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Can we really perceive absences, i.e., missing things? Sartre tells us that when he arrived late for his appointment at the café, he saw the absence of his friend Pierre. Is that really what he saw? Where was it, exactly? Why didn’t Sartre see the absence of other people who were not there? Why did other people who were there not see the absence of Pierre? The perception of absences gives rise to a host of conundrums and is constantly on the verge of conceptual confusion. Here I focus on the need to be clear about four sorts of distinctions: (i) the difference between perceiving an absence and perceiving something that is absent; (ii) the difference between perceiving an absence and an absence of perceiving; (iii) the difference between perceiving an absence and perceiving something as an absence; and (iv) the difference between perceiving an absence and perceiving that something is absent. more...

Background: Infectious diseases remain a major public health problem in the world with a considerable impact in developing countries. Bacterial infections are of increasing concern due to the emergence and spread of bacteria resistant to antibiotics. Thus, it is necessary to develop methods and means to tackle drug resistance. The present study aimed at evaluating the antibacterial and antibiotic-potentiating activities of eleven Cameroonian medicinal plants: Sambucus nigra, Erigeron floribundus, Desmodium uncinatum, Neoboutonia glabrescens, Ficus exasperata, Sida rhombifolia, Echinaceae augustifolia, Centella asiatica, Tradescantia zebrina, Desmodium intortum and Ternstroemia cameroonensis against bacteria with multidrug-resistant (MDR) phenotypes. Methods: The microdilution method was used to assess the antibacterial activities of the extracts as well as the effect of their combination with antibiotics. The phytochemical screening of the extracts was carried out according to qualitative described methods. Results: The phytochemical screening revealed the presence of tannins, triterpenes, polyphenols, and flavonoids in almost all the extracts, with the other classes of secondary metabolites being selectively distributed. The tested extracts exhibited variable antibacterial activities, with minimum inhibitory concentrations (MICs) ranging between 512 and 1024 μg/mL. The Ficus exasperata leaves extract, Ternstroemia cameroonensis back extract, Erigeron floribundus whole plant extract, and Neoboutonia glabrescens leave extracts, presented the best spectra of inhibitions evaluated respectively at 60%, 60%, 70%, and 70% vis-à-vis all the bacterial strains tested. The whole plant extracts of Desmodium uncinatum and Centella asiatica, and of Ternstroemia cameroonensis have shown synergistic effects with more than 50% of the antibiotics (chloramphenicol, tetracycline, kanamycin, ciprofloxacin, ofloxacin, azithromycin and erythromycin) against more than 70% of the MDR bacteria tested. Conclusion: The present study demonstrated that extracts from the bark of Ternstroemia cameroonensis, Neoboutonia glabrescens and Ficus exasperata leaves, Desmodium uncinatum, and Erigeron floribundus whole plants can be used alone or in combination with antibiotics against bacterial infections involving MDR bacteria. Keywords: Antibacterial; antibiotics; medicinal plants; multidrug resistance. more...

David Lewis’s counterpart theory (CT) is often seen as involving a radical departure from the standard, Kripke-style semantics for modal logic (ML), suggesting that we are dealing with deeply divergent accounts of our modal talk. However, CT captures but one version of the relevant semantic intuition, and does so on the basis of metaphysical assumptions (all worlds are equally real, individuals are world-bound) that are ostensibly discretionary. Just as ML can be translated into a language that quantifies explicitly over worlds, CT may be formulated as a semantic theory in which world quantification is purely metalinguistic. And just as Kripke-style semantics is formally compatible with the doctrine of world-boundedness, a counterpart-based semantics may in principle allow for cases of trans-world identity. In fact, one may welcome a framework that is general enough to include both Lewis’s counterpart-based account and Kripke’s identity-based account as distinguished special cases. There are several ways of doing so. The purpose of this paper is to outline a fully general option and to illustrate its philosophical significance, showing how the large variety of intermediate relations that lie between Lewisian counterparthood and Kripkean identity yield a corresponding variety of modal theories that would otherwise remain uncharted. more...

Cities are mysteriously attractive. The more we get used to being citizens of the world, the more we feel the need to identify ourselves with a city. Moreover, this need seems in no way distressed by the fact that the urban landscape around us changes continuously: new buildings rise, new restaurants open, new stores, new parks, new infrastructures… Cities seem to vindicate Heraclitus’s dictum: you cannot step twice into the same river; you cannot walk twice through the same city. But, as with the river, we want and need to say that it is the same city we are walking through every day. It is always different, but numerically self-identical. How is that possible? What sort of mysterious thing is a city? The answer, I submit, is that cities aren’t things. They are processes. Like rivers, cities unfold in time just as they extend in space, by having different temporal parts for each time at which they exist. And walking though one part and then again through another is, literally, walking through the same whole. more...

This chapter provides a brief illustration of the centrality of part-whole inquiry throughout the history of philosophy, West and East. It explains two original motivations for the contemporary formal explorations of mereological systems. Husserl’s approach, stemming from Brentano, sought to treat part-whole relations as formal ontology – comprising a set of general structural principles applying to any objects whatsoever. Leśniewski’s approach was motivated by nominalism and the search for an alternative foundation for mathematics not beset by the paradoxes of naïve set theory. Some attention is paid to the different uses of ‘part’ in natural language and to whether mereology should be thought of as providing a single, overarching account. The final section details the logical machinery used throughout the book. more...

This chapter considers whether mereology should rightly be thought of as a first-order theory with parthood as a binary predicate. It considers extensions of classical mereology aimed at overcoming the expressive limits of standard first-order languages, focusing on second-order and plural formulations. Relatedly, Lewis’s megethology and applications to the philosophy of mathematics are discussed. Then, several ways of modifying the framework to make room for mereological considerations involving time and modality are presented, such as the possibility that an object may have different parts at different times, or that it could have had different parts from the ones it actually has. Finally, a number of theories are expounded that can be developed in order to deal with the phenomenon of mereological indeterminacy, i.e., the fact that in some cases the very question of whether something is part of something else does not appear to have a definite answer. more...

