bluuebunny/crossref_metadata_2025 huggingface dataset:
Eukaryotic Picoplankton in Surface Oceans
Authors: Massana Ramon
Published: September 2010

The eukaryotic picoplankton is a heterogeneous collection of small protists 1 to 3 μm in size populating surface oceans at abundances of 102 to 104 cells ml−1. Pigmented cells are important primary producers that are at the base of food webs. Colorless cells are mostly bacterivores and play key roles in channeling bacteria to higher trophic levels as well as in nutrient recycling. Mixotrophy and parasitism are relevant but less investigated trophic paths. Molecular surveys of picoeukaryotes have unveiled a large phylogenetic diversity and new lineages, and it is critical to understand the ecological and evolutionary significance of this large and novel diversity. A main goal is to assess how individuals are organized in taxonomic units and how they participate in ecological processes. Picoeukaryotes are convincingly integral members of marine ecosystems in terms of cell abundance, biomass, activity, and diversity and they play crucial roles in food webs and biogeochemical cycles.
Prospects for the Future Using Genomics and Proteomics in Clinical Microbiology
Authors: Fournier Pierre-Edouard , Raoult Didier
Published: September 2010

The availability of genome sequences has revolutionized the fields of microbiology and infectious diseases. Indeed, more than 1,000 bacterial genomes and 3,000 viral genomes, including representatives of all significant human pathogens, have been sequenced to date. Owing to this tremendous amount of data, genomes are regarded as chimeras of sequence fragments from various origins. Coupled with novel proteomic analyses, genome sequencing has also resulted in unprecedented advances in pathogen diagnosis and genotyping and in the detection of virulence and antibiotic resistance. Herein, we review current achievements of genomics and proteomics and discuss potential developments for clinical microbiology laboratories.
Regulation of DnaA Assembly and Activity: Taking Directions from the Genome
Authors: Leonard Alan C. , Grimwade Julia E.
Published: September 2010

To ensure proper timing of chromosome duplication during the cell cycle, bacteria must carefully regulate the activity of initiator protein DnaA and its interactions with the unique replication origin oriC. Although several protein regulators of DnaA are known, recent evidence suggests that DnaA recognition sites, in multiple genomic locations, also play an important role in controlling assembly of pre-replicative complexes. In oriC, closely spaced high- and low-affinity recognition sites direct DnaA-DnaA interactions and couple complex assembly to the availability of active DnaA-ATP. Additional recognition sites at loci distant from oriC modulate DnaA-ATP availability by repressing new synthesis, recharging inactive DnaA-ADP, or titrating DnaA. Relying on genomic DnaA binding sites, as well as protein regulators, to control DnaA function appears to provide the best combination of high precision and dynamic regulation necessary to couple DNA replication with cell growth over a range of nutritional conditions.
Structure and Function of MARTX Toxins and Other Large Repetitive RTX Proteins
Authors: Satchell Karla J.F.
Published: September 2010

The Repeats-in-Toxins (RTX) family of proteins classically consists of cytolysins and hemolysins. Over the past decade, genome sequencing revealed the existence of very large members of this family. These are all repetitive proteins ranging in size from 200 to 900 kDa that function as toxins or adhesins. Many are exported by Type I secretion. One major new subfamily is the large repetitive RTX adhesins and biofilm-associated proteins. These are characterized by 80- to 300-amino-acid repeats ordered in tandem, although the sequence and number of the repeats vary by protein. The second major new subfamily is the multifunctional-autoprocessing RTX toxins, which are associated with cytotoxicity and pathogenesis. These proteins are in turn distantly related to Yersinia hypothetical RTX proteins that may autoprocess by a similar mechanism. This review discusses current knowledge regarding the structure and function of these new subfamilies of RTX proteins.
Turning Hepatitis C into a Real Virus
Authors: Murray Catherine L. , Rice Charles M.
Published: September 2010

The reality of hepatitis C is inescapable for the estimated 130 million people worldwide chronically infected with the virus. Yet this pathogen has been notoriously difficult to move from the infected individual into experimental systems, and each advance—from the identification of the infectious agent to its culture and study—has been a significant challenge. As a result of unrelenting technical hurdles, preventative and therapeutic options have been slow to reach hepatitis C patients. More than 35 years since the recognition of the disease, there is no vaccine available, and the only approved treatment, a combination of pegylated interferon-alpha (IFN-α) and ribavirin, is frequently ineffective. Decades of research, however, have resulted in systematic progress and much is now known about this once elusive pathogen. Most importantly, key breakthroughs have stimulated drug discovery, and the first generation of specifically targeted antiviral inhibitors is poised to enter the market. This review provides a look back at progress in developing tractable model systems for this important agent of chronic hepatitis.
Structure and Regulation of the Type VI Secretion System
Authors: Silverman Julie M. , Brunet Yannick R. , Cascales Eric , Mougous Joseph D.
Published: September 2010

