Prenatal ultrasonographic detection of gastrointestinal obstruction: results from 18 European congenital anomaly registries.

OBJECTIVES: We evaluated the prenatal detection of gastrointestinal obstruction (GIO, including atresia, stenosis, absence or fistula) by routine ultrasonographic examination in an unselected population all over Europe. METHODS: Data from 18 congenital malformation registries in 11 European countries were analysed. These multisource registries used the same methodology. All fetuses/neonates with GIO confirmed within 1 week after birth who had prenatal sonography and were born during the study period (1 July 1996 to 31 December 1998) were included. RESULTS: There were 670 793 births in the area covered and 349 fetuses/neonates had GIO. The prenatal detection rate of GIO was 34%; of these 40% were detected < or = 24 weeks of gestation (WG). A total of 31% (60/192) of the isolated GIO were detected prenatally, as were 38% (59/157) of the associated GIO (p=0.26). The detection rate was 25% for esophageal obstruction (31/122), 52% for duodenal obstruction (33/64), 40% for small intestine obstruction (27/68) and 29% for large intestine obstruction (28/95) (p=0.002). The detection rate was higher in countries with a policy of routine obstetric ultrasound. Fifteen percent of pregnancies were terminated (51/349). Eleven of these had chromosomal anomalies, 31 multiple malformations, eight non-chromosomal recognized syndromes, and one isolated GIO. The participating registries reflect the various national policies for termination of pregnancy (TOP), but TOPs after 24 WG (11/51) do not appear to be performed more frequently in countries with a liberal TOP policy. CONCLUSION: This European study shows that the detection rate of GIO depends on the screening policy and on the sonographic detectability of GIO subgroups.

The Exotic Palaeo-Thethys Terrane in Central Iran: New geological data from Anarak, Jandaq and Posht-e-Badam areas

