DNA methylation profiles of human active and inactive X chromosomes.

X-chromosome inactivation (XCI) is a dosage compensation mechanism that silences the majority of genes on one X chromosome in each female cell. To characterize epigenetic changes that accompany this process, we measured DNA methylation levels in 45,X patients carrying a single active X chromosome (X(a)), and in normal females, who carry one X(a) and one inactive X (X(i)). Methylated DNA was immunoprecipitated and hybridized to high-density oligonucleotide arrays covering the X chromosome, generating epigenetic profiles of active and inactive X chromosomes. We observed that XCI is accompanied by changes in DNA methylation specifically at CpG islands (CGIs). While the majority of CGIs show increased methylation levels on the X(i), XCI actually results in significant reductions in methylation at 7% of CGIs. Both intra- and inter-genic CGIs undergo epigenetic modification, with the biggest increase in methylation occurring at the promoters of genes silenced by XCI. In contrast, genes escaping XCI generally have low levels of promoter methylation, while genes that show inter-individual variation in silencing show intermediate increases in methylation. Thus, promoter methylation and susceptibility to XCI are correlated. We also observed a global correlation between CGI methylation and the evolutionary age of X-chromosome strata, and that genes escaping XCI show increased methylation within gene bodies. We used our epigenetic map to predict 26 novel genes escaping XCI, and searched for parent-of-origin-specific methylation differences, but found no evidence to support imprinting on the human X chromosome. Our study provides a detailed analysis of the epigenetic profile of active and inactive X chromosomes.

Physical and chemical attributes of archaeological soils developed from shell middens in the Região dos Lagos, Rio de Janeiro, Brazil

In prehistoric times, innumerous shell middens, called "sambaquis", consisting mainly of remains of marine organisms, were built along the Brazilian coast. Although the scientific community took interest in these anthropic formations, especially since the nineteenth century, their pedological context is still poorly understood. The purpose of this study was to characterize and identify the physical and chemical changes induced by soil-forming processes, as well as to compare the morphology of shell midden soils with other, already described, anthropogenic soils of Brazil. Four soil profiles developed from shell middens in the Região dos Lagos - RJ were morphologically described and the physical and chemical properties determined. The chemical analysis showed that Ca, Mn, Mg, and particularly P and Zn are indicators of anthropic horizons of midden soils, as in the Amazon Dark Earths (Terras Pretas de Índio). After the deposition of P-rich material, P reaction and leaching can mask or disturb the evidence of in situ man-made strata, but mineralogical and chemical studies of phosphate forms can elucidate the apparent complexity. Lower phosphate-rich strata without direct anthropic inputs indicate P leaching and precipitation in secondary forms. The total and bioavailable contents of Ca, Mg, Zn, Mn, Cu, P, and organic C of midden soils were much higher than of regional soils without influence of ancient human settlements, demonstrating that the high fertility persisted for long periods, at some sites for more than 4000 years. The physical analysis showed that wind-blown sand contributed significantly to increase the sand fraction in the analyzed soils (texture classes sand, sandy loam and sandy clay loam) and that the aeolian sand accumulation occurred simultaneously with the midden formation.

The sandstone-hosted Beverley uranium Deposit, Lake Frome Basin, South Australia: Mineralogy, geochemistry, and a time-constrained model for its genesis

The sandstone-hosted Beverley uranium deposit is located in terrestrial sediments in the Lake Frome basin in the North Flinders Ranges, South Australia. The deposit is 13 km from the U-rich Mesoproterozoic basement of the Mount Painter inlier, which is being uplifted 100 to 200 m above the basin by neotectonic activity that probably initiated in the early Pliocene. The mineralization was deposited mainly in organic matter-poor Miocene lacustrine sands and partly in the underlying reductive strata comprising organic matter-rich clays and silts. The bulk of the mineralization consists of coffinite and/or uraninite nodules, growing around Co-rich pyrite with an S isotope composition (delta S-34 = 1.0 +/- 0.3 parts per thousand), suggestive of an early diagenetic lacustrine origin. In contrast, authigenic sulfides in the bulk of the sediments have a negative S isotope signature (delta S-34 ranges from -26.2 to -35.5 parts per thousand), indicative of an origin via bacterially mediated sulfate reduction. Minor amounts of Zn-bearing native copper and native lead also support the presence of specific, reducing microenvironments in the ore zone. Small amounts of carnotite are associated with the coffinite ore and also occur beneath a paleosoil horizon overlying the uranium deposit. Provenance studies suggest that the host Miocene sediments were derived from the reworking of Early Cretaceous glacial or glaciolacustrine sediments ultimately derived from Paleozoic terranes in eastern Australia. In contrast, the overlying Pliocene strata were in part derived from the Mesoproterozoic basement inlier. Mass-balance and geochemical data confirm that granites of the Mount Painter domain were the ultimate source of U and BEE at Beverley. U-Pb dating of coffinite and carnotite suggest that the U mineralization is Pliocene (6.7-3.4 Ma). The suitability of the Beverley deposit for efficient mining via in situ leaching, and hence its economic value, are determined by the nature of the hosting sand unit, which provides the permeability and low reactivity required for high fluid flow and low chemical consumption. These favorable sedimentologic and geometrical features result from a complex conjunction of factors, including deposition in lacustrine shore environment, reworking of angular sands of glacial origin, deep Pliocene weathering, and proximity to an active fault exposing extremely U rich rocks.

