bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytochrome P450 2D6 enzyme neuroprotects against 1‐methyl‐4‐phenylpyridinium toxicity in SH‐SY5Y neuronal cells
Authors: Mann Amandeep , Tyndale Rachel F.
Published: March 2010

Cytochrome P450 (CYP) 2D6 is an enzyme that is expressed in liver and brain. It can inactivate neurotoxins such as 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine, 1,2,3,4‐tetrahydroisoquinoline and β‐carbolines. Genetically slowCYP2D6metabolizers are at higher risk for developing Parkinson’s disease, a risk that increases with exposure to pesticides. The goal of this study was to investigate the neuroprotective role of CYP2D6 in anin‐vitroneurotoxicity model. SH‐SY5Y human neuroblastoma cells express CYP2D6 as determined by western blotting, immunocytochemistry and enzymatic activity. CYP2D6 metabolized 3‐[2‐(N,N‐diethyl‐N‐methylammonium)ethyl]‐7‐methoxy‐4‐methylcoumarin and the CYP2D6‐specific inhibitor quinidine (1 μm) blocked 96 ± 1% of this metabolism, indicating that CYP2D6 is functional in this cell line. Treatment of cells with CYP2D6 inhibitors (quinidine, propanolol, metoprolol or timolol) at varying concentrations significantly increased the neurotoxicity caused by 1‐methyl‐4‐phenylpyridinium (MPP+) at 10 and 25 μmby between 9 ± 1 and 22 ± 5% (P < 0.01). We found that CYP3A is also expressed in SH‐SY5Y cells and inhibiting CYP3A with ketoconazole significantly increased the cell death caused by 10 and 25 μmof MPP+by between 8 ± 1 and 30 ± 3% (P < 0.001). Inhibiting both CYP2D6 and CYP3A showed an additive effect on MPP+neurotoxicity. These data further support a possible role for CYP2D6 in neuroprotection from Parkinson’s disease‐causing neurotoxins, especially in the human brain where expression of CYP2D6 is high in some regions (e.g. substantia nigra).
Semaphorin 3A‐Neuropilin‐1 signaling regulates peripheral axon fasciculation and pathfinding but not developmental cell death patterns
Authors: Haupt Corinna , Kloos Karina , Faus‐Kessler Theresa , Huber Andrea B.
Published: March 2010

In early development, an excess of neurons is generated, of which later about half will be lost by cell death due to a limited supply of trophic support by their respective target areas. However, some of the neurons die when their axons have not yet reached their target, thus suggesting that additional causes of developmental cell death exist. Semaphorin 3A (Sema3A), in addition to its function as a guidance cue and mediator of timing and fasciculation of motor and sensory axon outgrowth, can also induce death of sensory neurons in vitro. However, it is unknown whether Neuropilin‐1 (Npn‐1), its binding receptor in axon guidance, also mediates the death‐inducing activity. We show here that abolished Sema3A‐Npn‐1 signaling does not influence the cell death patterns of motor or sensory neurons in mouse during the developmental wave of programmed cell death. The number of motor and sensory neurons was unchanged at embryonic day 15.5 when this wave is concluded. Interestingly, the defasciculation of early motor and sensory projections that is observed in the absence of Sema3A or Npn‐1 persists to postnatal stages. Thus, Sema3A‐Npn‐1 signaling plays an important role in the guidance and fasciculation of motor and sensory axons but does not contribute to the developmental elimination of these neurons.
Fundamentals of neuronal apoptosis relevant to pediatric anesthesia
Authors: BLAYLOCK MORGAN , ENGELHARDT THOMAS , BISSONNETTE BRUNO
Published: March 2010

The programmed cell death or apoptosis is a complex biochemical process that has risen to prominence in pediatric anesthesia. Preclinical studies report a dose‐dependant neuronal apoptosis during synaptogenesis following exposure to intravenous and volatile anesthetic agents. Although emerging clinical data do not universally indicate an increased neurodegenerative risk of general anesthesia in early human life, a great deal of uncertainty was created within the pediatric anesthesia community. This was at least partially caused by the demand of understanding of basic science concepts and knowledge of apoptosis frequently out of reach to the clinician. It is, however, important for the pediatric anesthesiologist to be familiar with the basic science concepts of neuronal apoptosis to be able to critically evaluate current and future preclinical data in this area and future clinical studies. This current review describes the extrinsic and intrinsic pathways involved in the cell death process and discusses techniques commonly employed to determine apoptosis. In addition, potential mechanisms of anesthesia‐induced neuronal apoptosis are illustrated in this review.
Anesthesia for videoscopic left cardiac sympathetic denervation in children with congenital long QT syndrome and catecholaminergic polymorphic ventricular tachycardia – a case series
Authors: KENYON CHRISTINE A. , FLICK RANDALL , MOIR CHRISTOPHER , ACKERMAN MICHAEL J. , PABELICK CHRISTINA M.
Published: March 2010

Objective:  To describe our experience in the anesthetic management of pediatric patients who have undergone left cardiac sympathetic denervation (LCSD) for congenital long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT).

Background:  Long QT syndrome and CPVT predispose patients to ventricular arrhythmias and sudden death. One treatment option for these patients is LCSD. When these patients present for LCSD or other surgical procedures, anesthetic management is challenging, as many medications may exacerbate QT prolongation.

