Common variants in the ATP2B1 gene are associated with susceptibility to hypertension: the Japanese Millennium Genome Project.

Hypertension is one of the most common complex genetic disorders. We have described previously 38 single nucleotide polymorphisms (SNPs) with suggestive association with hypertension in Japanese individuals. In this study we extend our previous findings by analyzing a large sample of Japanese individuals (n=14 105) for the most associated SNPs. We also conducted replication analyses in Japanese of susceptibility loci for hypertension identified recently from genome-wide association studies of European ancestries. Association analysis revealed significant association of the ATP2B1 rs2070759 polymorphism with hypertension (P=5.3×10(-5); allelic odds ratio: 1.17 [95% CI: 1.09 to 1.26]). Additional SNPs in ATP2B1 were subsequently genotyped, and the most significant association was with rs11105378 (odds ratio: 1.31 [95% CI: 1.21 to 1.42]; P=4.1×10(-11)). Association of rs11105378 with hypertension was cross-validated by replication analysis with the Global Blood Pressure Genetics consortium data set (odds ratio: 1.13 [95% CI: 1.05 to 1.21]; P=5.9×10(-4)). Mean adjusted systolic blood pressure was highly significantly associated with the same SNP in a meta-analysis with individuals of European descent (P=1.4×10(-18)). ATP2B1 mRNA expression levels in umbilical artery smooth muscle cells were found to be significantly different among rs11105378 genotypes. Seven SNPs discovered in published genome-wide association studies were also genotyped in the Japanese population. In the combined analysis with replicated 3 genes, FGF5 rs1458038, CYP17A1, rs1004467, and CSK rs1378942, odds ratio of the highest risk group was 2.27 (95% CI: 1.65 to 3.12; P=4.6×10(-7)) compared with the lower risk group. In summary, this study confirmed common genetic variation in ATP2B1, as well as FGF5, CYP17A1, and CSK, to be associated with blood pressure levels and risk of hypertension.

Direct evidence for the existence of dairying farms in prehistoric Central Europe (4th millennium BC)

The molecular and isotopic chemistry of organic residues from archaeological potsherds was used to obtain further insight into the dietary trends and economies at the Constance lake-shore Neolithic settlements. The archaeological organic residues from the Early Late Neolithic (3922-3902 BC) site Hornstaad-Hornle IA/Germany are, at present, the oldest archaeological samples analysed at the Institute of Mineralogy and Geochemistry of the University of Lausanne. The approach includes 13C/12C and 15N/14N ratios of the bulk organic residues, fatty acids distribution and 13C/12C ratios of individual fatty acids. The results are compared with those obtained from the over 500 years younger Neolithic (3384-3370 BC) settlement of Arbon Bleiche 3/Switzerland and with samples of modern vegetable oils and fat of animals that have been fed exclusively on C3 forage grasses. The overall fatty acid composition (C9 to C24 range, maximizing at C14 and C16), the bulk 13C/12C and 15N/14N ratios (delta13C, delta15N) and the 13C/12C ratios of palmitic (C16:0), stearic (C18:0) and oleic acids (C18:1) of the organic residues indicate that most of the studied samples (25 from 47 samples and 5 from 41 in the delta13C18:0 vs. delta13C16:0 and delta13C18:0 vs. delta13C18:1 diagrams, respectively) from Hornstaad-Hornle IA and Arbon Bleiche 3 sherds contain fat residues of pre-industrial ruminant milk, and young suckling calf/lamb adipose. These data provide direct proof of milk and meat (mainly from young suckling calves) consumption and farming practices for a sustainable dairying in Neolithic villages in central Europe around 4000 BC.dagger

Sirolimus-induced acneiform eruption.

Sirolimus is a new immunosuppressive agent used to prevent rejection in renal allograft recipients in order to reduce the need of potentially nephrotoxic calcineurin inhibitors (cyclosporine, tacrolimus). The cutaneous side effects of sirolimus are not well known and they may have been underestimated. We report 2 cases of follicular acneiform eruptions induced by sirolimus in renal allograft recipients. This dermatologic complication was severe and difficult to treat, and resolved only after discontinuation of sirolimus.

