Clonal expansion of T‐lymphocyte populations results from interactions of antigenic structures presented in combination with accessory cells (macrophages) and antibody recognition sites on the surface of T cells. The resulting activation of a membrane phospholipase C plays a crucial role in lymphocyte responses by releasing diglyceride and PIP3. The released diglyceride activates a cellular protein kinase C while PIP3 stimulates Ca2+ influx. Arachidonic acid released by the action of diglyceride lipase serves as substrate for the synthesis of bioactive eicosanoids (prostaglandins (...) and leukotrienes) which in turn modulate cellular adenyl and guanyl cyclases. The eicosanoids serve as both intra‐ and extra‐cellular signals for lymphocytes, regulating the production and expression of lymphokines and mediating the complex interactions between the monocyte‐macrophage components and helper and suppressor T cells.Aspirin and other anti‐inflammatory drugs stimulate mitogenesis by inhibiting production of the negative modulator prostaglandin E2 in accessory cells and by enhancing the production of the lymphokine 1L‐2 by producer T‐cells. (shrink)

How does aspirin reduce pain and inflammation? How does it prevent heart attacks? Why does it upset the stomach? How do scientists discover the answers? This article examines research and development in the history from willow bark to aspirin to “super aspirins” Celebrex and Vioxx. Scientists adopt various approaches: trial and error, laboratory experiment, clinical test, elucidation of underlying mechanisms, concept-directed research, and rational drug design. Each approach is limited, but they complement each other in unraveling the mystery (...) of a wonder drug. (shrink)

Everyone has heard the claim, "Correlation does not imply causation." What might sound like a reasonable dictum metastasized in the twentieth century into one of science's biggest obstacles, as a legion of researchers became unwilling to make the claim that one thing could cause another. Even two decades ago, asking a statistician a question like "Was it the aspirin that stopped my headache?" would have been like asking if he believed in voodoo, or at best a topic for conversation (...) at a cocktail party rather than a legitimate target of scientific inquiry. Scientists were allowed to posit only that the probability that one thing was associated with another. This all changed with Judea Pearl, whose work on causality was not just a victory for common sense, but a revolution in the study of the world. (shrink)

In a recent article in Argumentation, O’Keefe (Argumentation 21:151–163, 2007) observed that the well-known ‘framing effects’ in the social psychological literature on persuasion are akin to traditional fallacies of argumentation and reasoning and could be exploited for persuasive success in a way that conflicts with principles of responsible advocacy. Positively framed messages (“if you take aspirin, your heart will be more healthy”) differ in persuasive effect from negative frames (“if you do not take aspirin, your heart will be (...) less healthy”), despite containing ‘equivalent’ content. This poses a potential problem, because people might be unduly (and unsuspectingly) influenced by mere presentational differences. By drawing on recent cognitive psychological work on framing effects in choice and decision making paradigms, however, we show that establishing whether two arguments are substantively equivalent—and hence, whether there is any normative requirement for them to be equally persuasive—is a difficult task. Even arguments that are logically equivalent may not be information equivalent. The normative implications of this for both speakers and listeners are discussed. (shrink)

There appear to be multifunctional artefacts of a type such that none of their functions can be attributed only to some proper part of the artefact. I use two examples of allegedly multifunctional artefacts of this kind in what follows, one due to Lynne Rudder Baker (aspirin) and another of my own (a spork). The two examples are meant to make the same point. I discuss her aspirin example, since its discussion has entered the literature, but without its (...) being dealt with satisfactorily. My example is, I believe, more intuitive than that of aspirin, which Baker introduced in her response to a challenge to her views, and so I will mostly rely on my example of a spork, especially at the end of the paper, to make my case. -/- I argue that in at least those two cases, if the standard arguments for distinguishing between an object and what constitutes it are sound, an argument showing that what we might have taken to be a single multifunctional object is in fact a case of multiple single-function artefacts which collocate. Or almost. There is one further assumption needed for these cases, beyond what the constitution cases require, and I produce reasons for accepting that assumption. (shrink)