Résumé Le « terrane » d'Anarak-Jandak occupe une position géologique clé au nord-ouest du Microcontinent Centre-East Iranien (CE1M), connecté avec le Bloc du Grand Kavir et la ceinture métamorphique de Sanandaj-Sirjan. Nous discutons ici l'origine de ces différentes unités, reliées jusqu'à présent à des épisodes orogéniques d'âge Précambrien à Paléozoïque inférieur, pour conclure finalement de leur affinité paléotéthysienne. Leur histoire commence par un épisode de rifting d'âge Ordovicien supérieur-Dévonien inférieur, pour se terminer au Trias par la collision des blocs Cimmériens dérivé du Gondwana avec le Bloc du Turan d'affinité asiatique (événement Eocimmérien). La plus importante unité métamorphique affleurant au sud-ouest de la région de Jandak-Anarak-Kaboudan est une épaisse séquence silicoclastique à grains fins contenant des blocs ophiolitiques (marginal-sea-type), et des associations basalte-gabbro à signatures géochimiques de type supra-subduction. Dans la région de Nakhlak, nous avons daté ces gabbros par la méthode U-Pb à 387f0.11 Ma ; les roches métamorphiques pélitiques ont donné des âges de refroidissement Ar-Ar pour la muscovite de 320 à 333 Ma. Ce complexe d'accrétion "varisque" a été métamorphisé dans le faciès schiste vert-amphibolite au cours de l'accrétion de la ceinture granitique d'Airekan, d'âge Cambrien inférieur (549±15 Ma par la méthode U/Pb), qui affleure aujourd'hui à l'extrémité nord-ouest du terrane d'Anarak-Jandak . La subduction vers le nord de l'océan Paléotéthys depuis le Paléazoïque supérieur jusqu'au Trias, a permis l'accumulation de grandes quantités de matériel océanique dans la zone de subduction. Par exemple, une succession de guyots (Anarak, Kaboudan, et Meraji Seamounts) et de hauts sous-marins, entrés en collision oblique avec le prisme d'accrétion, est à l'origine d'un léger métamorphisme de type HP qui affecte ces séries {âges Ar-Ar de 280 à 230 Ma). De plus, le magmatisme bimodal de Chah Gorbeh est caractérisé d'une part par des roches de type trondjémite-gabbros (262 Ma), d'autre part par des laves en coussin de type basaltes alcalins-rhyolites; ces roches magmatiques ont recoupé l'ophiolite d'Anarak lors de la mise en place de cette dernière dans la fosse interne de subduction. Quant au prisme d'accrétion de Doshakh, d'âge essentiellement Permien supérieur, i1 a été accrété le long de la marge continentale et métamorphisé dans le faciès schiste vert. La fermeture de la Paléotéthys s'enregistre finalement par la sédimentation dans le bassin d'avant pays du flysch de Bayazeh, d'âge probable Triasique. Le matériel issu de l'arc magmatique de la Paléotéthys est très bien préservé dans les dépôts infra-arc Dévonien supérieur-Carbonifère de Godar-e-Siah, ainsi que dans la succession d'avant-arc de Nakhlak. Pendant l'intervalle Paléozoïque supérieur-Trias, la région de Jandak a été soumise à un régime extensif de type bassin d'arrière-arc, dont un témoin pourrait être la ceinture ophiolitique d'Arusan, elle-même comparable aux écailles ophiolitiques d'Aghdarband au nord-est de l'Iran. Cet ensemble métamorphique est recoupé par des granites d'arc à collisionnel datés à 215±15 Ma. Dans la région de Yazd, témoin de la marge passive Cimmérienne, la sédimentation syn-rift Silurienne à Dévonienne inférieure a été interrompue pendant l'intervalle Trias moyen-Trias supérieur; il en a été de même pour les dépôts de plate-forme Paléozoïque supérieur. L'érosion, qui dans ce dernier cas a atteint le Permien, pourrait être liée au bombement flexural de la marge passive. La collision finale n'a pas induit de déformations trop importantes, et se caractérise par la mise en place de nappes sur la marge passive. Cet événement est scellé par des dépôts molassique du Lias. D'un point de vue régional, la zone s'étendant actuellement de la Mer Noire au Pamir a été soumise à six épisodes d'extension-compression du Jurassique inférieur (début du l'ouverture en position arrière-arc de la Néotéthys) à l'Eocène moyen. Par exemple, le terrane d'AnarakJandak, probablement situé entre le Kopeh Dagh et la plate-forme nord Afghane, s'est complètement détaché de sa patrie d'origine au début du Crétacé supérieur. Des preuves de cet événement se retrouvent dans les séries de plate-forme de Khur (préservation de séries syn-rift puis de marge passive). Les ophiolites de Nain et de Sabzevar sont de plus interprétée comme un témoin de l'existence de ce bassin d'arrière-arc. Dans l'intervalle Eocène-Oligocène, l'indentation par la plaque indienne de l'Eurasie a été contemporaine de la rotation horaire de fragments de l'ancien microcontinent Iranien et de la formation du CEIM. Cette rotation est responsable du transport du terrane d'Anarak-Jandak vers sa position actuelle en Iran Central, et de la dislocation de Terranes de moindre importance, comme le bloc de Posht-e Badam. Depuis le Miocène supérieur, et à la suite de la collision entre l'Arabie et l'Iran, le ternane d'Anarak-Jandak a subi des déformations liées à l'activité d'une zone de cisaillement dextre parallèle à la suture du Zagros, à l'arrière de l'arc magmatique d'Uromieh-Dokhtar. Résumé large public Le Microcontinent Centre-Est Iranien occupe une position géologique clé au centre de l'Iran. Les différentes unités qui le composent, reliées jusqu'à présent à des épisodes orogéniques d'âge Précambrien à Paléozoïque inférieur, sont maintenant rajeunies et liés à la fermeture de l'océean Paléotéthys. Leur histoire commence par un épisode de rifting d'âge Ordovicien supérieur à Dévonien inférieur, pour se terminer au Trias par la collision des- blocs Cimmériens, dérivés du Gondwana, avec le Bloc du Turan d'affinité asiatique. Dans la marge active asiatique de la Paléotéthys, nous avons daté les restes d'un océan marginal à 387±0.11 Ma. Ce complexe d'accrétion a été métamorphisé au cours de la réaccrétion de la ceinture granitique d'Airekan, d'âge Cambrien inférieur (549±15 Ma), qui affleure aujourd'hui à l'extrémité nord-ouest du « terrane » d'Anarak-Jandak correspondant à la plus grande partie de la région étudiée. Le matériel issu de l'arc