Methods:  Retrospective review of the electronic medical records of 22 pediatric patients who underwent LCSD between November 2005 and December 2008.

Results:  Six patients (27%) received midazolam as a premedication. Eleven patients (50%) underwent inhalation induction with sevoflurane. Eighty‐six percentage received either sevoflurane or isoflurane for maintenance of anesthesia, while the remaining 14% received a propofol infusion. Nine patients (41%) received esmolol infusions intraoperatively, while one patient (4.5%) received a labetalol infusion. Three patients (14%) received lidocaine infusions. No significant cardiac or other events occurred in any of these patients in the perioperative period.

Conclusions:  Important anesthetic considerations in this population include avoidance of sympathetic stimulation, correction of any abnormal electrolytes, and the immediate availability of a defibrillator and magnesium sulfate to treat arrhythmias. Anxious patients may benefit from premedication to reduce sympathetic tone. We have safely used both volatile agents and propofol for induction and maintenance of anesthesia. In our experience, intraoperative infusions of β‐blockers and lidocaine seem to be helpful in reducing arrhythmogenic potential, especially in patients with profound QT prolongation.
Effects of interleukin‐6 treatment on neurovascular function, nerve perfusion and vascular endothelium in diabetic rats
Authors: Cotter M. A. , Gibson T. M. , Nangle M. R. , Cameron N. E.
Published: March 2010

Aim: Interleukin‐6 (IL‐6), a member of the neuropoietic cytokine family, participates in neural development and has neurotrophic activity. Recent research has also indicated actions to improve vasa nervorum function in diabetes. Both these facets are potentially relevant for treatment of diabetic neuropathy. The aim of this study was to determine whether IL‐6 treatment corrected changes in neurovascular function in streptozotocin‐induced diabetic rats.

Methods: After 1 month of diabetes, rats were given IL‐6 for 1 month. The rats were subjected to sensory testing and measurements of nerve conduction velocities and nerve blood flow by hydrogen clearance microelectrode polarography. Further groups were used to study responses of the isolated gastric fundus and renal artery. Results were statistically analysed using ANOVA and post hoc tests.

Results: Diabetic rats showed mechanical hyperalgesia, thermal hyperalgesia, and tactile allodynia. The former was unaffected by IL‐6 treatment, whereas the latter two measures were corrected. Immunohistochemical staining of dorsal root ganglia for IL‐6 did not reveal any changes with diabetes or treatment. The results showed that 22 and 17.4% slowing of sciatic motor and saphenous sensory nerve conduction velocities, respectively, with diabetes were improved by IL‐6. Sciatic endoneurial perfusion was halved by diabetes and corrected by IL‐6. A 40.6% diabetic deficit in maximal non‐adrenergic, non‐cholinergic relaxation of gastric fundus to nerve stimulation was unaffected by IL‐6. Renal artery endothelium‐dependent relaxation was halved by diabetes, the endothelium‐derived hyperpolarizing factor (EDHF) component being severely attenuated. IL‐6 did not affect nitric oxide‐mediated vasorelaxation, but markedly improved EDHF responses.

Conclusions: IL‐6 improved aspects of small and large nerve fibre and vascular endothelium dysfunction in diabetic rats. The functional benefits related to increased nerve blood flow via an EDHF mechanism, and IL‐6 could have therapeutic potential in diabetic neuropathy and vasculopathy, which should be further evaluated.
Efficacy and safety of vildagliptin and voglibose in Japanese patients with type 2 diabetes: a 12‐week, randomized, double‐blind, active‐controlled study
Authors: Iwamoto Y. , Kashiwagi A. , Yamada N. , Terao S. , Mimori N. , Suzuki M. , Tachibana H.
Published: March 2010

Aim: To confirm the efficacy of vildagliptin in patients with type 2 diabetes (T2D) by testing the hypothesis that glycosylated haemoglobin (HbA1c) reduction with vildagliptin is superior to that with voglibose after 12 weeks of treatment.

Methods: In this 12‐week, randomized, double‐blind, active‐controlled, parallel‐group study, the efficacy and safety of vildagliptin (50 mg bid, n = 188) was compared with that of voglibose (0.2 mg tid, n = 192) in patients with T2D who were inadequately controlled with diet and exercise.

Results: The characteristics of two groups were well matched at baseline. The mean age, body mass index (BMI) and HbA1c were 59.1 years, 24.9 kg/m2 and 7.6%, respectively. At baseline, fasting plasma glucose (FPG) and 2‐h postprandial glucose (PPG) were 9.01 mmol/l (162.2 mg/dl) and 13.57 mmol/l (244.3 mg/dl), respectively. The adjusted mean change in HbA1c from baseline to endpoint was −0.95 ± 0.04% in the vildagliptin‐treated patients and −0.38 ± 0.04% in those receiving voglibose (between‐group change = 0.57 ± 0.06%, 95% confidence interval (CI) (−0.68 to −0.46%), p < 0.001), showing that vildagliptin was superior to voglibose. Endpoint HbA1c ≤ 6.5% was achieved in 51% vildagliptin‐treated patients compared with 24% patients who were on voglibose (p < 0.001). Vildagliptin also exhibited significantly (p < 0.001) greater reduction compared with voglibose in both FPG [1.34 vs. 0.43 mmol/l (24.1 vs. 7.8 mg/dl)] and 2‐h PPG [2.86 vs. 1.1 mmol/l (51.5 vs. 19.8 mg/dl)]. Overall adverse events (AEs) were lower in the vildagliptin‐treated patients compared with that in the voglibose‐treated patients (61.2 vs. 71.4%), with no incidence of hypoglycaemia and serious adverse events with vildagliptin. Gastrointestinal AEs were significantly lower with vildagliptin compared with that of the voglibose (18.6 vs. 32.8%; p = 0.002).

