bluuebunny/crossref_metadata_2025 huggingface dataset:
Helicobacter pylori and its role in vocal folds' minimal lesions
Authors: Tiba Medhat , Fawaz Samia , Osman Hala
Published: March 2010

Background:  Chronic laryngitis and/or vocal fold minimal lesions (VFMLs) are common associations with gastro esophageal reflux disease. Helicobacter pylori (HP) is a Gram‐negative spiral organism accused of being a common cause of gastritis, gastroesophageal reflux disease and peptic ulcer. HP has been recently isolated from tonsils, adenoids, sinus and middle ear mucosa in patients with chronic sinusitis or chronic middle ear effusion.

Objective:  The objective of this study is to assess the presence of HP in VFMLs.

Methods:  The study included 14 patients with VFMLs [six cases with vocal fold polyps and four cases with vocal fold nodules, and four cases with posterior granulomas; one of them associated with right vocal fold (VF) nodule]; all underwent carbon‐13 urea breath test, esophago‐gastro‐duodenoscopy with gastric biopsy and direct laryngoscopy with microlaryngosurgery to extract the VF lesions. Biopsies were subjected for two tests: detection of the 23S ribosomal RNA gene of HP by real‐time polymerase chain reaction (RT‐PCR) and immunohistochemical reactions (IHC).

Results:  HP was detected by RT‐PCR in 10 of 14 patients with VFML; HP was also detected by IHC in the same number of VFML and gastric mucosa specimens.

Conclusion:  HP is a common finding in cases of VFML; its eradication should be considered when dealing with a patient with VFML.

Please cite this paper as: Tiba M, Fawaz S and Osman H. Helicobacter pylori and its role in vocal folds' minimal lesions. Clin Respir J 2010; 4: 237–240.
Charting the Road of Inquiry: Deleuze's Humean Pragmatics and the Challenge of Badiou
Authors: Bell Jeffrey
Published: March 2010

This essay responds to Badiou's charge that Deleuze fails to set forth a philosophy that is “beyond Gategorical oppositions.” It is argued that this criticism of Deleuze is founded upon a misreading of the Deleuzean distinction between the virtual and the actual, a reading that carries forward Badiou's misreading of Spinoza and, hence, of Deleuze's Spinozism. With this corrected, we show how the virtual‐actual distinction operates within the experimental philosophy, or pragmatics, that Deleuze, and later Deleuze and Guattari, sets forth. It is this pragmatics that is precisely the philosophy of difference that is beyond categorical oppositions. Through a comparison of Deleuzean pragmatics with the work of Hume and Peirce, we are able to respond to Badiou's further criticism that Deleuze's philosophy fails to understand the conditions for creativity in thought and culture. This criticism is itself resolved once one corrects for Badiou's misreading of Deleuze's virtual‐actual distinction.
Plato on a Mistake about Pleasure
Authors: Erginel Mehmet M.
Published: March 2010

Plato argues in Republic IX that people are often mistaken about their own pleasures and pains. One of the mistakes he focuses on is judging that an experience of ours is pleasant when, in fact, it is not. The view that such a mistake is possible is an unpopular one, and scholars have generally been dismissive of Plato's position. Thus Urmson argues not only that this position is deeply flawed, but also that it results from a confusion on Plato's part. In this paper, I show that Urmson's criticism is misguided. I then defend Plato against the idea that it is impossible for someone to make the mistake in question. In doing so, I bring out details in Plato's text and show that his account of the phenomenology involved in making this mistake is far more sophisticated than has so far been recognized.
Logic as a Universal Medium or Logic as a Calculus? Husserl and the Presuppositions of “the Ultimate Presupposition of Twentieth Century Philosophy”
Authors: Hartimo Mirja
Published: March 2010

This paper discusses Jean van Heijenoort's (1967) and Jaakko and Merrill B. Hintikka's (1986, 1997) distinction between logic as a universal language and logic as a calculus, and its applicability to Edmund Husserl's phenomenology. Although it is argued that Husserl's phenomenology shares characteristics with both sides, his view of logic is closer to the model‐theoretical, logic‐as‐calculus view. However, Husserl's philosophy as transcendental philosophy is closer to the universalist view. This paper suggests that Husserl's position shows that holding a model‐theoretical view of logic does not necessarily imply a calculus view about the relations between language and the world. The situation calls for reflection about the distinction: It will be suggested that the applicability of the van Heijenoort and the Hintikkas distinction either has to be restricted to a particular philosopher's views about logic, in which case no implications about his or her more general philosophical views should be inferred from it; or the distinction turns into a question of whether our human predicament is inescapable or whether it is possible, presumably by means of model theory, to obtain neutral answers to philosophical questions. Thus the distinction ultimately turns into a question about the correct method for doing philosophy.
The Euthyphro Argument (9d–11b)
Authors: O'Sullivan Brendan
Published: March 2010

A sizable literature exists concerning the structure of Socrates' argument at Euthyphro 9d–11b. Although there is some dispute, a substitutional reading has emerged as a leading interpretation. However, some rear‐guard maneuvers are in order to defend this reading against its competitors. In this paper, I articulate a substitutional reading and argue that it is invalid on two counts: one, Socrates oversteps the logic of his reductio ad absurdum, and two, he illicitly substitutes coreferring expressions in explanatory contexts. Next, I defend the substitutional reading by (1) rebutting its leading contender, Sharvy's formal causation interpretation, and (2) showing how a similar substitutional argument is made in the Protagoras.
Meaning‐Theories and the Principle of Humanity
Authors: Whiting Daniel
Published: March 2010