magmatique de la Paléotéthys est très bien préservé et daté du Dévonien supérieur-Carbonifère. Pendant l'intervalle Paléozoïque supérieur-Trias, la région a été soumise à un régime extensif de type bassin d'arrière-arc, dont un témoin pourrait être la ceinture ophiolitique d'Arusan, comparable aux écailles ophiolitiques d'Aghdarband au nord-est de l'Iran. Cet ensemble métamorphique est recoupé par des granites datés à 215±15 Ma. La subduction vers le nord de l'océan Paléotéthys depuis le Paléozoïque supérieur jusqu'au Trias, a permis l'accumulation de grandes quantités de matériel océanique dans la zone de subduction. Par exemple, une succession de volcans sous-marins, entrés en collision avec le prisme d'accrétion, est à l'origine d'un léger métamorphisme de type HP qui affecte ces séries (280 à 230 Ma). Quant au prisme d'accrétion de Doshakh, d'âge essentiellement Permien supérieur, il a été mis en place le long de la marge continentale et métamorphisé dans le faciès schiste vert. La fermeture de la Paléotéthys s'enregistre finalement par la sédimentation dans le bassin d'avant pays du flysch de Bayazeh, d'âge Triasique. Dans la région de Yazd, on trouve les témoins de la marge passive Cimmérienne, la sédimentation syn-rift Silurienne à Dévonienne inférieure a été interrompue pendant l'intervalle Trias moyen-Trias supérieur, marqué par la flexuration de la marge passive lorsqu'elle rentra en collision avec la marge active asiatique. Cet événement est scellé par des dépôts molassique à charbon du Lias. Le «terrane» d'Anarak-Jandak, probablement situé à l'origine entre le Kopeh Dagh et la plate-forme nord Afghane, s'est complètement détaché de cette région au début du Crétacé supérieur lors de l'ouverture d'un bassin d'arrière-arc, engendré, cette fois, par la subduction de l'océan Néotéthys situé au sud des blocs cimmériens. Des preuves de cet événement se retrouvent dans les séries syn-rift, puis de marge passive de Khour. Les ophiolites de Nain et de Sabzevar sont interprétées comme un témoin de l'existence de ce bassin d'arrière-arc. Dans l'intervalle Eocène-Oligocène, l'indentation de l'Eurasie par la plaque indienne a été contemporaine de la rotation horaire de fragments de l'ancien microcontinent centre-Iranien. Cette rotation de près de 90° est responsable du transport du « terrane » d'Anarak-Jandak vers sa position actuelle. Abstract The Anarak-Jandaq terrane occupies a strategic geological situation at the north-western part of the Central-East Iranian Microcontinent (CEIM) and in connection with the Great Kavir Block and Sanandaj-Sirjan metamorphic belt. Our recent findings redefine the origin of these mentioned areas so far attributed to the Precambrian-Early Palaeozoic orogenic episodes, to be now directly related to the tectonic evolution of the Palaeo-Tethys Ocean, commenced by Late Ordovician-Early Devonian rifting events and terminated in the Triassic by the Eocimmerian tectonic event due to the collision of the Cimmerian blocks with the Asiatic Turan block. The most distributed metamorphic unit that is exposed from the south-west of Jandaq to the Anarak and Kaboudan areas is a thick and fine grain siliciclastic sequence accompanied by marginal-sea-basin ophiolitic blocks including basalt-gabbro association with supra-subduction-geochemical signature. These gabbros in the Nakhlak area were dated by U/Pb method at 387.6 ± 0.11 Ma and the metamorphic pelitic rocks yielded a range of 320 to 333 Ma muscovite-cooling ages based on 40Ar/39 Ar method. This "Variscan" accretionary complex was metamorphosed in greenschist-amphibolite facies during accretion to the Lower Cambrian Airekan granitic belt (549 ± 15 Ma by U/Pb method) that crops out at the northwestern edge of the Anarak-Jandaq terrane. Continued northward subduction of the Palaeo-Tethys Ocean during the entire Late Palaeozoic-Middle Triassic brought huge amount of oceanic material to the subduction zone. One chain of Carboniferous-Triassic oceanic rises and seamounts (the Anarak, Kaboudan, and Meraji Seamounts) obliquely collided with the accretionary wedge and created a mild HP metamorphic event (280-230 Ma based on 40Ar/39Ar results). Bimodal magmatism of the Chah Gorbeh area is characterized by a 262 Ma trondjemite-gabbro as well as pillow alkalibasalts-rhyolites which intruded the Anarak ophiolite when it was being emplaced within the inner-wall trench. The mainly Late Permian-Triassic Doshakh wedge was accreted along the continent and metamorphosed under lower greenschist facies and the probable Triassic Bayazeh flysch filled the foreland basin during the final closure. The Palaeo-Tethys magmatic arc products have been well preserved in the Late Devonian-Carboniferous Godar-e-Siah intra-arc deposits and the Triassic Nakhlak fore-arc succession. During the Late Palaeozoic-Triassic times, the Jandaq area has been affected by back-arc extension and probably the Arusan ophiolitic belt is the remnant of this narrow basin comparable to the Aqdarband ophiolitic remnant in north-east Iran. This metamorphic belt was intruded by 215 ± 15 Ma arc to collisional granites. In the passive margin of the Cimmerian block, on the Yazd region, the Silurian-Early Devonian syn-rift succession as well as the nearly continuous Upper Palaeozoic platform-type deposition was interrupted during the Middle to Late Triassic time, local erosion down to Devonian levels may be related to flexural bulge erosion. The collision event was not so strong to generate intensive deformation but was accompanied by some nappe thrusting onto the passive margin. It is finally unconformably covered by Liassic continental molassic deposits. Related to the onset of Neo-Tethyan back-arc opening in Early Jurassic to Mid-Eocene times, six periods of extensional-compressional events have differently influenced an elongated area, extending from the West Black Sea to Pamir. The Anarak-Jandaq terrane which was situated somewhere in this affected area, probably between the Kopeh Dagh and North Afghan platform, was completely detached from its source at the beginning of the Late Cretaceous

