bluuebunny/crossref_metadata_2025 huggingface dataset:
Conditioned taste aversion learning
Authors: Davis Catherine M. , Riley Anthony L.
Published: January 2010

Drugs of abuse are typically discussed in terms of their rewarding effects and how these effects mediate drug taking. However, these drugs produce aversive effects that could have an important role in the overall acceptability of a drug and its likelihood of being self‐administered. Rewarding and aversive effects, then, could be interpreted as separate behavioral effects, with the balance of the two determining overall drug acceptability. Interestingly, the role of aversive effects on drug acceptability in the self‐administration preparation has received limited attention in this context. This chapter examines the aversive effects of drugs and discusses their role in drug taking. If these aversive effects serve a protective function, manipulations that alter or decrease these effects could have implications for drug taking. Several factors have been reported to alter conditioned taste aversion (CTA) learning, a preparation used in the assessment of the aversive effects of drugs in general. Two of these factors, drug history and strain, are reviewed here. By reviewing these, we intend to demonstrate the protective nature of aversive effects in the initiation and escalation of drug taking and to provide evidence that reductions in aversive effects could produce changes in patterns of drug self‐administration that could lead to an increased vulnerability to abuse drugs by altering the reward–aversion balance. The aim of this chapter is not to question the importance of rewarding effects in self‐administration but rather to provide evidence that aversive effects are an important factor that needs to be considered in discussions of drug‐taking behavior.
Regulation of the dopamine transporter
Authors: Schmitt Kyle C. , Reith Maarten E. A.
Published: January 2010

Dopaminergic signaling in the brain is primarily modulated by dopamine transporters (DATs), which actively translocate extraneuronal dopamine back into dopaminergic neurons. Transporter proteins are highly dynamic, continuously trafficking between plasmalemmal and endosomal membranes. Changes in DAT membrane trafficking kinetics can rapidly regulate dopaminergic tone by altering the number of transporters present at the cell surface. Various psychostimulant DAT ligands—acting either as amphetamine‐like substrates or cocaine‐like nontranslocated inhibitors—affect transporter trafficking, triggering rapid insertion or removal of plasmalemmal DATs. In this review, we focus on the effects of psychostimulants of addiction (particularlyd‐methamphetamine and cocaine) on DAT regulation and membrane trafficking, with an emphasis on how these drugs may influence intracellular signaling cascades and transporter‐associated scaffolding proteins to affect DAT regulation. In addition, we consider involvement of presynaptic receptors for dopamine and other ligands in DAT regulation. Finally, we discuss possible implications of transporter regulation to the putative toxicity of several substituted amphetamine derivatives commonly used as recreational drugs, as well as to the design of therapeutics for cocaine addiction.
Addictions and their familiality in Iceland
Authors: Tyrfingsson Thorarinn , Thorgeirsson Thorgeir E. , Geller Frank , Runarsdóttir Valgerdur , Hansdóttir Ingunn , Bjornsdottir Gyda , Wiste Anna K. , Jonsdottir Gudrun A. , Stefansson Hreinn , Gulcher Jeffrey R. , Oskarsson Hogni , Gudbjartsson Daniel , Stefansson Kari
Published: January 2010

Here, we provide an overview of previous family studies of addiction and present a new family study based on clinical data for more than 19,000 individuals who have been treated for addiction in Iceland over the last three decades. Coupled with the extensive Icelandic genealogy information, this population‐based sample provides a unique opportunity for family studies. The relative risk (RR) was determined for up to fifth‐degree relatives of probands diagnosed with alcohol, cannabis, sedative, and amphetamine dependence. We observe highly significant RR values for all substances ranging from 2.27 for alcohol to 7.3 for amphetamine, for first‐degree relatives, and RRs significantly above 1 for distant relations, where the effect of shared environmental factors is minimized. The magnitude of risk in psychostimulant dependence is particularly striking. These findings emphasize the role of genetics in the etiology of addiction and highlight the importance of substance‐specific effects.
Synaptic plasticity in the mesolimbic system
Authors: Chen Billy T. , Hopf F. Woodward , Bonci Antonello
Published: January 2010

In an ever‐changing environment, animals must learn new behavioral strategies for the successful procurement of food, sex, and other needs. Synaptic plasticity within the mesolimbic system, a key reward circuit, affords an animal the ability to adapt and perform essential goal‐directed behaviors. Ironically, drugs of abuse can also induce synaptic changes within the mesolimbic system, and such changes are hypothesized to promote deleterious drug‐seeking behaviors in lieu of healthy, adaptive behaviors. In this review, we will discuss drug‐induced neuroadaptations in excitatory transmission in the ventral tegmental area and the nucleus accumbens, two critical regions of the mesolimbic system, and the possible role of dopamine receptors in the development of these neuroadaptations. In particular, we will focus our discussion on recent studies showing changes in AMPA receptor function as a common molecular target of addictive drugs, and the possible behavioral consequences of such neuroadaptations.
Electrophysiological correlates of abused drugs
Authors: Deadwyler Sam A.
Published: January 2010

