical, cortical, or small deep infarcts.

Methods—

Patients with a transient or minor ischemic attack (modified Rankin Scale grade of ≤3) who had a single relevant supratentorial infarct of presumed noncardioembolic origin on CT were classified as suffering from a large subcortical (n=120), small deep (n=324), or cortical (n=211) infarct. Mean follow-up was 8 years. Rates of recurrent stroke were compared with Cox regression.

Results—

The clinical deficits caused by large subcortical infarcts resembled either those of a cortical or those of a small deep infarct. Risk factor profiles were similar in the 3 groups. The rate of recurrent stroke in patients with a large subcortical infarct (25/120; 21%) did not differ from that of patients with a cortical infarct (46/211; 22%) or with a small deep infarct (60/324; 19%). After adjustment for age, sex, and vascular risk factors, hazard ratios for recurrent stroke of large subcortical and cortical infarcts were 1.05 (95% CI, 0.65 to 1.70) and 1.17 (95% CI, 0.79 to 1.73), respectively, compared with small deep infarcts.

Conclusions—

Clinical features, risk factor profiles, and stroke recurrence rate in patients with a large subcortical infarct only differ slightly from those in patients with small deep or cortical infarcts.
Left Ventricular Systolic Dysfunction and the Risk of Ischemic Stroke in a Multiethnic Population
Authors: Hays Allison G. , Sacco Ralph L. , Rundek Tanja , Sciacca Robert R. , Jin Zhezhen , Liu Rui , Homma Shunichi , Di Tullio Marco R.
Published: June 2006

Background and Purpose—

Left ventricular dysfunction (LVD) is associated with cardiovascular mortality. Its association with ischemic stroke has been mainly documented after myocardial infarction. The stroke risk associated with LVD, especially of mild degree, in the general population is unclear. The purpose of this study was to evaluate the relationship between LVD and ischemic stroke in a multiethnic cohort.

Methods—

LV systolic function was assessed by transthoracic 2-dimensional echocardiography in a subset of subjects from the Northern Manhattan Study (NOMAS), 270 patients with first ischemic stroke and 288 age-, gender- and race-matched community controls. LV ejection fraction was measured by a simplified cylinder-hemiellipsoid formula, and categorized as normal (>50%), mildly (41% to 50%), moderately (31% to 40%) or severely (≤30%) decreased. The association between impaired ejection fraction and ischemic stroke was evaluated by logistic regression analysis after adjustment for established stroke risk factors.

Results—

LVD of any degree was more frequent in stroke patients (24.1%) than in controls (4.9%;
P
<0.0001), as was moderate/severe LVD (13.3% versus 2.4%;
P
<0.001). A decreased ejection fraction was associated with ischemic stroke even after adjusting for other stroke risk factors. The adjusted odds ratio for any degree of LVD was 3.92 (95% CI, 1.93 to 7.97). The adjusted odds ratio for mild LVD was 3.96 (95% CI, 1.56 to 10.01) and for moderate/severe LVD 3.88 (95% CI, 1.45 to 10.39). The association between LVD of any degree and stroke was present in all age, gender and race-ethnicity subgroups.

Conclusions—

LVD, even of mild degree, is independently associated with an increased risk of ischemic stroke. The assessment of LV function should be considered in the assessment of the stroke risk.
On the nonexistence of strictly monotonic Hölder continuous functions
Authors: Amat Sergio , Busquier Sonia , Escudero Antonio
Published: June 2006

This note is devoted to the study of the monotony of the Hölder continuous functions. We prove the nonexistence of a strictly monotonic (increasing or decreasing) hölder continuous function with exponent s ϵ (0, 1) such that it does not belongs for anypoint in a Hölder space with exponent s + ε ε > 0. We use simple analysis’ tools.
An Algorithm for Optical Flow Computation Based on a Quasi-Interpolant Operator
Authors: Francomano E. , Lodato C. , Lopes S. , Tortorici A.
Published: June 2006