Rules of origin : from analysis to reform

General Introduction This thesis can be divided into two main parts :the first one, corresponding to the first three chapters, studies Rules of Origin (RoOs) in Preferential Trade Agreements (PTAs); the second part -the fourth chapter- is concerned with Anti-Dumping (AD) measures. Despite wide-ranging preferential access granted to developing countries by industrial ones under North-South Trade Agreements -whether reciprocal, like the Europe Agreements (EAs) or NAFTA, or not, such as the GSP, AGOA, or EBA-, it has been claimed that the benefits from improved market access keep falling short of the full potential benefits. RoOs are largely regarded as a primary cause of the under-utilization of improved market access of PTAs. RoOs are the rules that determine the eligibility of goods to preferential treatment. Their economic justification is to prevent trade deflection, i.e. to prevent non-preferred exporters from using the tariff preferences. However, they are complex, cost raising and cumbersome, and can be manipulated by organised special interest groups. As a result, RoOs can restrain trade beyond what it is needed to prevent trade deflection and hence restrict market access in a statistically significant and quantitatively large proportion. Part l In order to further our understanding of the effects of RoOs in PTAs, the first chapter, written with Pr. Olivier Cadot, Celine Carrère and Pr. Jaime de Melo, describes and evaluates the RoOs governing EU and US PTAs. It draws on utilization-rate data for Mexican exports to the US in 2001 and on similar data for ACP exports to the EU in 2002. The paper makes two contributions. First, we construct an R-index of restrictiveness of RoOs along the lines first proposed by Estevadeordal (2000) for NAFTA, modifying it and extending it for the EU's single-list (SL). This synthetic R-index is then used to compare Roos under NAFTA and PANEURO. The two main findings of the chapter are as follows. First, it shows, in the case of PANEURO, that the R-index is useful to summarize how countries are differently affected by the same set of RoOs because of their different export baskets to the EU. Second, it is shown that the Rindex is a relatively reliable statistic in the sense that, subject to caveats, after controlling for the extent of tariff preference at the tariff-line level, it accounts for differences in utilization rates at the tariff line level. Finally, together with utilization rates, the index can be used to estimate total compliance costs of RoOs. The second chapter proposes a reform of preferential Roos with the aim of making them more transparent and less discriminatory. Such a reform would make preferential blocs more "cross-compatible" and would therefore facilitate cumulation. It would also contribute to move regionalism toward more openness and hence to make it more compatible with the multilateral trading system. It focuses on NAFTA, one of the most restrictive FTAs (see Estevadeordal and Suominen 2006), and proposes a way forward that is close in spirit to what the EU Commission is considering for the PANEURO system. In a nutshell, the idea is to replace the current array of RoOs by a single instrument- Maximum Foreign Content (MFC). An MFC is a conceptually clear and transparent instrument, like a tariff. Therefore changing all instruments into an MFC would bring improved transparency pretty much like the "tariffication" of NTBs. The methodology for this exercise is as follows: In step 1, I estimate the relationship between utilization rates, tariff preferences and RoOs. In step 2, I retrieve the estimates and invert the relationship to get a simulated MFC that gives, line by line, the same utilization rate as the old array of Roos. In step 3, I calculate the trade-weighted average of the simulated MFC across all lines to get an overall equivalent of the current system and explore the possibility of setting this unique instrument at a uniform rate across lines. This would have two advantages. First, like a uniform tariff, a uniform MFC would make it difficult for lobbies to manipulate the instrument at the margin. This argument is standard in the political-economy literature and has been used time and again in support of reductions in the variance of tariffs (together with standard welfare considerations). Second, uniformity across lines is the only way to eliminate the indirect source of discrimination alluded to earlier. Only if two countries face uniform RoOs and tariff preference will they face uniform incentives irrespective of their initial export structure. The result of this exercise is striking: the average simulated MFC is 25% of good value, a very low (i.e. restrictive) level, confirming Estevadeordal and Suominen's critical assessment of NAFTA's RoOs. Adopting a uniform MFC would imply a relaxation from the benchmark level for sectors like chemicals or textiles & apparel, and a stiffening for wood products, papers and base metals. Overall, however, the changes are not drastic, suggesting perhaps only moderate resistance to change from special interests. The third chapter of the thesis considers whether Europe Agreements of the EU, with the current sets of RoOs, could be the potential model for future EU-centered PTAs. First, I have studied and coded at the six-digit level of the Harmonised System (HS) .both the old RoOs -used before 1997- and the "Single list" Roos -used since 1997. Second, using a Constant Elasticity Transformation function where CEEC exporters smoothly mix sales between the EU and the rest of the world by comparing producer prices on each market, I have estimated the trade effects of the EU RoOs. The estimates suggest that much of the market access conferred by the EAs -outside sensitive sectors- was undone by the cost-raising effects of RoOs. The chapter also contains an analysis of the evolution of the CEECs' trade with the EU from post-communism to accession. Part II The last chapter of the thesis is concerned with anti-dumping, another trade-policy instrument having the effect of reducing market access. In 1995, the Uruguay Round introduced in the Anti-Dumping Agreement (ADA) a mandatory "sunset-review" clause (Article 11.3 ADA) under which anti-dumping measures should be reviewed no later than five years from their imposition and terminated unless there was a serious risk of resumption of injurious dumping. The last chapter, written with Pr. Olivier Cadot and Pr. Jaime de Melo, uses a new database on Anti-Dumping (AD) measures worldwide to assess whether the sunset-review agreement had any effect. The question we address is whether the WTO Agreement succeeded in imposing the discipline of a five-year cycle on AD measures and, ultimately, in curbing their length. Two methods are used; count data analysis and survival analysis. First, using Poisson and Negative Binomial regressions, the count of AD measures' revocations is regressed on (inter alia) the count of "initiations" lagged five years. The analysis yields a coefficient on measures' initiations lagged five years that is larger and more precisely estimated after the agreement than before, suggesting some effect. However the coefficient estimate is nowhere near the value that would give a one-for-one relationship between initiations and revocations after five years. We also find that (i) if the agreement affected EU AD practices, the effect went the wrong way, the five-year cycle being quantitatively weaker after the agreement than before; (ii) the agreement had no visible effect on the United States except for aone-time peak in 2000, suggesting a mopping-up of old cases. Second, the survival analysis of AD measures around the world suggests a shortening of their expected lifetime after the agreement, and this shortening effect (a downward shift in the survival function postagreement) was larger and more significant for measures targeted at WTO members than for those targeted at non-members (for which WTO disciplines do not bind), suggesting that compliance was de jure. A difference-in-differences Cox regression confirms this diagnosis: controlling for the countries imposing the measures, for the investigated countries and for the products' sector, we find a larger increase in the hazard rate of AD measures covered by the Agreement than for other measures.