The addictive consequences of abused substances depend upon activation of neurons in reward centers of the brain. Investigations aimed at determining the underlying basis for substance abuse have resulted in breakthroughs related to drug actions on normal neural processes; for example, the singular role of dopamine as the basis for drug addiction has been revised to include effects that, with other transmitter systems, produce changes in target neuronal firing that are different from those previously assumed, including “reward value” at the neuronal and systems levels and changes in the significance of pursued stimuli as a function of motivational state, context, effort, salience, and cognitive demand. Studies comparing these factors directly show differences between the actions of abused substances and less potent food‐related rewards. Characterization of the change in reward‐encoding processes for drug and natural rewards has provided insight into how abused substances gain control over behavior. This report explores how abused drugs alter neuron firing in reward‐sensitive brain regions and how those alterations effect drug‐seeking activity in animals and humans.
Search for genetic markers and functional variants involved in the development of opiate and cocaine addiction and treatment
Authors: Yuferov Vadim , Levran Orna , Proudnikov Dmitri , Nielsen David A. , Kreek Mary Jeanne
Published: January 2010

Addiction to opiates and illicit use of psychostimulants is a chronic, relapsing brain disease that, if left untreated, can cause major medical, social, and economic problems. This article reviews recent progress in studies of association of gene variants with vulnerability to develop opiate and cocaine addictions, focusing primarily on genes of the opioid and monoaminergic systems. In addition, we provide the first evidence of acis‐acting polymorphism and a functional haplotype in thePDYNgene, of significantly higher DNA methylation rate of theOPRM1gene in the lymphocytes of heroin addicts, and significant differences in genotype frequencies of three single‐nucleotide polymorphisms of the P‐glycoprotein gene (ABCB1) between “higher” and “lower” methadone doses in methadone‐maintained patients. In genomewide and multigene association studies, we found association of several new genes and new variants of known genes with heroin addiction. Finally, we describe the development and application of a novel technique: molecular haplotyping for studies in genetics of drug addiction.
Office of National Drug Control Policy
Authors: Madras Bertha K.
Published: January 2010

This essay describes how a basic scientist was thrust into the epicenter, the political cauldron of our national drug control policy, and how the experience altered her professional trajectory and perspective.
Physicochemical Effects of the Lipid Phase and Protein Level on Meat Emulsion Stability, Texture, and Microstructure
Authors: Youssef M.K. , Barbut S.
Published: January 2010

ABSTRACT:  The effects of beef fat (25%) substitution with rendered beef fat, canola oil, palm oil, or hydrogenated palm oil at varying meat protein levels (8%, 11%, and 14%) were studied in emulsified beef meat batters. There was no significant difference in fat loss among meat batters made with beef fat, rendered beef fat, or palm oil. Hydrogenated palm oil provided the most stable batters at all protein levels. Increasing meat protein to 14% resulted in high fat loss in batters prepared with canola oil, which did not occur in the other formulations. This indicates that the physicochemical characteristics of fat/oil affect emulsion stability. Cooked batter hardness was higher (P < 0.05) when protein level was raised; highest in hydrogenated palm oil batters when compared at similar protein levels. As protein level was raised springiness values were increased in all the meat treatments. Springiness was higher in the canola oil treatments. Light microscopy revealed fat globule coalescence in canola oil meat batters prepared with 14% protein, as well as the development of fat channels and more protein aggregation; both seem to result in lower emulsion stability. Hydrogenated palm oil batters showed fat particles with sharp edges as opposed to the round ones seen in all other treatments.
Potent Anticariogenic Activity of Aceriphyllum rossii and Its Components, Aceriphyllic Acid A and 3‐oxoolean‐12‐en‐27‐oic Acid
Authors: Zheng Chang‐Ji , Oh Hyun‐Woo , Kim Won‐Gon
Published: January 2010

ABSTRACT:  Aceriphyllum rossii Engler (Saxifragaceae) have been used as a nutritious food in Korea. We found that the methanol extract of A. rossii root and its components, aceriphyllic acid A and 3‐oxoolean‐12‐en‐27‐oic acid, potently inhibited the growth of the key cariogenic bacteria, Streptococcus mutans, with MIC of 2 to 4 μg/mL. They also showed antibacterial activity against other cariogenic bacteria such as S. oralis, S. sobrinus, and S. salivarius with the similar potency. In the time‐kill study, aceriphyllic acid A reduced the viable counts of S. mutans by 90% in 1 min at 8 μg/mL, indicating that aceriphyllic acid A had the fast bacteriostatic activity. Severe damages of the cell surface of S. mutans by aceriphyllic acid A were observed by transmission electron microscopy, suggesting with its fast antibacterial activity that its mechanism of action might be membrane disruption. These results suggest that the methanol extract of A. rossii root and its components, aceriphyllic acid A and 3‐oxoolean‐12‐en‐27‐oic acid, could have the great potential as natural agents for preventing dental caries.
Inactivation of Listeria monocytogenes in Skim Milk and Liquid Egg White by Antimicrobial Bottle Coating with Polylactic Acid and Nisin
Authors: Jin Tony
Published: January 2010

