Slab Geometry and Upper Mantle Flow Patterns in the Central Mediterranean From 3D Anisotropic P-Wave Tomography.

We present the first three-dimensional (3D) anisotropic teleseismic P-wave tomography model of the upper mantle covering the entire Central Mediterranean. Compared to isotropic tomography, it is found that including the magnitude, azimuth, and, importantly, dip of seismic anisotropy in our inversions simplifies isotropic heterogeneity by reducing the magnitude of slow anomalies while yielding anisotropy patterns that are consistent with regional tectonics. The isotropic component of our preferred tomography model is dominated by numerous fast anomalies associated with retreating, stagnant, and detached slab segments. In contrast, relatively slower mantle structure is related to slab windows and the opening of back-arc basins. To better understand the complexities in slab geometry and their relationship to surface geological phenomenon, we present a 3D reconstruction of the main Central Mediterranean slabs down to 700 km based on our anisotropic model. P-wave seismic anisotropy is widespread in the Central Mediterranean upper mantle and is strongest at 200-300 km depth. The anisotropy patterns are interpreted as the result of asthenospheric material flowing primarily horizontally around the main slabs in response to pressure exerted by their mid-to-late Cenezoic horizontal motion, while sub-vertical anisotropy possibly reflects asthenospheric entrainment by descending lithosphere. Our results highlight the importance of anisotropic P-wave imaging for better constraining regional upper mantle geodynamics.

Shallow slip amplification and enhanced tsunami hazard unravelled by dynamic simulations of mega-thrust earthquakes.

The 2011 Tohoku earthquake produced an unexpected large amount of shallow slip greatly contributing to the ensuing tsunami. How frequent are such events? How can they be efficiently modelled for tsunami hazard? Stochastic slip models, which can be computed rapidly, are used to explore the natural slip variability; however, they generally do not deal specifically with shallow slip features. We study the systematic depth-dependence of slip along a thrust fault with a number of 2D dynamic simulations using stochastic shear stress distributions and a geometry based on the cross section of the Tohoku fault. We obtain a probability density for the slip distribution, which varies both with depth, earthquake size and whether the rupture breaks the surface. We propose a method to modify stochastic slip distributions according to this dynamically-derived probability distribution. This method may be efficiently applied to produce large numbers of heterogeneous slip distributions for probabilistic tsunami hazard analysis. Using numerous M9 earthquake scenarios, we demonstrate that incorporating the dynamically-derived probability distribution does enhance the conditional probability of exceedance of maximum estimated tsunami wave heights along the Japanese coast. This technique for integrating dynamic features in stochastic models can be extended to any subduction zone and faulting style.

SIK1 localizes with nephrin in glomerular podocytes and its polymorphism predicts kidney injury.

Mutant α-adducin and endogenous ouabain levels exert a causal role in hypertension by affecting renal Na-K ATPase. In addition, mutant ß-adducin is involved in glomerular damage through nephrin down-regulation. Recently, the salt-inducible kinase 1 (SIK1) has been shown to exert a permissive role on mutant α-adducin effects on renal Na-K ATPase activity involved in blood pressure (BP) regulation and a SIK1 rs3746951 polymorphism has been associated with changes in vascular Na-K ATPase activity and BP. Here, we addressed the role of SIK1 on nephrin and glomerular functional modifications induced by mutant ß-adducin and ouabain, by using congenic substrains of the Milan rats expressing either mutant α- or ß-adducin, alone or in combination, ouabain hypertensive rats (OHR) and hypertensive patients. SIK1 co-localized and co-immunoprecipitated with nephrin from glomerular podocytes and associated with caveolar nephrin signaling. In cultured podocytes, nephrin-gene silencing decreased SIK1 expression. In mutant ß-adducin congenic rats and in OHR, the podocyte damage was associated with decreased nephrin and SIK1 expression. Conversely, when the effects of ß-adducin on podocytes were blocked by the presence of mutant α-adducin, nephrin and SIK1 expressions were restored. Ouabain effects were also reproduced in cultured podocytes. In hypertensive patients, nephrinuria, but not albuminuria, was higher in carriers of mutant SIK1 rs3746951 than in wild-type, implying a more direct effect of SIK1 on glomerular damage. These results demonstrate that, through nephrin, SIK1 is involved in the glomerular effects of mutant adducin and ouabain and a direct effect of SIK1 is also likely to occur in humans.