This chapter carefully attends to how decomposition principles are supposed to work, and how different variants and formulations affect the resulting theory in different ways. It begins with the philosophically familiar notion of Boolean complementation, and then gradually discusses ever weaker variants of this notion in the form of various supplementation principles. The chapter evaluates which of these principles are linked to extensionality and which (if any) are constitutive of the minimal concept of parthood. Other decomposition questions include: Can we continually decompose objects into smaller and smaller parts (gunk)? Must there be smallest parts (atoms)? Is there a mereological correlate to the empty set, namely the ‘null object’? Each of these questions is explored in full formal detail, including a characterization of the maximally consistent extensions of classical mereology. more...

Classical mereology is based on the idea that parthood is a reflexive, transitive, antisymmetric relation—a weak partial order. Proper parthood is irreflexive, transitive, and asymmetric—serving as the corresponding strict partial order. This chapter critically and carefully evaluates each of these conditions, and considers a range of alternate definitions for proper parthood and other basic notions.. Along the way, it discusses formal relationships between these definitions, and the logical implications of adopting them. The philosophical controversies surrounding these axioms are addressed: discussing self-parts, parthood loops, mutual parts and extensionality, and non-transitive notions such as immediate parthood, local transitivity, and more. more...

The aim of this chapter is to provide a comprehensive introduction to classical mereology. It examines this theory by providing a clear and perspicuousaxiom system that isolates several important elements of any mereological theory. The chapter examines, algebraic, and set-theoretic models of classical mereology, sketching proofs of their equivalence. The new axiom system facilitates algebraic comparisons, showing that models of these axioms are complete Boolean algebras without a bottom element. Then set-theoretic models are presented, and are shown to satisfy the axioms. The chapter explains the important relationship between models and powersets, and the role of Stone’s Representation Theorem in this connection. Finally, a number of significant rival axiom systems using different mereological primitives are introduced. more...

Mereology is the formal theory of parthood relations. Mereological theories—have become a chapter of central interest in metaphysics, but also with applications in logic, the philosophy of mathematics, the philosophy of language, and the philosophy of science. This book provides a critical survey and an up-to-date assessment of the main results in this area, with an eye to both their philosophical underpinnings and their formal properties. In doing so, it also aims to investigate the varieties of formal systems currently available. After a brief history of the development of mereology, introductions to different axiomatizations of so-called classical mereology, alongside set-theoretic and algebraic models, are presented in a clear and accessible manner. The book addresses formal and philosophical issues surrounding the notions of parthood, identity, decomposition, atomism, composition, and more. As a result, the book, provides resources to aide the development of new, non-classical theories of parthood (such as non-well-founded mereologies, non-transitive mereologies, non-extensional mereologies, and more). Consideration is devoted to impact that the logical background has on mereological results (including higher-order, temporal, modal, non-classical logics). A detailed index, appendices, and a comprehensive bibliography makes this book an indispensable resource to researchers in every field where part-whole theorizing plays a fundamental role. more...

Euclid’s definition of a point as “that which has no part” has been a major source of controversy in relation to the epistemological and ontological presuppositions of classical geometry, from the medieval and modern disputes on indivisibilism to the full development of point-free geometries in the 20th century. Such theories stem from the general idea that all talk of points as putative lower-dimensional entities must and can be recovered in terms of suitable higher-order constructs involving only extended regions (or bodies). This chapter focuses on what is arguably the first thorough proposal of this sort, Whitehead’s theory of “extensive abstraction”, offering a critical reconstruction of the theory through its successive installments: from the purely mereological version of ‘La théorie relationniste de l’espace’ (1916) to the refined versions presented in An Enquiry Concerning the Principles of Natural Knowledge (1919) and in The Concept of Nature (1920) to the last, mereotopological version of Process and Reality (1929). more...

Classical propositional logic can be characterized, indirectly, by means of a complementary formal system whose theorems are exactly those formulas that are not classical tautologies, i.e., contradictions and truth-functional contingencies. Since a formula is contingent if and only if its negation is also contingent, the system in question is paraconsistent. Hence classical propositional logic itself admits of a paraconsistent characterization, albeit “in the negative”. More generally, any decidable logic with a syntactically incomplete proof theory allows for a paraconsistent characterization of its set of theorems. This, we note, has important bearing on the very nature of paraconsistency as standardly characterized. more...

Why did Emanuel Carnevali submit his short poem to the 1919 Whitman issue of Poetry if the only apparent connection with Walt Whitman is in the title? He did so, I argue, because the poem is as Whitmanesque as one could possibly imagine. Carnevali’s philosophy of the commonplace is more than just an ars poetica of sorts. It is Philosophy with a capital “P.” It is an endorsement of Whitman’s perspective on things along with the sense of wonder that, as Aristotle said (and Plato before him), is the beginning of all philosophy. more...

Mereological atomism is the thesis that everything is ultimately composed of atomic parts, i.e., parts lacking proper parts. Standardly, this thesis is characterized by an axiom that says, more simply, that everything has atomic parts. Anthony Shiver has argued that this characterization is satisfied by models that are not atomistic, and is therefore inadequate. I argue that Shiver’s conclusion can and ought to be resisted, for (i) the models in question are atomistic in the intended sense, and (ii) even though the standard characterization does not say that everything is composed of atoms, it implies so. If there is a sense in which the relevant models are problematic, it lies elsewhere. more...

It is customary practice to define ‘x is composed of the ys’ as ‘x is a sum of the ys and the ys are pairwise disjoint (i.e., no two of them have any parts in common)’. This predicate has played a central role in the debate on the special composition question and on related metaphysical issues concerning the mereological structure of objects. In this note we show that the customary characterization is nonetheless inadequate. We do so by constructing a mereological model where everything qualifies as composed of atoms even though some elements in the domain are gunky, i.e., can be divided indefinitely into smaller and smaller proper parts. more...