ABSTRACT: This study was to develop an antimicrobial bottle coating method to reduce the risk of outbreaks of human listeriosis caused by contaminated liquid foods. Liquid egg white and skim milk were inoculated with Listeria monocytogenes Scott A and stored in glass jars that were coated with a mixture of polylactic acid (PLA) polymer and nisin. The efficacy of PLA per nisin coating in inactivating L. monocytogenes was investigated at 10 and 4 °C. The pathogen grew well in skim milk without PLA/nisin coating treatments, reaching 8 log CFU/mL after 10 d and then remained constant up to 42 d at 10 °C. The growth of Listeria at 4 °C was slower than that at 10 °C, taking 21 d to obtain 8 log CFU/mL. At both storage temperatures, the PLA coating with 250 mg nisin completely inactivated the cells of L. monocytogenes after 3 d and throughout the 42‐d storage period. In liquid egg white, Listeria cells in control and PLA coating without nisin samples declined 1 log CFU/mL during the first 6 d at 10 °C and during 28 d at 4 °C, and then increased to 8 or 5.5 log CFU/mL. The treatment of PLA coating with 250 mg nisin rapidly reduced the cell numbers of Listeria in liquid egg white to undetectable levels after 1 d, then remained undetectable throughout the 48 d storage period at 10 °C and the 70 d storage period at 4 °C. These data suggested that the PLA/nisin coating treatments effectively inactivated the cells of L. monocytogenes in liquid egg white and skim milk samples at both 10 and 4 °C. This study demonstrated the commercial potential of applying the antimicrobial bottle coating method to milk, liquid eggs, and possibly other fluid products.
BECOMING NEGLECTED: A PERVERSE RELATIONSHIP TO CARE
Authors: Ruszczynski Stanley
Published: January 2010

abstract

In this paper the author describes clinical work with forensic and anti‐social personality disordered patients where the clinician is placed in a countertransference situation where, in the course of what is good therapeutic work, he experiences an overwhelming sense of having failed the patient. The author utilizes Glasser's idea of ‘identification with the neglector’ and Hinshelwood's writings on patients with disordered relations to care, to examine this experience, and he differentiates it from the concept of ‘identification with the aggressor’. Two clinical illustrations are used to highlight the issues discussed and show how with this patient group much of the clinical work is done in the countertransference.
SEXUAL BOUNDARY VIOLATIONS: A PSYCHOANALYTIC PERSPECTIVE
Authors: Levine Howard B.
Published: January 2010

abstract

The problem of sexual boundary violations in psychoanalytic therapies was endemic for the founding generation of psychoanalysts and remains so for analytic therapists to this day. Its persistence in our field reflects the fact that each of us contains powerful unconscious forces that can drive us towards boundary crossings and boundary violations. Contemporary views of the analytic process, including the impossibility of neutrality, objectivity and abstinence and the therapist's irreducible subjectivity, are used to explicate the dynamic forces involved. Personal and institutional responses to sexual boundary violations are considered.
SEDUCTION AND BETRAYAL
Authors: Gerrard Jackie
Published: January 2010

abstract

This paper addresses the issues of seduction and betrayal, in particular as they manifest in the consulting room. The author notes the universality and primitive nature of these issues, which originate between mother and child at a pre‐oedipal level and are rife between parents and children during the oedipal stage. In addition, the author highlights a post‐oedipal stage of development and illustrates her themes with clinical material from work with two male patients. She claims that revenge is the natural response to the feeling of having been seduced and then betrayed. Finally, she suggests that moments of seduction are vital and can be a significant focal point during analyses of patients.
TEACHING AND LEARNING ABOUT PSYCHOANALYSIS: FILM AS A TEACHING TOOL, WITH REFERENCE TO A PARTICULAR FILM, MORVERN CALLAR
Authors: Edwards Judith
Published: January 2010

abstract

Using the film, Morvern Callar, directed by Lynne Ramsay (2002a) in order to reflect on the impact of the countertransference, the author suggests that film is a powerful medium which can be used to communicate intense emotional and preverbal states, and to make sense of certain key psychoanalytic concepts via a direct emotional experience. Describing the film's narrative, with particular reference to the central character, she links this with predominantly Kleinian psychoanalytic thinking about schizoid states, and puts forward the idea that, by watching the film in a particular way, non‐clinical students may have the proto‐experience of aspects of clinical work, especially those linked with the countertransference. This, she suggests, offers a bridge towards clinical experience possibly obtained at a later date, where emotional states may be projected into the clinician.
Pregnenolone, Dehydroepiandrosterone, and Schizophrenia: Alterations and Clinical Trials
Authors: Ritsner Michael S.
Published: January 2010

Neurosteroids, such as pregnenolone (PREG), dehydroepiandrosterone (DHEA), and their sulfates (PREGS and DHEAS) are reported to have a modulatory effect on neuronal excitability and synaptic plasticity. They also have many other functions associated with neuroprotection, response to stress, mood regulation, and cognitive performance. Furthermore, these neurosteroids have been linked to, and their levels are altered in, neuropsychiatric disorders. This review highlights what is currently known about the metabolism and mode of action of PREG and DHEA, as well as about alterations of these neurosteroids in schizophrenia. This review also provides substantial information about clinical trials with DHEA and PREG augmentation with of antipsychotic agents in schizophrenia.
Pregabalin in the Treatment of Alcohol and Benzodiazepines Dependence
Authors: Oulis Panagiotis , Konstantakopoulos George
Published: January 2010