Conclusions: Vildagliptin (50 mg bid) showed superior efficacy and better tolerability compared with voglibose in Japanese patients with T2D.
PRECAUTIONARY DEMAND FOR LABOUR AND FIRM SIZE
Authors: Kudoh Noritaka , Sasaki Masaru
Published: March 2010

This paper studies firms' job creation decisions in a labour market with search frictions. A simple labour market search model is developed in which a firm can search for a second employee while producing with a first worker, and this creates the equilibrium size distribution of firms. A firm expands employment even if the instantaneous payoff to a large firm is less than that of staying small – a firm has a precautionary motive to expand its size. In addition, this motive is enhanced by a greater market tightness. Because of this effect, firms’ decisions become interdependent – a firm creates a vacancy if it expects other firms to do the same, creating strategic complementarity among firms and thereby self‐fulfilling multiple equilibria. An increase in productivity can cause a qualitative change in labour market tightness and the rate of unemployment.
HORIZONTAL MERGERS: A SOLUTION OF THE INSIDERS' DILEMMA
Authors: Cesi Berardino
Published: March 2010

We show that in a three‐firm infinitely repeated Cournot game, there exists a stick and carrot strategy equilibrium in which an exogenous bilateral horizontal merger is profitable and the incentive to remain out of the merger disappears. In this sub‐game perfect equilibrium, the merged entity produces the duopoly quantity and the outsider limits its production to half the duopoly quantity. Our stick and carrot strategy entails that the merged entity threatens to produce twice the triopoly quantity for two periods if the outsider does not produce half the duopoly quantity. In this equilibrium, the aggregate price remains high enough to make the merger profitable for the insiders. Also, the quantity produced by the outsider is sufficiently low to eliminate the difference between the profit of the outsider and the merging firm.
ROBUST MONETARY POLICY UNDER UNCERTAINTY ABOUT CENTRAL BANK PREFERENCES
Authors: Qin Li , Sidiropoulos Moïse , Spyromitros Eleftherios
Published: March 2010

In this paper, we study the impact of central bank opacity on macroeconomic performances in a new Keynesian framework with model uncertainty using robust control techniques. We identify a new source of central bank opacity, which refers to the lack of information about the central bank's preference for robustness in the sense of Hansen and Sargent. We find closed‐form solutions for the robust control problem, analysing the impact of the lack of transparency about the central bank's preferences for robustness. We show that an increased transparency about the central bank's preference for robustness makes monetary policy respond less aggressively to cost‐push shocks, thus reducing the inflation and output gap variability. As a consequence, inflation and output gap are less volatile than under central bank opacity about its preference for robustness.
Using a Visual Attention Model to Improve Gaze Tracking Systems in Interactive 3D Applications
Authors: Hillaire S. , Breton G. , Ouarti N. , Cozot R. , Lécuyer A.
Published: March 2010

This paper introduces the use of a visual attention model to improve the accuracy of gaze tracking systems. Visual attention models simulate the selective attention part of the human visual system. For instance, in a bottom‐up approach, a saliency map is defined for the image and gives an attention weight to every pixel of the image as a function of its colour, edge or intensity.

Our algorithm uses an uncertainty window, defined by the gaze tracker accuracy, and located around the gaze point given by the tracker. Then, using a visual attention model, it searches for the most salient points, or objects, located inside this uncertainty window, and determines a novel, and hopefully, better gaze point. This combination of a gaze tracker together with a visual attention model is considered as the main contribution of the paper.

We demonstrate the promising results of our method by presenting two experiments conducted in two different contexts: (1) a free exploration of a visually rich 3D virtual environment without a specific task, and (2) a video game based on gaze tracking involving a selection task.

Our approach can be used to improve real‐time gaze tracking systems in many interactive 3D applications such as video games or virtual reality applications. The use of a visual attention model can be adapted to any gaze tracker and the visual attention model can also be adapted to the application in which it is used.
Accurate Simplification of Multi‐Chart Textured Models
Authors: Coll N. , Paradinas T.
Published: March 2010

Scanning and acquisition methods produce highly detailed surface meshes that need multi‐chart parameterizations to reduce stretching and distortion. From these complex shape surfaces, high‐quality approximations are automatically generated by using surface simplification techniques. Multi‐chart textures hinder the quality of the simplification of these techniques for two reasons: either the chart boundaries cannot be simplified leading to a lack of geometric fidelity; or texture distortions and artefacts appear near the simplified boundaries. In this paper, we present an edge‐collapse based simplification method that provides an accurate, low‐resolution approximation from a multi‐chart textured model. For each collapse, the model is reparameterized by local bijective mappings to avoid texture distortions and chart boundary artefacts on the simplified mesh due to the geometry changes. To better apply the appearance attributes and to guarantee geometric fidelity, we drive the simplification process with the quadric error metrics weighted by a local area distortion measure.
On the semantics of “embedded exclamatives”*
Authors: Sæbø Kjell Johan
Published: March 2010