Background Current guidelines recommend use of the aldosterone‐renin ratio ( ARR ) for the case detection of primary aldosteronism followed by confirmatory tests to exclude false‐positive results from further diagnostic workup. We investigated the hypothesis that this could be unnecessary in patients with a high ARR value if the quantitative information carried by the ARR is taken into due consideration. Methods and Results We interrogated 2 large data sets of prospectively collected patients studied with the same predefined protocol, which included the captopril challenge test. We used an unambiguous diagnosis of aldosterone‐producing adenoma as reference index. We also assessed whether the post‐captopril ARR and plasma aldosterone concentration fall furnished a diagnostic gain over baseline ARR values. We found that the false‐positive rate fell exponentially, and, conversely, the specificity increased with rising ARR values. At receiver operating characteristics curves and diagnostic odds ratio analysis, the high baseline ARR values implied very high positive likelihood ratio and diagnostic odds ratio values. The baseline and post‐captopril ARR showed similar diagnostic accuracy (area under the receiver operating characteristics curve) in both the exploratory and validation cohorts, indicating lack of diagnostic gain with this confirmatory test (between‐area under the curve difference, 0.005; 95% CI , −0.031 to 0.040; P =0.7 for comparison, and 0.05; 95% CI , −0.061 to 0.064; P =0.051 for comparison, respectively). Conclusions These results indicate that the ARR conveys key quantitative information that, if properly used, can simplify the diagnostic workup, resulting in saving of money and resources. This can offer the chance of diagnosis and ensuing adrenalectomy to a larger number of hypertensive patients, ultimately resulting in better control of blood pressure. more...

This is a brief sequel to Max Black's classic dialogue on the Identity of Indiscernibles. Interlocutor A defends the bundle theory by endorsing the (by now popular) view according to which Black's world does not contain two indiscernible spheres but rather a single, bi-located sphere. His opponent, B, objects that A cannot distinguish such a world from a world with a single, uniquely located sphere, hence that the view in question adds nothing to A's original response to Black's challenge. A is simply denying that there can be worlds with two or more indiscernible entities. more...

Fictionalism in ontology is a mixed bag. Here I focus on three main variants – which I label after the names of Pascal, Berkeley, and Hume – and consider their relative strengths and weaknesses. The first variant is just a version of the epistemic Wager, applied across the board. The second variant builds instead on the fact that ordinary language is not ontologically transparent; we speak with the vulgar, but deep down we think with the learned. Finally, on the Humean variant it’s the structure of the ontological inventory, not its content, that may turn out to involve fictional elements. That is, for the Humean the fiction lies, not in the reality of common-sense ontology, but in the laws – of unity, identity, causation, etc. – in terms of which we articulate our experience of that reality. In the end, this is the kind of fictionalism that I find most interesting, sensible, and tenable. And I argue that it is even compatible with the sort of “naive” realism we have all come to appreciate in the work of Paolo Bozzi, to whom the paper is dedicated. more...

Injury of vascular endothelium, crucial in vascular disease, is repaired via circulating endothelial progenitor cells (cEPCs). In hypertension, cEPCs number is reduced and function impaired adding further risk for cardiovascular (CV) events. Angiotensin II (Ang II)-induced oxidative stress (OxSt), accelerates cEPCs senescence. Calcitonin gene-related peptide (CGRP), able to prevent and reverse Ang II-induced cEPCs senescence, is reduced in hypertension and stimulated by the antioxidant and anti-inflammatory heme oxygenase (HO)-1. In essential hypertensive patients olmesartan reduced OxSt and markers of CV remodeling and increased HO-1. This study reports in essential hypertensive patients the effect of 6 months treatment with olmesartan on plasma level of CGRP and number and survival of cEPCs.In 20 essential hypertensive patients treated with olmesartan medoxomil (20 mg per day for 6 months), cEPCs (CD34(+)KDR(+), CD133(+)KDR(+) and CD34(+)CD133(+)KDR(+)) (direct 3-color flow cytometry analysis), apoptosis of cEPCs (CD133(+)KDR(+) cells with Annexin V expression), CGRP determination (ELISA) and HO-1 protein level (western blot) were assessed at baseline and after 3 and 6 months of treatments. Olmesartan normalized blood pressure (P 0.001), increased cEPCs from baseline (CD34(+)KDR(+): P 0.003; CD133(+)KDR(+): P 0.0002; CD34(+)CD133(+)KDR(+): P = 0.0008), reduced cEPCs apoptosis (P 0.001) and increased CGRP (P 0.013) and HO-1 (P = 0.039).These results provide a mechanistic rationale for the olmesartan's antioxidant and anti-inflammatory potential translation toward antiatherosclerotic and antiremodeling effects reported on clinical ground. more...

CASE REPORT A young patient presented with a history of resistant arterial hypertension, associated with disabling symptoms. He was subjected to an enormous number of tests to identify a pheochromocytoma that was never found. He was eventually discovered to make factitious use of amphetamine to mimic this condition in order to gain medical attention. Munchausen syndrome was thus diagnosed. The patient was discharged and was lost to follow-up until he presented again in 2012 for 'resistant hypertension' in our outpatient clinic. He reported that because of poor blood pressure, he had been referred to a Cardiology department where transcatheter renal denervation was performed with no effect on blood pressure. Thereafter, he was presented to an Endocrinology unit where a left adrenalectomy was performed with diagnosis of pheochromocytoma that was not found at pathology. DISCUSSION Munchausen syndrome is a rare psychiatric condition that leads affected patients to cause intentionally signs and symptoms of an illness or injury by inflicting medical harm to their body to attract the attention of the physician and get admission to the hospital. CONCLUSION To our knowledge, this is the first case of causing drug-resistant hypertension and leading to unnecessary renal denervation and adrenalectomy. more...

Objectives: A gluten-free diet (GFD) may carry high energy and fat load. We verified lipid profile and dietary indicators cross-sectionally and prospectively in patients with celiac disease (CD). Methods: In any consecutive child receiving a GFD (group 1) or newly diagnosed as having CD (group 2), total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) cholesterol, blood pressure (BP), anthropometric data, physical activity, and a 24-hour food diary were collected during follow-up visits (yearly in group 1 and during the first year of GFD in group 2). Results: In group 1 (132 girls, 73 boys, 10.7±4.2 years), TC (P=0.006), TG (P=0.014), and HDL (P=0.019) were significantly higher in girls than in boys. Compared with the general pediatric population, group 1 girls had higher TC, TG, HDL, and low-density lipoprotein; group 1 boys had lower TC, TG, and low-density lipoprotein and higher HDL. TC was significantly and positively affected by age, sex, and time receiving GFD, whereas HDL was significantly and positively affected by body mass index, diastolic BP, and sex; TG was negatively affected by diastolic BP. Compared with recommendations, group 1 children introduced less calories, iron, and calcium; one-third more sodium; similar amounts of fiber; and twice as many proteins. In group 2 (20 girls, 10 boys, 8.6±3.55 years), TC did not change over time and TG diminished, whereas HDL, blood glucose, and body mass index increased; saturated fats and caloric intake were below recommendations, whereas proteins were excessively introduced. Fibers were optimal. HDL was inversely correlated to calories and saturated fat (R2=80, P=0.011). Conclusions: Lipid profiles of children with CD differ across sexes and from reference population. GFD, being unexpectedly appropriate in fibers and fat proportion, may be a contributor. more...