Intravenous lacosamide for treatment of status epilepticus.

Objectives -  Treatment of established status epilepticus (SE) requires immediate intravenous anticonvulsant therapy. Currently used first-line drugs may cause potentially hazardous side effects. We aimed to assess the efficacy and safety of intravenous lacosamide (LCM) in SE after failure of standard treatment. Methods -  We retrospectively analyzed 39 patients (21 women, 18 men, median age 62 years) from the hospital databases of five neurological departments in Germany, Austria and Switzerland between September 2008 and January 2010 who were admitted in SE and received at least one dose of intravenous LCM. Results -  Types of SE were generalized convulsive (n = 6), complex partial (n = 17) and simple partial (n = 16). LCM was administered after failure of benzodiazepins or other standard drugs in all but one case. Median bolus dose of LCM was 400 mg (range 200-400 mg), which was administered at 40-80 mg/min in those patients where infusion rate was documented. SE stopped after LCM in 17 patients, while 22 patients needed further anticonvulsant treatment. The success rate in patients receiving LCM as first or second drug was 3/5, as third drug 11/19, and as fourth or later drug 3/15. In five subjects, SE could not be terminated at all. No serious adverse events attributed to LCM were documented. Conclusions -  Intravenous LCM may be an alternative treatment for established SE after failure of standard therapy, or when standard agents are considered unsuitable.

Long-term follow-up of European APL 2000 trial, evaluating the role of cytarabine combined with ATRA and Daunorubicin in the treatment of nonelderly APL patients.

All-trans retinoic acid (ATRA) combined to anthracycline-based chemotherapy is the reference treatment of acute promyelocytic leukemia (APL). Whereas, in high-risk patients, cytarabine (AraC) is often considered useful in combination with anthracycline to prevent relapse, its usefulness in standard-risk APL is uncertain. In APL 2000 trial, patients with standard-risk APL [i.e., with baseline white blood cell (WBC) count <10,000/mm(3) ] were randomized between treatment with ATRA with Daunorubicin (DNR) and AraC (AraC group) and ATRA with DNR but without AraC (no AraC group). All patients subsequently received combined maintenance treatment. The trial had been prematurely terminated due to significantly more relapses in the no AraC group (J Clin Oncol, (24) 2006, 5703-10), but follow-up was still relatively short. With long-term follow-up (median 103 months), the 7-year cumulative incidence of relapses was 28.6% in the no AraC group, compared to 12.9% in the AraC group (P = 0.0065). In standard-risk APL, at least when the anthracycline used is DNR, avoiding AraC may lead to an increased risk of relapse suggesting that the need for AraC is regimen-dependent.

Exome Sequencing Identifies INPPL1 Mutations as a Cause of Opsismodysplasia.

Opsismodysplasia (OPS) is a severe autosomal-recessive chondrodysplasia characterized by pre- and postnatal micromelia with extremely short hands and feet. The main radiological features are severe platyspondyly, squared metacarpals, delayed skeletal ossification, and metaphyseal cupping. In order to identify mutations causing OPS, a total of 16 cases (7 terminated pregnancies and 9 postnatal cases) from 10 unrelated families were included in this study. We performed exome sequencing in three cases from three unrelated families and only one gene was found to harbor mutations in all three cases: inositol polyphosphate phosphatase-like 1 (INPPL1). Screening INPPL1 in the remaining cases identified a total of 12 distinct INPPL1 mutations in the 10 families, present at the homozygote state in 7 consanguinous families and at the compound heterozygote state in the 3 remaining families. Most mutations (6/12) resulted in premature stop codons, 2/12 were splice site, and 4/12 were missense mutations located in the catalytic domain, 5-phosphatase. INPPL1 belongs to the inositol-1,4,5-trisphosphate 5-phosphatase family, a family of signal-modulating enzymes that govern a plethora of cellular functions by regulating the levels of specific phosphoinositides. Our finding of INPPL1 mutations in OPS, a severe spondylodysplastic dysplasia with major growth plate disorganization, supports a key and specific role of this enzyme in endochondral ossification.

