The Continuous Skolem-Pisot Problem: On the Complexity of Reachability for Linear Ordinary Differential Equations

We study decidability and complexity questions related to a continuous analogue of the Skolem-Pisot problem concerning the zeros and nonnegativity of a linear recurrent sequence. In particular, we show that the continuous version of the nonnegativity problem is NP-hard in general and we show that the presence of a zero is decidable for several subcases, including instances of depth two or less, although the decidability in general is left open. The problems may also be stated as reachability problems related to real zeros of exponential polynomials or solutions to initial value problems of linear differential equations, which are interesting problems in their own right.Comment: 14 pages, no figur

Validation of Surrogates of Urine Osmolality in Population Studies

The importance of vasopressin and/or urine concentration in various kidney, cardiovascular, and metabolic diseases has been emphasized recently. Due to technical constraints, urine osmolality (Uosm), a direct reflect of urinary concentrating activity, is rarely measured in epidemiologic studies. We analyzed 2 possible surrogates of Uosm in 4 large population-based cohorts (total n = 4,247) and in patients with chronic kidney disease (CKD, n = 146). An estimated Uosm (eUosm) based on the concentrations of sodium, potassium, and urea, and a urine concentrating index (UCI) based on the ratio of creatinine concentrations in urine and plasma were compared to the measured Uosm (mUosm). eUosm is an excellent surrogate of mUosm, with a highly significant linear relationship and values within 5% of mUosm (r = 0.99 or 0.98 in each population cohort). Bland-Altman plots show a good agreement between eUosm and mUosm with mean differences between the 2 variables within ±24 mmol/L. This was verified in men and women, in day and night urine samples, and in CKD patients. The relationship of UCI with mUosm is also significant but is not linear and exhibits more dispersed values. Moreover, the latter index is no longer representative of mUosm in patients with CKD as it declines much more quickly with declining glomerular filtration rate than mUosm. The eUosm is a valid marker of urine concentration in population-based and CKD cohorts. The UCI can provide an estimate of urine concentration when no other measurement is available, but should be used only in subjects with normal renal function

The evolution of mammalian brain size

Relative brain size has long been considered a reflection of cognitive capacities and has played a fundamental role in developing core theories in the life sciences. Yet, the notion that relative brain size validly represents selection on brain size relies on the untested assumptions that brain-body allometry is restrained to a stable scaling relationship across species and that any deviation from this slope is due to selection on brain size. Using the largest fossil and extant dataset yet assembled, we find that shifts in allometric slope underpin major transitions in mammalian evolution and are often primarily characterized by marked changes in body size. Our results reveal that the largest-brained mammals achieved large relative brain sizes by highly divergent paths. These findings prompt a reevaluation of the traditional paradigm of relative brain size and open new opportunities to improve our understanding of the genetic and developmental mechanisms that influence brain size

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Drug-Induced Kidney Stones and Crystalline Nephropathy: Pathophysiology, Prevention and Treatment

International audienceDrug-induced calculi represent 1–2% of all renal calculi. The drugs reported to produce calculi may be divided into two groups. The first one includes poorly soluble drugs with high urine excretion that favour crystallisation in the urine. Among them, drugs used for the treatment of patients with human immunodeficiency, namely atazanavir and other protease inhibitors, and sulphadiazine used for the treatment of cerebral toxoplasmosis, are the most frequent causes. Besides these drugs, about 20 other molecules may induce nephrolithiasis, such as ceftriaxone or ephedrine-containing preparations in subjects receiving high doses or long-term treatment. Calculi analysis by physical methods including infrared spectroscopy or X-ray diffraction is needed to demonstrate the presence of the drug or its metabolites within the calculi. Some drugs may also provoke heavy intra-tubular crystal precipitation causing acute renal failure. Here, the identification of crystalluria or crystals within the kidney tissue in the case of renal biopsy is of major diagnostic value. The second group includes drugs that provoke the formation of urinary calculi as a consequence of their metabolic effects on urinary pH and/or the excretion of calcium, phosphate, oxalate, citrate, uric acid or other purines. Among such metabolically induced calculi are those formed in patients taking uncontrolled calcium/vitamin D supplements, or being treated with carbonic anhydrase inhibitors such as acetazolamide or topiramate. Here, diagnosis relies on a careful clinical inquiry to differentiate between common calculi and metabolically induced calculi, of which the incidence is probably underestimated. Specific patient-dependent risk factors also exist in relation to urine pH, volume of diuresis and other factors, thus providing a basis for preventive or curative measures against stone formation

L’étude de la cristallurie améliore le diagnostic et la prise en charge thérapeutique de la lithiase rénale