European climate variations over the past half-millennium reconstructed from groundwater

Temperature reconstructions for recent centuries are the basis of estimations of the natural variability in the climate system before and during the onset of anthropogenic perturbation. Here we present, for the first time, an independent and physically based reconstruction of mean annual temperature over the past half millennium obtained from groundwater in France. The reconstructed noble gas temperature (NGT) record suggests cooler than present climate conditions throughout the 16th-19th centuries. Periods of warming occur in the 17th-18th and 20th century, while cooling is reconstructed in the 19th century. A noticeable coincidence with other temperature records is demonstrated. Deuterium excess varies in parallel with the NGT, and indicates variation in the seasonality of the aquifer recharge; whereas high excess air in groundwater indicates periods with high oscillations of the water table.

Vedolizumab as induction and maintenance therapy for Crohn's disease.

BACKGROUND: The efficacy of vedolizumab, an α4β7 integrin antibody, in Crohn's disease is unknown. METHODS: In an integrated study with separate induction and maintenance trials, we assessed intravenous vedolizumab therapy (300 mg) in adults with active Crohn's disease. In the induction trial, 368 patients were randomly assigned to receive vedolizumab or placebo at weeks 0 and 2 (cohort 1), and 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 2); disease status was assessed at week 6. In the maintenance trial, 461 patients who had had a response to vedolizumab were randomly assigned to receive placebo or vedolizumab every 8 or 4 weeks until week 52. RESULTS: At week 6, a total of 14.5% of the patients in cohort 1 who received vedolizumab and 6.8% who received placebo were in clinical remission (i.e., had a score on the Crohn's Disease Activity Index [CDAI] of ≤150, with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity) (P=0.02); a total of 31.4% and 25.7% of the patients, respectively, had a CDAI-100 response (≥100-point decrease in the CDAI score) (P=0.23). Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0% and 36.4% of those assigned to vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6% assigned to placebo (P<0.001 and P=0.004 for the two vedolizumab groups, respectively, vs. placebo). Antibodies against vedolizumab developed in 4.0% of the patients. Nasopharyngitis occurred more frequently, and headache and abdominal pain less frequently, in patients receiving vedolizumab than in patients receiving placebo. Vedolizumab, as compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%). CONCLUSIONS: Vedolizumab-treated patients with active Crohn's disease were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolizumab (rather than switching to placebo) were more likely to be in remission at week 52. Adverse events were more common with vedolizumab. (Funded by Millennium Pharmaceuticals; GEMINI 2 ClinicalTrials.gov number, NCT00783692.).

Stratigraphy and palaeoenvironment of Early Jurassic dinosaur-bearing volcaniclastic deposits from Toundoute (Province of Ouarzazate, Haut-Atlas, Morocco)

The Early Jurassic dinosaur site of Toundoute which yielded the basal sauropod Tazoudasaurus naimi is examined in the light of its stratigraphic, sedimentological and palaeoenvironmental context. A thin succession of Early Liassic marine carbonates (probably Hettangian-Sinemurian in age) is continuously overlain by continental beds with dinosaurs. These latter are assumed to be of Middle to Late Liassic age. The continental deposits include a large part of volcanoclastics, different from the Triassic basalts. The Jurassic volcanoclastics originated from an unknown but obviously close eruption centre. The continental sediments (channels and flood plain) were deposited under tropical climate conditions with alternating humid and dry episodes. The bones occur as isolated or partly articulated elements (parts of carcasses). The two bone-beds are related to typical mud-flows. This type of transport protected the bones from erosion, and favoured their burying and fossilization.

The role of basalt replenishment in the generation of basaltic andesites of the ongoing activity at Arenal volcano, Costa Rica: evidence from clinopyroxene and spinel