The type VI secretion system (T6SS) is a complex and widespread gram-negative bacterial export pathway with the capacity to translocate protein effectors into a diversity of target cell types. Current structural models of the T6SS indicate that the apparatus is composed of at least two complexes, a dynamic bacteriophage-like structure and a cell-envelope-spanning membrane-associated assembly. How these complexes interact to promote effector secretion and cell targeting remains a major question in the field. As a contact-dependent pathway with specific cellular targets, the T6SS is subject to tight regulation. Thus, the identification of regulatory elements that control T6S expression continues to shape our understanding of the environmental circumstances relevant to its function. This review discusses recent progress toward characterizing T6S structure and regulation.
Ligand-Binding PAS Domains in a Genomic, Cellular, and Structural Context
Authors: Henry Jonathan T. , Crosson Sean
Published: September 2010

Per-Arnt-Sim (PAS) domains occur in proteins from all kingdoms of life. In the bacterial kingdom, PAS domains are commonly positioned at the amino terminus of signaling proteins such as sensor histidine kinases, cyclic-di-GMP synthases/hydrolases, and methyl-accepting chemotaxis proteins. Although these domains are highly divergent at the primary sequence level, the structures of dozens of PAS domains across a broad section of sequence space have been solved, revealing a conserved three-dimensional architecture. An all-versus-all alignment of 63 PAS structures demonstrates that the PAS domain family forms structural clades on the basis of two principal variables: (a) topological location inside or outside the plasma membrane and (b) the class of small molecule that they bind. The binding of a chemically diverse range of small-molecule metabolites is a hallmark of the PAS domain family. PAS ligand binding either functions as a primary cue to initiate a cellular signaling response or provides the domain with the capacity to respond to secondary physical or chemical signals such as gas molecules, redox potential, or photons. This review synthesizes the current state of knowledge of the structural foundations and evolution of ligand recognition and binding by PAS domains.
Food Quality: The Design of Incentive Contracts
Authors: Goodhue Rachael E.
Published: September 2010

Quality considerations are increasingly important drivers of production and coordination choices for players in the agrofood chain. Incentive contracts between farmers and processors, shippers, and other buyers are an increasingly popular means of coordinating to improve food quality. This review examines the economic literature regarding incentive contracts and the provision of food quality, with a focus on empirical analyses. Studies of specific value chains find that a desire for higher quality or specific quality attributes increases the likelihood that a contract, rather than the spot market, is used. Consistent with economic theory, studies regarding the selection of contract provisions find that financial incentives are used when an attribute is easily observable at the time of sale, whereas requirements for specific inputs and actions tend to be used when an attribute is not easily observable.
The Economics of Natural Disasters
Authors: Kellenberg Derek , Mobarak A. Mushfiq
Published: September 2010

This review discusses the ways in which countries are affected by natural disasters, depending on their socioeconomic characteristics, their level of development, and their inherent levels of natural disaster risk. We also explore various aspects of ex ante disaster mitigation such as improvements in natural disaster risk information and natural disaster insurance markets, as well as ex post responses to natural disaster in the form of postdisaster aid and long-run growth prospects. By highlighting some of the recent findings in this literature, we synthesize what we know about the economics of natural disasters and identify research areas of interest for future work.
Plowing Through the Data
Authors: Mundlak Yair
Published: September 2010

In this paper I report on work that has aimed at measuring and understanding the sources of productivity differences among firms and their changes over time. These issues have been investigated at the micro level, which is the decision-making level. The relationship between inputs and the economic environment is informed by an underlying economic model. The issues involved in the specification and estimation of production functions are related to the role played by errors in production and optimization decisions. Under this general umbrella, the paper traces my interaction with the literature on some key subjects in production and supply. Turning to the macro level, I review subjects related to the analysis of agriculture as a sector of the economy and the determinants of agricultural growth. The incentives and constraints are affected by sector-specific and sector-neutral policies, by world prices, and by the implementation of new technology. The paper concludes with a review of empirical work on these subjects.
Carbon Sequestration in Forests and Soils
Authors: Sedjo Roger , Sohngen Brent
Published: September 2010

Forests can play a large role in climate change through the sequestration or emission of carbon, an important greenhouse gas; through biological growth, which can increase forest stocks; or through deforestation, which can increase carbon emissions. Carbon is captured not only in tree biomass but also in forest soils. Forest management and public policy can strongly influence the sequestration process. Economic policies can provide incentives for both forest expansion and contraction. Systems that provide prices for carbon sequestration or taxes for emissions can have important effects on emission and sequestration levels. Issues involve carbon additionality, permanence, and leakage. Forest measurement, monitoring, and verification also provide serious challenges. Various economic models are used to estimate the effects of various economic policies on forest carbon stocks. Estimates from the literature of some actual and potential levels of forest carbon are presented.
The Environment and Trade
Authors: Karp Larry
Published: September 2010

Reflecting the emphasis of recent work in the field of trade and the environment, this review focuses on empirical issues, primarily econometric estimates of the pollution haven effect and simulation-based calculations of carbon leakage. A brief discussion of the theory explains why intuition from partial equilibrium models may not carry over to a general equilibrium setting.
Climate and Culture: Anthropology in the Era of Contemporary Climate Change
Authors: Crate Susan A.
Published: September 2010

This review provides an overview of foundational climate and culture studies in anthropology; it then tracks developments in this area to date to include anthropological engagements with contemporary global climate change. Although early climate and culture studies were mainly founded in archaeology and environmental anthropology, with the advent of climate change, anthropology's roles have expanded to engage local to global contexts. Considering both the unprecedented urgency and the new level of reflexivity that climate change ushers in, anthropologists need to adopt cross-scale, multistakeholder, and interdisciplinary approaches in research and practice. I argue for one mode that anthropologists should pursue—the development of critical collaborative, multisited ethnography, which I term “climate ethnography.”
Capsules of Streptococcus pneumoniae and Other Bacteria: Paradigms for Polysaccharide Biosynthesis and Regulation
Authors: Yother Janet
Published: September 2010