Ouabain-dependent signaling in caveolae as a novel therapeutic target for hypertension.

Experimental and clinical evidence indicates that Endogenous Ouabain (EO) and Adducin polymorphism play a pathogenetic role in hypertension and related organ complications. These effects occur through a complex interaction of genetic molecular mechanisms regulating renal sodium reabsorption and vascular function. The activation of a Na-K ATPase-Src-EGFr-ERK signaling pathway within the restricted membrane subdomains of caveolae by Ouabain has been associated to hypertension and cardiac remodeling. Rostafuroxin (PST 2238) is a novel anti-hypertensive compound able to selectively antagonize EO/Ouabain and Adducin hypertensive effect and Ouabain-induced cardiac hypertrophy in rats. Studies have been conducted in vivo and in a cell-free system to prove that Rostafuroxin exerts its antihypertensive and antihypertrophic effects by antagonizing the Src-dependent signaling triggered by Ouabain. At the vascular level, Rostafuroxin antagonizes the Ouabain-mediated increase of myogenic vascular tone. This peculiar and novel mechanism of action, together with a good tolerability and efficacy both in animal models and hypertensive patients, make Rostafuroxin the prototype of a new class of antihypertensive compounds able to antagonize EO/ Ouabain and Adducin molecular effects.

Ouabain antagonists as antihypertensive agents.

The evidence that high levels of endogenous ouabain (EO), a closely related isomer of ouabain, are implicated in human hypertension and cardiac hypertrophy and failure stimulated the pharmacological research for developing novel anti-hypertensive agents active as ouabain antagonists. The pathogenetic mechanisms through which increased EO levels affect cardiovascular system involve the modulation of Na-K ATPase, the key enzyme responsible for renal tubular sodium reabsorption and the activation of signalling transduction pathways implicated in growth-related gene transcription. By studying both genetic and experimental rat models of hypertension and comparing them with humans, our group has demonstrated that elevated levels of circulating EO and the genetic polymorphism of the cytoskeletal protein adducin associate with hypertension and high renal Na-K pump activity. Ouabain itself induces hypertension and up-regulates renal Na-K pump when chronically infused at low doses into rats (OS). In renal cultured cells, either incubated for several days with nanomolar concentrations of ouabain or transfected with the hypertensive adducin genetic variant, the Na-K pump results enhanced. Moreover, both EO and adducin polymorphism affect cardiac complications associated to hypertension, the former through the activation of a signalling transduction pathway. As a consequence, a compound able to interact with the cellular and molecular alterations, sustained by EO or mutated adducin, may represent the suitable treatment for those patients in whom these mechanisms are at work. A new antihypertensive compound, PST 2238, that selectively antagonises the pressor effect and the alteration of renal Na-K pump, sustained both by ouabain and adducin polymorphism, is described. A selective ability of PST 2238 to antagonise the ouabain-induced organ hypertrophy is also documented. The specificity of PST 2238 mechanism of action is supported by the absence of interactions with receptors or hormones involved in blood pressure regulation and by the lack of diuretic activity and diuretic-associated side effects. It is concluded that this compound could be useful for the treatment of those forms of essential hypertension in which renal Na handling alterations and cardiac complications are associated with either increased EO levels and/or adducin polymorphism.

[Fecal elastase-1: a useful test in pediatric practice]. / Intérêt pratique du dosage de l'élastase-1 fécale chez l'enfant: comparaison au dosage de la chymotrypsine fécale.