The Anarak, Jandaq and Posht-e-Badam metamorphic complexes in central Iran: New geological data, relationships and tectonic implications

The Anarak, Jandaq and Posht-e-Badam metamorphic complexes occupy the NW part of the Central-East Iranian Microcontinent and are juxtaposed with the Great Kavir block and Sanandaj-Sirjan zone. Our recent findings redefine the origin of these complexes, so far attributed to the Precambrian-Early Paleozoic orogenic episodes, and now directly related to the tectonic evolution of the Paleo-Tethys Ocean. This tectonic evolution was initiated by Late Ordovician-Early Devonian rifting events and terminated in the Triassic by the Eocimmerian collision event due to the docking of the Cimmerian blocks with the Asiatic Turan block. The ``Variscan accretionary complex'' is a new name we proposed for the most widely distributed metamorphic rocks connected to the Anarak and Jandaq complexes. This accretionary complex exposed from SW of Jandaq to the Anarak and Kabudan areas is a thick and fine grain siliciclastic sequence accompanied by marginal-sea ophiolitic remnants, including gabbro-basalts with a supra-subduction-geochemical signature. New Ar-40/Ar-39 ages are obtained as 333-320 Ma for the metamorphism of this sequence under greenschist to amphibolite facies. Moreover, the limy intercalations in the volcano-sedimentary part of this complex in Godar-e-Siah yielded Upper Devonian-Tournaisian conodonts. The northeastern part of this complex in the Jandaq area was intruded by 215 +/- 15 Ma arc to collisional granite and pegmatites dated by ID-TIMS and its metamorphic rocks are characterized by Some Ar-40/Ar-39 radiometric ages of 163-156 Ma. The ``Variscan'' accretionary complex was northwardly accreted to the Airekan granitic terrane dated at 549 +/- 15 Ma. Later, from the Late Carboniferous to Triassic, huge amounts of oceanic material were accreted to its southern side and penetrated by several seamounts such as the Anarak and Kabudan. This new period of accretion is supported by the 280-230 Ma Ar-40/Ar-39 ages for the Anarak mild high-pressure metamorphic rocks and a 262 Ma U-Pb age for the trondhjemite-rhyolite association of that area. The Triassic Bayazeh flysch filled the foreland basin during the final closure of the Paleo-Tethys Ocean and was partly deposited and/or thrusted onto the Cimmerian Yazd block. The Paleo-Tethys magmatic arc products have been well-preserved in the Late Devonian-Carboniferous Godar-e-Siah intra-arc deposits and the Triassic Nakhlak fore-arc succession. On the passive margin of the Cimmerian block, in the Yazd region, the nearly continuous Upper Paleozoic platform-type deposition was totally interrupted during the Middle to Late Triassic. Local erosion, down to Lower Paleozoic levels, may be related to flexural bulge erosion. The platform was finally unconformably covered by Liassic continental molassic deposits of the Shemshak. One of the extensional periods related to Neo-Tethyan back-arc rifting in Late Cretaceous time finally separated parts of the Eocimmerian collisional domain from the Eurasian Turan domain. The opening and closing of this new ocean, characterized by the Nain and Sabzevar ophiolitic melanges, finally transported the Anarak-Jandaq composite terrane to Central Iran, accompanied by large scale rotation of the Central-East Iranian Microcontinent (CEIM). Due to many similarities between the Posht-e-Badam metamorphic complex and the Anarak-Jandaq composite terrane, the former could be part of the latter, if it was transported further south during Tertiary time. (C) 2007 Elsevier B.V. All rights reserved.

Demographic and behavioral factors associated with adolescent pregnancy in Switzerland.

Switzerland has the lowest adolescent fertility rate in Western Europe. According to data collected in 1993 as part of the Swiss Multicentre Adolescent Survey on Health, 5% of 1,726 sexually active adolescents in a group of 3,993 15-20-year-old women enrolled in academic or vocational classes had ever been pregnant; most of these women (80%) had terminated their pregnancy. Adolescents who had ever been pregnant did not differ significantly from those who had not by demographic characteristics. Multiple logistic regression analysis identified seven factors associated with pregnancy: having had four or more sexual partners; not having used contraceptives at first intercourse; ever use of less-effective contraceptive methods; having used illicit drugs during the last 30 days; living apart from one's parents; recently experiencing stress; and perceiving a lack of future prospects.

Intravenous Lacosamide for Treatment of Status Epilepticus after Failing First-Line Therapy

Rationale: Treatment of status epilepticus (SE) usually requires intravenous anticonvulsant therapy. Although there are established drugs of first choice for its treatment, potentially hazardous side effects of these agents are not uncommon. Lacosamide (LCM) is a novel anticonvulsant drug that is available as infusion solution. LCM could be an alternative for treatment of SE when the standard drugs fail or should be avoided. Methods: We retrospectively identified patients from the hospital databases of two German and one Swiss neurological departments (University Hospital Marburg, Klinikum Osnabrueck, University Hospital Lausanne) between September 1st 2008 and May 22nd 2009 who were admitted because of SE and received at least one dose of intravenous LCM for treatment of SE. Results: Seventeen patients (11 female, 6 male) were identified. Median age was 71 years. 3 patients suffered from generalized convulsive SE, 8 patients had significant reduction of awareness with or without subtle motor symptoms, 6 patients had a simple focal status without relevant reduction of awareness. Etiology was acute symptomatic in 5 patients, remote symptomatic without pre-existing epilepsy in 6 patients, remote symptomatic and pre-existing epilepsy in 5 patients, and unknown in 1 patient. LCM was administered after failure of first line therapy in all cases. The first LCM bolus was 400mg in 13 patients and 200mg in 4 patients. LCM administration stopped SE in 7 patients. In 2 of them, LCM was administered immediately after benzodiazepine administration, in the others after failure of benzodiazepines and other first-line and/or second-line drugs. In 3 patients, SE was terminated by other anticonvulsants like Phenytoin, Phenobarbital or Oxcarbazepine. In 5 patients, SE could only be terminated by intubation and application of high-dose Midazolam, Propofol and/or Thiopental. In 2 patients, SE could not be terminated in spite of high doses of barbiturates. There was no serious adverse event documented that could possibly be attributed to LCM Conclusions: Intravenous LCM may be an alternative treatment for SE after failure of benzodiazepins and other established drugs, or when such agents are considered unsuitable.

