Today’s and tomorrow’s imaging and circulating biomarkers for pulmonary arterial hypertension

The pathobiology of pulmonary arterial hypertension (PAH) involves a remodeling process in distal pulmonary arteries, as well as vasoconstriction and in situ thrombosis, leading to an increase in pulmonary vascular resistance, right heart failure and death. Its etiology may be idiopathic, but PAH is also frequently associated with underlying conditions such as connective tissue diseases. During the past decade, more than welcome novel therapies have been developed and are in development, including those increasingly targeting the remodeling process. These therapeutic options modestly increase the patients' long-term survival, now approaching 60% at 5 years. However, non-invasive tools for confirming PAH diagnosis, and assessing disease severity and response to therapy, are tragically lacking and would help to select the best treatment. After exclusion of other causes of pulmonary hypertension, a final diagnosis still relies on right heart catheterization, an invasive technique which cannot be repeated as often as an optimal follow-up might require. Similarly, other techniques and biomarkers used for assessing disease severity and response to treatment generally lack specificity and have significant limitations. In this review, imaging as well as current and future circulating biomarkers for diagnosis, prognosis, and follow-up are discussed.     

On the equivalence of Goodman’s and Hempel’s paradoxes

Historically, Nelson Goodman’s paradox involving the predicates ‘grue’ and ‘bleen’ has been taken to furnish a serious blow to Carl Hempel’s theory of confirmation in particular and to purely formal theories of confirmation in general. In this paper, I argue that Goodman’s paradox is no more serious of a threat to Hempel’s theory of confirmation than is Hempel’s own paradox of the ravens. I proceed by developing a suggestion from R. D. Rosenkrantz into an argument for the conclusion that these paradoxes are, in fact, equivalent. My argument, if successful, is of both historical and philosophical interest. Goodman himself maintained that Hempel’s theory of confirmation was capable of handling the paradox of the ravens. And Hempel eventually conceded that Goodman’s paradox showed that there could be no adequate, purely syntactical theory of confirmation. The conclusion of my argument entails, by contrast, that Hempel’s theory of confirmation is incapable of handling Goodman’s paradox if and only if it is incapable of handling the paradox of the ravens. It also entails that for any adequate solution to one of these paradoxes, there is a corresponding and equally adequate solution to the other.     

Borelli’s edition of books V–VII of Apollonius’s Conics,and Lemma 12 in Newton’s Principia

To solve the direct problem of central forces when the trajectory is an ellipse and the force is directed to its centre, Newton made use of the famous Lemma 12 (Principia, I, sect. II) that was later recognized equivalent to proposition 31 of book VII of Apollonius’s Conics. In this paper, in which we look for Newton’s possible sources for Lemma 12, we compare Apollonius’s original proof, as edited by Borelli, with those of other authors, including that given by Newton himself. Moreover, after having retraced its editorial history, we evaluate the dissemination of Borelli's edition of books V-VII of Apollonius’s Conics before the printing of the Principia.

     

The law of refraction and Kepler’s heuristics

Archive for History of Exact Sciences - Johannes Kepler dedicated much of his work to discover a law for the refraction of light. Unfortunately, he formulated an incorrect law. Nevertheless, it was...     

Experiencing deep and global currents at a ‘Prototypical Strait’, 1870s and 1980s

Deep ocean currents are not accessible to direct human perception. Their insertion into global structures of circulation is even more profoundly removed from individual sensorial experience. But oceanographers tend to use wider concepts of experience to include instruments, traditions of observation and theoretical models. Historians and philosophers of science, as well as STS scholars, have also redefined scientific experience as operational and collective transformations of parts of the world around us into fragments of larger bodies of knowledge. This paper pursues this definition to follow the instrumental and epistemological resources available to those “observing” deep-water circulation at the Strait of Gibraltar in two very distinct moments, ca. 1870 and ca. 1985, respectively through the works of scientists like William B. Carpenter and the transnational team involved in the Gibraltar Experiment. Detecting and mapping the Gibraltar undercurrent necessitated taking data of temperature and salinity as proxies for masses of water. Making it relevant to world ocean currents required the use of models and moving across scales. In both contexts, empires of global reach provided the globalizing motivations and infrastructures.     

The natures of numbers in and around Bombelli’s L’algebra

The purpose of this article is to analyse the mathematical practices leading to Rafael Bombelli’s L’algebra (1572). The context for the analysis is the Italian algebra practiced by abbacus masters and Renaissance mathematicians of the fourteenth to sixteenth centuries. We will focus here on the semiotic aspects of algebraic practices and on the organisation of knowledge. Our purpose is to show how symbols that stand for underdetermined meanings combine with shifting principles of organisation to change the character of algebra.     