We review all available studies on the use of the newer anticonvulsant drug pregabalin (PGB) in the treatment of both alcohol dependence (AD) and benzodiazepine dependence (BD). In AD, the available evidence includes one open‐label and one double‐blind randomized studies, whereas in BD, only a few case reports and one open‐label study are as yet available. In both conditions, PGB was found efficacious with significant improvement in withdrawal symptoms at the dosage ranges of 150–450 mg/day (AD) and 225–900 mg/day (BD). Moreover, its side effects were mild and transient. Despite the limited quality of the studies design, their findings suggest that PGB might constitute a novel efficacious and safe option in the treatment of both AD and BD.
Managing the Challenges of Complex Interdependence: China and the United States in the Era of Globalization
Authors: Zhao Quansheng , Liu Guoli
Published: January 2010

This article examines the increasing complex interdependence of China and the United State in an era of globalization. Deng Xiaoping's strategy of reform and opening requires a peaceful international environment. The normalization of relations with Washington was critical for China's move toward modernization. As China opens its door wider, Sino‐American relations have matured to a much higher level. As the recent Strategic Economic Dialogue between Beijing and Washington indicate, bilateral relations have become truly interdependent. Interdependence creates both sensitivity and vulnerability. Lampton has described U.S.‐China relations in terms of “same bed, different dreams” (tongchuang yimeng). Considering the common challenges of global financial crisis and international terrorism, perhaps it is more appropriate to think of China and the United States as strategic partners sailing in the same boat (tongzhou gongji). The complex interdependence between the two countries is particularly critical in an age of global turbulence. This article analyzes the current challenges of China‐U.S. relations in the context of turbulent globalization.
Toward Understanding Islamic Corporate Governance Issues in Islamic Finance
Authors: Bhatti Maria , Bhatti M. Ishaq
Published: January 2010

This article presents recent developments on legal issues associated with corporate governance in the Islamic finance industry based on a contractual pyramid. It presents the Islamic corporate governance (ICG) model and discusses its viability in a 21st‐century corporate structure. The model is based on the institution of Hisba, which demands proper and honest bookkeeping, disclosure, and transparency based on the Shariah principles of Islamic ethics. This article proposes a model of ICG that reconciles the objectives of Shariah law with the stakeholder model of corporate governance. It argues that this may be viable due to the emphasis that Shariah laws place on property and Islamic financial contractual rights. The article also discusses a model of ICG that is consistent with principles outlined by the Organisation for Economic Co‐operation and Development as well as Shariah law. Such a model of corporate governance would encourage capital formation, foster strong markets, and encourage judgment and transparency, which are all principles central to Shariah laws.
Co‐Opting the Wolves: National Film Industry Reform in China After 1978
Authors: Chu Katherine Kit Ling
Published: January 2010

This article is about the relationship between the film industry, society, and the state, in the context of economic reforms. I first provide an overview of current writings on the field and then explain the film industry's structure since 1949. I also examine policy changes over the past 30 years. What exactly did the state change? And why did it change? By way of analyzing Chinese cinema, this article examines the relationship between the market, the state, society, and transnational capital. Although the government has increasingly been in favor of a market economy, it has never given up its official ideology over films. Moreover, the domestic film industry did not collapse after the entry of transnational capital; instead, the state successfully co‐opted the “wolves” not only to save the film industry but also to enable the state to accumulate both economic and political capital.
Passivation of AlN∕GaN high electron mobility transistor using ozone treatment
Authors: Lo C. F. , Chang C. Y. , Pearton S. J. , Kravchenko I. I. , Dabiran A. M. , Wowchak A. M. , Cui B. , Chow P. P. , Ren F.
Published: January 2010

Ozone treatment of AlN on AlN∕GaN heterostructures produces effective surface passivation and chemical resistance to the AZ positive photoresist developer used for subsequent device fabrication. The ozone-passivated AlN∕GaN high electron mobility transistors (HEMTs) exhibited low gate leakage currents, high gate modulation voltage, and minimal drain current degradation during gate pulse measurements. With an additional oxygen plasma treatment on the gate area prior to the gate metal deposition, enhancement-mode AlN∕GaN high electron mobility transistors were realized. The gate characteristics of the HEMTs treated with the ozone and oxygen plasma behaved in a manner similar to a metal oxide semiconductor diodelike gate current-voltage characteristic instead of a Schottky diode. Drain breakdown voltages of 23 and 43V for d- and e-mode HEMTs were obtained, respectively. For d-mode HEMTs, there was no reduction in the drain current during the gate pulse measurements at frequencies of 1, 10, and 100kHz. For the e-mode HEMT, the drain current was reduced 5% at 100kHz.
Axon Extension Occurs Independently of Centrosomal Microtubule Nucleation
Authors: Stiess Michael , Maghelli Nicola , Kapitein Lukas C. , Gomis-Rüth Susana , Wilsch-Bräuninger Michaela , Hoogenraad Casper C. , Tolić-Nørrelykke Iva M. , Bradke Frank
Published: January 2010

Centrosome-Free Axonal Regeneration

Neuronal axon growth is thought to depend on microtubules that are assembled at the centrosome, the classical microtubule organizing center (MTOC), which may even dictate axon growth. However, such a local trigger of neuronal polarization and focal microtubule nucleation in the cell body appears difficult to reconcile with the sophisticated microtubule arrays observed in neurons. Now,

Stiess
et al.