Most of the regularities that get represented as ‘laws’ in our sciences arise from, and are to be found regularly associated with, the successful operation of a nomological machine. Reference to the nomological machine must be included in the cp-clause of a cp-law if the entire cp-claim is to be true. We agree, for example, ‘ceteris paribus aspirins cure headaches’, but insist that they can only do so when swallowed by someone with the right physiological makeup and a headache. Besides (...) providing a necessary condition on the truth of the cp-law claim, recognising the nomological machine has great practical importance. Referring to the nomological machine makes explicit where the regularities are to be found, which is of central importance to the use of cp-laws for prediction and manipulation. Equally important, bringing the nomological machine to the fore brings into focus the make-up of the machine—its parts, their powers and their arrangements—and its context case-by-case. (shrink)

“Unconscionable.” “Outrageous.” “Indefensible.” These are just some of the tamer descriptions for the billing practices of most hospitals, and also many physicians, that have recently come to the public's attention. Earlier this year, Time magazine published an extraordinary 24,000‐word exposé—the longest article it has ever published—detailing how even charitable hospitals routinely price‐gouge their patients.1 With characteristic flare for telling details, journalist Steven Brill documented ten‐fold markups of charges over costs at some prominent hospitals for common services like X rays and (...) lab tests, and one‐hundred‐fold mark‐ups on mundane supplies such as gauze pads and generic aspirin. Just as the buzz from Brill's article was abating, the Centers for Medicare & Medicaid Services released a comprehensive data set in May that galvanized local and national media across the country. This news tsunami caught hospital managers flat‐footed and tongue‐tied. Typical responses conceded that hospitals’ pricing practices are based neither on actual cost structures nor rational marketplace dynamics. Instead, hospitals attempted to deflect blame by noting that hardly anyone actually pays list prices, and they characterized their indefensible pricing as a symptom of a broken system that is beyond them to fix. There are two glaring faults in these standard defenses. (shrink)

Discovery of a second, inducible prostaglandin synthase provides explanations for many previously puzzling observations, but also raises new questions about prostanoid synthesis. A cis‐acting sequence closely related to the cyclic AMP response element has been shown to play a role in both basal and induced prostaglandin synthase 2 gene expression. Aspirin and other currently available non‐steroidal anti‐inflammatory drugs that inhibit prostaglandin synthase activity do not effectively discriminate between the inducible prostaglandin synthase 2 and constitutive prostaglandin synthase 1 enzymes. Identification (...) of a second prostaglandin synthase, induced by inflammatory stimuli, initiated a search for isoform‐specific inhibitors. Use of prostaglandin synthase 2 specific inhibitors and antisense oligonucleotides has led to the suggestion that specific ligands activate alternative pathways of prostanoid production, using one of the prostaglandin synthase isoforms preferentially. The coupling mechanisms by which these pathways are activated in response to alternative stimuli should provide additional routes of intervention in prostanoid production. (shrink)