Monocytes and their pathophysiological role in Crohn’s disease

Our immune system shows a stringent dichotomy, on the one hand displaying tolerance towards commensal bacteria, but on the other hand vigorously combating pathogens. Under normal conditions the balance between flora tolerance and active immunity is maintained via a plethora of dynamic feedback mechanisms. If, however, the balancing act goes faulty, an inappropriate immune reaction towards an otherwise harmless intestinal flora causes disease, Crohn’s disease for example. Recent developments in the immunology and genetics of mucosal diseases suggest that monocytes and their derivative cells play an important role in the pathophysiology of Crohn’s disease. In our review, we summarize the recent studies to discuss the dual function of monocytes - on the one hand the impaired monocyte function initiating Crohn’s disease, and on the other hand the overactivation of monocytes and adaptive immunity maintaining the disease. With a view to developing new therapies, both aspects of monocyte functions need to be taken into account. Received 1 June 2008; received after revision 24 July 2008; accepted 13 August 2008     

Newton’s De gravitatione: a review and reassessment

The widely accepted supposition that Newton’s De gravitatione was written in 1684/5 just before composing the Principia is examined. The basis for this determination has serious difficulties starting with the failure to examine the numerical estimates for the resistance of aether. The estimated range is not nearly nil as claimed but comparable with air at or near the earth’s surface. Moreover, the evidence provided most likely stems from experiments by Boyle, Hooke, and others in the 1660s and does not use evidence available in the late 1684. The document supports Newton’s contention that the aether medium incorporates very large voids thereby proving that body and space differ but does by no means completely reject its corporeal nature or eliminate its resistance. Newton’s use of the term inertia provides no conclusive evidence for a late date as often claimed and his definition of gravitas is difficult to reconcile with a late one.     

Common features between diabetes mellitus and Alzheimer’s disease

Epidemiological studies establish a link between Type 2 diabetes (T2DM) and Alzheimer’s disease (AD), both leading causes of morbidity and mortality in the elderly. These diseases also share clinical and biochemical features suggesting common pathogenic mechanisms. Specifically, both are amyloidoses as they are characterized by fibrillar protein aggregates – amylin in T2DM pancreatic islets, and β-amyloid (Aβ) and neurofibrillary tangles (NFTs) in AD brain. Amylin aggregation is associated with pancreatic β-cell loss, and Aβ and NFT formation with neuronal cell loss. We discuss the possibility that amylin and Aβ exert their toxicity by similar mechanisms, with components of the pathocascades shared, and that therapies based on amyloidogenic properties are beneficial for both T2DM and AD. Received 27 January 2009; received after revision 17 February 2009; accepted 23 February 2009     

Novelty,coherence, and Mendeleev’s periodic table

Predictivism is the view that successful predictions of “novel” evidence carry more confirmational weight than accommodations of already known evidence. Novelty, in this context, has traditionally been conceived of as temporal novelty. However temporal predictivism has been criticized for lacking a rationale: why should the time order of theory and evidence matter? Instead, it has been proposed, novelty should be construed in terms of use-novelty, according to which evidence is novel if it was not used in the construction of a theory. Only if evidence is use-novel can it fully support the theory entailing it. As I point out in this paper, the writings of the most influential proponent of use-novelty contain a weaker and a stronger version of use-novelty. However both versions, I argue, are problematic. With regard to the appraisal of Mendeleev’ periodic table, the most contentious historical case in the predictivism debate, I argue that temporal predictivism is indeed supported, although in ways not previously appreciated. On the basis of this case, I argue for a form of so-called symptomatic predictivism according to which temporally novel predictions carry more confirmational weight only insofar as they reveal the theory’s presumed coherence of facts as real.     