(p.
704
, published online 7 January) provide evidence, through physical ablation of the centrosome in mammalian neurons, that axon growth is regulated by acentrosomal microtubule nucleation. The findings suggest that the centrosome loses its function as an MTOC during neuronal development, that axon growth depends on decentralized microtubule assembly, and that neuronal differentiation takes place in the absence of a functional centrosome.
The Future of Antiplatelet Therapy in Cardiovascular Disease
Authors: Patrono Carlo , Rocca Bianca
Published: January 2010

Mechanisms of platelet inhibition are reviewed with emphasis on the pharmacokinetic and pharmacodynamic determinants of clinical efficacy and safety of antiplatelet drugs. Current developments in antiplatelet therapy are discussed in relation to both primary and secondary prevention of atherothrombotic complications. Interindividual variability in response to antiplatelet agents and new drug targets are outlined within the context of optimizing the balance between the cardiovascular benefits and bleeding risks of antiplatelet therapy. Recent advances in the pharmacogenetics of thienopyridines open the realistic prospect of a personalized choice of the most appropriate antiplatelet agent and tailored dose adjustment for an individual patient.
Contemporary Use of Ventricular Assist Devices
Authors: Terracciano Cesare M. , Miller Leslie W. , Yacoub Magdi H.
Published: January 2010

The introduction of the heart lung machine more than 50 years ago proved in principle that heart function can be replaced, albeit for short periods. This was followed by attempts to produce total or partial artificial hearts that could function for prolonged periods of time. Progress in this field has been intermittent but has accelerated considerably in the past 10 years, with ventricular assist devices (VADs) reaching an impressive degree of sophistication and complexity owing to the contributions from clinicians, engineers, scientists, industrialists, and others. This review describes the currently available types of VADs, their current clinical use, the patient selection process, the trend toward use of VADs in patients with less severe heart failure, and the use of VADs for myocardial recovery in combination with novel pharmacological strategies, gene therapy, and cell therapy.
Heparin-Induced Thrombocytopenia
Authors: Arepally Gowthami M. , Ortel Thomas L.
Published: January 2010

Heparin-induced thrombocytopenia (HIT) is an immune-mediated hypercoagulable disorder caused by antibodies to platelet factor 4 (PF4) and heparin. HIT develops in temporal association with heparin therapy and manifests either as an unexplained thrombocytopenia or thrombocytopenia complicated by thrombosis. The propensity for thrombosis distinguishes HIT from other common drug-induced thrombocytopenias. Diagnosing HIT in hospitalized patients is often challenging because of the frequency of heparin use, occurrence of thrombocytopenia from other causes, and development of asymptomatic PF4/heparin antibodies in patients treated with heparin. This review summarizes our current understanding of the pathogenesis, clinical features, diagnostic criteria, and management approaches in HIT.
Stem Cells in the Treatment of Heart Disease
Authors: Janssens Stefan
Published: January 2010

Progenitor cells residing in bone marrow, adipose tissue, and skeletal muscle or circulating in the blood are capable of improving myocardial function in preclinical models. In contrast, early clinical studies using bone marrow cells have shown mixed results and reflect our incomplete understanding of underlying mechanisms. Recent identification of various cardiac precursor cells has suggested an endogenous reservoir for cell-based repair. However, confronted with massive cardiac cell loss, inventive strategies and enabling technologies are required to mobilize or deliver functionally competent progenitor cells to sites of injury or to effectively stimulate endogenous repair. We review our present knowledge in this promising and rapidly evolving development in cardiovascular medicine and highlight obstacles as well as opportunities.
The Role of Clock Genes in Pharmacology
Authors: Paschos Georgios K. , Baggs Julie E. , Hogenesch John B. , FitzGerald Garret A.
Published: January 2010

The physiology of a wide variety of organisms is organized according to periodic environmental changes imposed by the earth's rotation. This way, a large number of physiological processes present diurnal rhythms regulated by an internal timing system called the circadian clock. As part of the rhythmicity in physiology, drug efficacy and toxicity can vary with time. Studies over the past four decades present diurnal oscillations in drug absorption, distribution, metabolism, and excretion. On the other hand, diurnal variations in the availability and sensitivity of drug targets have been correlated with time-dependent changes in drug effectiveness. In this review, we provide evidence supporting the regulation of drug kinetics and dynamics by the circadian clock. We also use the examples of hypertension and cancer to show current achievements and challenges in chronopharmacology.
Epac: Defining a New Mechanism for cAMP Action
Authors: Gloerich Martijn , Bos Johannes L.
Published: January 2010

cAMP is a second messenger that is essential for relaying hormonal responses in many biological processes. The discovery of the cAMP target Epac explained various effects of cAMP that could not be attributed to the established targets PKA and cyclic nucleotide–gated ion channels. Epac1 and Epac2 function as guanine nucleotide exchange factors for the small G protein Rap. cAMP analogs that selectively activate Epac have helped to reveal a role for Epac in processes ranging from insulin secretion to cardiac contraction and vascular permeability. Advances in the understanding of the activation mechanism of Epac and its regulation by diverse anchoring mechanisms have helped to elucidate the means by which cAMP fulfills these functions via Epac.
Allosteric Receptors: From Electric Organ to Cognition
Authors: Changeux Jean-Pierre
Published: January 2010