Capsular polysaccharides and exopolysaccharides play critical roles in bacterial survival strategies, and they can have important medical and industrial applications. An immense variety of sugars and glycosidic linkages leads to an almost unlimited diversity of potential polysaccharide structures. This diversity is reflected in the large number of serologically and chemically distinct polysaccharides that have been identified among both gram-positive and gram-negative bacteria. Despite this diversity, however, the genetic loci and mechanisms responsible for polysaccharide biosynthesis exhibit conserved features and can be classified into a small number of groups. In Streptococcus pneumoniae, capsule synthesis occurs by one of two distinct mechanisms that involve the polymerization of either individual sugars in a processive reaction (synthase dependent) or discrete repeat units in a nonprocessive reaction (Wzy dependent). Characterization of these systems has provided novel insights that are applicable to polymers synthesized by many gram-positive and gram-negative bacteria, as well as eukaryotes.
Erythropoietin enhances hydrogen peroxide-mediated dilatation of canine coronary collateral arterioles during myocardial ischemia in dogs in vivo
Authors: Yada Toyotaka , Shimokawa Hiroaki , Hiramatsu Osamu , Satoh Minoru , Kashihara Naoki , Takaki Aya , Goto Masami , Ogasawara Yasuo , Kajiya Fumihiko
Published: September 2010

We have previously demonstrated that endothelium-derived hydrogen peroxide (H2O2) plays an important role in the canine coronary microcirculation as an endothelium-derived hyperpolarizing factor in vivo. However, it remains to be examined whether endogenous H2O2 is involved in the dilatation of coronary collaterals during myocardial ischemia in vivo and, if so, whether erythropoietin (EPO) enhances the responses. Canine subepicardial native collateral small arteries (CSA; ≥ 100 μm) and arterioles (CA; <100 μm) were observed using an intravital microscope. Experiments were performed after left anterior descending coronary artery ischemia (90 min) under the following eight conditions ( n = 5 each): control, EPO, EPO+catalase, EPO+ N-monomethyl-l-arginine (l-NMMA), EPO+l-NMMA+catalase, EPO+l-NMMA+iberiotoxin [Ca2+-activated K+ (KCa) channel blocker], EPO+l-NMMA+apamin+charybdotoxin (KCa channel blocker), and EPO+wortmannin (phosphatidylinositol 3-kinase inhibitor). Myocardial ischemia caused significant vasodilatation in CA but not in CSA under control conditions, which was significantly decreased by catalase in CA. After EPO, the vasodilatation was significantly increased in both sizes of arteries and was significantly decreased by catalase. The enhancing effect of EPO was reduced by l-NMMA but not by catalase in CSA and was reduced by l-NMMA+catalase in CA, where the greater inhibitory effects were noted with l-NMMA+catalase, l-NMMA+iberiotoxin, L-NMMA+apamin+charybdotoxin, or wortmannin. EPO significantly ameliorated ischemia-induced impairment of myocardial Akt phosphorylation, which was abolished by l-NMMA+catalase or wortmannin. EPO also ameliorated oxidative stress and myocardial injury, as assessed by plasma 8-hydroxydeoxyguanosine and troponin-T, respectively. These results indicate that EPO enhances H2O2-mediated dilatation of coronary collateral arterioles during myocardial ischemia in dogs in vivo.
A new function for ATP: activating cardiac sympathetic afferents during myocardial ischemia
Authors: Fu Liang-Wu , Longhurst John C.
Published: September 2010

Myocardial ischemia activates cardiac sympathetic afferents leading to chest pain and reflex cardiovascular responses. Brief myocardial ischemia leads to ATP release in the interstitial space. Furthermore, exogenous ATP and α,β-methylene ATP (α,β-meATP), a P2X receptor agonist, stimulate cutaneous group III and IV sensory nerve fibers. The present study tested the hypothesis that endogenous ATP excites cardiac afferents during ischemia through activation of P2 receptors. Nerve activity of single unit cardiac sympathetic afferents was recorded from the left sympathetic chain or rami communicates (T2-T5) in anesthetized cats. Single fields of 45 afferents (conduction velocities = 0.25–4.92 m/s) were identified in the left ventricle with a stimulating electrode. Five minutes of myocardial ischemia stimulated 39 of 45 cardiac afferents (8 Aδ, 37 C fibers). Epicardial application of ATP (1–4 μmol) stimulated six ischemically sensitive cardiac afferents in a dose-dependent manner. Additionally, epicardial ATP (2 μmol), ADP (2 μmol), a P2Y agonist, and α,β-meATP (0.5 μmol) significantly activated eight other ischemically sensitive afferents. Third, pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid, a P2 receptor antagonist, abolished the responses of six afferents to epicardial ATP (2 μmol) and attenuated the ischemia-related increase in activity of seven other afferents by 37%. In the absence of P2 receptor blockade, cardiac afferents responded consistently to repeated application of ATP ( n = 6) and to recurrent myocardial ischemia ( n = 6). Finally, six ischemia-insensitive cardiac spinal afferents did not respond to epicardial ATP (2–4 μmol), although these afferents did respond to epicardial bradykinin. Taken together, these data indicate that, during ischemia, endogenously released ATP activates ischemia-sensitive, but not ischemia-insensitive, cardiac spinal afferents through stimulation of P2 receptors likely located on the cardiac sensory neurites.
Role of the PI3-kinase signaling pathway in trafficking of the surfactant protein A receptor P63 (CKAP4) on type II pneumocytes
Authors: Kazi Altaf S. , Tao Jian-Qin , Feinstein Sheldon I. , Zhang Li , Fisher Aron B. , Bates Sandra R.
Published: September 2010