Item does not contain fulltext CONTEXT: In patients who seek surgical cure of primary aldosteronism (PA), The Endocrine Society Guidelines recommend the use of adrenal vein sampling (AVS), which is invasive, technically challenging, difficult to interpret, and commonly held to be risky. OBJECTIVE: The aim of this study was to determine the complication rate of AVS and the ways in which it is performed and interpreted at major referral centers. DESIGN AND SETTINGS: The Adrenal Vein Sampling International Study is an observational, retrospective, multicenter study conducted at major referral centers for endocrine hypertension worldwide. PARTICIPANTS: Eligible centers were identified from those that had published on PA and/or AVS in the last decade. MAIN OUTCOME MEASURE: The protocols, interpretation, and costs of AVS were measured, as well as the rate of adrenal vein rupture and the rate of use of AVS. RESULTS: Twenty of 24 eligible centers from Asia, Australia, North America, and Europe participated and provided information on 2604 AVS studies over a 6-yr period. The percentage of PA patients systematically submitted to AVS was 77% (median; 19-100%, range). Thirteen of the 20 centers used sequential catheterization, and seven used bilaterally simultaneous catheterization; cosyntropin stimulation was used in 11 centers. The overall rate of adrenal vein rupture was 0.61%. It correlated directly with the number of AVS performed at a particular center (P = 0.002) and inversely with the number of AVS performed by each radiologist (P = 0.007). CONCLUSIONS: Despite carrying a minimal risk of adrenal vein rupture and at variance with the guidelines, AVS is not used systematically at major referral centers worldwide. These findings represent an argument for defining guidelines for this clinically important but technically demanding procedure. 01 mei 2012 more...

The Padua ESH 2011 Satellite Symposium on uncontrolled hypertension was focused on why only a relatively small percentage of patients under treatment do not reach ‘safe’ blood pressure levels; the major reason being the modest use of combination therapy. It was also an occasion to discuss new pharmacological and nonpharmacological tools, some of which appear to be efficacious when even the ‘appropriate’ traditional therapeutic strategy fails to work. more...

BackgroundAdrenal vein sampling (AVS) is the gold standard for identifying the surgically curable forms of primary aldosteronism. Dopamine modulates adrenocortical steroidogenesis and tonically inhibits aldosterone secretion via D2 receptor. However, whether it could also affect the release of cortisol and chromogranin A (ChA), which can be used to assess the selectivity of AVS, is unknown.ObjectiveTo investigate whether metoclopramide increased the release of cortisol and ChA and could thereby improve assessment of the selectivity at AVS.Design and methodsWe investigated the effect of acute D2 antagonism with metoclopramide on cortisol and ChA release from the adrenal gland by comparing the adrenal vein and infrarenal inferior vena cava (IVC) hormone levels at baseline and after metoclopramide administration in 34 consecutive patients undergoing AVS.ResultsMetoclopramide increased plasma aldosterone in the IVC (PPConclusionsThis study shows that the release of cortisol and ChA is not subjected to tonic D2 dopaminergic inhibition. Therefore, these findings lend no evidence for the usefulness of acute metoclopramide administration for enhancing the assessment of the selectivity of blood sampling during AVS with the use of either cortisol or ChA assay. more...

We correct an error and expose two redundancies in the axiom systems presented by Paul Hovda in his 2009 influential paper, ‘What is classical mereology?’.

The prevalence of secondary hypertension is lower than that of primary (essential) hypertension, but it is likely that it has been underestimated because appropriate tests were not generally performed. Hence, before embarking on a search for secondary hypertension physicians are generally advised to select populations of patients with a high pre-test probability of secondary forms of hypertension in order to maximize the positive predictive value and the gain in "ruling in" of the diagnostic tests. Based on updated information on prevalence and pathophysiology we herein critically review the general diagnostic strategy and the management of the main forms of secondary hypertension. In particular, strategies for identifying primary aldosteronism, the most frequent form of endocrine secondary hypertension, and for determining its unilateral or bilateral causes are discussed in details, because of the differences of treatment that requires adrenalectomy in the unilateral forms and mineralocorticoid receptor blockade in the bilateral forms. The tests available for the diagnosing pheochromocytoma (pheo), which is much rarer but extremely important to identify, as it can be fatal if unrecognized are also discussed, with emphasis on the recent developments in genetic testing. Renovascular hypertension is also a common curable form of hypertension, which should be identified as early as possible to avoid the onset of cardiovascular target organ damage and events, is also discussed. more...

Metabolic syndrome (MetS), which is a cluster of cardiovascular risk factors, has been acknowledged as a predictor of cardiovascular disease and chronic kidney disease in the general population. This has been particularly observed in middle-aged subjects, raising the question of whether MetS maintains a prognostic role in the elderly as well. In a few recent studies, it has been suggested that MetS is, in the elderly, nothing more than a artificial group term, in which one single risk factor has the same or even a greater prognostic value than the aggregated risk factors. However, the early identification of MetS is important in clinical practice in order to identify those subjects who present with multiple risk factors. Furthermore, the concept of MetS may help clinicians to perform a strategy-based approach aimed at reducing global cardiovascular risk, particularly by recognizing and treating dyslipidemia, hypertension and diabetes. Clinicians should encourage their sedentary elderly patients to become more physically activity and to improve their cardiorespiratory fitness as part of primary prevention of MetS. In conclusion, in elderly individuals from the general population, the prognostic role of MetS is not greater than the sum of its components. more...