In this paper, I briefly outline the notion of a truth‐conditional meaning‐theory and introduce two prominent problems it faces. The “extensionality problem” arises because not all correct specifications of truth‐conditions are meaning‐giving. The “explanatory problem” concerns the extent to which truth‐conditional meaning‐theories can contribute to the task of clarifying the nature of linguistic meaning. The “principle of humanity” is supposed to resolve both issues simultaneously. I argue that it fails to do so.
Groupthink versus The Wisdom of Crowds: The Social Epistemology of Deliberation and Dissent
Authors: Solomon Miriam
Published: March 2010

Trust in the practice of rational deliberation is widespread and largely unquestioned. This paper uses recent work from business contexts to challenge the view that rational deliberation in a group improves decisions. Pressure to reach consensus can, in fact, lead to phenomena such as groupthink and to suppression of relevant data. Aggregation of individual decisions, rather than deliberation to a consensus, surprisingly, can produce better decisions than those of either group deliberation or individual expert judgment. I argue that dissent is epistemically valuable, not because of the discussion it can provoke (Mill's and Longino's view about the benefit of dissent), but because dissenting positions often are associated with particular data or insights that would be lost in consensus formation. Social epistemologists can usefully pay attention to various methods of aggregation of individual opinion for their effectiveness at realizing epistemic goals.
Socially Naturalized Norms of Epistemic Rationality: Aggregation and Deliberation
Authors: Wylie Alison
Published: March 2010

In response to those who see rational deliberation as a source of epistemic norms and a model for well‐functioning scientific inquiry, Solomon cites evidence that aggregative techniques often yield better results; deliberative processes are vulnerable to biasing mechanisms that impoverish the epistemic resources on which group judgments are based. I argue that aggregative techniques are similarly vulnerable and illustrate this in terms of the impact of gender schemas on both individual and collective judgment. A consistently externalist and socially naturalized approach calls for symmetrical treatment of these strategies for capitalizing on what groups know.
Kantian Lessons about Mind, Meaning, and Rationality*
Authors: Brandom Robert
Published: March 2010

Kant's innovative normative characterization of what one is doing in judging is appealed to as the basis of a story about how he moves from an inferential to a representational characterization of the contents of judgment. His normative notion of freedom and his demarcation of the normative in terms of autonomy are connected to his account of the status of modal concepts.
Group Agency and Supervenience
Authors: List Christian , Pettit Philip
Published: March 2010

Can groups be rational agents over and above their individual members? We argue that group agents are distinguished by their capacity to mimic the way in which individual agents act and that this capacity must “supervene” on the group members' contributions. But what is the nature of this supervenience relation? Focusing on group judgments, we argue that, for a group to be rational, its judgment on a particular proposition cannot generally be a function of the members' individual judgments on that proposition. Rather, it must be a function of their individual sets of judgments across many propositions. So knowing what the group members individually think about some proposition does not generally tell us how the group collectively adjudicates that proposition: the supervenience relation must be “setwise,” not “proposition‐wise.” Our account preserves the individualistic view that group agency is nothing mysterious but also suggests that a group agent may hold judgments that are not directly continuous with its members' corresponding individual judgments.
The Social Diffusion of Warrant and Rationality
Authors: Goldberg Sanford C.
Published: March 2010

Many people agree that a proper epistemological treatment of testimonial knowledge will regard testimonial warrant — the total truth‐conducive support enjoyed by a belief grounded on a piece of testimony — as socially diffuse, in the sense that it is not something that supervenes on the proper functionality of the hearer's cognitive resources together with the reasons she has for accepting the testimony. After arguing for such a view, I go on to identify a challenge many people think flows from an acknowledgment of the social diffusion of warrant. In particular, such an acknowledgment appears to preclude a happy account of the rationality of testimony‐based belief. After identifying the nature of this challenge and the various positions that one can take on it, I develop a response according to which rationality itself (like warrant) is socially diffuse.
Epistemic Risk and Community Policing:
Authors: Mathiesen Kay
Published: March 2010

In his paper “The Social Diffusion of Warrant and Rationality,” Sanford Goldberg argues that relying on testimony makes the warrant for our beliefs “socially diffuse” and that this diminishes our capacity to rationally police our beliefs. Thus, according to Goldberg, rationality itself is socially diffuse. I argue that while testimonial warrant may be socially diffuse (because it depends on the warrants of other epistemic agents) this feature has no special link to our capacity to rationally police our beliefs. Nevertheless, I endorse Goldberg's claim about rationality and I propose that a Foley‐style account of rationality might help to better articulate Goldberg's proposal.
How to Collaborate: Procedural Knowledge in the Cooperative Development of Science
Authors: Thagard Paul
Published: March 2010

This paper argues that collaboration in scientific and other fields requires a substantial amount of procedural knowledge about how to collaborate. It discusses how scientists collaborate, how they learn to collaborate, and why they collaborate. Knowledge how does not always reduce to knowledge that, and collaboration has many purposes besides the pursuit of power and resources. The relative scarcity of philosophical collaborations can be overcome by more naturalistic approaches to philosophy and by philosophers learning how to collaborate.
Yielding Actuality: Trust and Reason in Gillian Rose's Vision of Community
Authors: Lathangue Robin
Published: March 2010