Abstract.  It is sometimes assumed that there is a special exclamative semantics, in particular, that some wh clauses have an exclamative semantics even when embedded, maybe beside an interrogative semantics. In this paper I investigate what such an exclamative semantics might consist in, arguing that there are indeed different readings of wh clauses involved, but that these nuances do not concern the meaning type common to exclamatives and interrogatives: a function assigning to any world a true proposition.
Exclamatives in Scandinavian*
Authors: Delsing Lars‐Olof
Published: March 2010

Abstract.  In this article, I define exclamatives pragmatically, as a speech act which contains an assertion, and where there is a mismatch between this assertion and a presupposition. The assertion normally expresses a higher degree than expected, i.e. they are scalar. The speech act is instantiated in various ways in the Scandinavian languages. The aim of this article is to describe and characterise the syntactic variation in Scandinavian exclamative clauses, in the standard languages, as well as in some regional variants. First, I discuss the definition of exclamatives, and I recognise three main types, which I call degree, polar and reinforcing exclamatives. Second, I give a survey of the syntactic variation of the three types in Scandinavian, where I discuss syntactic properties such as word order and extraction possibilities as well as lexical, syntactic and prosodic features that are exclusive to exclamatives. Last, I conclude the paper by a taxonomy of exclamatives in Scandinavian.
Financial Constraints and Firm Export Behaviour
Authors: Bellone Flora , Musso Patrick , Nesta Lionel , Schiavo Stefano
Published: March 2010

The paper analyses the link between financial constraints and firm export behaviour. Our main finding is that firms enjoying better financial health are more likely to become exporters. The result contrasts with the previous empirical literature which found evidence that export participation improves firm financial health, but not that export starters display any ex ante financial advantage. On the contrary, we find that financial constraints act as a barrier to export participation. Better access to external financial resources increases the probability to start exporting and also shortens the time before firms decide to serve foreign customers. This finding has important policy implications as it suggests that, in the presence of financial market imperfections, public intervention can be called for to help efficient but financially constrained firms to overcome the sunk entry costs into export markets and expand their activities abroad.
Analysis of serious non‐AIDS events among HIV‐infected adults at Latin American sites
Authors: Belloso WH , Orellana LC , Grinsztejn B , Madero JS , La Rosa A , Veloso VG , Sanchez J , Ismerio Moreira R , Crabtree‐Ramirez B , Garcia Messina O , Lasala MB , Peinado J , Losso MH
Published: March 2010

Objective

Acquired immune deficiency appears to be associated with serious non‐AIDS (SNA)‐defining conditions such as cardiovascular disease, liver and renal insufficiency and non‐AIDS‐related malignancies. We analysed the incidence of, and factors associated with, several SNA events in the LATINA retrospective cohort.

Materials and methods

Cases of SNA events were recorded among cohort patients. Three controls were selected for each case from cohort members at risk. Conditional logistic models were fitted to estimate the effect of traditional risk factors as well as HIV‐associated factors on non‐AIDS‐defining conditions.

Results

Among 6007 patients in follow‐up, 130 had an SNA event (0.86 events/100 person‐years of follow‐up) and were defined as cases (40 with cardiovascular events, 54 with serious liver failure, 35 with non‐AIDS‐defining malignancies and two with renal insufficiency). Risk factors such as diabetes, hepatitis B and C virus coinfections and alcohol abuse showed an association with events, as expected. The last recorded CD4 T‐cell count prior to index date (P=0.0056, with an average difference of more than 100 cells/μL) and area under the CD4 cell curve in the year previous to index date (P=0.0081) were significantly lower in cases than in controls. CD4 cell count at index date was significantly associated with the outcome after adjusting for risk factors.

Conclusions

The incidence and type of SNA events found in this Latin American cohort are similar to those reported in other regions. We found a significant association between immune deficiency and the risk of SNA events, even in patients under antiretroviral treatment.
The Importance of Being Connected. City Networks and Urban Government: Lyon and Eurocities (1990–2005)
Authors: PAYRE RENAUD
Published: March 2010

The international dimension of cities and their role in inter‐urban markets and inter‐urban competition are now often studied and analysed from the perspective of public policy, urban planning or geography. Yet few studies highlight the political work that goes on in acquiring this dimension. Focusing on an inter‐urban network such as Eurocities sheds light on this work and makes it possible to move away from an analysis of the Europeanization of cities in terms of centre and periphery. In this network, a horizontal form of Europeanization can be observed. The article examines this inter‐urban network as an inter‐urban configuration. The network is based on relationships between city councils, but due to a sort of cluster effect, it becomes more autonomous and — through resources as well as constraints — influences those relationships, indeed influences urban governance.