This autobiography covers the past 50 years beginning with the development of the concept of allosteric proteins and its application to pharmacological receptors. It continues with the identification of the nicotinic acetylcholine receptor, the discovery of its molecular organization, the structure of the acetylcholine-binding site and of the ion channel, and the demonstration of its allosteric transitions. The article then traces the origins of the concept of allosteric modulator and its consequences in pharmacology. It proceeds with the theory of selective stabilization of synapses and with experimental studies carried out on the contribution of the nicotinic receptor in the morphogenesis of the neuromuscular junction. The knowledge acquired with the nicotinic receptor is further exploited to reach higher levels of brain organization, and the contribution of nicotinic receptors to the action of nicotine on reward and cognition is explored, in particular, using a novel experimental strategy that combines nicotinic receptor genes knock-out and stereotaxic gene re-expression. Theoretical models of cognitive functions are proposed that link the molecular to the cognitive level. The report ends with a discussion on nicotinic receptors and the pharmacology of the future.
Economic Opportunities and Challenges for Pharmacogenomics
Authors: Deverka Patricia A. , Vernon John , McLeod Howard L.
Published: January 2010

Economic evaluation provides health care decision makers with a powerful tool for resource allocation decisions because it offers a framework for comparing the costs and benefits of competing interventions or options. This paper reviews how economic analyses have been applied to the field of pharmacogenomics, both by the pharmaceutical industry to inform investment decisions and by payers to make coverage decisions. There is much anticipation that pharmacogenomic testing is likely to be cost-effective because it uses genomic information to improve drug effectiveness and reduce toxicity both in the drug development process and at the bedside. However, the demonstration of economic benefits first requires that pharmacogenomic testing show evidence of clinical effectiveness. This will only be achieved by greater participation of pharmacogenomics experts in comparative effectiveness research and additional emphasis on including costs in the determination of the relative value of pharmacogenomic testing to the health care system.
Circadian Timing in Cancer Treatments
Authors: Lévi Francis , Okyar Alper , Dulong Sandrine , Innominato Pasquale F. , Clairambault Jean
Published: January 2010

The circadian timing system is composed of molecular clocks, which drive 24-h changes in xenobiotic metabolism and detoxification, cell cycle events, DNA repair, apoptosis, and angiogenesis. The cellular circadian clocks are coordinated by endogenous physiological rhythms, so that they tick in synchrony in the host tissues that can be damaged by anticancer agents. As a result, circadian timing can modify 2- to 10-fold the tolerability of anticancer medications in experimental models and in cancer patients. Improved efficacy is also seen when drugs are given near their respective times of best tolerability, due to (a) inherently poor circadian entrainment of tumors and (b) persistent circadian entrainment of healthy tissues. Conversely, host clocks are disrupted whenever anticancer drugs are administered at their most toxic time. On the other hand, circadian disruption accelerates experimental and clinical cancer processes. Gender, circadian physiology, clock genes, and cell cycle critically affect outcome on cancer chronotherapeutics. Mathematical and systems biology approaches currently develop and integrate theoretical, experimental, and technological tools in order to further optimize and personalize the circadian administration of cancer treatments.
Macrophage-mediated phagocytosis of apoptotic cholangiocytes contributes to reversal of experimental biliary fibrosis
Authors: Popov Yury , Sverdlov Deanna Y. , Bhaskar K. Ramakrishnan , Sharma Anisha K. , Millonig Gunda , Patsenker Eleonora , Krahenbuhl Stephan , Krahenbuhl Lukas , Schuppan Detlef
Published: January 2010

Studies have suggested the reversibility of liver fibrosis, but the mechanisms of fibrosis reversal are poorly understood. We investigated the possible functional link between apoptosis, macrophages, and matrix turnover in rat liver during reversal of fibrosis secondary to bile duct ligation (BDL). Biliary fibrosis was induced by BDL for 4 wk. After Roux-en-Y (RY)-bilio-jejunal-anastomosis, resolution of fibrosis was monitored for up to 12 wk by hepatic collagen content, matrix metalloproteinase (MMP) expression and activities, and fibrosis-related gene expression. MMP expression and activities were studied in macrophages after engulfment of apoptotic cholangiocytes in vitro. Hepatic collagen decreased to near normal at 12 wk after RY-anastomosis. During reversal, profibrogenic mRNA declined, whereas expression of several profibrolytic MMPs increased. Fibrotic septa showed fragmentation at week 4 and disappeared at week 12. Peak histological remodeling at week 4 was characterized by massive apoptosis of cytokeratin 19+ cholangiocytes, >90% in colocalization with CD68+ macrophages, and a 2- to 7.5-fold increase in matrix-degrading activities. In vitro, phagocytosis of apoptotic cholangiocytes induced matrix-degrading activities and MMP-3, -8, and -9 in rat peritoneal macrophages. We concluded that reconstruction of bile flow after BDL leads to an orchestrated fibrolytic program that results in near complete reversal of advanced fibrosis. The peak of connective tissue remodeling and fibrolytic activity is associated with massive apoptosis of cholangiocytes and their phagocytic clearance by macrophages in vivo. Macrophages upregulate MMPs and become fibrolytic effector cells upon apoptotic cholangiocyte engulfment in vitro, suggesting that phagocytosis-associated MMP induction in macrophages significantly contributes to biliary fibrosis reversal.
Preoxygenated hemoglobin-based oxygen carrier HBOC-201 annihilates myocardial ischemia during brief coronary artery occlusion in pigs
Authors: te Lintel Hekkert Maaike , Dubé Gregory P. , Regar Evelyn , de Boer Martine , Vranckx Pascal , van der Giessen Wim J. , Serruys Patrick W. , Duncker Dirk J.
Published: January 2010