This article explores the conviction that the durability of communities is contingent, at least in part, on the conception of reason in play. It proposes that prospects for building and sustaining community are enhanced to the degree that rationalistic theories of rationality are rejected. The resulting equivocation in the processes of rule‐making, moral thinking, analysis, and critique, while problematic, will be preferable to the alternative and caricatured approaches premised on a strong division between reason and its so‐called others. This desirable equivocation involves an analysis of the role of trust in human relations and a revised conception of reason developed by philosopher and social critic Gillian Rose (1947–1995). Through an analysis of Rose's commentary on the folk legend of Camelot and the phenomenology of friendship, this article tries to show how relations constrained by alterity can be transformed.
Socrates and Superiority
Authors: Hanna Nathan
Published: March 2010

I propose an alternative interpretation of the Crito. The arguments that are typically taken to be Socrates' primary arguments against escape are actually supplementary arguments that rely on what I call the Superiority Thesis, the thesis that the state and its citizens are members of a moral hierarchy where those below are tied by bonds of obligation to those above. I provide evidence that Socrates holds this thesis, demonstrate how it resolves a number of apparent difficulties, and show why my interpretation is preferable to competing interpretations.
Color, Externalism, and Switch Cases
Authors: Bain David
Published: March 2010

I defend externalism about color experiences and color thoughts, which I argue color objectivism requires. Externalists face the following question: would a subject's wearing inverting lenses eventually change the color content of, for instance, those visual experiences the subject reports with “red”? From the work of Ned Block, David Velleman, Paul Boghossian, Michael Tye, and Fiona Macpherson, I extract problems facing those who answer “Yes” and problems facing those who answer “No.” I show how these problems can be overcome, leaving externalism available to the color objectivist.
Is Conceptual Atomism a Plausible Theory of Concepts?
Authors: Kwong Jack M. C.
Published: March 2010

Conceptual atomism is the view according to which most lexical concepts lack ‘internal’ or constituent structure. To date, it has not received much attention from philosophers and psychologists. A central reason is that it is thought to be an implausible theory of concepts, resulting in untenable implications. The main objective of this paper is to present conceptual atomism as a viable alternative, with a view to achieving two aims: the first, to characterize and to elucidate conceptual atomism; and the second, to dispel some misconceptions associated with it. My aim is to show that the prospect of conceptual atomism is a promising one.
Quine's Naturalized Epistemology and the Third Dogma of Empiricism
Authors: Sinclair Robert
Published: March 2010

This essay reconsiders Davidson's critical attribution of the scheme‐content distinction to Quine's naturalized epistemology. It focuses on Davidson's complaint that the presence of this distinction leads Quine to mistakenly construe neural input as evidence. While committed to this distinction, Quine's epistemology does not attempt to locate a justificatory foundation in sensory experience and does not then equate neural intake with evidence. Quine's central epistemological task is an explanatory one that attempts to scientifically clarify the route from stimulus to science. Davidson's critical remarks wrongly assign concerns to Quine's view that it does not have and further obscures the status of his naturalized conception of epistemology.
Time for Change
Authors: Hales Steven D. , Johnson Timothy A.
Published: March 2010

Metaphysical theories of change incorporate substantive commitments to theories of persistence. The two most prominent classes of such theories are endurantism and perdurantism. Defenders of endurancestyle accounts of change, such as Klein, Hinchliff, and Oderberg, do so through appeal to a priori intuitions about change. We argue that this methodology is understandable but mistaken—an adequate metaphysics of change must accommodate all experiences of change, not merely intuitions about a limited variety of cases. Once we examine additional experiences of change, particularly those in (special) relativistic circumstances, it becomes clear that only a perdurance account of change is adequate.
Personal Perspectives
Authors: Drummond John J.
Published: March 2010

This paper attempts to clarify how one might understand philosophy as necessarily involving both third‐person and first‐person perspectives. It argues, first, that philosophy must incorporate the first‐person perspective in order to provide an adequate account of consciousness and the prereflective awareness of the self and, second, in opposition to Dennett's hetero‐phenomenology that this incorporation is possible only within a transcendental perspective. The paper also attempts to meet the challenge of those who claim that the notion of the self — and along with it, the idea of first‐person perspective — is dependent upon a second‐person perspecive. It argues that the second‐person challenge depends upon a sense of “self” different from that at stake in the first‐person perspective operative in prereflective self‐awareness.
Subjectivity and the First‐Person Perspective
Authors: Zahavi Dan
Published: March 2010

Phenomenology and analytical philosophy share a number of common concerns, and it seems obvious that analytical philosophy can learn from phenomenology, just as phenomenology can profit from an exchange with analytical philosophy. But although I think it would be a pity to miss the opportunity for dialogue that is currently at hand, I will in the following voice some caveats. More specifically, I wish to discuss two issues that complicate what might otherwise seem like rather straightforward interaction. The first issue concerns the question of whether the current focus on the first‐person perspective might have a negative side‐effect by giving us a slanted view of what subjectivity amounts to. The second issue concerns the question of whether superficial similarities in the descriptive findings might actually conceal some rather deep‐rooted differences in the systematic use these findings serve.
In What Sense Is Phenomenology Transcendental?
Authors: Thomasson Amie L.
Published: March 2010