Theo C. Meyering, in “Mind Matters: Physicalism and the Autonomy of the Person,” takes yet a third approach to the issue of reduction. He states that “if (true, downward) mental causation implies nonreducibility [as Stoeger and Murphy argue] and physicalism implies the converse, it is hard to see how these two views could be compatible.” Meyering distinguishes three versions of reductionism: radical (industrial strength) physicalism; ideal (regular strength) physicalism, and mild or token physicalism. Radical physicalism asserts that all special sciences (...) are reducible to physics in the sense that their laws can be deduced via bridge laws from those of physics. Ideal physicalism asserts that while it is practically impossible to reduce the special sciences, such reduction would be possible were there an ideally complete physics" (Note: This distinction parallels Stoeger’s recognition that epistemological reducibility is relative to the meaning of “laws of nature). Token physicalism is ontologically reductionist: there are no events that are not “token-identical” with some physical event or other (Note: See above, sec. 3.3). However, there are no identities between higher-level and lower- level types of events; consequently some events described by the special sciences have no physical explanation at all. -/- All of these reductionist positions are to be contrasted with compositional (milder than mild) physicalism, which asserts that some higher-level events are not even token-identical with physical events because the higher-level event (say, a crash in the stock market) is constituted by innumerable physical particulars in all sorts of states and interactions. -/- Meyering then surveys some of the existing arguments for the nonreducibility of the special sciences. One of the most important is the argument from multiple realizability. The claim is that economics, for example, is not reducible to physics because economic concepts (for example, monetary exchange) are “wildly multiply realizable” (for example, using coins, strings of wampum, signing a check). Thus, there can be no bridge laws and no reduction. Such an argument, however, only cuts against radical physicalism, not the weaker (and a priori more plausible) ideal physicalism. -/- A stronger argument for the indispensability of special-science explanations is based on the role of functional explanations. For example, the functional description of aspirin as an analgesic is in some instances a more useful explanation of its causal role (relieving a headache) than is its description as the chemical level. -/- Meyering’s own contribution focuses neither on multiple realizability of supervenient properties nor on multiple “fillers” of functional roles, but on “multiple supervenience.” In particular, a single subvenient state of affairs (for example, a cloud of free electrons permeating the metal of which a ladder is constructed) may realize a variety of supervenient dispositional properties (in this case, electrical conductivity, thermal conductivity, opacity). An explanation (say, of the cause of a deadly accident) requires reference to the dispositional property (electrical conductivity), not merely to the subvenient property. Meyering argues that it is this possibility of multiple supervenience, not multiple realizability, that gives arguments against reduction based on functional properties their real force. Downward causation, then, can be understood in terms of selective activation of one of several dispositional properties of a lower-level state, and thus can be assigned a stable place in our picture of how the world is organized without upsetting our conception of physics as constituting a closed and complete system of physical events. (shrink)

Modern longitudinal studies collect feature data at many timepoints, often of the same order of sample size. Such studies are typically affected by dropout and positivity violations. We tackle these problems by generalizing effects of recent incremental interventions to accommodate multiple outcomes and subject dropout. We give an identifying expression for incremental intervention effects when dropout is conditionally ignorable and derive the nonparametric efficiency bound for estimating such effects. Then we present efficient nonparametric estimators, showing that they converge at fast (...) parametric rates and yield uniform inferential guarantees, even when nuisance functions are estimated flexibly at slower rates. We also study the variance ratio of incremental intervention effects relative to more conventional deterministic effects in a novel infinite time horizon setting, where the number of timepoints can grow with sample size and show that incremental intervention effects yield near-exponential gains in statistical precision in this setup. Finally, we conclude with simulations and apply our methods in a study of the effect of low-dose aspirin on pregnancy outcomes. (shrink)

The making and taking of psychotropic drugs, whether on medical prescription or as self-medication, whether marketed by pharmaceutical companies or clamoured for by an anxious population, has been an integral part of the twentieth century. In this modern era of speed, uncertainty, pleasure and anguish the boundaries between healing and enhancing the mind by chemical means have been redefined. Long before Prozac would become a household name for an ‘emotional aspirin’ did consumers embrace the idea and practice of taking (...) psychotropics not only to treat mental illness but also to make them feel better about living in a modern world. The Freudian promise that each individual can remake him- or herself in the pursuit of health and happiness was helpful in promoting and legitimizing the idea and practice of seeking wellness on prescription. We will argue that the modern consumer-driven political culture of medicine will continue to transverse the boundaries of therapy and enhancement of the mind into the largely unexplored territories of human cognition and behaviour. However exciting, this endeavour will come at the cost of further widening the problem of iatrogenic addiction in the age of happiness pills as ‘botox’ for the mind. (shrink)