Thomas Harriot’s optics,between experiment and imagination: the case of Mr Bulkeley’s glass

Some time in the late 1590s, the Welsh amateur mathematician John Bulkeley wrote to Thomas Harriot asking his opinion about the properties of a truly gargantuan (but totally imaginary) plano-spherical convex lens, 48 feet in diameter. While Bulkeley’s original letter is lost, Harriot devoted several pages to the optical properties of “Mr Bulkeley his Glasse” in his optical papers (now in British Library MS Add. 6789), paying particular attention to the place of its burning point. Harriot’s calculational methods in these papers are almost unique in Harriot’s optical remains, in that he uses both the sine law of refraction and interpolation from Witelo’s refraction tables in order to analyze the passage of light through the glass. For this and other reasons, it is very likely that Harriot wrote his papers on Bulkeley’s glass very shortly after his discovery of the law and while still working closely with Witelo’s great Optics; the papers represent, perhaps, his very first application of the law. His and Bulkeley’s interest in this giant glass conform to a long English tradition of curiosity about the optical and burning properties of large glasses, which grew more intense in late sixteenth-century England. In particular, Thomas Digges’s bold and widely known assertions about his father’s glasses that could see things several miles distant and could burn objects a half-mile or further away may have attracted Harriot and Bulkeley’s skeptical attention; for Harriot’s analysis of the burning distance and the intensity of Bulkeley’s fantastic lens, it shows that Digges’s claims could never have been true about any real lens (and this, I propose, was what Bulkeley had asked about in his original letter to Harriot). There was also a deeper, mathematical relevance to the problem that may have caught Harriot’s attention. His most recent source on refraction—Giambattista della Porta’s De refractione of 1593—identified a mathematical flaw in Witelo’s cursory suggestion about the optics of a lens (the only place that lenses appear, however fleetingly, in the writings of the thirteenth-century Perspectivist authors). In his early notes on optics, in a copy of Witelo’s optics, Harriot highlighted Witelo’s remarks on the lens and della Porta’s criticism (which he found unsatisfactory). The most significant problem with Witelo’s theorem would disappear as the radius of curvature of the lens approached infinity. Bulkeley’s gigantic glass, then, may have provided Harriot an opportunity to test out Witelo’s claims about a plano-spherical glass, at a time when he was still intensely concerned with the problems and methods of the Perspectivist school.     

Euler’s beta integral in Pietro Mengoli’s works

Beta integrals for several non-integer values of the exponents were calculated by Leonhard Euler in 1730, when he was trying to find the general term for the factorial function by means of an algebraic expression. Nevertheless, 70 years before, Pietro Mengoli (1626–1686) had computed such integrals for natural and half-integer exponents in his Geometriae Speciosae Elementa (1659) and Circolo(1672) and displayed the results in triangular tables. In particular, his new arithmetic–algebraic method allowed him to compute the quadrature of the circle. The aim of this article is to show how Mengoli calculated the values of these integrals as well as how he analysed the relation between these values and the exponents inside the integrals. This analysis provides new insights into Mengoli’s view of his algorithmic computation of quadratures.     

Boyle’s teleological mechanism and the myth of immanent teleology

According to recent commentators, medieval natural philosophers endorsed immanent teleology, the view that natural agents possess immanent active powers to achieve certain ends. Moreover, some scholars have argued that Robert Boyle, despite his intentions, failed to eliminate immanent teleology from his natural philosophy. I argue in this paper that it is not at all clear that immanent teleology was widely endorsed in the medieval period. Moreover, I argue that a proper understanding of immanent teleology, and why it was rejected by mainstream medieval natural philosophers, reveals that Boyle did not fail to eliminate immanent teleology from his natural philosophy. I conclude that any attempt to describe the break between medieval and early modern natural philosophy in terms of a break with immanent teleology is likely not on target.     

Mach׳s principle as action-at-a-distance in GR: The causality question

A part of the revival of interest in Mach׳s principle since the early 1960s has involved work by physicists aimed at calculating various sorts of frame-dragging effects by matter shells surrounding an interior region, and arguing that under certain conditions or in certain limits (ideally, ones that can be viewed as plausibly similar to conditions in our cosmos) the frame dragging becomes “complete” (e.g. Lynden-Bell, Katz, & Bičák, 1995) . Such results can bolster the argument for the satisfaction of Mach׳s principle by certain classes of models of GR. Interestingly, the frame-dragging “effect” of (say) a rotational movement of cosmic matter around a central point is argued by these physicists to be instantaneous—not an effect propagating at the speed of light. Not all physicists regard this as unproblematic. But rather than exploring whether there is something unphysical about such instantaneous “action at a distance”, or a violation of the precepts of Special Relativity, I am interested in exploring whether these physicists׳ calculations should be thought of as showing local inertia (resistance to acceleration) to be an effect, with distant matter distributions being the cause. I will try to apply some leading philosophical accounts of causation to the physical models of frame dragging, to see whether they imply that the frame dragging is superluminal causation. I will then offer reflections on the difficulties of applying causal talk in physical theories.