Universalism (also known as Conjunctivism, or Collectivism) is the thesis that mereological composition is unrestricted. More precisely: Any non-empty collection of things has a fusion, i.e., something that has all those things as parts and has no part that is disjoint from each of them. Extensionalism is the thesis that sameness of composition is sufficient for identity. More precisely: No two things have exactly the same proper parts (unless they are atomic, i.e., have no proper parts at all). Clearly these two theses are not equivalent. They are, however, more closely related than one might think. More precisely, the entailment holds as long as it is agreed that the following postulates are constitutive of the meaning of ‘part’: Transitivity: Any part of any part of a thing is itself part of that thing. Supplementation: Whenever a thing has a proper part, it has at least another part that is disjoint from the first. more...

Contexte : Sous certaines conditions, les technologies de l’information et de la communication (TIC) peuvent apporter une valeur ajoutee a l’apprentissage des etudiants et apporter des solutions dans les milieux ou les ressources professorales sont limitees. But : Evaluer l’impact de la mise en ligne d’un module d’histologie-embryologie consacre a l’etude de l’estomac, sur les performances a l’examen d’etudiants de premiere annee de medecine a faculte des sciences de la sante (FSS) de l’Universite Abdou Moumouni (UAM) de Niamey. Materiel et methodes : 50 etudiants ont ete selectionnes au hasard et repartis en deux groupes : un groupe experimental de 25 etudiants a utilise les ressources mises en ligne du module d’histologie-embryologie, dans une demarche d’auto-formation ; un groupe temoin de 25 etudiants de la meme promotion a suivi le meme cours, dispense traditionnellement de facon magistrale. Les deux groupes ont ete evalues ensemble sur une meme epreuve de type traditionnel. Resultats : Les etudiants du groupe « experimental » ont obtenu des resultats superieurs en termes de scores aux epreuves. En revanche, la proportion d’etudiants ayant obtenu le score d’au moins 10 sur 20 n’est pas differente d’un groupe a l’autre. Conclusion : Nos resultats suggerent que l’inscription des etudiants dans un dispositif d’auto-formation associe a la mise en ligne des ressources didactiques ne les penalise pas quant a leurs chances de reussite lors d’epreuves d’evaluation sommative des apprentissages. more...

OBJECTIVE Regulator of G-protein signaling (RGS)-2 is a regulator of angiotensin II (Ang II) signaling. In Bartter's syndrome/Gitelman's syndrome (BS/GS), we have demonstrated increased RGS-2 levels and blunted Ang II signaling which contribute to their reduced vasomotor tone and remodeling. The present study investigates the effect of silencing RGS-2 in fibroblasts from six BS/GS patients on intracellular Ca2+ (CaI2+) mobilization and extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, established Ang II-mediated responses. METHODS Fibroblasts were RGS-2 silenced by transfecting chemically synthesized small interfering RNA. Silencing efficiency and Ang II-induced ERK 1/2 phosphorylation were evaluated by western blot and Ang II-induced Cai2+ using Fura-2 AM. RESULTS RGS-2 expression in not silenced BS/GS fibroblasts from patients is increased compared with healthy controls [0.34 +/- 0.02 vs. 0.19 +/- 0.01 densitometric units (d.u.), P = 0.0005]. Silencing RGS-2 in BS/GS patients was achieved to the level of controls. Ang II-induced Cai2+ release and ERK 1/2 phosphorylation were reduced in not silenced cells from BG/GS patients compared with controls (112.16 +/- 13.2 vs. 130.33 +/- 13.64 mmol/l, P = 0.011 and 0.64 +/- 0.08 vs. 0.91 +/- 0.03 mmol/l, P < 0.006, respectively). Silencing RGS-2 in BS/GS patients increased Ang II-induced Cai2+ release and ERK 1/2 phosphorylation in silenced cells compared with not silenced cells [59.3 +/- 10.8 (peak-basal) vs. 40.5 +/- 14.1 nmol/l, P = 0.017 and 0.84 +/- 0.06 vs. 0.64 +/- 0.08 nmol/l, P < 0.03, respectively], whereas they were not different compared with controls (60.1 +/- 4.3 and 0.91 +/- 0.03 nmol/l). Integrating the Cai2+ response over time showed increased Cai2+ area under the curve (AUC) of BS/GS silenced cells compared with that of not silenced cells (P = 0.013). CONCLUSION This is the first report of silencing RGS-2 effect on Ang II signaling in a human clinical condition of altered vascular tone regulation and remodeling and establishes RGS-2 as a key regulatory element of Ang II signaling in humans. more...

The question on whether the electrocardiographic criteria are reliable for detection of left ventricular hypertrophy (LVH) and play a role in predicting outcome is open. Answer can only proceed from population-based studies over unselected people followed up for years. In this study, 1,699 subjects from general population underwent echocardiogram and standard electrocardiogram (ECG) codified for LVH with Minnesota code and with other five methods. Other items were also recorded and used as covariables. Left ventricular mass index (LVMI) was 127.6 +/- 44.9 g m(-2) in men and 120.8 +/- 41.2 g m(-2 )in women, and correlated directly with age in both genders. Prevalence of echocardiographic LVH was 36.6% in men and 53.4% in women. LVMI correlated directly with the Sokolow-Lyon score in both genders at any age, with the Romhilt-Estes, Cornell and R(aVL) scores in all subjects but elderly men, and with the Lewis score in men and women agedor =69 years. Sensitivity and the predictive value of electrocardiographic tests, as well as the prevalence of LVH diagnosed with electrocardiographic criteria, were always low. Specificity was high for all the tests, and in particular for the Cornell index. Only when diagnosed with echocardiogram or with the Sokolow-Lyon criterion, LVH was an independent predictor of mortality. We conclude that electrocardiographic tests cannot be used as a surrogate of echocardiogram in detecting LVH in the general population because their positive predictive value (PPV) is unacceptably low. On the contrary, they could replace echocardiography in the follow up and for prediction of outcome, when LVH has previously been correctly diagnosed with other methods. more...