Because of their ability to perfuse remote regions and deliver oxygen, hemoglobin-based oxygen carriers (HBOCs) may be considered in the treatment of several ischemic conditions such as acute coronary syndromes or high-risk percutaneous intervention. Here we studied the effects of intracoronary infusion of ex vivo preoxygenated HBOC-201 during brief total coronary artery occlusion (CAOs) on myocardial oxygenation and left ventricular (LV) function in a large animal model and investigated the influence of HBOC-201 temperature and infusion rate on these effects. Thirteen open-chest anesthetized swine were instrumented for measurement of global and regional LV function and metabolism. CAOs were induced by inflating an intracoronary balloon catheter; preoxygenated HBOC-201 (12 g/dL) was infused distally through the central lumen of the balloon catheter. Animals underwent consecutive 3-min CAOs interspersed by 30 min of reperfusion, accompanied by different HBOC-201 infusion rates (0, 15, 23, 30, 40, and 50 ml/min) and/or two infusion temperatures (18°C or 37°C) in random order. CAO elicited immediate loss of systolic shortening (SS) in the ischemic region (19 ± 1% at baseline vs. −3 ± 2% at end of CAO), resulting in decreases in maximum rate of rise in LV pressure (15 ± 5%) and stroke volume (12 ± 4%; all P < 0.05). Balloon deflation resulted in marked coronary reactive hyperemia (to 472 ± 74% of baseline), increases in coronary venous concentrations of adenosine + inosine (to 218 ± 26% of baseline; both P < 0.05) and rapid restoration of SS toward baseline. HBOC-201 ameliorated the CAO-induced changes in SS, stroke volume, reactive hyperemia, and coronary venous adenosine + inosine. The effects were temperature and flow dependent with full preservation of SS at 50 ml/min HBOC-201 of 37°C. In conclusion, intracoronary preoxygenated HBOC-201 preserved myocardial oxygenation and LV function in swine during CAO in a dose- and temperature-dependent manner. In our study setting, preoxygenated HBOC-201 can match the oxygen delivery role of endogenous blood in the heart on an almost equivalent-volume basis.
Carbohydrate feeding during recovery alters the skeletal muscle metabolic response to repeated sessions of high-intensity interval exercise in humans
Authors: Cochran Andrew J. R. , Little Jonathan P. , Tarnopolsky Mark A. , Gibala Martin J.
Published: January 2010

Exercise training under conditions of reduced carbohydrate (CHO) availability has been reported to augment gains in skeletal muscle oxidative capacity; however, the underlying mechanisms are unclear. We examined the effect of manipulating CHO intake on the acute metabolic response to high-intensity interval exercise, including signaling cascades linked to mitochondrial biogenesis. Ten men performed two trials in random order separated by ≥1 wk. Each trial consisted of a morning (AM) and afternoon (PM) training session (5 × 4 min cycling at ∼90–95% of heart rate reserve) separated by 3 h of recovery during which subjects ingested a high-CHO drink (HI-HI) or nonenergetic placebo (HI-LO) before PM exercise. Biopsies (vastus lateralis) revealed that muscle phosphocreatine and ATP content were similar after AM exercise but decreased to a greater extent during PM exercise in HI-LO vs. HI-HI. Phosphorylation of p38 mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) increased ∼4-fold and 2-fold, respectively, during AM exercise with no difference between conditions. After PM exercise, p38 MAPK phosphorylation was higher in HI-LO vs. HI-HI, whereas AMPK was not different between conditions. Peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) gene expression increased ∼8-fold during recovery from AM exercise and remained elevated during PM exercise with no differences between conditions. Cytochrome oxidase subunit 4 (COXIV) mRNA was also elevated 3 h after AM exercise, with no difference between conditions. These data provide evidence that p38 MAPK is a nutrient-sensitive signaling molecule that could be involved in the altered skeletal muscle adaptive response reported after exercise training under conditions of restricted CHO intake, but further research is required to confirm this hypothesis.
Retrograde arterial leg blood flow during tilt-back from a head-up posture: importance of capacitive flows when arterial pressure changes
Authors: Sheriff Don D. , Nådland Inger Helene , Toska Karin
Published: January 2010