Dan Zahavi raises doubts about the prospects for combining phenomenological and analytical approaches to the mind, based chiefly on the claim that phenomenology is a form of transcendental philosophy. I argue that there are two ways in which one might understand the claim that phenomenology is transcendental: (1) as the claim that the methods of phenomenology essentially involve addressing transcendental questions or making transcendental arguments, or (2) as the claim that phenomenology is committed to substantive theses of antirealism and the like, which are sometimes thought to follow from a transcendental approach. I argue that while (1) is appropriate, it in no way leads to conflicts with analytic work in philosophy of mind. Moreover, adopting this method and practicing phenomenology in no way commits us to claims of type (2) that might be thought to conflict with common assumptions in analytic philosophy of mind.
First‐Person Methodologies: A View From Outside the Phenomenological Tradition
Authors: Georgalis Nicholas
Published: March 2010

It is argued that results from first‐person methodologies are unacceptable for incorporation into a fundamental philosophical theory of the mind unless they satisfy a necessary condition, which I introduce and defend. I also describe a narrow,nonphenomenal, first‐person concept that I callminimal contentthat satisfies this condition.

Minimal content is irreducible to third‐person concepts, but it is required for an adequate account of intentionality, representation, and language. Consequently, consciousness is implicated in these as strongly — but differently — than it is in our phenomenal states. Minimal content provides a foundation for an objective philosophical theory of the mind and language. (Some support for these claims is given here. They are extensively argued for in myThe Primacy of the Subjective.)
A Biological Alternative to Moral Explanations
Authors: Millum Joseph
Published: March 2010

Some moral realists claim that moral facts are a species of natural fact, amenable to scientific investigation. They argue that these moral facts are needed in the best explanations of certain phenomena and that this is evidence that they are real. In this paper I present part of a biological account of the function of morality. The account allows the identification of a plausible natural kind that could play the explanatory role that a moral kind would play in naturalist realist theories. It is therefore a candidate for being the moral kind. I argue, however, that it will underdetermine the morally good, that is, identifying the kind is not sufficient to identify what is good. Hence this is not a natural moral kind. Its explanatory usefulness, however, means that we do not have to postulate any further (moral) facts to provide moral explanations. Hence there is no reason to believe that there are any natural moral kinds.
Puzzles about Trust
Authors: Smolkin Doran
Published: March 2010

This article is an attempt to deepen our understanding of trust. To this end, several elements frequently present in trust‐relationships are first identified, and then three underappreciated puzzles about trust are described. Next, it is argued that certain leading analyses of trust are unsatisfactory, in part, because they are unable to solve these puzzles succesfully. Finally, an alternative way of thinking about trust is proposed. It is agued that this new way of thinking about trust is both independently plausible and better able to solve these puzzles about trust.
A Euthyphronic Problem for Kitcher's Epistemology of Science
Authors: Roland Jeffrey W.
Published: March 2010

Philip Kitcher has advanced an epistemology of science that purports to be naturalistic. For Kitcher, this entails that his epistemology of science must explain the correctness of belief‐regulating norms while endorsing a realist notion of truth. This paper concerns whether or not Kitcher's epistemology of science is naturalistic on these terms. I find that it is not but that by supplementing the account we can secure its naturalistic standing.
Passing‐over: The Death of the Author in Hegel's Philosophy
Authors: Berthold Daniel
Published: March 2010

Criticism of Hegel has been a central preoccupation of “postmodern” philosophy, from critical theory and deconstruction to Lacanian psychoanalytic theory and Foucauldian “archaeology.” One of the most frequent criticisms is that Hegel's invocation of “absolute knowledge” installs him in a position of authorial arrogance, of God‐like authority, leaving the reader in a position of subservience to the Sage's perfect wisdom. The argument of this article is that this sort of criticism is profoundly ironic, since Hegel's construction of the role of the Sage possessing absolute knowledge is in fact an elaborate mask covering over a radical project of disappearance of the author by which it becomes the reader who is left to author the text. The article explores Hegel's commitment to his own death as an author in his invention of a new method of demonstration, his epistemology, his philosophy of language, his theory of desire, and even in the seemingly least likely place of all, his portrait of “absolute knowledge.”
A New Kantian Solution to the Third Antinomy of Pure Reason and to the Free Will Problem
Authors: Vaida Iuliana Corina
Published: March 2010

The goal of this paper is to articulate a new solution to Kant's third antinomy of pure reason, one that establishes the possibility of incompatibilist freedom—the freedom presupposed by our traditional conceptions of moral responsibility, moral worth, and justice—without relying on the doctrine of transcendental idealism (TI). A discussion of Henry Allison's “two‐aspect” interpretation of Kant's TI allows me both to criticize one of the best defenses of TI today and to advance my own TI‐free solution to the third antinomy by appeal to a thesis of epistemic modesty based on Paul Guyer's realist interpretation of Kant's theory of experience. According to this interpretation, the a priori forms of our sensibility and understanding are not forms that the mind imposes on a material whose real properties are unknowable to us but are instead forms that limit or filter the kinds of things we can experience and know. In particular, being causally determined is a real feature of things as they are in themselves, but the necessity and universality of our deterministic claims are relative, restricted to the objects of possible experience. Consequently, though a causally determined event cannot be free, the necessity and universality of determinism does not entail that free events (choices) cannot exist but that they cannot constitute objects of possible experience. After arguing that freedom is possible, I outline an argument for the reality of freedom, based on the requirements of morality. Finally, I argue that my view, though opposed to metaphysical naturalism, is consistent with scientific realism and methodological naturalism.
A mutation of the epithelial sodium channel associated with atypical cystic fibrosis increases channel open probability and reduces Na+ self inhibition
Authors: Rauh Robert , Diakov Alexei , Tzschoppe Anja , Korbmacher Judit , Azad Abul Kalam , Cuppens Harry , Cassiman Jean‐Jaques , Dötsch Jörg , Sticht Heinrich , Korbmacher Christoph
Published: March 2010