The bulk composition of magma erupted from Volcan Arenal has remained nearly constant (SiO2 = 53.6-54.9 wt%; MgO = 5.0-4.5 wt%) during almost 30 years of continuous activity (1969-1996). None the less, clinopyroxene (cpx) phenocrysts and their spinel inclusions record a much more complex open-system evolution in which steady-state production of the erupted basaltic andesitic magma is linked to episodic injections of basalt into Arenal's magma conduit/reservoir system. High-resolution major element zoning profiles (electron microprobe) on a large number of phenocrysts (>14,000 analyses), tied to back-scattered electron (BSE) images, have been used to assess the compositional characteristics of the magmatic end members as well as the timing and dynamics of magma replenishment events. No two cpx phenocrysts have exactly the same zoning profile. The vast majority of our analyses record the crystallization of cpx (Cr2O3 < 0.12 wt%; Mg# = 65-79; Al/Ti = 2-7) from a liquid comparable to or more evolved than erupted magma compositions. However, half of all cpx grains are cored by high-Cr cpx (Cr2O3 = 0.2-0.72 wt%) or contain similar basaltic compositions as abrupt growth bands in phenocrysts with and without high-Cr cores; phenocrysts with high-Cr cpx occur throughout the ongoing activity. In a few cases, high-Cr cpx occurs very near the outer margin of the grain without an apparent growth hiatus, particularly in 1968/69 and 1992/93. The main conclusions are: (1) all basaltic andesitic lavas erupted at Arenal during the ongoing activity that began in July, 1968, are the products of magma mixing, (2) clinopyroxenes record multiple replenishment events of basaltic magma in contrast to the near constancy of erupted bulk compositions, (3) some phenocrysts preserve records of multiple interactions with basaltic magmas requiring magmatic processes to operate on time-scales shorter than residence times of some phenocrysts, (4) multiple occurrences of clinopyroxene with high-Cr rims suggest that basalt replenishment events have occurred with sub-decadal frequency and may predate eruption by months or less. From this we infer that Arenal volcano is underlain by a continuously active, small-volume magmatic reservoir maintained in quasi-steady state by basalt recharge over several decades. The monotony of erupting Arenal magmas implies that fractionation, recharge, ascent, and eruption are well balanced in order for magmas to be essentially uniform while containing phenocrysts with vastly different growth histories at the time of eruption.

From the vendor in the hemp shop to the dealer in the alleyway? A comparison of the sources of supply of cannabis in a time of 'de-normalising' cannabis use.

Objectives: After several years of increasing 'normalisation' of cannabis use in Switzerland at the beginning of the new millennium, a reversed tendency, marked among others by a more stringent law-enforcement, set in. The presentation examines the question of where adolescents and young adults obtained cannabis, within the context of this societal change. In addition, it compares the sources of supply for cannabis with those found in studies of other European countries. Methods: Analyses are based on data from the Swiss Cannabis Monitoring Study. As part of this longitudinal, representative population survey, more than 5000 adolescents and young adults were interviewed by telephone on the topic of cannabis. Within the total sample, 593 (2004) or 554 (2007) respectively, current cannabis users replied to the questions on sources of supply. Changes in law-enforcement and societal climate concerning cannabis are assessed based on relevant literature, media reports and parliamentary discussions. Results: Whereas 22% of cannabis users stated in 2004 that they bought their cannabis from vendors in hemp shops, this proportion drastically decreased to 6% three years later. At the same time, cannabis was obtained increasingly from friends, while the proportion of users who purchased cannabis from dealers in the alleyway, more than doubled from 6% (2004) to 13% (2007). It was male cannabis users, and in particular, young adult and frequent users, who have moved into the alleyways. Generally, users who buy cannabis in the alleyway show more cannabis-related problems than those who mainly name other sources of supply, even when adjusted for sex, age and frequency of cannabis use. Discussion: Possible consequences of these changes in cannabis supply, like the risk of merging a previously cannabis-only market with other 'harder' drugs markets, are discussed.

Insights into shallow magmatic processes in large silicic magma bodies: the trace element record in the Fish Canyon magma body, Colorado

Highly evolved rhyolite glass plus near-solidus mineral assemblages in voluminous, dacitic, crystal-rich ignimbrites provide an opportunity to evaluate the late magmatic evolution of granodiorite batholiths. This study reports laser-ablation ICP-MS analyses of trace element concentrations in feldspars, hornblende, biotite, titanite, zircon, magnetite, and interstitial glass of the crystal-rich Fish Canyon Tuff. The high-silica rhyolite glass is characterized by relatively high concentrations of feldspar-compatible elements (e.g., 100 ppm Sr and 500 ppm Ba) and low concentrations of Y (< 7 ppm) and HREE (&SIM; 1 ppm Yb), hence high LREE/HREE (Ce/Yb > 40) compared to many well-studied high-silica rhyolite glasses and whole-rock compositions. Most minerals record some trace element heterogeneities, with, in particular, one large hornblende phenocryst showing four- to six-fold core-to-rim increases in Sr and Ba coupled with a decrease in Sc. The depletions of Y and HREE in the Fish Canyon glass relative to the whole-rock composition (concentrations in glass &SIM; 30% of those in whole rocks) reflect late crystallization of phases wherein these elements were compatible. As garnet is not stable at the low-P conditions at which the Fish Canyon magma crystallized, we show that a combination of modally abundant hornblende (&SIM; 4%) + titanite (&SIM; 0.5-1%) and the highly polymerized nature of the rhyolitic liquid led to Y and HREE depletions in melt. Relatively high Sr and Ba contents in glass and rimward Sr and Ba increases in euhedral, concentrically zoned hornblende suggest partial feldspar dissolution and a late release of these elements to the melt as hornblende was crystallizing, in agreement with textural evidence for feldspar (and quartz) resorption. Both observations are consistent with thermal rejuvenation of the magma body prior to eruption, during which the proportion of melt increased via feldspar and quartz dissolution, even as hydrous and accessory phases were crystallizing. Sr/Y in Fish Canyon glass (13-18) is lower than the typical ``adakitic'' value (> 40), confirming that high Sr/Y is a reliable indicator of high-pressure magma generation and/or differentiation wherein garnet is implicated.