Surfactant protein A (SP-A) plays an important role in the maintenance of lung lipid homeostasis. Previously, an SP-A receptor, P63 (CKAP4), on type II pneumocyte plasma membranes (PM) was identified by chemical cross-linking techniques. An antibody to P63 blocked the specific binding of SP-A to pneumocytes and the ability of SP-A to regulate surfactant secretion. The current report shows that another biological activity of SP-A, the stimulation of surfactant uptake by pneumocytes, is inhibited by P63 antibody. cAMP exposure resulted in enrichment of P63 on the cell surface as shown by stimulation of SP-A binding, enhanced association of labeled P63 antibody with type II cells, and promotion of SP-A-mediated liposome uptake, all of which were inhibited by competing P63 antibody. Incubation of A549 and type II cells with SP-A also increased P63 localization on the PM. The phosphatidylinositol 3-kinase (PI3-kinase) signaling pathway was explored as a mechanism for the transport of this endoplasmic reticulum (ER)-resident protein to the PM. Treatment with LY-294002, an inhibitor of the PI3-kinase pathway, prevented the SP-A-induced PM enrichment of P63. Exposure of pneumocytes to SP-A or cAMP activated Akt (PKB). Blocking either PI3-kinase or Akt altered SP-A-mediated lipid turnover. The data demonstrate an important role for the PI3-kinase-Akt pathway in intracellular transport of P63. The results add to the growing body of evidence that P63 is critical for SP-A receptor-mediated interactions with type II pneumocytes and the resultant regulation of surfactant turnover.
Western AmazonianTicapimpla(Hymenoptera: Ichneumonidae: Pimplinae): Four New Species from Colombia, Ecuador, and Peru, with a Key to Species of the Genus
Authors: Palacio Edgard , Broad Gavin R. , Sääksjärvi Ilari E. , Veijalainen Anu
Published: September 2010

Ticapimplais a small genus closely related to the New World generaAcrotaphusandHymenoepimecis. It has been previously reported from Costa Rica and Brazil. In this paper, we describe four new species:T. amazonicafrom Ecuador and Peru,T. carinatafrom Colombia and Peru,T. matamataefrom Colombia, andT. soiniifrom Colombia, Ecuador, and Peru. All have been collected in Western Amazonia, suggesting a South American origin for the genus. A key to the known species of the genus is provided.
Prediction of Carbohydrate-Binding Proteins from Sequences Using Support Vector Machines
Authors: Someya Seizi , Kakuta Masanori , Morita Mizuki , Sumikoshi Kazuya , Cao Wei , Ge Zhenyi , Hirose Osamu , Nakamura Shugo , Terada Tohru , Shimizu Kentaro
Published: September 2010

Carbohydrate-binding proteins are proteins that can interact with sugar chains but do not modify them. They are involved in many physiological functions, and we have developed a method for predicting them from their amino acid sequences. Our method is based on support vector machines (SVMs). We first clarified the definition of carbohydrate-binding proteins and then constructed positive and negative datasets with which the SVMs were trained. By applying the leave-one-out test to these datasets, our method delivered 0.92 of the area under the receiver operating characteristic (ROC) curve. We also examined two amino acid grouping methods that enable effective learning of sequence patterns and evaluated the performance of these methods. When we applied our method in combination with the homology-based prediction method to the annotated human genome database, H-invDB, we found that the true positive rate of prediction was improved.
Existence and Uniqueness of Solutions for Coupled Systems of Higher-Order Nonlinear Fractional Differential Equations
Authors: Ahmad Bashir , Alsaedi Ahmed
Published: September 2010

We study an initial value problem for a coupled Caputo type nonlinear fractional differential system of higher order. As a first problem, the nonhomogeneous terms in the coupled fractional differential system depend on the fractional derivatives of lower orders only. Then the nonhomogeneous terms in the fractional differential system are allowed to depend on the unknown functions together with the fractional derivative of lower orders. Our method of analysis is based on the reduction of the given system to an equivalent system of integral equations. Applying the nonlinear alternative of Leray-Schauder, we prove the existence of solutions of the fractional differential system. The uniqueness of solutions of the fractional differential system is established by using the Banach contraction principle. An illustrative example is also presented.
Characteristic Features of Stone‐Wales Defects in Single‐Walled Carbon Nanotube; Adsorption, Dispersion, and Field Emission
Authors: Roh Seungkwang , Lee Jongtaek , Jang Mira , Shin Mingyeong , Ahn Juone , Park Taehee , Yi Whikun
Published: September 2010