La dimension internationale et la place des villes dans le marché et la compétition inter‐urbaines sont aujourd'hui des objets bien étudiés à la fois en analyse de l'action publique, en urbanisme ou en géographie. Mais peu de travaux repèrent le travail politique à l'œuvre pour acquérir cette dimension. Le détour par un réseau de villes comme Eurocités éclaire ce travail comme il permet de se défaire d'une analyse de l'européanisation des villes en termes de centre et de périphérie. C'est une européanisation horizontale qui est mise au jour à travers ce réseau. Le réseau de villes est ici saisi comme une configuration interurbaine: il repose sur des relations entre municipalités urbaines mais par un effet d'agrégation, le réseau gagne en autonomie et pèse —à travers des ressources comme des contraintes — sur ces relations voire sur le gouvernement des villes.
The practical implication of comparing how adults with and without intellectual disability respond to music
Authors: Hooper Jeff , Wigram Tony , Carson Derek , Lindsay Bill
Published: March 2010

Accessible summary

I found out how people with an intellectual disability and people without an intellectual disability reacted to different pieces of music.

People with an intellectual disability reacted in the same way as people without an intellectual disability.

If you have difficulty deciding the type of music that helps you stay calm, ask your parents or carers what music helps them relax when they feel anxious. The type of music they like might help you stay calm too.

Previous researchers who compared how people with, and without, an intellectual disability respond to music focused on musical aptitude, but not on arousal. This paper presents the background, methodology, and results of a study that selected fifteen different pieces of music, and compared the arousal response of adults with (n = 48), and without (n = 48), an intellectual disability. There was a very strong significant positive correlation (rho = 0.831, N = 15, P < 0.001, two‐tailed), which the present authors believe implies that music, identified as sedative by individuals who do not have an intellectual disability, can be used appropriately in an intervention predicated for lowering the arousal levels of the intellectually disabled population.
Downward hydrocarbon migration predicted from numerical modeling of fluid overpressure in the Paleozoic Anticosti Basin, eastern Canada
Authors: CHI G. , LAVOIE D. , BERTRAND R. , LEE M.‐K.
Published: March 2010

The Anticosti Basin is a large Paleozoic basin in eastern Canada where potential source and reservoir rocks have been identified but no economic hydrocarbon reservoirs have been found. Potential source rocks of the Upper Ordovician Macasty Formation overlie carbonates of the Middle Ordovician Mingan Formation, which are underlain by dolostones of the Lower Ordovician Romaine Formation. These carbonates have been subjected to dissolution and dolomitization and are potential hydrocarbon reservoirs. Numerical simulations of fluid‐overpressure development related to sediment compaction and hydrocarbon generation were carried out to investigate whether hydrocarbons generated in the Macasty Formation could migrate downward into the underlying Mingan and Romaine formations. The modeling results indicate that, in the central part of the basin, maximum fluid overpressures developed above the Macasty Formation due to rapid sedimentation. This overpressured core dissipated gradually with time, but the overpressure pattern (i.e. maximum overpressure above source rock) was maintained during the generation of oil and gas. The downward impelling force associated with fluid‐overpressure gradients in the central part of the basin was stronger than the buoyancy force for oil, whereas the buoyancy force for gas and for oil generated in the later stage of the basin is stronger than the overpressure‐related force. Based on these results, it is proposed that oil generated from the Macasty Formation in the central part of the basin first moved downward into the Mingan and Romaine formations, and then migrated laterally up‐dip toward the basin margin, whereas gas throughout the basin and oil generated in the northern part of the basin generally moved upward. Consequently, gas reservoirs are predicted to occur in the upper part of the basin, whereas oil reservoirs are more likely to be found in the strata below the source rocks.

Geofluids(2010)10, 334–350
Faults and fault properties in hydrocarbon flow models
Authors: MANZOCCHI T. , CHILDS C. , WALSH J. J.
Published: March 2010

Geofluids (2010) 10, 94–113

The petroleum industry uses subsurface flow models for two principal purposes: to model the flow of hydrocarbons into traps over geological time, and to simulate the production of hydrocarbon from reservoirs over periods of decades or less. Faults, which are three‐dimensional volumes, are approximated in both modelling applications as planar membranes onto which predictions of the most important fault‐related flow properties are mapped. Faults in porous clastic reservoirs are generally baffles or barriers to flow and the relevant flow properties are therefore very different to those which are important in conductive fracture flow systems. A critical review and discussion is offered on the work‐flows used to predict and model capillary threshold pressure for exploration fault seal analysis and fault transmissibility multipliers for production simulation, and of the data from which the predictions derive. New flow simulation models confirm that failure of intra‐reservoir sealing faults can occur during a reservoir depressurization via a water‐drive mechanism, but contrary to anecdotal reports, published examples of production‐induced seal failure are elusive. Ignoring the three‐dimensional structure of fault zones can sometimes have a significant influence on production‐related flow, and a series of models illustrating flow associated with relay zones are discussed.
The effect of the Infant Behavioral Assessment and Intervention Program on mother–infant interaction after very preterm birth
Authors: Meijssen Dominique , Wolf Marie‐Jeanne , Koldewijn Karen , Houtzager Bregje A. , van Wassenaer Aleid , Tronick Ed , Kok Joke , van Baar Anneloes
Published: March 2010

Background:  Prematurity and perinatal insults lead to increased developmental vulnerability. The home‐based Infant Behavioral Assessment and Intervention Program (IBAIP) was designed to improve development of preterm infants. In a multicenter randomized controlled trial the effect of IBAIP on mother–infant interaction was studied as a secondary outcome.

Method:  Mother–infant interaction was assessed during the Still‐face procedure at 6 months corrected age. One hundred and twelve mother–infant dyads (57 intervention, 55 control) were studied.