AIM: To study fecal elastase-1 (E1F) and chymotrypsin (ChT) in stools for the diagnosis of pancreatic insufficiency in pediatric practice. MATERIALS AND METHODS: E1F and ChT were measured in stools of 198 children divided in 3 groups: 49 children without any digestive disease (group A), 71 children with pancreatic diseases (group B), and 78 children with non-pancreatic digestive diseases (group C). RESULTS: In group B, E1F values were very low in 64 children and normal in 7 children without pancreatic insufficiency (6 children with cystic fibrosis and 1 with chronic pancreatitis). ChT values were normal in children without pancreatic insufficiency but also in half of children treated with pancreatic enzymes. Decreased E1F values were seen in 2 children (4%) in the group A and 22 children (28%) in the group C, especially those with acute gastroenteritis or celiac disease. CONCLUSION: E1F is a simple, non-invasive, useful tool for the diagnosis of pancreatic insufficiency in children with growth failure or chronic diarrhea, and those with cystic fibrosis. Nevertheless, low values may be found in diseases with villous atrophy or very liquid stools.

Antihypertensive compounds that modulate the Na-K pump.

A primary impairment of the kidney sodium excretion has been documented both in hypertensive patients (EH) and genetic animal models (Milan hypertensive rat [MHS]) carrying mutations of the cytoskeletal protein adducin and/or increased plasma levels of endogenous ouabain (EO). Ouabain (OU) itself induces hypertension in rats and both OU and mutated adducin activate the renal Na/K-ATPase function both in vivo and in cultured renal cells (NRK). A new antihypertensive agent, PST 2238, able to selectively interact with these alterations has been developed. PST lowers blood pressure (BP) by normalizing the expression and activity of the renal Na-K pump selectively in those rat models carrying the adducin mutation (MHS) and/or increased EO levels (OS) at oral doses of 0.1-10 micro g/kg. In NRK cells either transfected with mutated adducin or incubated with 10(-9) M OU, PST normalizes the Na-K pump activity. Recently, an association between EO and cardiac complications has been observed in both EH and rat models consistent with a prohypertrophic activity of OU. OS rats showed a 10% increase of left ventricle and kidney weights as compared with controls, and PST 2238 (1 micro g/kg OS) prevented both ventricle and renal hypertrophy. This effect was associated with the ability of PST to antagonize the OU-dependent activation of growth-related genes, in the membrane subdomains of caveolae. In conclusion, PST is a new antihypertensive agent that may prevent cardiovascular complications associated with hypertension through the selective modulation of the Na-K pump function.

Changes in haemostasis after laparoscopic surgery in gynaecology: contribution of the thrombin generation test.

Surgery induces immediate hypercoagulability by direct alteration of the vascular bed, release of procoagulant substances from the extravascular spaces and blood flow decrease, and delayed hypercoagulation in response to tissue damage which triggers inflammatory responses. Thus, the postoperative period represents a high-risk time for thrombosis. Recognition of high-risk individuals would make it possible to improve thromboembolism prevention. We studied in women undergoing laparoscopic surgery a series of markers known to be related to the thrombotic risk and confronted their results with those of a global test, the thrombin generation test (TGT) described by Hemker's group. Our results show that two groups of patients can be distinguished according to usual risk markers (PAI-1, TAT, body mass index): the higher risk group demonstrates higher initial TGT values, but also a postoperative decrease of the TGT values whose mechanisms remain to be defined.

A new rat model for studying the calpain-calpastatin system.

A recombinant rat strain--Milan low-calpastatin strain (MLCS)--was derived from Milan hypertensive (MHS/Gib) and Milan normotensive (MNS/Gib) strains. The MLCS rats have normal blood pressure and low calpastatin activity, and this strain is proposed as a model for studies of the calpain-calpastatin system, which is involved in important cellular mechanisms. Calpastatin polymorphism was observed in 10 different strains of laboratory rats and a single locus hypothesis is suggested as the mode of inheritance.

A genetic deficiency in calpastatin and isovalerylcarnitine treatment is associated with enhanced hippocampal long-term potentiation.