A fundamental problem in the processing of image sequences is the computation of the velocity field of the apparent motion of brightness patterns usually referred to optical flow. In this paper a novel optical flow estimator based on a bivariate quasi-interpolant operator is presented. Namely, a non linear minimizing technique has been employed to compute the velocity vectors by modeling the flow field with a 2D quasi-interpolant operator based on centered cardinal B-spline functions. In this way an efficient computational scheme for optical flow estimate is provided. In addition the large solving linear systems involved in the process are sparse. Experiments on several image sequences have been carried out in order to investigate the performance of the optical flow estimator.
Medicaid Nursing Facility Utilization
Authors: Kitchener Martin , Swan James H. , Harrington Charlene
Published: June 2006

This study uses a longitudinal California data set (1995 to 2000) to address two concerns about Medicaid nursing facility (NF) utilization. First, to consider the impact of national cost-control policies, the authors analyze data trends in Medicaid NF participants, days of care, and expenditures. Second, the authors investigate the percentage of Medicaid days of care (%MDOC) using a panel regression model to consider resident, facility, and county market predictors. The findings show that although statewide Medicaid NF participants, expenditures, and%MDOC remain stable, Medicaid market segmentation persistes, with program participants distributed unevenly among facilities. Factors associated positively with facility%MDOC are the proportion of minority residents, a larger facility size, for-profit status, the percentage of aged Black persons in the county, and market concentration. The factors associated negatively with%MDOC are the percentages of resident men, residents aged 85 or older, residents with Alzheimer’s disease, Medicaid reimbursement rates, and county wealth.
Implications of Cancer Staging Uncertainties in Radiation Therapy Decisions
Authors: Lee Robert C. , Ekaette Edidiong , Kelly Karie-Lynn , Craighead Peter , Newcomb Chris , Dunscombe Peter
Published: June 2006

Introduction . Radiation therapy (RT) for cancer is a critical medical procedure that occurs in a complex environment involving numerous health professionals, hardware, software, and equipment. Uncertainties and potential incidents can lead to inappropriate administration of radiation to patients, with sometimes catastrophic consequences such as premature death or appreciably impaired quality of life. The authors evaluate the impact of incorrectly staging (i.e., estimation of extent of cancer) breast cancer patients and resulting inappropriate treatment decisions. Methods . The authors employ analytic and simulation methods in an influence-diagram framework to estimate the probability of incorrect staging and treatment decisions. As inputs, they use a combination of literature information on the accuracy and precision of pathology and tests as well as expert judgment. Sensitivity and value-of-information analyses are conducted to identify important uncertainties. Results and conclusions . The authors find a small but nontrivial probability that breast cancer patients will be incorrectly staged and thus may be subjected to inappropriate treatment. Results are sensitive to a number of variables, and some routinely used tests for metastasis have very limited information value. This work has implications for the methods used in cancer staging, and the methods are generalizable for quantitative risk assessment of treatment errors.
Assessing Health State Utilities in Elderly Patients at Cardiovascular Risk
Authors: Winkelmayer Wolfgang C. , Benner Joshua S. , Glynn Robert J. , Schneeweiss Sebastian , Wang Philip S. , Brookhart M. Alan , Levin Raisa , Jackson Joseph D. , Avorn Jerry
Published: June 2006