Increased activity of the epithelial sodium channel (ENaC) in the respiratory airways contributes to the pathophysiology of cystic fibrosis (CF), a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In some patients suffering from atypical CF a mutation can be identified in only one CFTR allele. We recently identified in this group of CF patients a heterozygous mutation (W493R) in the α‐subunit of ENaC. Here, we investigate the functional effects of this mutation by expressing wild‐type αβγENaC or mutant αW493RβγENaC in Xenopus oocytes. The αW493R mutation stimulated amiloride‐sensitive whole‐cell currents (ΔIami) by ∼4‐fold without altering the single‐channel conductance or surface expression of ENaC. As these data suggest that the open probability (Po) of the mutant channel is increased, we investigated the proteolytic activation of ENaC by chymotrypsin. Single‐channel recordings revealed that chymotrypsin activated near‐silent channels in outside‐out membrane patches from oocytes expressing wild‐type ENaC, but not in membrane patches from oocytes expressing the mutant channel. In addition, the αW493R mutation abolished Na+ self inhibition of ENaC, which might also contribute to its gain‐of‐function effects. We conclude that the αW493R mutation promotes constitutive activation of ENaC by reducing the inhibitory effect of extracellular Na+ and decreasing the pool of near‐silent channels. The resulting gain‐of‐function phenotype of the mutant channel might contribute to the pathophysiology of CF in patients carrying this mutation.
Differences in the control of breathing between Himalayan and sea‐level residents
Authors: Slessarev M. , Prisman E. , Ito S. , Watson R. R. , Jensen D. , Preiss D. , Greene R. , Norboo T. , Stobdan T. , Diskit D. , Norboo A. , Kunzang M. , Appenzeller O. , Duffin J. , Fisher J. A.
Published: March 2010

We compared the control of breathing of 12 male Himalayan highlanders with that of 21 male sea‐level Caucasian lowlanders using isoxic hyperoxic (= 150 mmHg) and hypoxic (= 50 mmHg) Duffin's rebreathing tests. Highlanders had lower mean ±s.e.m. ventilatory sensitivities to CO2 than lowlanders at both isoxic tensions (hyperoxic: 2.3 ± 0.3 vs. 4.2 ± 0.3 l min−1 mmHg−1, P= 0.021; hypoxic: 2.8 ± 0.3 vs. 7.1 ± 0.6 l min−1 mmHg−1, P < 0.001), and the usual increase in ventilatory sensitivity to CO2 induced by hypoxia in lowlanders was absent in highlanders (P= 0.361). Furthermore, the ventilatory recruitment threshold (VRT) CO2 tensions in highlanders were lower than in lowlanders (hyperoxic: 33.8 ± 0.9 vs. 48.9 ± 0.7 mmHg, P < 0.001; hypoxic: 31.2 ± 1.1 vs. 44.7 ± 0.7 mmHg, P < 0.001). Both groups had reduced ventilatory recruitment thresholds with hypoxia (P < 0.001) and there were no differences in the sub‐threshold ventilations (non‐chemoreflex drives to breathe) between lowlanders and highlanders at both isoxic tensions (P= 0.982), with a trend for higher basal ventilation during hypoxia (P= 0.052). We conclude that control of breathing in Himalayan highlanders is distinctly different from that of sea‐level lowlanders. Specifically, Himalayan highlanders have decreased central and absent peripheral sensitivities to CO2. Their response to hypoxia was heterogeneous, with the majority decreasing their VRT indicating either a CO2‐independent increase in activity of peripheral chemoreceptor or hypoxia‐induced increase in [H+] at the central chemoreceptor. In some highlanders, the decrease in VRT was accompanied by an increase in sensitivity to CO2, while in others VRT remained unchanged and their sub‐threshold ventilations increased, although these were not statistically significant.
Vasoresponsiveness of collateral vessels in the rat hindlimb: influence of training
Authors: Colleran Patrick N. , Li Zeyi , Yang Hsiao T. , Laughlin M. Harold , Terjung Ronald L.
Published: March 2010