The Milan hypertensive strain (MHS) of rats, in addition to having hypertension, is also characterized by a genetic deficiency in calpastatin, the endogenous inhibitor of calpain. Since this protease has been implicated in long-term potentiation (LTP), we have investigated whether induction of this form of plasticity was altered in this strain of rats as compared to control animals (Milan normotensive strain, MNS). Progressive induction of LTP by increasing numbers of high frequency trains resulted in a greater degree of potentiation measured with all inducing protocols in MHS as compared with MNS animals. This difference was not related to the hypertension, since another hypertensive strain (the SHR strain) and a segregated Milan hypertensive strain, expressing only the hypertension but not the calpastatin deficiency (the MHNE strain), exhibited an LTP indistinguishable from control rats. Treatment of MHNE rats for 2 months with isovalerylcarnitine, a compound that increases calpain activity, also resulted in a greater amount of LTP induced by high frequency trains. These effects were not related to an enhancement of the NMDA receptor dependent component of responses to burst stimulation. These results are consistent with the idea that conditions under which calpain activation is facilitated are associated with a greater degree of synaptic potentiation.

Bombesin receptor antagonists. 2. Analogues based on substance P antagonists.

Although bombesin (BN) and substance P share only the C-terminal dipeptide amide, some substance P receptor antagonists are also weak bombesin receptor antagonists. In order to increase the selectivity of the antagonism for the BN receptor, a series of hybrid peptides were synthesized by the solid-phase methodology, and screened on 3T3 fibroblasts for binding and mitogenic activity. The analogues inhibiting BN-induced thymidine incorporation were further tested for peripheral (amylase release and urinary bladder contraction) and central activity (grooming behaviour).

Bombesin receptor antagonists. 3. Irreversible alkylating analogues: melphalan derivatives.

Bombesin (BN)-like peptides (such as GRP, gastrin-releasing peptide) are autocrine growth factors for small cell lung carcinoma (SCLC). BN receptor antagonists can therefore find clinical application in the treatment of this highly malignant disease. The present paper deals with a new class of bombesin analogues carrying a nitrogen mustard at their N-terminus. Due to the irreversible binding to the BN receptor(s), these peptides eventually block the mitogenic effects of the natural ligand(s), regardless of their intrinsic "agonistic" or "antagonistic" structures. In Swiss 3T3 fibroblasts they inhibit [125I]GRP binding in the nanomolar/micromolar range. According to their "agonistic" or "antagonistic" structural features, they do or do not induce [3H]thymidine incorporation and p 115 phosphorylation. In competition experiments, alkylating "antagonists" selectively inhibit BN-induced thymidine incorporation either when given simultaneously with or 24 hours before the BN challenge. Alkylating "agonists" display antagonistic effects only in the sequential treatment.

Calpastatin level in spontaneously hypertensive rats.

We studied calpastatin activity in erythrocytes of Milan hypertensive and prehypertensive rats, in their normotensive controls, in F1 and F2 hybrids, and in two inbred strains derived from F2, one hypertensive and the other normotensive. Our results show that the decrease in calpastatin activity observed in Milan hypertensive rats was not caused by hypertension, it was transmitted in a recessive way in heterozygous, and it was not correlated to hypertension.

Bombesin receptor antagonists [corrected]. 1. Analogues with deleted, inverted or substituted amino acid residues.

Bombesin is a 14-residue peptide hormone which serves a variety of biological functions, including cell growth control in Swiss 3T3 cultured fibroblasts. It has been also involved in an autocrine system regulating the growth of small cell lung carcinoma. A series of bombesin analogues were developed by amino acid deletion, inversion or substitution in the carboxy-terminal region, identified by the target cell receptor. Their properties were examined for: i) competitive binding assays; ii) mitogenic induction and inhibition assays; iii) effects on early cellular events (inositol phosphates production and protein tyrosine phosphorylation). Inversion of the Trp residue, or deletion of the C-terminal tripeptide amide, induced complete loss of receptor affinity and biological effects. Deletion of the His residue, or its derivatization as His (Dnp) in conjunction with Met deletion or modification, gave rise to compounds with reduced receptor affinity and weak antagonistic properties. Other modifications in the C-terminal tripeptide affected the potency but not the biological profile of the parent peptide. These results indicate the basis for the eventual design of improved, specific bombesin receptor antagonists and stimulate further studies on their possible application in the therapy of human small cell lung cancer.