Adaptive frequency tracking of the baseline ECG identifies the site of atrial fibrillation termination by catheter ablation

Multiple organization indices have been used to predict the outcome of stepwise catheter ablation in long-standing persistent atrial fibrillation (AF), however with limited success. Our study aims at developinginnovative organization indices from baseline ECG (i.e. during the procedure, before ablation) in orderto identify the site of AF termination by catheter ablation. Seventeen consecutive male patients (age60 ± 5 years, AF duration 7 ± 5 years) underwent a stepwise catheter ablation. Chest lead V6 was placedin the back (V6b). QRST cancelation was performed from chest leads V1 to V6b. Using an innovativeadaptive harmonic frequency tracking, two measures of AF organization were computed to quantify theharmonics components of ECG activity: (1) the adaptive phase difference variance (APD) between theAF harmonic components as a measure of AF regularity, and (2) and adaptive organization index (AOI)evaluating the cyclicity of the AF oscillations. Both adaptive indices were compared to indices computedusing a time-invariant approach: (1) ECG AF cycle length (AFCL), (2) the spectrum based organizationindex (OI), and (3) the time-invariant phase difference TIPD. Long-standing persistent AF was terminatedinto sinus rhythm or atrial tachycardia in 13/17 patients during stepwise ablation, 11 during left atriumablation (left terminated patients - LT), 2 during the right atrium ablation (right terminated patients -RT), and 4 were non terminated (NT) and required electrical cardioversion. Our findings showed that LTpatients were best separated from RT/NT before ablation by the duration of sustained AF and by AOI onchest lead V1 and APD from the dorsal lead V6b as compared to ECG AFCL, OI and TIPD, respectively. Ourresults suggest that adaptive measures of AF organization computed before ablation perform better thantime-invariant based indices for identifying patients whose AF will terminate during ablation within theleft atrium. These findings are indicative of a higher baseline organization in these patients that could beused to select candidates for the termination of AF by stepwise catheter ablation.© 2013 Elsevier Ltd. All rights reserved.

Termination of Atrial Fibrillation by Catheter Ablation can be Successfully Predicted from Baseline ECG

Purpose Multiple organization indices (OIs) have been used to predict the outcome of stepwise catheter ablation (step-CA) in long-standing persistent AF (pers-AF), however with limited success. Our study aims at developing innovative OIs from baseline (BL, before ablation) ECG in order to predict the outcome of step-CA. Methods Fourteen consecutive patients (pts) (60±5 y, AF duration 21±9 m) underwent a step-CA consisting in pulmonary veins isolation, left atrial (LA) defragmentation and linear ablations, and right atrial (RA) ablations if non terminated. Chest lead V6 was placed in the back (V6b). After QRST cancellation from chest leads V1 to V6b, two OIs were computed to quantify the harmonic components of ECG atrial activity: 1) phase difference variance (PD) between the AF harmonic components as a measure of AF regularity, and 2) adaptive OI (AOI) evaluating the time evolution of the AF harmonic components. Both indices were compared to classical ones: a spectrum-based OI (SOI) and ECG AF cycle length (AFCL). Results Pers-AF was terminated into sinus rhythm or atrial tachycardia in 10/14 pts during step-CA, 8 during LA (LT), 2 during RA (RT) ablation, and 4 were non terminated (NT). The figure shows that LT was best separated from RT/NT before ablation by AOI computed on lead V1 (A) and PD from lead V6b (B) as compared to SOI and AFCL respectively. Conclusion Our results suggest that adaptive OIs computed before ablation perform better than classical OIs for separating LT from RT/NT pts. These findings are indicative of a higher baseline organization in LT pts that could be used to select candidates for the restoration of sinus rhythm by step-CA.

Stratigraphic, sedimentological and palaeoenvironmental constraints on the rise of the Urgonian platform in the western Swiss Jura