Results:  Findings partially supported our hypothesis that the intervention would increase maternal sensitivity in interaction with their preterm infants. No effects were found on infant self‐regulatory behavior or positive interaction behavior.

Conclusion:  The family‐centered and strength‐based approach of IBAIP appears to be a promising intervention method to promote sensitive mother–infant interaction at home after discharge from hospital. However, no positive effects were found on infant interaction behavior.
Failure of Bay K 8644 to induce RhoA kinase‐dependent calcium sensitization in rabbit blood vessels
Authors: Alvarez SM , Miner AS , Browne BM , Ratz PH
Published: March 2010

Background and purpose:  RhoA kinase (ROCK) participates in K+ depolarization (KCl)‐induced Ca2+ sensitization of contraction. Whether constitutive, depolarization‐ or Ca2+‐activated ROCK plays the major role in this signalling system remains to be determined. Here, we determined whether Bay K 8644, a dihydropyridine that promotes Ca2+ channel clusters to operate in a persistent Ca2+ influx mode, could cause ROCK‐dependent Ca2+ sensitization.

Experimental approach:  Renal and femoral artery rings from New Zealand white rabbits were contracted with Bay K 8644. Tissues were frozen and processed to measure active RhoA and ROCK substrate (myosin phosphatase targeting subunit, MYPT1) and myosin light chain (MLC) phosphorylation, or loaded with fura‐2 to measure intracellular free Ca2+ ([Ca2+]i). Effects of selective inhibitors of contraction were assessed in resting (basal) tissues and those contracted with Bay K 8644.

Key results:  Bay K 8644 produced strong increases in [Ca2+]i, MLC phosphorylation and tension, but not in MYPT1 phosphorylation. ROCK inhibition by H‐1152 abolished basal MYPT1‐pT853, diminished basal MLC phosphorylation and inhibited Bay K 8644‐induced increases in MLC phosphorylation and tension. MLC kinase inhibition by wortmannin abolished Bay K 8644‐induced contraction and increase in MLC phosphorylation but did not inhibit basal MYPT1‐pT853. H‐1152 and wortmannin had no effect on MYPT1‐pT696, but 1 µM staurosporine inhibited basal MYPT1‐pT853, MYPT1‐pT696 and MLC phosphorylation.

Conclusions and implications:  These data suggest that the constitutive activities of ROCK and a staurosporine‐sensitive kinase regulate basal phosphorylation of MYPT1, which participates along with activation of MLC kinase in determining the strength of contraction induced by the Ca2+ agonist, Bay K 8644.
Effects of cytochrome P450 3A (CYP3A) and the drug transporters P‐glycoprotein (MDR1/ABCB1) and MRP2 (ABCC2) on the pharmacokinetics of lopinavir
Authors: van Waterschoot RAB , ter Heine R , Wagenaar E , van der Kruijssen CMM , Rooswinkel RW , Huitema ADR , Beijnen JH , Schinkel AH
Published: March 2010

Background and purpose: Lopinavir is extensively metabolized by cytochrome P450 3A (CYP3A) and is considered to be a substrate for the drug transporters ABCB1 (P‐glycoprotein) and ABCC2 (MRP2). Here, we have assessed the individual and combined effects of CYP3A, ABCB1 and ABCC2 on the pharmacokinetics of lopinavir and the relative importance of intestinal and hepatic metabolism. We also evaluated whether ritonavir increases lopinavir oral bioavailability by inhibition of CYP3A, ABCB1 and/or ABCC2.

Experimental approach: Lopinavir transport was measured in Madin‐Darby canine kidney cells expressing ABCB1 or ABCC2. Oral lopinavir kinetics (+/− ritonavir) was studied in mice with genetic deletions of Cyp3a, Abcb1a/b and/or Abcc2, or in transgenic mice expressing human CYP3A4 exclusively in the liver and/or intestine.

Key results: Lopinavir was transported by ABCB1 but not by ABCC2in vitro. Lopinavir area under the plasma concentration – time curve (AUC)oralwas increased in Abcb1a/b−/−mice (approximately ninefold vs. wild‐type) but not in Abcc2−/−mice. Increased lopinavir AUCoral(>2000‐fold) was observed in cytochrome P450 3A knockout (Cyp3a−/−) mice compared with wild‐type mice. No difference in AUCoralbetween Cyp3a−/−and Cyp3a/Abcb1a/b/Abcc2−/−mice was observed. CYP3A4 activity in intestine or liver, separately, reduced lopinavir AUCoral(>100‐fold), compared with Cyp3a−/−mice. Ritonavir markedly increased lopinavir AUCoralin all CYP3A‐containing mouse strains.

Conclusions and implications: CYP3A was the major determinant of lopinavir pharmacokinetics, far more than Abcb1a/b. Both intestinal and hepatic CYP3A activity contributed importantly to low oral bioavailability of lopinavir. Ritonavir increased lopinavir bioavailability primarily by inhibiting CYP3A. Effects of Abcb1a/b were only detectable in the presence of CYP3A, suggesting saturation of Abcb1a/b in the absence of CYP3A activity.
Ca2+signalling by P2Y receptors in cultured rat aortic smooth muscle cells
Authors: Govindan Sriram , Taylor Emily JA , Taylor Colin W
Published: March 2010

Background and purpose: P2Y receptors evoke Ca2+signals in vascular smooth muscle cells and regulate contraction and proliferation, but the roles of the different P2Y receptor subtypes are incompletely resolved.