Magma generation at the easternmost section of the Hellenic arc: Hf, Nd, Pb and Sr isotope geochemistry of Nisyros and Yali volcanoes (Greece)

Geochemical and petrographical studies of lavas and ignimbrites from the Quaternary Nisyros-Yali volcanic system in the easternmost part of the Hellenic arc (Greece) reveal insight into magma generating processes. A compositional gap between 61 and 68 wt.% SiO2 is recognized that coincides with the stratigraphic distinction between pre-caldera and postcaldera volcanic units. Trace element systematics support the subdivision of Nisyros and Yali volcanic units into two distinct suites of rocks. The variation of Nd and Hf present day isotope data and the fact that they are distinct from the isotope compositions of MORB rule out an origin by pure differentiation and require assimilation of a crustal component. Lead isotope ratios of Nisyros and Yali volcanic rocks support mixing of mantle material with a lower crust equivalent. However, Sr-87/Sr-86 ratios of 0.7036-0.7048 are incompatible with a simple binary mixing scenario and give low depleted mantle extraction ages (< 0.1 Ga), in contrast with Pb model ages of 0.3 Ga and Hf and Nd model ages of ca. 0.8 Ga. The budget of fluid-mobile elements Sr and Pb is likely to be dominated by abundant hydrous fluids characterised by mantle-like Sr isotope ratios. Late stage fluids probably were enriched in CO2, needed to explain the high Th concentrations. The occurrence of hydrated minerals (e.g., amphibole) in the first post-caldera unit with the lowermost Sr-87/Sr-86 ratio of 0.7036 +/- 2 can be interpreted as the result of the increased water activity in the source. The presence of two different plagioclase phenocryst generations in the first lava subsequent to the caldera-causing event is indicative for a longer storage time of this magma at a shallower level. A model capable of explaining these observations involves three evolutionary stages. First stage, assimilation of lower crustal material by a primitive magma of mantle origin (as modelled by Nd-Hf isotope systematics). This stage ended by an interruption in replenishment that led to an increase of crystallization and, hence, an increase in viscosity, suppressing eruption. During this time gap, differentiation by fractional crystallization led to enrichment of incompatible species, especially aqueous fluids, to silica depolymerisation and to a decrease in viscosity, finally enabling eruption again in the third stage. (c) 2005 Elsevier B.V. All rights reserved.

Malaria: une espèce en voie de disparition [Malaria: an endangered species?].

The implementation at scale of preventive measures and the use of effective treatments in populations living in endemic areas has led to a drastic reduction of the burden of malaria in all continents. The considerable investment of international agencies to support local governments in the fight against malaria allows hoping to achieve the millennium goals for malaria and child mortality in several countries. Malaria elimination, and even eradication becomes a realistic objective, especially so because a vaccine may be soon available to complement the armamentarium. For travelers, the tendency will be to reduce the number of countries where chemoprophylaxis or stand-by treatment is recommended and to insist on the rigorous use of measures to prevent mosquito bites such as repellents and insecticide-impregnated bednets.

Lupus-like syndrome associated with statin therapy.

Statins are among the most widely prescribed drugs. An increasing number of lupus-like syndrome has recently been reported with these lipid-lowering agents. We describe a new case associated with simvastatin therapy. The presence of anti-dsDNA antibodies in the serum is for the first time reported confirming that statins may also induce a systemic autoimmune reaction. Statin-induced lupus-like syndrome is characterized by the long delay between the beginning of therapy and the skin eruption. Antinuclear antibodies may persist for many months after drug discontinuation. The causal relationship may be therefore difficult to establish, and probably many cases are unrecognized. Early diagnosis may avoid unnecessary immunosuppressive therapy.