Urgonian-type carbonates are a characteristic feature of many late Early Cretaceous shallow-marine, tropical and subtropical environments. The presence of typical photozoan carbonate-producing communities including corals and rudists indicates the prevalence of warm, transparent and presumably oligotrophic conditions in a period otherwise characterized by the high density of globally occurring anoxic episodes. Of particular interest, therefore, is the exploration of relationships between Urgonian platform growth and palaeoceanographic change. In the French and Swiss Jura Mountains, the onset and evolution of the Urgonian platform have been controversially dated, and a correlation with other, better dated, successions is correspondingly difficult. It is for this reason that the stratigraphy and sedimentology of a series of recently exposed sections (Eclepens, Vaumarcus and Neuchatel) and, in addition, the section of the Gorges de l'Areuse were analysed. Calcareous nannofossil biostratigraphy, the evolution of phosphorus contents of bulk rock, a sequence-stratigraphic interpretation and a correlation of drowning unconformities with better dated sections in the Helvetic Alps were used to constrain the age of the Urgonian platform. The sum of the data and field observations suggests the following evolution: during the Hauterivian, important outward and upward growth of a bioclastic and oolitic carbonate platform is documented in two sequences, separated by a phase of platform drowning during the late Early Hauterivian. Following these two phases of platform growth, a second drowning phase occurred during the latest Hauterivian and Early Barremian, which was accompanied by significant platform erosion and sediment reworking. The Late Barremian witnessed the renewed installation of a carbonate platform, which initiated with a phase of oolite production, and which progressively evolved into a typical Urgonian carbonate platform colonized by corals and rudists. This phase terminated at the latest in the middle Early Aptian, due to a further drowning event. The evolution of this particular platform segment is compatible with that of more distal and well-dated segments of the same northern Tethyan platform preserved in the Helvetic zone of the Alps and in the northern subalpine chains (Chartreuse and Vercors).

A nucleosome-dependent static loop potentiates estrogen-regulated transcription from the Xenopus vitellogenin B1 promoter in vitro.

We describe the transcriptional potentiation in estrogen responsive transcription extracts of the Xenopus vitellogenin B1 gene promoter through the formation of a positioned nucleosome. Nuclease digestion and hydroxyl radical cleavage indicate that strong, DNA sequence-directed positioning of a nucleosome occurs between -300 and -140 relative to the start site of transcription. Deletion of this DNA sequence abolishes the potentiation of transcription due to nucleosome assembly. The wrapping of DNA around the histone core of the nucleosome positioned between -300 and -140 creates a static loop in which distal estrogen receptor binding sites are brought close to proximal promoter elements. This might facilitate interactions between the trans-acting factors themselves and/or RNA polymerase. Such a nucleosome provides an example of how chromatin structure might have a positive effect on the transcription process.

Effects of polymer-coated multi-wall carbon nanotubes on mouse RAW 264.7 macrophages

Surface characteristics (area, chemical reactivity) play an important role in cell response to nanomaterials. The aim of this study was to evaluate the oxidative and inflammatory effects of multi−wall carbon nanotubes (MWCNT) uncoated (P0) or coated with carboxylic polyacid or polystyrene polybutadiene polymetacrylate of methyl polymers (P1 and P2 respectively) on murine macrophages (RAW 264.7 cell line). Carbon black nanoparticles (CB, diameter 95 nm) and crocidolite fibers (diameter: 80 nm, length: < 10 μm) were used as controls. Surface functional groups present on MWCNTs were analyzed by Knudsen flow reactor. The amount of acidic sites was P1> P0> P2, for basic sites was P0> P1>> P2 and for oxidizable sites was P0> P2> P1. In contact with cells, P2 formed smaller aggregates than P0 and P1, which were of similar size. Optical microscopy showed the formation of vacuoles after exposure only to P0, P1 and crocidolite. Incubation of cells with P0, P1 and crocidolite fibers induced a significant and similar decrease in metabolic activity, whereas P2 and CB had no effect. Cell number and membrane permeability were unmodified by incubation with the different particles. Incubation of macrophages with P0, P1 and crocidolite induced a dose− and time−dependent increase in mRNA expression of oxidative stress marker (HO−1, GPX1) and inflammatory mediators (TNF−a, MIP−2). No such responses were observed with P2 and CB. In conclusion, MWCNT coated with a carboxylic polyacid polymer exerted similar oxidative and inflammatory effects to uncoated MWCNT. By contrast, no such effects were observed with MWCNT coated with a polystyrene−based polymer. This kind of coating could be useful to decrease MWCNT toxicity.

Exome sequencing identifies INPPL1 mutations as a cause of opsismodysplasia.

Opsismodysplasia (OPS) is a severe autosomal-recessive chondrodysplasia characterized by pre- and postnatal micromelia with extremely short hands and feet. The main radiological features are severe platyspondyly, squared metacarpals, delayed skeletal ossification, and metaphyseal cupping. In order to identify mutations causing OPS, a total of 16 cases (7 terminated pregnancies and 9 postnatal cases) from 10 unrelated families were included in this study. We performed exome sequencing in three cases from three unrelated families and only one gene was found to harbor mutations in all three cases: inositol polyphosphate phosphatase-like 1 (INPPL1). Screening INPPL1 in the remaining cases identified a total of 12 distinct INPPL1 mutations in the 10 families, present at the homozygote state in 7 consanguinous families and at the compound heterozygote state in the 3 remaining families. Most mutations (6/12) resulted in premature stop codons, 2/12 were splice site, and 4/12 were missense mutations located in the catalytic domain, 5-phosphatase. INPPL1 belongs to the inositol-1,4,5-trisphosphate 5-phosphatase family, a family of signal-modulating enzymes that govern a plethora of cellular functions by regulating the levels of specific phosphoinositides. Our finding of INPPL1 mutations in OPS, a severe spondylodysplastic dysplasia with major growth plate disorganization, supports a key and specific role of this enzyme in endochondral ossification.