Genetic research into ageing, longevity and late-onset disease is becoming increasingly common. Yet, there is a paucity of knowledge related to clinical actionability and the return of pathogenic variants to otherwise healthy elderly individuals. Whether or not genetic research in the elderly should be managed differently from standard practices adapted for younger populations has not yet been defined. In this article, we provide an overview of ethical and practical challenges in preparing for a genetic study of over 14 000 healthy (...) Australians aged 70 years or older enrolled in the ASPirin in Reducing Events in the Elderly Healthy Ageing Biobank. At the time of consent, all participants in this study were free of life-threatening illness, cardiovascular disease or cognitive impairment. ASPREE is thus a cohort of healthy elderly individuals with seemingly minimal burden of genetic disease recruited without ascertainment bias. The cohort presents a unique opportunity to address the penetrance of known pathogenic variants in a population without disease symptoms; however, it also raises a number of ethical concerns regarding the interpretation and disclosure of variants with known clinical actionability. Some of the challenges include how to manage the interpretation, disclosure and actioning of pathogenic variants found in otherwise healthy elderly adults without disease symptoms, whether or not to disclose findings for the benefit of family members rather than elderly consented donors themselves, how to manage the return of genetic findings to the elderly individuals who are now in severe cognitive decline or terminal illness, how to ensure quality of information and clinical service upon disclosure of results to this demographic and how to prepare for the insurance implications of disclosing genetic information under Australian law. We discuss these and other dilemmas and propose a defensible plan of management. Trial registration number ISRCTN83772183. (shrink)

Justin D’Ambrosio and I have recently and independently defended perceptual adverbialism from Frank Jackson’s well-known Many-Properties Problem. Both of us make use of a similar strategy: characterizing ways of perceiving by using the language of objects, and not just of properties. But while D’Ambrosio’s view does indeed validate the inferences that Jackson’s challenge highlights, it does so at the price of validating additional, invalid inferences, such as the inference from the claim that a small child hallucinates a bottle of (...) class='Hi'>aspirin to the claim that the child hallucinates a bottle of acetylsalicylic acid. My view avoids this. The crucial difference is that D’Ambrosio appeals to success conditions, which are extensional, while I appeal to informational content, which is not. (shrink)

Cartesian separation and enlightenment have led to a widespread conceptual separation of science and technology. Consequently a certain philosophical tradition holds pure science as a metaphysical striving for irrefutable truth that is morally neutral and only ( dirty?) applications as morally accountable. An opposite extreme position holds scientists responsible for everything that is done with their discoveries. Based on an interpretation of science to be a social construct and the observation that moral criteria are the results of social processes the (...) paper demonstrates by the example of synthetic chemistry that science is not an elite end in itself and as such is not free from obligation to moral criteria. The moral responsibility of a scientist, which arises from his professional expertise, is limited to the available knowledge of his discipline. The moral responsibility, which he carries beyond that as responsible acting human, derives from the cultural identity and the normative values under which his action is carried out. This conclusion is illustrated by the examples of DDT, Aspirin and Heroin. (shrink)

A love-based reason theory as a new perspective in the debate on practical reasons. Reasons and obligations pervade our lives. The alarm clock gives us a reason to get up in the morning, the expectations of colleagues or clients give us a reason to do our jobs well, the misery in developing countries gives us a reason to donate money, headaches give us a reason to take an aspirin. Looking for unity in variety, philosophers wonder what makes a consideration (...) count as a reason to do something. The nature and source of practical reasons has been debated intensively over the last three decennia in analytic philosophy. This book discusses the three most influential theories in current debates, referred to as the desire-based, the value-based, and the rationality-based theories of practical reasons. The author argues that all three are defective because they overlook the role of what agents care about. (shrink)

In clinical trials, it is common practice to follow up significant interactions between the factors under investigation with subgroup analyses. Such analyses pose at least two analytical and interpretational challenges. The first challenge is that performing multiple subgroup analyses increases the likelihood of obtaining spuriously significant results. This has been acknowledged and relevant guidance exists in the medical literature. The second challenge is that the effects that are obtained at the level of subgroup are composite. This has yet to be (...) fully acknowledged and discussed in the context of medical research. This paper aims to fill this lacuna. Using a simple additive model, we use recent findings from the CHARISMA trial on the efficacy of clopidogrel in addition to aspirin in the treatment of patients at risk for atherothrombotic events to demonstrate quantitatively the composition of effects at the level of subgroups. In the simplest case of a design involving an interaction (two crossed factors, with two levels each, i.e. a 2 x 2 design), effects at the level of subgroup consist of influences that stem (i) from the incidence of the measured outcome in the study population as a whole; (ii) from the factor of interest (e.g. treatment vs. placebo); (iii) from the second factor (e.g. patient group membership); (iv) from the interaction between the two factors; and (v) from random error in the measured outcome. The value of the approach illustrated here is that it is generalizable to any research design irrespective of its complexity and that it prompts clinicians to consider the multiple causality underlying medical research findings. (shrink)