Exercise training is known to be an effective means of improving functional capacity and quality of life in patients with peripheral arterial insufficiency (PAI). However, the specific training‐induced physiological adaptations occurring within collateral vessels remain to be clearly defined. The purpose of this study was to determine the effect of exercise training on vasomotor properties of isolated peripheral collateral arteries. We hypothesized that daily treadmill exercise would improve the poor vasodilatory capacity of collateral arteries isolated from rats exposed to surgical occlusion of the femoral artery. Following femoral artery ligation, animals were either kept sedentary or exercise trained daily for a period of 3 weeks. Hindlimb collateral arteries were then isolated, cannulated and pressurized via hydrostatic reservoirs to an intravascular pressure of either 45 or 120 cmH2O. Non‐occluded contralateral vessels of the sedentary animals served as normal Control. Vasodilatory responses to acetylcholine (ACh; 1 × 10−9–1 × 10−5 m) and sodium nitroprusside (SNP; 1 × 10−9–1 × 10−4 m), constrictor responses to phenylephrine (PE; 1 × 10−9–1 × 10−4 m), and flow‐induced vasodilatation were determined. Endothelium‐mediated vasodilatation responses were significantly greater to either ACh (P < 0.02) or intravascular flow (P < 0.001) in collateral arteries of trained rats. Neither blockade of cyclooxygenase with indomethacin (Indo; 5 μm) nor blockade of endothelial nitric oxide synthase with NG‐nitro‐l‐arginine methyl ester (l‐NAME; 300 μm) eliminated this ACh‐ or flow‐induced vasodilatation. The depressed vasodilatory response to SNP caused by vascular occlusion was reversed with training. These data indicate that exercise training improves endothelium‐mediated vasodilatory capacity of hindlimb collateral arteries, apparently by enhanced production of the putative endothelium‐derived hyperpolarizing factor(s). If these findings were applicable to patients with PAI, they could contribute to an improved collateral vessel function and enhance exercise tolerance during routine physical activity.
Polycomb Group Proteins as Epigenetic Mediators of Neuroprotection in Ischemic Tolerance
Authors: Stapels Martha , Piper Chelsea , Yang Tao , Li Minghua , Stowell Cheri , Xiong Zhi-gang , Saugstad Julie , Simon Roger P. , Geromanos Scott , Langridge James , Lan Jing-quan , Zhou An
Published: March 2010

Polycomb group proteins protect neurons from injury through a mechanism involving decreased potassium channel function.
Crystal Structure of the α-Kinase Domain of
Dictyostelium
Myosin Heavy Chain Kinase A
Authors: Ye Qilu , Crawley Scott W. , Yang Yidai , Côté Graham P. , Jia Zongchao
Published: March 2010

Structural analysis identifies features of atypical serine-threonine kinases that may account for their different activities relative to those of conventional kinases.
Characterization of a Domain That Transiently Converts Class 2 DYRKs into Intramolecular Tyrosine Kinases
Authors: Kinstrie Ross , Luebbering Nathan , Miranda-Saavedra Diego , Sibbet Gary , Han Jingfen , Lochhead Pamela A. , Cleghon Vaughn
Published: March 2010

An N-terminal region of a dual-specificity kinase temporarily enables it to phosphorylate a tyrosine rather than a serine or a threonine residue.
Tripartite Toxin
Authors: Hurtley Stella M.
Published: March 2010

A bacterial toxin targets and modifies the actin cytoskeleton in insect larvae.
Efflux Pumps, OprD Porin, AmpC β-Lactamase, and Multiresistance in
Pseudomonas aeruginosa
Isolates from Cystic Fibrosis Patients
Authors: Tomás Maria , Doumith Michel , Warner Marina , Turton Jane F. , Beceiro Alejandro , Bou German , Livermore David M. , Woodford Neil
Published: March 2010

Expression of
ampC
,
oprD
,
mexA
,
mexC
,
mexE
, and
mexX
was studied in 25
Pseudomonas aeruginosa
isolates from cystic fibrosis patients, including 14 isolates of the Liverpool epidemic strain. Overexpressed
mexA
or
ampC
and reduced
oprD
were associated with β-lactam resistance. A specific combination of
mexR
,
nalC
, and
nalD
mutations occurred in 11 Liverpool strain isolates, including 7 with upregulated
mexA
.
3-Hydroxyphthalic Anhydride-Modified Chicken Ovalbumin Exhibits Potent and Broad Anti-HIV-1 Activity: a Potential Microbicide for Preventing Sexual Transmission of HIV-1
Authors: Li Lin , He Lili , Tan Suiyi , Guo Xinhua , Lu Hong , Qi Zhi , Pan Chungen , An Xiuli , Jiang Shibo , Liu Shuwen
Published: March 2010

Heterosexual transmission is the primary route by which women acquire human immunodeficiency virus (HIV)/AIDS. Thus, development of woman-controlled topical microbicides for prevention of sexual transmission of HIV is urgently needed. Here we report that 3-hydroxyphthalic anhydride-modified chicken ovalbumin (HP-OVA) exhibits potent antiviral activity against a broad spectrum of human immunodeficiency virus type 1 (HIV-1) isolates with different genotypes and biotypes. Its antiviral activity is correlated with the percentages of the chemically modified and unmodified lysines and arginines in OVA. HP-OVA inhibits HIV-1 fusion and entry through multiple mechanisms of action, including (i) blocking gp120 binding to CD4 and (ii) interfering with gp41 six-helix bundle formation. Because of the widespread availability and established safety profile of OVA, HP-OVA has good potential to be developed as an effective, safe, and affordable microbicide for prevention of HIV sexual transmission.
Antiviral Properties, Metabolism, and Pharmacokinetics of a Novel Azolo-1,2,4-Triazine-Derived Inhibitor of Influenza A and B Virus Replication
Authors: Karpenko Inna , Deev Sergey , Kiselev Oleg , Charushin Valerey , Rusinov Vladimir , Ulomsky Eugeney , Deeva Ella , Yanvarev Dmitry , Ivanov Alexander , Smirnova Olga , Kochetkov Sergey , Chupakhin Oleg , Kukhanova Marina
Published: March 2010