OBJECTIVES: The 825T allele of the GNB3 gene is implicated in adipose distribution, predisposing to obesity and hypertension. Menopause is also considered a condition leading to excess adiposity and hypertension. The aim of the present study was to clarify whether the effects of menopause on body weight and blood pressure are influenced by the C825T polymorphism of the GNB3 gene. METHODS: The study involved 1339 subjects (43% men) aged 18-95 years, genotyped at the GNB3 825 locus, undergoing, in an epidemiological population-based frame, questionnaire, anthropometrics and blood examinations. RESULTS: Mean skinfold thickness (MST), truncal obesity and excess subcutaneous adiposity (MST greater than median) were higher in women than in men. A significant interaction was detected between menopausal status and the C825T polymorphism (Pint > 0.0001). MST, truncal obesity and excess subcutaneous adiposity were lower in CC fertile than menopausal women, but were comparable in TT fertile and menopausal women. In a multivariate logistic model for excess subcutaneous adiposity, the relative risk of menopause was 4.12 (95% confidence interval 2.35-7.22) in CC women but was insignificant in the other two genotypes. In fertile women only, higher systolic blood pressure (SBP) was detected in TT than in CC genotypes. CONCLUSION: An interaction exists between the C825T polymorphism and menopause in controlling body adiposity and blood pressure in women. Adiposity and SBP are higher in menopausal than in fertile women, provided they have the CC genotype. TT fertile women show the same adiposity as those in menopause. Men have the same excess adiposity as menopausal women, independent of the GNB3 genotype. more...

I focus on three mereological principles: the extensionality of parthood (EP), the uniqueness of composition (UC), and the extensionality of composition (EC). These principles are not equivalent. Nevertheless they are closely related (and often equated), since they all reflect the basic nominalistic dictum ‘No difference without a difference maker’. All of them, individually or collectively, have been challenged on philosophical grounds. In the first part I argue that such challenges do not quite threaten (EP), because they are either self-defeating or unsupported. In the second part I argue that they do little to undermine the tenability of (UC) and (EC) either. more...

Amidst many discussions on super-valuational algebras and their philosophical applications - on which I was writing my dissertation - Hans and I once paused to ponder the mystical experience of the square. I mean A Square, the hero of Flatland. I mean that perfectly two-dimensional being, with no depth whatsoever, citizen of an equally two-dimensional depthless world, who one day had the good fortune of receiving a visit from a Sphere. What's more, he had the fortune of being able to visit, albeit briefly, the undreamt-of three-dimensional world his guest came from - which is to say, our threedimensional world. He visited and experienced our world before falling back for all eternity into the total flatness of his: Flatland, the plane world, the world with no aboves and no belows, the world in which cars and airplanes alike, so to speak, belong to the same category, and everything, literally everything, is reduced to fragile shadows on an enormous and eternally illuminated floor. more...

In his celebrated Romanes Lecture of 1907, George Curzon of Kedleston—former British Viceroy of India under Queen Victoria and King Edward VII and future Secretary for Foreign Affairs under King George V—emphasized the overwhelming influence of political frontiers in the history of the modern world. more...

Aldosterone-producing adenomas (APAs) are a common cause of arterial hypertension, but the underlying molecular mechanisms are unknown, although a transcriptional modulation of aldosterone synthase (CYP11B2) has been suggested. Aldosterone synthesis involves 2 main rate-limiting steps: cholesterol transport into mitochondria and CYP11B2 gene transcription. Evidence supports a role of Ca 2+ /calmodulin-dependent protein kinases (CAMKs) in the regulation of angiotensin II– and potassium-stimulated aldosterone production. CAMK-I mediates CYP11B2 transcription via cAMP response element binding protein and activating transcription factor 1 transcription factors and nuclear receptor Nur-related factor 1. CAMK-II affects cholesterol transport into mitochondria by acting on steroidogenic acute regulatory protein and/or cytoskeleton proteins. We analyzed the whole transcriptome of APAs as compared with a pool of normal human adrenocortical tissues. Based on steroidogenic enzyme gene expression profiles, we identified 2 APA subgroups: 1 featuring overexpression of CYP11B2, CAMK-I, 11-β-hydroxylase, 3-β-hydroxysteroid dehydrogenase, and 21-hydroxylase and the underexpression of CAMK-IIB and the other one with an opposite profile. The low CYP11B2 group exhibited a longer known duration of hypertension and a lower rate of long-term cure. Thus, aldosterone overproduction in APAs involves complex alterations of aldosterone synthesis regulation rather than simply increased aldosterone synthase gene expression. Whether the molecular signature of APA carries prognostic information is worth further investigation. more...

Hypertension and diabetes mellitus occur together frequently. There is general consensus in the literature that in patients with hypertension and diabetes, the heart and kidneys are locked in a vice, between arterial stiffening and damage to the microcirculation, with each condition feeding the other in a vicious cycle of events. Decreased glucose tolerance is associated with increased thickness and stiffness of large blood vessels, which contributes to increased blood pressure, macrovascular complications and impaired renal function. Large artery stiffness causes damage to the microvasculature, which in turn increases both capillary rarefaction, initially generated by hypertension and diabetes, and wave reflection. Systolic and pulse pressure are consequently increased, which results in completion of the cycle with more microvascular damage. In addition, macro and microvascular damage appears to increase blood pressure and impair tissue perfusion to target organs, and alterations to the vascular structure of peripheral microvessels in hypertension are related to the impairment of coronary vasodilator capacity. These mechanisms are supported by a large body of data from studies investigating the effects of diabetes and hypertension on the morphology and function of the microvasculature, some of which appear to occur in impaired glucose metabolism, preceding the development of full-blown diabetes. These changes also have important prognostic value, with direct correlations between coronary artery vasoconstriction and the incidence of cardiovascular events. Interventions to break the cycle of events are available, and regimens containing angiotensin-converting enzyme inhibitors have demonstrated good efficacy in increasing coronary reserve. Some of the mechanisms appear to be centred around the inhibition of bradykinin degradation rather than an effect on the renin-angiotensin-aldosterone system. more...