Background . Health state preferences can be a crucial component of cost-effectiveness analyses, but off-the-shelf health state utilities specifically for older people are not available. Objectives . Among participants in PROSPER, a trial of pravastatin in patients > 70 years, the authors assessed utilities for the health states that were relevant for the trial’s cost-utility analysis. Subjects and Methods . The authors cross-sectionally administered the Health Utilities Index, Mark 3 (HUI) to all PROSPER participants to assess each patient’s health state at the time of interview; they then used the scale’s multiattribute utility function to estimate the resulting utilities. The population was then stratified into 3 health states, and the mean utility function for each was calculated: recent myocardial infarction (MI, within 3 months), previous MI (> 3 months), or no prior MI. Linear and logistic regression were used to control for potential demographic and clinical characteristics. Results . Of the 5804 patients enrolled in the trial, 4677 were administered the HUI instrument. The likelihood of having a complete HUI response set decreased with higher age ( P < 0.001) but not with the other variables studied. A complete utility score could be calculated for 3390 participants. Of these, 2755 (81.3%) had no history of MI, 546 (16.1%) had an MI> 3 months previously, and 89 (2.6%) had an MI within 3 months. The mean (median) utilities were virtually identical for these states: 0.75 (0.84), 0.74 (0.84), and 0.74 (0.84), respectively. From multivariate analyses, utilities decreased with higher age and the presence of several other comorbidities (diabetes, stroke, peripheral vascular disease); women had lower utilities than men (all P < 0.01). Conclusions . In this large implementation of the HUI in elderly patients, the instrument did not detect any differences in estimated utilities related to having a MI. Potential causes of nondiscrimination for MI include the possibility that competing comorbidities may reduce the impact of MI on quality of life in this age group, as well as the possibility that a standard instrument derived from and validated in younger populations may not perform as well in elderly people.
Cost-Effectiveness Analysis of Screening for Celiac Disease in the Adult Population
Authors: Shamir Raanan , Hernell Olle , Leshno Moshe
Published: June 2006

Background . Celiac disease (CD) is common and, when undiagnosed, may result in increased mortality, suggesting that mass screening could be justified. The authors examined the cost-effectiveness (CE) of such an approach, assuming a higher mortality rate in undiagnosed CD and that adhering to a gluten-free diet (GFD) reduces the mortality rate. Methods . The authors developed a state transition Markov model, evaluating the CE of screening an entire population at the age of 18. Screening strategies included no screening v. screening by IgA antiendomysial antibodies (EMA), IgA human antitissue transglutaminase antibodies (TTG), and TTG verified by EMA. All strategies were examined with and without evaluation for IgA deficiency, and they all included an intestinal biopsy. Effects of variables were examined using sensitivity analysis. Effectiveness was assessed by life expectancy for each strategy and the incremental average CE ratio for each. Results . Base-case analysis revealed US$49,491 and US$572,616 per life year gained for screening compared to no screening using EMA or TTG, respectively. The CE of screening with EMA was most influenced by the prevalence of CD and the standardized mortality ratio (SMR) for untreated CD patients. Screening was cost-effective in populations with a relatively high prevalence of CD or when the SMR for untreated CD patients was higher than 1.5. The model was insensitive to changes in the cost of serological markers and diagnostic endoscopy. Conclusion . Assuming an SMR of 1.5 or higher for untreated CD patients, mass screening for CD is cost-effective in populations with a relatively high prevalence of CD over a wide range of ages at screening. From a CE perspective, EMA is the preferred serological marker for mass screening. Screening for CD would be justified only if the uncertainties regarding the validity of our assumptions are substantiated.
Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2 V617F mutation
Authors: Szpurka Hadrian , Tiu Ramon , Murugesan Gurunathan , Aboudola Samer , Hsi Eric D. , Theil Karl S. , Sekeres Mikkael A. , Maciejewski Jaroslaw P.
Published: June 2006

JAK2 V617F mutation recently was identified as a pathogenic factor in typical chronic myeloproliferative diseases (CMPD). Some forms of myelodysplastic syndromes (MDS) show a significant overlap with CMPD (classified as MDS/MPD), but the diagnostic assignment may be challenging. We studied blood or bone marrow from 270 patients with MDS, MDS/MPD, and CMPD for the presence of JAK2 V617F mutation using polymerase chain reaction, sequencing, and melting curve analysis. The detection rate of JAK2 V617F mutants for polycythemia vera, chronic idiopathic myelofibrosis, and essential thrombocythemia (n = 103) was similar to the previously reported results. In typical forms of MDS (n = 89) JAK2 V617F mutation was very rare (n = 2). However, a higher prevalence of this mutation was found in patients with MDS/MPD-U (9 of 35). Within this group, most of the patients harboring JAK2 V617F mutation showed features consistent with the provisional MDS/MPD-U entity refractory anemia with ringed sideroblasts and thrombocytosis (RARS-T). Among 9 RARS-T patients, 6 showed the presence of JAK2 V617F mutation, and in 1 patient without mutation, aberrant, positive phospho-STAT5 staining was seen that is typically present in association with JAK2 V617F mutation. In summary, we found that RARS-T reveals a high frequency of JAK2 V617F mutation and likely constitutes another JAK2 mutation-associated form of CMPD.
Immunoglobulin free light chains and solitary plasmacytoma of bone
Authors: Dingli David , Kyle Robert A. , Rajkumar S. Vincent , Nowakowski Grzegorz S. , Larson Dirk R. , Bida John P. , Gertz Morie A. , Therneau Terry M. , Melton L. Joseph , Dispenzieri Angela , Katzmann Jerry A.
Published: June 2006