Influenza viruses of types A and B cause periodic pandemics in the human population. The antiviral drugs approved to combat influenza virus infections are currently limited. We have investigated an effective novel inhibitor of human influenza A and B viruses, triazavirine {2-methylthio-6-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazine-7(4Í)-one} (TZV). TZV suppressed the replication of influenza virus in cell culture and in chicken chorioallantoic membranes, and it protected mice from death caused by type A and B influenza viruses. TZV was also effective against a rimantadine-resistant influenza virus strain and against avian influenza A virus H5N1 strains. The pharmacokinetic parameters and bioavailability of TZV were calculated after the administration of TZV to rabbits. The TZV metabolite AMTZV {2-methylthio-6-amino-1,2,4-triazolo[5,1-
s
]-1,2,4-triazin(e)-7(4Í)-one} was discovered in ÍÅK 293T and Huh7 cell cultures, a liver homogenate, and rabbit blood after intragastric administration of TZV. AMTZV was nontoxic and inactive as an inhibitor of influenza virus in cell culture. Most likely, this metabolite is a product of TZV elimination.
Skin Concentrations and Pharmacokinetics of Posaconazole after Oral Administration
Authors: Krishna Gopal , Beresford Eric , Ma Lei , Vickery Donna , Martinho Monika , Yu Xin , Komjathy Steven , Tavakkol Amir
Published: March 2010

A randomized, single-center, open-label study of posaconazole (POS) was performed to determine the concentration of POS in the skin of 30 healthy adult human subjects receiving 400 mg POS oral suspension twice daily for 8 days with a high-fat meal. Blood samples for plasma POS level determination were collected at prespecified times on day 1 and day 8. From each subject, two 4-mm skin punch biopsy samples were obtained, one immediately before or after both the first and last doses of POS. A MIC
90
value of 250 ng/ml, which encompasses the majority of common dermatophytes, was used to calculate the time above the MIC
90
in plasma and skin. On days 1 and 8, POS attained peak plasma concentrations at median times of 8 and 5 h, respectively. On days 1 and 8, POS peak skin concentrations were attained at 12 and 3 h, respectively; peak skin concentrations were produced from a single composite profile. On day 8, POS concentrations in skin and plasma for the entire dosing interval were severalfold higher than the MIC
90
. POS dosed at 400 mg twice daily per os was well tolerated in healthy subjects. Two subjects reported increased alanine aminotransferase (ALT) levels. The findings of this study demonstrate adequate skin penetration and have certain implications for the treatment of dermatophytic skin and nail infections.
Interaction of
Candida albicans
Biofilms with Antifungals: Transcriptional Response and Binding of Antifungals to Beta-Glucans
Authors: Vediyappan Govindsamy , Rossignol Tristan , d'Enfert Christophe
Published: March 2010

Candida albicans
can form biofilms that exhibit elevated intrinsic resistance to various antifungal agents, in particular azoles and polyenes. The molecular mechanisms involved in the antifungal resistance of biofilms remain poorly understood. We have used transcript profiling to explore the early transcriptional responses of mature
C. albicans
biofilms exposed to various antifungal agents. Mature
C. albicans
biofilms grown under continuous flow were exposed for as long as 2 h to concentrations of fluconazole (FLU), amphotericin B (AMB), and caspofungin (CAS) that, while lethal for planktonic cells, were not lethal for biofilms. Interestingly, FLU-exposed biofilms showed no significant changes in gene expression over the course of the experiment. In AMB-exposed biofilms, 2.7% of the genes showed altered expression, while in CAS-exposed biofilms, 13.0% of the genes had their expression modified. In particular, exposure to CAS resulted in the upregulation of hypha-specific genes known to play a role in biofilm formation, such as
ALS3
and
HWP1
. There was little overlap between AMB- or CAS-responsive genes in biofilms and those that have been identified as AMB, FLU, or CAS responsive in
C. albicans
planktonic cultures. These results suggested that the resistance of
C. albicans
biofilms to azoles or polyenes was due not to the activation of specific mechanisms in response to exposure to these antifungals but rather to the intrinsic properties of the mature biofilms. In this regard, our study led us to observe that AMB physically bound
C. albicans
biofilms and beta-glucans, which have been proposed to be major constituents of the biofilm extracellular matrix and to prevent azoles from reaching biofilm cells. Thus, enhanced extracellular matrix or beta-glucan synthesis during biofilm growth might prevent antifungals, such as azoles and polyenes, from reaching biofilm cells, thus limiting their toxicity to these cells and the associated transcriptional responses.
Use of a High-Resolution Melt Assay To Characterize Codon 54 of the
cyp51A
Gene of
Aspergillus fumigatus
on a Rotor-Gene 6000 Instrument
Authors: Tuohy M. J. , Reja V. , Park S. , Perlin D. S. , Wnek M. , Procop G. W. , Yen-Lieberman B.
Published: March 2010

A high-resolution melt (HRM) assay using a Rotor-Gene 6000 instrument was developed to characterize the codon for glycine 54 in the
cyp51A
genes from 13 reference isolates and 12 clinical isolates of
Aspergillus fumigatus
. Mutations in this codon confer reduced susceptibility to itraconazole and posaconazole. The assay is simple to perform, and a result of “wild type” or “mutant” is available after approximately 1 h following DNA extraction using commercially available reagents and conventional primers.
Mechanism of the Synergistic Effect of Amiodarone and Fluconazole in
Candida albicans
Authors: Gamarra Soledad , Rocha Elousa Maria F. , Zhang Yong-Qiang , Park Steven , Rao Rajini , Perlin David S.
Published: March 2010