Those who write about pain management have focused almost entirely on delivery issues, paying essentially no attention to the federal regulatory challenges that affect the development of pain relief technologies — namely, pharmaceuticals and medical devices indicated for analgesic uses. The academic literature is strangely devoid of any sophisticated discussion of the difficulties that attend, first, the product approval decisions of the Food and Drug Administration and, second, the scheduling decisions made by the Drug Enforcement Administration. If a “bottleneck” develops (...) upstream, it could have serious repercussions downstream — without pain relief technologies, the issues of access that have preoccupied previous commentators would have little practical consequence.The modern pharmaceutical industry traces its origins back more than a century, around the time that the German company Bayer first synthesized aspirin and began marketing it as an analgesic. (shrink)

Those who write about pain management have focused almost entirely on delivery issues, paying essentially no attention to the federal regulatory challenges that affect the development of pain relief technologies — namely, pharmaceuticals and medical devices indicated for analgesic uses. The academic literature is strangely devoid of any sophisticated discussion of the difficulties that attend, first, the product approval decisions of the Food and Drug Administration and, second, the scheduling decisions made by the Drug Enforcement Administration. If a “bottleneck” develops (...) upstream, it could have serious repercussions downstream — without pain relief technologies, the issues of access that have preoccupied previous commentators would have little practical consequence.The modern pharmaceutical industry traces its origins back more than a century, around the time that the German company Bayer first synthesized aspirin and began marketing it as an analgesic. (shrink)

Those who write about pain management have focused almost entirely on delivery issues, paying essentially no attention to the federal regulatory challenges that affect the development of pain relief technologies — namely, pharmaceuticals and medical devices indicated for analgesic uses. The academic literature is strangely devoid of any sophisticated discussion of the difficulties that attend, first, the product approval decisions of the Food and Drug Administration (FDA) and, second, the scheduling decisions made by the Drug Enforcement Administration (DEA). If a (...) “bottleneck” develops upstream, it could have serious repercussions downstream — without pain relief technologies, the issues of access that have preoccupied previous commentators would have little practical consequence.The modern pharmaceutical industry traces its origins back more than a century, around the time that the German company Bayer first synthesized aspirin (acetylsalicylic acid) and began marketing it as an analgesic. (shrink)

Consider four elite female runners who trained hard for a 1500‐meter race. Runner 1 took extra‐strength aspirin before the race. Runner 2 has a genetic condition that results in greater levels of testosterone in her body than the typical range for a woman. Runner 3 has been on a carefully scheduled regimen of the hormone erythropoietin (EPO), which has increased her red blood cell count. Runner 4 has a team of diet, sleep, and exercise experts who ensured that she (...) coordinated the exactly right balance of carbs and protein with her rest and workouts. Which of them cheated? Thomas Murray's Good Sport: Why Our Games Matter—and How Doping Undermines Them does not answer this question, but it provides tools to figure it out, and it argues that trying to answer is important. (shrink)

This essay explores what Jewish ethics has to say about globalization in relation to the AIDS crisis. Special attention is paid to the consequences in affirming current intellectual trends to transcend traditional limits in both society and thought for rethinking traditional Jewish values. The discussion proceeds from two presuppositions. The first is that there is an intimate connection between ethics, science, and politics. The second is that the history of Jewish ethics involves three distinct forms that are generally correlated but (...) rarely identical in content and moral judgment. These three forms are law, wisdom or virtue, and covenant. The discussion considers related issues of accidental connections in time between the bubonic plague and Zionism and between AIDS and homosexuality in relation to moral–theological issues related to divine providence and distributive justice. (shrink)