The windkessel function of the arterial system converts the intermittent action of the heart into more continuous microcirculatory blood flow during diastole via the return of elastic energy stored in the walls of the arteries during systole. Might the same phenomenon occur regionally within the arterial system during tilting owing to regional differences in local arterial pressure imposed by gravity? We sought to test the hypothesis that during tilt-back from a head-up posture, the return of stored elastic energy in leg arteries would work to slow, or perhaps transiently reverse, the flow of blood in the femoral artery. Femoral artery blood flow and arterial pressure were recorded during tilt back from a 30° head-up posture to supine (∼0.5 G) in young, healthy subjects ( n = 7 males and 3 females) before and during clonidine infusion. During control (no drug) conditions femoral artery blood flow ceased for an entire heart beat during tilt-back. During clonidine infusion femoral artery blood flow reversed for at least one entire heart beat during tilt-back, i.e., blood flow in the retrograde direction in the femoral artery from the leg into the abdomen. Thus substantial capacitive effects of tilting on leg blood flow occur in humans during mild changes in posture.
An Interdisciplinary Approach to Teachers’ Voice Disorders and Psychosocial Working Conditions
Authors: Bermúdez de Alvear Rosa M. , Martínez Ginés A. , Barón F. Javier , Hernández-Mendo Antonio
Published: January 2010

Objectives: The goals of this epidemiological paper are focused on studying teachers’ vocal complaints, their voice pattern, and the impact of voice disorders on psychosocial working conditions. Patients: A representative stratified random sample of 282 teachers from kindergartens and elementary schools was studied. Two types of self-report questionnaires were applied: an inquiry about teachers’ occupational voice profile, and the adapted Spanish version of the Copenhagen Psychosocial Questionnaire (ISTAS-21). Pearson’s χ2 test was performed to search for statistical associations. Results: 62.7% of subjects were experiencing occupational voice disorders; these teachers showed significantly worse psychosocial conditions than their healthy voice colleagues. Conclusions: Occupational voice disorders affect more than 60% of teachers and have an impact on their psychosocial working conditions. Interdisciplinary work is essential to shed light on these multifactor mechanisms and effects.
The Impact of the Reactivity to Stress in Teachers with Voice Problems
Authors: Gassull Cecília , Casanova Cori , Botey Queralt , Amador Miquel
Published: January 2010

Aims: One of the objectives of our study on voice and vocal health was to find out whether there is a relation between the reactivity to stress and voice problems in teachers. Materials and Methods: For this, we used a sample of 447 individuals amongst future teachers and teachers in active service, since they form a group with both a high index of voice problems and stress. In order to gather the necessary information for the study, we applied the Voice Handicap Index and the ‘índice de reactividad al estrés’ (IRE; Stress Reactivity Index). Results: The results indicate that those individuals with voice problems have a greater reactivity to stress. It was observed that some items of the IRE show a relatively great difference between the groups with and without voice problems. The majority of these items concern vegetative signs that are linked to aspects of voice emission. Conclusion: Reactivity to stress is a useful factor to bear in mind in teachers with voice problems.
A Systematic, Holistic and Integrative Process of Self-Control for Voicing with Optimal Coping Effects in Teachers. 1. A Process of Awareness – An Expert’s Opinion
Authors: Van Opstal Magda J.M. Carola
Published: January 2010

A learning strategy is presented for eustress-euvoicing, which prevails over distress-disvoicing. It is based on the understanding of the mechanisms of stress-voicing, conceived as a dynamic circular process of interacting entities, i.e. stressors/signals-arousal/activation-emotion-coping-effects (SAECE), which is the rationale for a multidisciplinary approach in coaching professional voice users. A systematic, holistic and integrative process of self-control (SHIPS) is directed by functional analysis and consists of awareness and change. Emotion, a mixture of appraisal, affect and movement, is the pivot in SHIPS. SHIPS with (student) teachers aims at the competence of voicing (V) in an optimal (O) way of coping (C), which means vocal communication that is effective (E) to meet a balance in physical, interpersonal and existential wellness when responding to demands and challenges in the individual teacher’s (T) field of communication (VOCE-T). The process of awareness intends to understand the course of multiple interactions in SAECE that condition eustressors and distressors related to (non)-integrated coping. The (student) teacher and coach are conscious and active participants in the process of awareness that is dynamic and evolving and aims at the preparedness to change non-desirable habits and skill modes into VOCE-T.
A Systematic, Holistic and Integrative Process of Self-Control for Voicing with Optimal Coping Effects in Teachers. 2. A Process of Change – An Expert’s Opinion
Authors: Van Opstal Magda J.M. Carola
Published: January 2010

A learning strategy is presented for eustress-euvoicing, which prevails over distress-disvoicing. It is based on the understanding of the mechanisms of stress-voicing, conceived as a dynamic circular process of interacting entities, i.e. stressors/signals-arousal/activation-emotion-coping-effects (SAECE), which is the rationale for a multidisciplinary approach in coaching professional voice users. A systematic, holistic and integrative process of self-control (SHIPS) is directed by functional analysis and consists of awareness and change. Emotion, a mixture of appraisal, affect and movement, is the pivot in SHIPS. SHIPS with (student) teachers aims at the competence of voicing (V) in an optimal (O) way of coping (C), which means vocal communication that is effective (E) to meet a balance in physical, interpersonal and existential wellness when responding to demands and challenges in the individual teacher’s (T) field of communication (VOCE-T). The process of change intends to influence the course of multiple interactions in SAECE. SHIPS (de)conditions distressors and eutressors related to (non)-integrated coping. The (student) teacher and coach are conscious and active participants in the process of change that aims at (un)learning of attitudes and skills for coping by VOCE-T.