The antiarrhythmic drug amiodarone has been found to have fungicidal activity. In
Saccharomyces cerevisiae
, its antifungal activity is mediated by calcium overload stress, which leads to a rapid nuclear accumulation of the calcineurin-regulated transcription factor
CRZ1
. In addition, low doses of amiodarone have been reported to be synergistic with fluconazole in fluconazole-resistant
Candida albicans
. To establish its mechanism of toxicity in
C. albicans
, we used expression profiling of key pathway genes to examine cellular responses to amiodarone alone and in combination with fluconazole. Gene expression profiling of 59 genes was done in five
C. albicans
strains (three fluconazole-susceptible strains and two fluconazole-resistant strains) after amiodarone and/or fluconazole exposure. Of the 59 genes, 27 analyzed showed a significant change (>2-fold) in expression levels after amiodarone exposure. The up- or downregulated genes included genes involved in Ca
2+
homeostasis, cell wall synthesis, vacuolar/lysosomal transport, diverse pathway regulation, stress response, and pseudohyphal morphogenesis. As expected, fluconazole induces an increase in ergosterol pathway genes expression levels. The combination treatment significantly dampened the transcriptional response to either drug, suggesting that synergism was due to an inhibition of compensatory response pathways. This dampening resulted in a decrease in total ergosterol levels and decreased pseudohyphal formation, a finding consistent with decreased virulence in a murine candidiasis model.
Evaluation of Nucleoside Hydrolase Inhibitors for Treatment of African Trypanosomiasis
Authors: Berg Maya , Kohl Linda , Van der Veken Pieter , Joossens Jurgen , Al-Salabi Mohammed I. , Castagna Valeria , Giannese Francesca , Cos Paul , Versées Wim , Steyaert Jan , Grellier Philippe , Haemers Achiel , Degano Massimo , Maes Louis , de Koning Harry P. , Augustyns Koen
Published: March 2010

In this paper, we present the biochemical and biological evaluation of
N
-arylmethyl-substituted iminoribitol derivatives as potential chemotherapeutic agents against trypanosomiasis. Previously, a library of 52 compounds was designed and synthesized as potent and selective inhibitors of
Trypanosoma vivax
inosine-adenosine-guanosine nucleoside hydrolase (IAG-NH). However, when the compounds were tested against bloodstream-form
Trypanosoma brucei brucei
, only one inhibitor,
N
-(9-deaza-adenin-9-yl)methyl-1,4-dideoxy-1,4-imino-
d
-ribitol (UAMC-00363), displayed significant activity (mean 50% inhibitory concentration [IC
50
] ± standard error, 0.49 ± 0.31 μM). Validation in an
in vivo
model of African trypanosomiasis showed promising results for this compound. Several experiments were performed to investigate why only UAMC-00363 showed antiparasitic activity. First, the compound library was screened against
T. b. brucei
IAG-NH and inosine-guanosine nucleoside hydrolase (IG-NH) to confirm the previously demonstrated inhibitory effects of the compounds on
T. vivax
IAG-NH. Second, to verify the uptake of these compounds by
T. b. brucei
, their affinities for the nucleoside P1 and nucleoside/nucleobase P2 transporters of
T. b. brucei
were tested. Only UAMC-00363 displayed significant affinity for the P2 transporter. It was also shown that UAMC-00363 is concentrated in the cell via at least one additional transporter, since P2 knockout mutants of
T. b. brucei
displayed no resistance to the compound. Consequently, no cross-resistance to the diamidine or the melaminophenyl arsenical classes of trypanocides is expected. Third, three enzymes of the purine salvage pathway of procyclic
T. b. brucei
(IAG-NH, IG-NH, and methylthioadenosine phosphorylase [MTAP]) were investigated using RNA interference. The findings from all these studies showed that it is probably not sufficient to target only the nucleoside hydrolase activity to block the purine salvage pathway of
T. b. brucei
and that, therefore, it is possible that UAMC-00363 acts on an additional target.
Disruption of theRickettsia rickettsiiSca2 Autotransporter Inhibits Actin-Based Motility
Authors: Kleba Betsy , Clark Tina R. , Lutter Erika I. , Ellison Damon W. , Hackstadt Ted
Published: March 2010

Rickettsii rickettsii, the etiologic agent of Rocky Mountain spotted fever, replicates within the cytosol of infected cells and uses actin-based motility to spread inter- and intracellularly. Although the ultrastructure of the actin tail and host proteins associated with it are distinct from those ofListeriaorShigella, comparatively little is known regarding the rickettsial proteins involved in its organization. Here, we have used random transposon mutagenesis ofR. rickettsiito generate a small-plaque mutant that is defective in actin-based motility and does not spread directly from cell to cell as is characteristic of spotted fever group rickettsiae. The transposon insertion site of this mutant strain was within Sca2, a member of a family of large autotransporter proteins. Sca2 exhibits several features suggestive of its apparent role in actin-based motility. It displays an N-terminal secretory signal peptide, a C-terminal predicted autotransporter domain, up to four predicted Wasp homology 2 (WH2) domains, and two proline-rich domains, one with similarity to eukaryotic formins. In a guinea pig model of infection, the Sca2 mutant did not elicit fever, suggesting that Sca2 and actin-based motility are virulence factors of spotted fever group rickettsiae.