RhoA/Rho-kinase signaling and its relationship/balance with the nitric oxide level, angiotensin II and vasopressors for cardiovascular pathophysiology is of increasing importance, and its involvement goes far beyond blood pressure regulation. The deep involvement of this pathway in cardiovascular biology is now known to include a wide spectrum of conditions relating to the long-term complications of hypertension, and in general of cardiovascular pathophysiology, such as changes in cardiovascular structure (remodeling) and the induction of atherosclerosis, involvement in the pathophysiological relationships between inflammation and hypertension, and in those between hypertension, glucose metabolism and insulin resistance. Studies from our laboratory have made an important contribution to the understanding of the cellular and molecular mechanisms mediated by the RhoA/Rho-kinase pathway, which include all the aspects of cardiovascular pathophysiology in which this pathway plays a role. In addition, if it is considered that our contribution to the clarification of these mechanisms only comes from studies in humans, their impact on the scenario of the RhoA/Rho-kinase pathway's biology, essentially supported by studies 'in vitro' or in animal models, is immediate. This review examines all the aspects of RhoA/Rho-kinase signaling in the light of the available data, and gives an updated and useful overall picture of its involvement in cardiovascular pathophysiology. more...

Psychological phenomena take place at the border between person and environment. Indeed, psychology as a whole may be seen as a science of human liminal constructions, a science concerned with the dynamic relationships that exist between people and what surrounds them and with the constant border crossing that defines the arena within which all human development takes place. From this perspective, the central question becomes: how do humans deal with such transitions throughout the course of their lives? Cultural psychology offers a way of addressing, theoretically and empirically, the epistemological and social dimensions of this question. In addition, we argue that mereotopology—the theory of the relations of part to whole and of part to part within a whole—provides a conceptual framework of enormous potential for appreciating its unexplored ontological underpinnings, thus contributing to the foundations of psychology as a developmental science of the inherent uncertainty that accompanies all individual and social becoming. more...

Objectives We prospectively investigated the prevalence of curable forms of primary aldosteronism (PA) in newly diagnosed hypertensive patients. Background The prevalence of curable forms of PA is currently unknown, although retrospective data suggest that it is not as low as commonly perceived. Methods Consecutive hypertensive patients referred to 14 hypertension centers underwent a diagnostic protocol composed of measurement of Na+and K+in serum and 24-h urine, sitting plasma renin activity, and aldosterone at baseline and after 50 mg captopril. The patients with an aldosterone/renin ratio >40 at baseline, and/or >30 after captopril, and/or a probability of PA (by a logistic discriminant function) ≥50% underwent imaging tests and adrenal vein sampling (AVS) or adrenocortical scintigraphy to identify the underlying adrenal pathology. An aldosterone-producing adenoma (APA) was diagnosed in patients who in addition to excess autonomous aldosterone secretion showed: 1) lateralized aldosterone secretion at AVS or adrenocortical scintigraphy, 2) adenoma at surgery and pathology, and 3) a blood pressure decrease after adrenalectomy. Evidence of excess autonomous aldosterone secretion without such criteria led to a diagnosis of idiopathic hyperaldosteronism (IHA). Results A total of 1,180 patients (age 46 ± 12 years) were enrolled; a conclusive diagnosis was attained in 1,125 (95.3%). Of these, 54 (4.8%) had an APA and 72 (6.4%) had an IHA. There were more APA (62.5%) and fewer IHA cases (37.5%) at centers where AVS was available (p = 0.002); the opposite occurred where AVS was unavailable. Conclusions In newly diagnosed hypertensive patients referred to hypertension centers, the prevalence of APA is high (4.8%). The availability of AVS is essential for an accurate identification of the adrenocortical pathologies underlying PA. more...

Background Although it is known that weight reduction reduces blood pressure (BP) in overweight patients, the optimal body weight (BW) loss in terms of BP response is not yet established. We evaluated the relationship between decrease in BW and BP over time in 796 stage 1 hypertensives. Methods The 166 subjects who lost BW were divided into four groups according to percent of BW loss at the end of a 74-month follow-up (G1, >2% to 5%, G2, >5% to 9%, G3, >9% to 13%, and G4, >13%) and were compared to the 219 subjects without changes in BW (G0, −2% to +2%). The BW increased (>2%) in the remaining 411 subjects. Results Among subjects with BW loss there was a progressive decrease in final systolic BP associated with BW loss category up to G3 (P = .007), therefore at the end of follow-up G3 had systolic BP 6.2 mm Hg lower than G0 (P = .06). However, among G3 and G4 subjects systolic BP decrease was almost identical (−6.2 v −5.7 mm Hg, respectively, P = not significant). Similar results were obtained for diastolic BP, which declined up to G3 (P = .013). G3 had final diastolic BP 3.6 mm Hg lower than G0 (P = .037), whereas change in diastolic BP in G4 subjects was similar to that in G0 (−0.9 v +0.1 mm Hg, respectively, P = not significant). Similar results were obtained in the group with body mass index (BMI) >27 kg/m2. Conclusions Our results indicate that in stage 1 hypertensives followed for more than 6 years the dose–response relationship between BW loss and decrease in BP is not linear irrespective of initial BW. The BW loss >13% of initial weight did not elicit additional BP decrease. more...

Background: The role of body mass index (BMI) as a factor influencing longevity of the elderly subject is still under debate. Objective: To evaluate at a population level whether or not BMI is a risk factor of mortality in the elderly, highlighting possible gender-related differences. Methods: 3,282 subjects aged 65–95 years, were recruited from an Italian general population and 12-year events were recorded. Blood tests and anthropometric measurements were performed. BMI as a continuous item was divided into quintiles and, for each quintile, adjusted hazard ratio (HR) with 95% confidence intervals for mortality was derived by classes of age and gender from Cox analysis. Results: BMI inversely predicted overall and cancer mortality in men only. Overall mortality rate was 64.7% (HR = 1.63 [1.23–2.71]) in the 1st quintile of BMI, 54.9% (1.21 [0.92–1.73]) in the 2nd, 54.1% (1.20 [0.85–1.67]) in the 3rd, 53.3% (1.04 [0.82–1.32]) in the 4th and 52.5% in the 5th; cancer mortality rate was 23.1% (HR = 2.35 [1.31–4.23]), 14.2% (HR = 1.19 [0.65–1.80]), 15.8% (HR = 1.49 [0.93–2.39]), 15.8% (HR = 1.36 [0.84–2.16]) and 13.4%, respectively. The relationship between BMI and mortality remained significant only in men aged 76 years or less. No relationship was found between BMI and coronary or cerebrovascular mortality. Conclusions: BMI 2 does not improve survival in the elderly, while it is an independent predictor of cancer mortality in men aged ≤76 years. No prediction based on BMI is possible in women. more...