International audienceThe search for crystalluria and morphologic analysis of urinary crystals is of interest in the diagnostic evaluation and assessment of efficacy of therapeutic strategies in stone formers. In common calcium oxalate (CaOx) nephrolithiasis, identification of the monohydrate or dihydrate form of CaOx orients toward hyperoxaluria or hypercalciuria as the main lithogenic mechanism, respectively. An unusual high abundance of crystals exclusively made of CaOx monohydrate is highly suggestive of primary hyperoxaluria, the most severe of all types of renal stone diseases. The identification of crystal species such as struvite, cystine, 2,8-dihydroxyadenine, which are not found in normal urine, is indicative of specific pathological conditions, namely, infection stones and hereditary diseases such as cystinuria and dihydroxyadeninuria. Such diseases expose to progressive loss of renal function unless they are prevented by specific therapeutic measures. The presence of crystals made of drugs may entail the risk of kidney dysfunction because of crystallization of the drug or its metabolites.Serial determination of crystalluria, which reflects the activity of stone disease and its response to therapeutic measures, is of major interest in the follow-up of patients suffering from nephrolithiasis. It should be more largely used in clinical practice in most stone formers, still more for the surveillance of patients affected by severe, hereditary renal stone diseases such as primary hyperoxaluria, cystinuria, and dihydroxyadeninuria, where determination of the global crystal volume allows assessing the efficacy of therapeutic measures and optimizing the medical management of the patients.L’étude de la cristallurie et de ses caractéristiques qualitatives et quantitatives est d'un intérêt clinique majeur pour le diagnostic de la maladie lithiasique et l’évaluation de l'efficacité des mesures thérapeutiques proposées aux patients. Dans la lithiase oxalocalcique commune, la forme cristalline, whewellite ou weddellite, oriente respectivement vers une hyperoxalurie ou une hypercalciurie. Une quantité élevée de cristaux de whewellite traduit une forte hyperoxalurie et doit faire rechercher une hyperoxalurie primaire. L'identification de cristaux particuliers tels que la struvite, la cystine, la dihydroxy-2,8-adénine permet le diagnostic de pathologies spécifiques qui exposent à une altération progressive de la fonction rénale lorsqu'elles ne sont pas traitées précocement par des mesures adaptées. La présence de cristaux médicamenteux peut expliquer l'origine d'une insuffisance rénale aiguë développée sous traitement.Au cours du suivi des patients souffrant de lithiase, la détermination de la cristallurie sur des prélèvements sériés est d'un grand intérêt pour la prévention du risque de récidive de calculscar elle reflète l'activité de la maladie lithiasique et sa réponse aux mesures diététiques et thérapeutiques. Elle peut donc bénéficier à la plupart des patients lithiasiques. Elle se doit d’être réalisée chez tout patient souffrant d'une forme héréditaire sévère de lithiase telle que cystinurie, hyperoxalurie primaire ou dihydroxyadéninurie pour en optimiser la prise en charge thérapeutique, la détermination du volume cristallin global dans ces pathologies cristallines sévères permettant d'adapter le traitement médical, d’évaluer l'efficacité des mesures thérapeutiques proposées et de modifier celles-ci en fonction des résultats obtenus

Recurrence rates of urinary calculi according to stone composition and morphology

International audienceFew studies have examined the relative risk of recurrence of different stone types. The object of the present study was to evaluate the tendency for stone recurrence as a function of major mineral composition of the stones and morphological characteristics of the stones. This study was carried out using 38,274 stones for which we had data available to specify if the stone was from the first or a subsequent urinary stone episode. Stones were analyzed for morphology by stereomicroscope and for composition by infrared spectroscopy. Overall, 42.7% of stones were from patients who had had a previous stone event, with these being more frequent in men (44.4%) than in women (38.9%, p < 0.0001). Age of first stone occurrence was lowest for dihydroxyadenine (15.7 ± 16.6 years) and highest for anhydrous uric acid (62.5 ± 14.9 years), with the average age of first stones of calcium oxalate falling in the middle (40.7 ± 14.6 years for calcium oxalate dihydrate, and 48.4 ± 15.1 years for calcium oxalate monohydrate, COM). By composition alone, COM was among the least recurrent of stones, with only 38.0% of COM stones coming from patients who had had a previous episode; however, when the different morphological types of COM were considered, type Ic—which displays a light color, budding surface and unorganized section—had a significantly greater rate of recurrence, at 82.4% (p < 0.0001), than did other morphologies of COM. Similarly, for stones composed of apatite, morphological type IVa2—a unique form with cracks visible beneath a glossy surface—had a higher rate of recurrence than other apatite morphologies (78.8 vs. 39–42%, p < 0.0001). Stone mineral type alone is insufficient for identifying the potential of recurrence of the stones. Instead, the addition of stone morphology may allow the diagnosis of highly recurrent stones, even among common mineral types (e.g., COM) that in general are less recurrent