Adsorption behaviors of dodecanethiol (C12H25SH) molecules are investigated on the surface of single‐walled carbon nanotubes (SWCNTs) with vibrational and X‐ray photoelectron spectrometers. The active adsorption sites are proved as Stone‐Wales (SW) defects (5–7 ring defects). The SW defect‐removed SWCNTs formed by reacting nanotubes with allyl acrylate molecules are compared with pristine SWCNTs in dispersion and field emission. The former shows higher dispersion and field emission than the latter.
Long-Term Effects of Antiviral Therapy in Patients with Chronic Hepatitis C
Authors: Kagawa Tatehiro , Keeffe Emmet B.
Published: September 2010

Chronic hepatitis C is a major cause of chronic liver disease globally, and the natural history of progression may lead to cirrhosis with liver failure, hepatocellular carcinoma, and premature liver-related death. Emerging data demonstrates that interferon-based therapy, particularly among those achieving a sustained virologic response (SVR), is associated with long-term persistence of SVR, improved fibrosis and inflammation scores, reduced incidence of hepatocellular carcinoma, and prolonged life expectancy. This reduction in the rate of progression has also been demonstrated in patients with chronic hepatitis C and cirrhosis in some but not all studies. The majority of these results are reported with standard interferon therapy, and long-term results of peginterferon plus ribavirin therapy with a higher likelihood of SVR should have a yet greater impact on the population of treated patients. The impact on slowing progression is greatest in patients with an SVR, less in relapsers, and equivocal in nonresponders. Thus, the natural history of chronic hepatitis C after completion of antiviral therapy is favorable with achievement of an SVR, although further data are needed to determine the likely incremental impact of peginterferon plus ribavirin, late long-term effects of therapy, and the benefit of treatment in patients with advanced hepatic fibrosis.
Carleson Measure in Bergman‐Orlicz Space of Polydisc
Authors: Xu An-Jian , Yang Zou
Published: September 2010

Let μ be a finite, positive measure on 𝔻n, the polydisc in ℂn, and let σn be 2n‐dimensional Lebesgue volume measure on 𝔻n. For an Orlicz function φ, a necessary and sufficient condition on μ is given in order that the identity map is bounded.
Numerical Analysis of Pool Fires in Oil Trunkline Networks
Authors: Seleznev Vadim E.
Published: September 2010

This paper presents a method for numerical evaluation of parameters of flammable liquid pool fires caused by storage tank or trunkline failures. The method may be useful for specialists working in oil, gas, and chemical industries. It was successfully applied in fire safety analysis of Russian gas and oil processing facilities.
Bortezomib in Kidney Transplantation
Authors: Raghavan Rajeev , Jeroudi Abdallah , Achkar Katafan , Gaber A. Osama , Patel Samir J. , Abdellatif Abdul
Published: September 2010

Although current therapies for pretransplant desensitization and treatment of antibody-mediated rejection (AMR) have had some success, they do not specifically deplete plasma cells that produce antihuman leukocyte antigen (HLA) antibodies. Bortezomib, a proteasome inhibitor approved for the treatment of multiple myeloma (a plasma cell neoplasm), induces plasma cell apoptosis. In this paper we review the current body of literature regarding the use of this biological agent in the field of transplantation. Although limited experience with bortezomib may seem to show promise in the realm of transplant recipients desensitization and treatment of AMR, there is also experience that may suggest otherwise. Bortezomib's role in desensitization protocols and treatment of AMR will be defined better as more clinical data and trials become available.
Free Volumes Associated with Sintering in Gadolinium Doped Ceria Solid Solutions
Authors: Kosaka Tomomi , Sato Kiminori
Published: September 2010

Gadolinium‐doped ceria (GDC) solid solution prepared by the oxalate coprecipitation method is investigated by X‐ray diffraction (XRD), complex impedance analysis, and positron lifetime spectroscopy. XRD reveals an expansion of GDC lattice constant by doping gadolinium into a ceria host crystal, in agreement with an oxygen vacancy model. The ionic conductivity of GDC measured at 773 K in air is two orders of magnitude higher than that of undoped ceria. Positron lifetime spectroscopy reveals the presence of vacancy‐sized free volumes and nanovoids in interfaces among crystallites. It is found that the vacancy‐sized free volumes shrink with increasing sintering temperatures. In the present paper, recent advances in the studies of GDC by XRD, complex impedance measurement, and positron lifetime spectroscopy are reviewed to gain an insight into the sintering mechanism.
Double-Blind, Randomized, Intraindividual Comparison Study of the Efficacy of Prilocaine and Lidocaine in Tumescent Local Anesthesia
Authors: Augustin Matthias , Maier Kristina , Sommer Boris , Sattler Gerhard , Herberger Katharina
Published: September 2010