An abnormal serum immunoglobulin free light chain (FLC) ratio at diagnosis may identify risk of progression to myeloma in patients with solitary bone plasmacytoma (SBP). In the cohort of 116 patients, 43 have progressed to myeloma, with a median time to progression of 1.8 years. The FLC ratio was determined in all 116 patients on serum collected at time of diagnosis and was abnormal in 54 patients (47%). An abnormal FLC ratio was associated with a higher risk of progression to myeloma (P = .039). The risk of progression at 5 years was 44% in patients with an abnormal serum FLC ratio at diagnosis compared with 26% in those with a normal FLC ratio. One to 2 years following diagnosis, a persistent serum M protein level of 5 g/L (0.5 g/dL) or higher was an additional risk factor for progression. A risk stratification model was constructed using the 2 variables of FLC ratio and M protein level: patients with a normal FLC ratio at baseline and M protein level less than 5 g/L (0.5 g/dL) at 1 to 2 years following diagnosis (low risk, n = 31); with either risk factor abnormal (intermediate risk, n = 26); and with both an abnormal FLC ratio and M protein level of 5 g/L (0.5 g/dL) or higher (high risk, n = 18). The corresponding progression rates at 5 years were significantly different in the low, intermediate, and high groups: 13%, 26%, and 62%, respectively (P < .001).
Benchmarking pKa prediction
Authors: Davies Matthew N , Toseland Christopher P , Moss David S , Flower Darren R
Published: June 2006

Background

pKa values are a measure of the protonation of ionizable groups in proteins. Ionizable groups are involved in intra-protein, protein-solvent and protein-ligand interactions as well as solubility, protein folding and catalytic activity. The pKa shift of a group from its intrinsic value is determined by the perturbation of the residue by the environment and can be calculated from three-dimensional structural data.

Results

Here we use a large dataset of experimentally-determined pKas to analyse the performance of different prediction techniques. Our work provides a benchmark of available software implementations: MCCE, MEAD, PROPKA and UHBD. Combinatorial and regression analysis is also used in an attempt to find a consensus approach towards pKa prediction. The tendency of individual programs to over- or underpredict the pKa value is related to the underlying methodology of the individual programs.

Conclusion

Overall, PROPKA is more accurate than the other three programs. Key to developing accurate predictive software will be a complete sampling of conformations accessible to protein structures.
The evolution of activity breaks in the nest cycle of annual eusocial bees: a model of delayed exponential growth
Authors: Mitesser Oliver , Weissel Norbert , Strohm Erhard , Poethke Hans-Joachim
Published: June 2006

Background

Social insects show considerable variability not only in social organisation but also in the temporal pattern of nest cycles. In annual eusocial sweat bees, nest cycles typically consist of a sequence of distinct phases of activity (queen or workers collect food, construct, and provision brood cells) and inactivity (nest is closed). Since the flight season is limited to the time of the year with sufficiently high temperatures and resource availability, every break reduces the potential for foraging and, thus, the productivity of a colony. This apparent waste of time has not gained much attention.

Results

We present a model that explains the evolution of activity breaks by assuming differential mortality during active and inactive phases and a limited rate of development of larvae, both reasonable assumptions. The model predicts a systematic temporal structure of breaks at certain times in the season which increase the fitness of a colony. The predicted pattern of these breaks is in excellent accordance with field data on the nest cycle of the halictidLasioglossum malachurum.

Conclusion

Activity breaks are a counter-intuitive outcome of varying mortality rates that maximise the reproductive output of primitively eusocial nests.