Insulin can generate oxygen free radicals. Statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, exert a powerful antioxidant effect. The present study aimed to clarify the mechanisms through which insulin generates free radicals and to assess whether pravastatin modulates such effects. In cultured skin fibroblasts from human volunteers exposed to high insulin concentration, either in the presence or in the absence of pravastatin, insulin induced translocation of the p47(phox) subunit of NAD(P)H oxidase from the cytosol to the membrane and generation of radical oxygen species through a PKC delta-dependent mechanism. The insulin-induced translocation of p47(phox) was PKC delta dependent and attenuated by pravastatin, but independent of the activation of Akt and Rac1. Insulin-induced Akt phosphorylation was increased by pravastatin and ERK1/2 phosphorylation attenuated. The present study demonstrates a novel mechanism by which insulin stimulates the generation of free radicals in human fibroblasts, ex vivo. It involves phosphatidylinositol 3-kinase, PKC delta, and p47(phox) translocation and promotes ERK1/2 phosphorylation. Pravastatin inhibited radical oxygen species production by inhibiting PKC delta. These observations offer a robust explanation for the positive effects of pravastatin treatment in patients with insulin resistance syndrome. more...

BACKGROUND Unhealthy lifestyle practices are risk factors for future hypertension. OBJECTIVES The aim of this study was to investigate the association between lifestyle changes over a 6-year period and the risk of developing sustained hypertension in a cohort of young hypertensive individuals, and to identify the predictors of lifestyle impairment over time. METHODS Seven-hundred and eighty never-treated hypertensive HARVEST participants, 18-45 years old, were studied. RESULTS Only modest mean behavioral changes were observed during follow-up. This, however, was the net result of many participants improving and others worsening their lifestyle. Participants with a family history of hypertension (FH+, n = 459) had more undesirable lifestyles (P = 0.004) and higher clinic and ambulatory blood pressures (P = 0.03) at baseline than participants without a family history of hypertension (FH-). During the 6-year follow-up, FH- individuals strikingly worsened their lifestyle while FH+ participants exhibited impressive improvements (P < 0.00001). Other predictors of lifestyle impairment were male gender (P = 0.003) and age (P = 0.02). Adoption of an unfavorable lifestyle was accompanied by an increased risk of developing sustained hypertension (P = 0.04). Initiation of drug therapy for hypertension was significantly higher among FH- than FH+ individuals (53 versus 45%, respectively; P = 0.045). CONCLUSIONS 'Lower risk' FH- stage 1 hypertensive individuals may initially be at higher risk of developing more severe hypertension in comparison with their FH+ counterparts. This increased risk may be attributed to worsening of their lifestyle profiles over time. Healthy lifestyles should be emphasized to all hypertensive individuals including patients with favorable lifestyle profiles. more...

Controversy remains concerning the pathogenetic mechanisms for the relationship between sympathetic activity, hypertension and lipid abnormalities. We tested the hypothesis that a condition characterized by sympathetic predominance may affect the evolution of blood pressure and lipids in the early stage of hypertension.We prospectively studied 163 young stage 1 hypertensive individuals and 28 normotensive control individuals. The hypertensive subjects were divided by cluster analysis into two groups according to low frequency and high frequency components of heart rate variability. Large artery and small artery compliance was assessed at the end of the follow-up.Fifty-nine subjects showed reduced total power and signs of sympathetic predominance in the resting condition, on standing and during mental stress (group 1). At baseline, they had similar blood pressure and metabolic data to the rest of the group (n = 104, group 2) and a greater white-coat effect (P = 0.03). During a 6-year follow-up, 23.7% of group 1 subjects versus 9.6% of group 2 subjects developed sustained hypertension requiring antihypertensive treatment (P = 0.02). In group 1 subjects, there was also a greater increase in total cholesterol (P = 0.01) than in group 2. In addition, at the end of follow-up group 1 subjects had impaired large artery compliance (P0.001 versus group 2).These data indicate that a condition characterized by sympathetic predominance may favour the development of sustained hypertension and hypercholesterolemia early in life, and lead to increased susceptibility to vascular complications. They further indicate that the increased white-coat effect is not an innocent phenomenon. more...

Context RGS2 (regulators of G-protein signaling) is a negative regulator of Gαq protein signaling, which mediates the action of several vasoconstrictors. RGS2-deficient mouse line exhibits a hypertensive phenotype and a prolonged response to vasoconstrictors. Objective To compare RGS2 expression in peripheral blood mononuclear cells (PBMs) and cultured fibroblasts from normotensive subjects and hypertensive patients. Methods PBMs were isolated from 100 controls and 150 essential hypertensives. Additionally, fibroblasts were isolated from skin biopsy of 11 normotensives and 12 hypertensives and cultured up to the third passage. Quantitative mRNA and protein RGS2 expression were performed by real-time quantitative reverse transcriptase-polymerase chain reaction and by immunoblotting, respectively. Free Ca2+ measurement was performed in monolayers of 24-h serum-deprived cells, using FURA-2 AM. Phosphorylation of the extracellular signal-regulated kinases ERK1/2 was measured by immunoblotting. Polymorphism (C1114G) in the 3′ untranslated region of the RGS2 gene was investigated by direct sequencing and real-time polymerase chain reaction (PCR). Results RGS2 mRNA expression was significantly lower in PBM and in fibroblasts from hypertensives, in comparison to normotensives. C1114G polymorphism was associated with RGS2 expression, with the lowest values in GG hypertensives. The 1114G allele frequency was increased in hypertensives compared with normotensives. Angiotensin II-stimulated intracellular Ca2+ increase and ERK1/2 phosphorylation were higher in fibroblasts from hypertensive patients compared with control subjects, and in those with the G allele, independently of the blood pressure status. The angiotensin II-stimulated Ca2+ mobilization and ERK1/2 phosphorylation were negatively correlated with RGS2 mRNA expression. Conclusion Low expression of RGS2 contributes to increased G-protein-coupled signaling in hypertensive patients. The allele G is associated with low RGS2 expression and blood pressure increase in humans. more...