Background: Tumescent local anesthesia (TLA) with lidocaine or prilocaine solutions is widely used in dermatology. Objective: Comparison of efficacy and safety of lidocaine and prilocaine in liposuctions with TLA. Methods: TLA was performed using defined dilutions of lidocaine or prilocaine. Half-side comparisons were applied on 26 patients undergoing symmetric liposuction. Pain reduction (overall sensation and pain at lancet prick) and tolerance were assessed before, during and 2–24 h after liposuction. Results: No differences in overall pain sensation between the substances were detected during and after liposuction except a more rapid onset with lidocaine (less pain after 15 min, p < 0.043). Local tolerance of both substances was excellent. Conclusion: Lidocaine and prilocaine used in TLA for liposuction show good efficacy and tolerance. A fixed combination of lidocaine and prilocaine may reduce the risk of side effects when great quantities of TLA are needed.
KIBRA Genetic Polymorphism Influences Episodic Memory in Alzheimer’s Disease, but Does Not Show Association with Disease in a Japanese Cohort
Authors: Hayashi Noriyuki , Kazui Hiroaki , Kamino Kouzin , Tokunaga Hiromasa , Takaya Masahiko , Yokokoji Mikiko , Kimura Ryo , Kito Yumiko , Wada Tamiki , Nomura Keiko , Sugiyama Hiromichi , Yamamoto Daisuke , Yoshida Tetsuhiko , Currais Antonio , Soriano Salvador , Hamasaki Toshimitsu , Yamamoto Mitsuko , Yasuda Yuka , Hashimoto Ryota , Tanimukai Hitoshi , Tagami Shinji , Okochi Masayasu , Tanaka Toshihisa , Kudo Takashi , Morihara Takashi , Takeda Masatoshi
Published: September 2010

Background/Aims: A single-nucleotide polymorphism (SNP) in the KIBRA gene, rs17070145, was reported to be significantly associated with episodic memory in cognitively normal cohorts. This observation has expanded genetic studies on KIBRA to Alzheimer’s disease (AD). Importantly, the association between KIBRA and episodic memory in AD has never been addressed. In this study, we investigated whether the KIBRA rs17070145 SNP influences AD episodic memory and the disease in a Japanese cohort. Methods: Blood samples from 346 AD patients and 375 normal cognitive controls were collected and genotyped for rs17070145. Episodic memory was measured in 32 AD patients, diagnosed for the first time, by use of the Rivermead Behavioral Memory Test (RBMT). Results: We found that KIBRA C allele carriers scored significantly lower than KIBRA non-C carriers on both RBMT total profile score (p = 0.042, effect size = 0.84) and RBMT total screening score (p < 0.001, effect size = 1.42). The KIBRA gene did not show association with AD in our Japanese cohort. Conclusion: Our results evidence a strong association between the KIBRA gene and episodic memory impairment in AD, but show no influence on AD in our Japanese cohort. We propose that KIBRA might have an effect similar to cognitive reserve.
Sairei-to Ameliorates Rat Peritoneal Fibrosis Partly through Suppression of Oxidative Stress
Authors: Kitamoto Masayuki , Kato Kozue , Sugimoto Akihisa , Kitamura Hisayo , Uemura Kazuhide , Takeda Toshiya , Wu Chunmo , Nogaki Fumiaki , Morimoto Tatsuya , Ono Takahiko
Published: September 2010

Background: Sairei-to is a herbal prescription originating from traditional Chinese medicine. We conducted an experimental study on rat peritoneal fibrosis to clarify the suppressive mechanisms of sairei-to. Methods: Wistar rats were intraperitoneally injected with chlorhexidine gluconate (CG) every day. Peritoneal specimens were collected after 28 days of CG injection and oral administration of sairei-to. Macrophage infiltration, extracellular matrix accumulation, and angiogenesis were evaluated by immunostaining for ED-1, fibronectin, and CD-31, respectively. To observe oxidative stress in the tissue, 4-hydroxy-2-noneal (HNE) accumulation and plasma levels of superoxide dismutase (SOD) activity were detected. As a candidate of antioxidative components in sairei-to, plasma levels of baicalin were determined by high-performance liquid chromatography. Results: Compared with the disease control group, serum total protein levels were significantly recovered in the sairei-to treatment group. Thickness of the submesothelial compact zone, trichrome-stained area, ED-1-positive cells, fibronectin-staining area, and HNE accumulation were suppressed in the treatment group. Concurrently, decreased plasma levels of SOD activity were recovered by sairei-to treatment. Increased CD-31-positive vessel number and area were also suppressed in the sairei-to group. Baicalin was detected in the plasma samples of the sairei-to group at 0.29 ± 0.11 µg/ml (mean±SEM). Conclusion: These results suggest that sairei-to ameliorates peritoneal fibrosis, partly through suppressing oxidative stress and macrophage infiltration.
What Is the Future of Stroke Prevention?
Authors: Kernan Walter N. , Launer Lenore J. , Goldstein Larry B.
Published: September 2010

Background and Purpose—

The control of stroke risk factors remains challenging. The “polypill” concept represents a novel approach for reducing stroke and cardiovascular risk factors in the entire population. The polypill would include several components and be provided without prescription to all adults of a certain age.

Results—

A polypill aimed at lowering blood pressure and cholesterol levels is estimated to potentially reduce the risk of a first ischemic stroke by 53%; this would translate to about 400 000 fewer strokes each year in the United States alone. Recommending a polypill for the entire older adult population would, however, include many individuals without the multiple risk factors targeted by its components, putting them at risk for drug-related side effects and responsible for the costs of a medication from which they would not derive benefit. Additional arguments for and against the polypill approach are discussed.