Experimental approach: Quantitative PCR was used to define expression of mRNA encoding P2Y receptor subtypes in freshly isolated and cultured rat aortic smooth muscle cells (ASMC). Fluorescent indicators in combination with selective ligands were used to measure the changes in cytosolic free [Ca2+] in cultured ASMC evoked by each P2Y receptor subtype.

Key results: The mRNA for all rat P2Y receptor subtypes are expressed at various levels in cultured ASMC. Four P2Y receptor subtypes (P2Y1, P2Y2, P2Y4 and P2Y6) evoke Ca2+signals that require activation of phospholipase C and comprise both release of Ca2+from stores and Ca2+entry across the plasma membrane.

Conclusions and implications: Combining analysis of P2Y receptor expression with functional analyses using selective agonists and antagonists, we isolated the Ca2+signals evoked in ASMC by activation of P2Y1, P2Y2, P2Y4 and P2Y6 receptors.
Being mindful of seven‐transmembrane receptor ‘guests’ when assessing agonist selectivity
Authors: Kenakin Terry
Published: March 2010

The time‐honored approach of quantifying agonist selectivity through measurement of agonist affinity with binding and efficacy through potency ratios in model assays for prediction of effect in therapeutic systems can fall short of providing useful answers for functionally selective agonists. Agonists are now known to have pluridimensional efficacies that are associated with selected signalling pathways coupled to the receptor. This necessitates specifically tailored assay formats to measure pre‐determined efficacies of ligands to characterize agonist selectivity fully. If such assays can access signalling that directly emanates from the interaction of the agonist‐bound receptor and a cytosolic signalling protein, then the Black/Leff operational model can be used to specifically quantify ‘transduction ratios’ (τ/KA) that fully characterize selective activation of signalling pathways by a given agonist. As whole‐cell processing of pleiotropic signalling cascades imposes cell‐specific phenotypic agonist profiles, ultimately the assessment of agonist selectivity is most reliably done in the therapeutically relevant primary cell system.

This article is a commentary on Baker, pp. 1048–1061 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476‐5381.2010.00754.x
Ants as a Measure of Effectiveness of Habitat Conservation Planning in Southern California
Authors: MITROVICH MILAN J. , MATSUDA TRITIA , PEASE KRISTA H. , FISHER ROBERT N.
Published: March 2010

Abstract:  In the United States multispecies habitat conservation plans were meant to be the solution to conflicts between economic development and protection of biological diversity. Although now widely applied, questions exist concerning the scientific credibility of the conservation planning process and effectiveness of the plans. We used ants to assess performance of one of the first regional conservation plans developed in the United States, the Orange County Central‐Coastal Natural Community Conservation Plan (NCCP), in meeting its broader conservation objectives of biodiversity and ecosystem‐level protection. We collected pitfall data on ants for over 3 years on 172 sites established across a network of conservation lands in coastal southern California. Although recovered native ant diversity for the study area was high, site‐occupancy models indicated the invasive and ecologically disruptive Argentine ant (Linepithema humile) was present at 29% of sites, and sites located within 200 m of urban and agricultural areas were more likely to have been invaded. Within invaded sites, native ants were largely displaced, and their median species richness declined by more than 60% compared with uninvaded sites. At the time of planning, 24% of the 15,133‐ha reserve system established by Orange County NCCP fell within 200 m of an urban or agricultural edge. With complete build out of lands surrounding the reserve, the proportion of the reserve system vulnerable to invasion will grow to 44%. Our data indicate that simply protecting designated areas from development is not enough. If habitat conservation plans are to fulfill their conservation promise of ecosystem‐level protection, a more‐integrated and systematic approach to the process of habitat conservation planning is needed.
Confronting Uncertainty and Missing Values in Environmental Value Transfer as Applied to Species Conservation
Authors: AKTER SONIA , GRAFTON R. QUENTIN
Published: March 2010

Abstract: The nonuse (or passive) value of nature is important but time‐consuming and costly to quantify with direct surveys. In the absence of estimates of these values, there will likely be less investment in conservation actions that generate substantial nonuse benefits, such as conservation of native species. To help overcome decisions about the allocation of conservation dollars that reflect the lack of estimates of nonuse values, these values can be estimated indirectly by environmental value transfer (EVT). EVT uses existing data or information from a study site such that the estimated monetary value of an environmental good is transferred to another location or policy site. A major challenge in the use of EVT is the uncertainty about the sign and size of the error (i.e., the percentage by which transferred value exceeds the actual value) that results from transferring direct estimates of nonuse values from a study to a policy site, the site where the value is transferred. An EVT is most useful if the decision‐making framework does not require highly accurate information and when the conservation decision is constrained by time and financial resources. To account for uncertainty in the decision‐making process, a decision heuristic that guides the decision process and illustrates the possible decision branches, can be followed. To account for the uncertainty associated with the transfer of values from one site to another, we developed a risk and simulation approach that uses Monte Carlo simulations to evaluate the net benefits of conservation investments and takes into account different possible distributions of transfer error. This method does not reduce transfer error, but it provides a way to account for the effect of transfer error in conservation decision making. Our risk and simulation approach and decision‐based framework on when to use EVT offer better‐informed decision making in conservation.
Science or Slaughter: Need for Lethal Sampling of Sharks
Authors: HEUPEL M. R. , SIMPFENDORFER C. A.
Published: March 2010