Conclusions—

Only clinical trials can provide the evidence needed to determine the usefulness of the polypill approach. Issues related to defining the components of the polypill, evaluating the pharmacodynamics and pharmacokinetics of a multiple-component formulation, and establishing safety and cost-effectiveness when given to large populations, however, are not trivial.
In Vivo 2-Photon Imaging of Fine Structure in the Rodent Brain
Authors: Sigler Albrecht , Murphy Timothy H.
Published: September 2010

The recent application of 2-photon microscopy to biological specimens has allowed investigators to examine individual synapses within live animals. The gain in resolution over conventional in vivo imaging techniques has been several orders of magnitude. We outline steps for the preparation and maintenance of animals for 2-photon microscopy of fine brain structure. We discuss the in vivo resolution of the method and the ability to image blood flow and synaptic structure in vivo. Applications of in vivo 2-photon microscopy include the study of synapse turnover in adult animals under normal conditions and during pathology such as stroke. In the case of stroke, 2-photon imaging has revealed marked swelling of dendrites and loss of spines within minutes of ischemic onset. Surprisingly, restoration of blood flow during reperfusion was associated with a return of relatively normal structure. Over longer time scales, 2-photon imaging revealed elevated rates of synaptogenesis within peri-infarct tissues recovering from stroke. These results provide an example of how high-resolution in vivo microscopy can be used to provide insight into both the acute pathology and recovery from stroke damage.
Intracerebral Hemorrhage and Head Trauma
Authors: Powers William J.
Published: September 2010

Nontraumatic intracerebral hemorrhage (ICH) remains a devastating condition with 30-day mortality rates of 35% to 52%. Until the pathophysiology of this condition is better understood, it will not be possible to develop effective therapies. Studies of cerebral blood flow and metabolism in patients with acute ICH show similar abnormalities to those that occur in patients with traumatic brain injury, thus raising the question of whether there are common mechanisms of injury shared by the 2 conditions. In both ICH and traumatic brain injury, there is an early reduction in the cerebral metabolic rate of oxygen without ischemia, mitochondrial dysfunction, and transient focal increases in regional glucose metabolism that occur after a few days. ICH and traumatic brain injury share barotrauma from pressure waves that propagate through the intracranial contents as a common mechanism of brain injury. Recent data demonstrating contralateral hemispheric damage in patients with acute ICH provide further support for this theory of common injury mechanisms.
Thrombolysis With Plasmin
Authors: Marder Victor J. , Jahan Reza , Gruber Theresa , Goyal Abha , Arora Vik
Published: September 2010

Plasmin is a direct-acting thrombolytic agent with a striking hemostatic safety advantage over plasminogen activators in animal models of thrombolysis and bleeding. In contradistinction to plasminogen activators, which risk bleeding at any effective thrombolytic dose, plasmin is tolerated without bleeding at several-fold higher amounts than those needed for thrombolysis. Plasmin has been safe in a current trial in patients with peripheral arterial or graft occlusion, and efforts are now directed toward therapy of stroke caused by cerebral artery occlusion. A rabbit (4 kg body weight) model of 2-hour, thrombin-induced middle cerebral artery occlusion using angiographic documentation of vascular patency and recanalization was used to perform a dose-ranging study of plasmin, delivered by catheter over a median duration of 10 minutes. Plasmin induced early recanalization in all animals (3 per group) within 10 minutes after discontinuation of 3, 2, or 1 mg of agent infusion. Control saline infusion failed to induce recanalization in 3 of 3 subjects. Plasmin rapidly induces middle cerebral artery recanalization, as determined in an angiogram-based animal model of arterial occlusion. Based on these data and other information, a phase I/IIa clinical trial of plasmin in human middle cerebral artery ischemic stroke has been initiated.
CADASIL
Authors: Ayata Cenk
Published: September 2010

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) syndrome is the most common monogenic inherited form of small vessel disease, characterized by frequent migraine attacks with aura, recurrent strokes and progressive white matter degeneration. Early vascular cognitive impairment progresses into frank dementia of subcortical type later in life. Linked to mutations in the
NOTCH3
gene, CADASIL vasculopathy is associated with accumulation of granular osmiophilic material and NOTCH3 extracellular domain around small caliber arteries and arterioles, and eventual loss of vascular smooth muscle cells. Cerebral blood flow dysregulation has been hypothesized as a major mechanism, largely based on evidence from hemodynamic studies in CADASIL patients. Although animal models expressing CADASIL mutations reproduced the pathology and cerebrovascular dysfunction, the phenotypic spectrum has been quite heterogeneous, possibly due to the choice of genetic constructs and obvious species differences between mouse and man. Nevertheless, these experimental models provide new opportunities to explore the molecular and physiological mechanisms of CADASIL, and address the fundamental question of whether CADASIL phenotype represents loss of NOTCH3 function or gain of a novel and pathological function. Here, I provide an overview of existing animal models of CADASIL and the pathophysiological insights gained from these models.
The Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)
Authors: Mantese Vito A. , Timaran Carlos H. , Chiu David , Begg Richard J. , Brott Thomas G.
Published: September 2010

Background and Purpose—

Carotid artery stenosis causes up to 10% of all ischemic strokes. Carotid endarterectomy (CEA) was introduced as a treatment to prevent stroke in the early 1950s. Carotid stenting (CAS) was introduced as a treatment to prevent stroke in 1994.