Abstract:  General consensus among scientists, commercial interests, and the public regarding the status of shark populations is leading to an increasing need for the scientific community to provide information to help guide effective management and conservation actions. Experience from other marine vertebrate taxa suggests that public, political, and media pressures will play an increasingly important part in setting research, management, and conservation priorities. We examined the potential implications of nonscientific influences on shark research. In particular, we considered whether lethal research sampling of sharks is justified. Although lethal sampling comes at a cost to a population, especially for threatened species, the conservation benefits from well‐designed studies provide essential data that cannot be collected currently in any other way. Methods that enable nonlethal collection of life‐history data on sharks are being developed (e.g., use of blood samples to detect maturity), but in the near future they will not provide widespread or significant benefits. Development of these techniques needs to continue, as does the way in which scientists coordinate their use of material collected during lethal sampling. For almost half of the known shark species there are insufficient data to determine their population status; thus, there is an ongoing need for further collection of scientific data to ensure all shark populations have a future. Shark populations will benefit most when decisions about the use of lethal sampling are made on the basis of scientific evidence that is free from individual, political, public, and media pressures.
Botulinum Toxin, Physical and Occupational Therapy, and Neuromuscular Electrical Stimulation to Treat Spastic Upper Limb of Children With Cerebral Palsy: A Pilot Study
Authors: Rodríguez‐Reyes Gerardo , Alessi‐Montero Aldo , Díaz‐Martínez Leticia , Miranda‐Duarte Antonio , Pérez‐Sanpablo Alberto Isaac
Published: March 2010

Spasticity has been successfully managed with different treatment modalities or combinations. No information is available on the effectiveness or individual contribution of botulinum toxin type A (BTA) combined with physical and occupational therapy and neuromuscular electrical stimulation to treat spastic upper limb. The purpose of this study was to assess the effects of such treatment and to inform sample‐size calculations for a randomized controlled trial. BTA was injected into spastic upper limb muscles of 10 children. They received 10 sessions of physical and occupational therapy followed by 10 sessions of neuromuscular electrical stimulation on the wrist extensors (antagonist muscles). Degree of spasticity using the Modified Ashworth scale, active range of motion, and manual function with the Jebsen hand test, were assessed. Meaningful improvement was observed in hand function posttreatment (P = 0.03). Median spasticity showed a reduction trend and median amplitude of wrist range of motion registered an increase; however, neither of these were significant (P > 0.05). There is evidence of a beneficial effect of the combined treatment. Adequate information has been obtained on main outcome‐measurement variability for calculating sample size for a subsequent study to quantify the treatment effect precisely.
Detergent Decellularization of Heart Valves for Tissue Engineering: Toxicological Effects of Residual Detergents on Human Endothelial Cells
Authors: Cebotari Serghei , Tudorache Igor , Jaekel Thomas , Hilfiker Andres , Dorfman Suzanne , Ternes Waldemar , Haverich Axel , Lichtenberg Artur
Published: March 2010

Detergents are powerful agents for tissue decellularization. Despite this, the high toxicity of detergent residua can be a major limitation. This study evaluated the efficacy of detergent removal from decellularized pulmonary valves (PVs) and the consequences of repopulation with human endothelial cells (HECs). Porcine PVs were treated with 1% sodium deoxycholate (SDC), group A; 1% sodium dodecyl sulfate (SDS), group B; and a mixture of 0.5% SDC/0.5% SDS, group C (n = 5 each). After each of 10 succeeding wash cycles (WCs), samples of the washing solution (WS) were analyzed by solid phase extraction and high performance liquid chromatography for the presence of detergents. Metabolic activity of HEC was also assessed in the WS samples (cytotoxicity and MTS assays). Decellularized and washed PVs were reseeded with HEC. Histological analysis demonstrated efficient tissue decellularization in all groups. Detergents' concentration in all WSs decreased exponentially and was below 50 mg/L after 6, 8, and 4 WCs in groups A, B, and C, respectively. This concentration resulted in no significant toxic influence on cell cultures, and scaffolds could be efficiently reseeded with HEC. In conclusion, intensive washing of detergent decellularized valvular scaffolds lowers the residual contamination below a hazardous threshold and allows their successful repopulation with HEC for tissue engineering purposes.
Shape Optimization of the Diffuser Blade of an Axial Blood Pump by Computational Fluid Dynamics
Authors: Zhu Lailai , Zhang Xiwen , Yao Zhaohui
Published: March 2010

Computational fluid dynamics (CFD) has been a viable and effective way to predict hydraulic performance, flow field, and shear stress distribution within a blood pump. We developed an axial blood pump with CFD and carried out a CFD‐based shape optimization of the diffuser blade to enhance pressure output and diminish backflow in the impeller–diffuser connecting region at a fixed design point. Our optimization combined a computer‐aided design package, a mesh generator, and a CFD solver in an automation environment with process integration and optimization software. A genetic optimization algorithm was employed to find the pareto‐optimal designs from which we could make trade‐off decisions. Finally, a set of representative designs was analyzed and compared on the basis of the energy equation. The role of the inlet angle of the diffuser blade was analyzed, accompanied by its relationship with pressure output and backflow in the impeller–diffuser connecting region.