Methods—

The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) is a randomized trial with blinded end point adjudication. Symptomatic and asymptomatic patients were randomized to CAS or CEA. The primary end point was the composite of any stroke, myocardial infarction, or death during the periprocedural period and ipsilateral stroke thereafter, up to 4 years.

Results—

There was no significant difference in the rates of the primary end point between CAS and CEA (7.2% versus 6.8%; hazard ratio, 1.11; 95% CI, 0.81 to 1.51;
P
=0.51). Symptomatic status and sex did not modify the treatment effect, but an interaction with age and treatment was detected (
P
=0.02). Outcomes were slightly better after CAS for patients aged <70 years and better after CEA for patients aged >70 years. The periprocedural end point did not differ for CAS and CEA, but there were differences in the components, CAS versus CEA (stroke 4.1% versus 2.3%,
P
=0.012; and myocardial infarction 1.1% versus 2.3%,
P
=0.032).

Conclusions—

In CREST, CAS and CEA had similar short- and longer-term outcomes. During the periprocedural period, there was higher risk of stroke with CAS and higher risk of myocardial infarction with CEA.

Clinical Trial Registration—

www.clinicaltrials.gov. Unique identifier: NCT00004732.
Early Experience of Translating pH-Weighted MRI to Image Human Subjects at 3 Tesla
Authors: Sun Phillip Zhe , Benner Thomas , Copen William A. , Sorensen A. Gregory
Published: September 2010

Background and Purpose—

In acute stroke, mismatch between lesions seen on diffusion- (DWI) and perfusion-weighted (PWI) MRI has been used to identify ischemic tissue before irreversible damage. Nevertheless, the concept of PWI/DWI mismatch is oversimplified and the ischemic tissue metabolic status and outcome are often heterogeneous. Tissue pH, a well-regulated physiological index that alters on disrupted tissue metabolism, may provide a surrogate metabolic imaging marker that augments the DWI and PWI for penumbra imaging.

Methods—

pH-weighted MRI was obtained by probing the pH-dependent amide proton transfer between endogenous mobile proteins/peptides and tissue water. The technique was validated using animal stroke models, optimized for human use, and preliminarily tested for imaging healthy volunteers.

Results—

pH-weighted MRI is sensitive and specific to ischemic tissue acidosis. pH MRI can be optimized for clinical use, and a pilot human study showed it is feasible using a standard 3 Tesla MRI scanner.

Conclusions—

Ischemic acidosis can be imaged via an endogenous pH-weighted MRI technique, which complements conventional PWI and DWI for penumbra imaging. pH-weighted MRI has been optimized and appears feasible and practical in imaging human subjects. Additional study is necessary to elucidate the diagnostic use of pH MRI in stroke patients.
Advanced Contrast-Enhanced MRI for Looking Beyond the Lumen to Predict Stroke
Authors: Wasserman Bruce A.
Published: September 2010

Carotid plaque MRI can identify components indicative of stroke risk, including the thin/ruptured fibrous cap and lipid core. Gadolinium contrast, typically administered for routine MR angiography acquisitions, can be used to improve plaque characterization, extending risk assessment beyond the plaque’s hemodynamic impact on the lumen. Gadolinium preferentially enhances the cap, improves reliability of vessel wall measurements, and highlights neovessels, improving stroke risk stratification. Additionally, the precontrast series from the contrast-enhanced MR angiography can help identify intraplaque hemorrhage, another important risk marker. Prospective validation of these features is needed to develop a carotid plaque risk profile for clinical implementation.
Targets for Neural Repair Therapies After Stroke
Authors: Carmichael S. Thomas
Published: September 2010

Studies of neural repair after stroke have developed from a relatively small number of laboratories doing highly creative discovery science to a field in which reproducible evidence supports distinct pathways, processes, and molecules that promote recovery. This review focuses on some emerging targets for neural repair or recovery in stroke and on their limitations.
The Economic Case for New Stroke Thrombolytics
Authors: Johnston S. Claiborne
Published: September 2010

Background—

The societal costs and health benefits of tissue plasminogen activator (tPA) for ischemic stroke can be modeled and extended to the US population. Similarly, the societal impact of new thrombolytics with improved efficacy or safety or extending eligibility can also be modeled.

Methods—

We previously modeled the impact of tPA on societal costs and health in the United States. Pertinent publications on utilization, societal cost, and health impact were identified by systematic review, updated to include studies describing the impact of extending the tPA time window. Information on utilization of tPA was integrated with published per-use data on costs and health impact (converted to 2004 dollars) to generate annual projections for the US population. Model inputs were modified to reflect various characteristics of new thrombolytics.

Results—

At its current price, tPA saves $6074 and adds 0.75 quality-adjusted life year (QALY) per use. If tPA were priced at $50 000/QALY, a standard benchmark for cost-effectiveness, it would cost $45 800 per dose and would be expected to generate $458 million in revenue annually for its manufacturer. Thrombolytics for stroke that extended the time window or improved efficacy could generate greater revenue if priced at an accepted level of cost-effectiveness. Given current clinical development costs, development of candidate drugs with 2.8% to 5.7% probability of ultimate FDA approval would be justified.

Conclusions—

tPA produces substantial health and economic benefits in the United States. Better thrombolytics for stroke could have substantial impact on society, and potential returns to developers would appear to justify greater investment in new candidates.