Major environmental change and bonebed genesis prior to the Triassic-Jurassic mass extinction

We present new geochemical and sedimentological data from marginal marine strata of Penarth Bay, south Wales (UK) to elucidate the origin of widespread but enigmatic concentrations of vertebrate hard parts (bonebeds) in marine successions of Rhaetian age (late Triassic). Sedimentological evidence shows that the phosphatic constituents of the bonebeds were subjected to intense phosphatization in shallow current-dominated settings and subsequently reworked and transported basinward by storms. Interbedded organic-rich strata deposited under quiescent and poorly oxygenated conditions record enhanced phosphorus regeneration from sedimentary organic matter into the water column and probably provided the main source of phosphate required for heavy bonebed clast phosphatization. The stratigraphically limited interval showing evidence for oxygen depletion and accelerated P-cycling coincides with a negative 4% organic carbon isotope excursion, which possibly reflects supra-regional changes in carbon cycling and clearly predates the 'initial isotope excursion' characterizing many Triassic-Jurassic boundary strata. our data indicate that Rhaetian bonebeds are the lithological signature of profound, climatically driven changes in carbon cycling and redox conditions and support the idea of a multi-pulsed environmental crisis at the end of the Triassic, possibly linked to successive episodes of igneous activity in the central Atlantic Magmatic Province.

Divergent fifteen-year trends in traditional and cardiometabolic risk factors of cardiovascular diseases in the Seychelles.

OBJECTIVE: Few studies have assessed secular changes in the levels of cardiovascular risk factors (CV-RF) in populations of low or middle income countries. The systematic collection of a broad set of both traditional and metabolic CV-RF in 1989 and 2004 in the population of the Seychelles islands provides a unique opportunity to examine trends at a fairly early stage of the "diabesity" era in a country in the African region. METHODS: Two examination surveys were conducted in independent random samples of the population aged 25-64 years in 1989 and 2004, attended by respectively 1081 and 1255 participants (participation rates >80%). All results are age-standardized to the WHO standard population. RESULTS: In 2004 vs. 1989, the levels of the main traditional CV-RF have either decreased, e.g. smoking (17% vs. 30%, p < 0.001), mean blood pressure (127.8/84.8 vs. 130.0/83.4 mmHg, p < 0.05), or only moderately increased, e.g. median LDL-cholesterol (3.58 vs. 3.36 mmol/l, p < 0. 01). In contrast, marked detrimental trends were found for obesity (37% vs. 21%, p < 0.001) and several cardiometabolic CVD-RF, e.g. mean HDL-cholesterol (1.36 vs. 1.40 mmol/l, p < 0.05), median triglycerides (0.80 vs. 0.78 mmol/l, p < 0.01), mean blood glucose (5.89 vs. 5.22 mmol/l, p < 0.001), median insulin (11.6 vs. 8.3 micromol/l, p < 0.001), median HOMA-IR (2.9 vs. 1.8, p < 0.001) and diabetes (9.4% vs. 6.2%, p < 0.001). At age 40-64, the prevalence of elevated total cardiovascular risk tended to decrease (e.g. WHO-ISH risk score > or =10; 11% vs. 13%, ns), whereas the prevalence of the metabolic syndrome (which integrates several cardiometabolic CVD-RF) nearly doubled (36% vs. 20%, p < 0.001). Data on physical activity and on intake of alcohol, fruit and vegetables are also provided. Awareness and treatment rates improved substantially for hypertension and diabetes, but control rates improved for the former only. Median levels of the cardiometabolic CVD-RF increased between 1989 and 2004 within all BMI strata, suggesting that the worsening levels of cardiometabolic CVD-RF in the population were not only related to increasing BMI levels in the interval. CONCLUSION: The levels of several traditional CVD-RF improved over time, while marked detrimental trends were observed for obesity, diabetes and several cardiometabolic factors. Thus, in this population, the rapid health transition was characterized by substantial changes in the patterns of CVD-RF. More generally, this analysis suggests the importance of surveillance systems to identify risk factor trends and the need for preventive strategies to promote healthy lifestyles and nutrition.

An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke.

OBJECTIVE: We aimed to create an index to stratify cryptogenic stroke (CS) patients with patent foramen ovale (PFO) by their likelihood that the stroke was related to their PFO. METHODS: Using data from 12 component studies, we used generalized linear mixed models to predict the presence of PFO among patients with CS, and derive a simple index to stratify patients with CS. We estimated the stratum-specific PFO-attributable fraction and stratum-specific stroke/TIA recurrence rates. RESULTS: Variables associated with a PFO in CS patients included younger age, the presence of a cortical stroke on neuroimaging, and the absence of these factors: diabetes, hypertension, smoking, and prior stroke or TIA. The 10-point Risk of Paradoxical Embolism score is calculated from these variables so that the youngest patients with superficial strokes and without vascular risk factors have the highest score. PFO prevalence increased from 23% (95% confidence interval [CI]: 19%-26%) in those with 0 to 3 points to 73% (95% CI: 66%-79%) in those with 9 or 10 points, corresponding to attributable fraction estimates of approximately 0% to 90%. Kaplan-Meier estimated stroke/TIA 2-year recurrence rates decreased from 20% (95% CI: 12%-28%) in the lowest Risk of Paradoxical Embolism score stratum to 2% (95% CI: 0%-4%) in the highest. CONCLUSION: Clinical characteristics identify CS patients who vary markedly in PFO prevalence, reflecting clinically important variation in the probability that a discovered PFO is likely to be stroke-related vs incidental. Patients in strata more likely to have stroke-related PFOs have lower recurrence risk.

Shade avoidance: phytochrome signalling and other aboveground neighbour detection cues.

Plants compete with neighbouring vegetation for limited resources. In competition for light, plants adjust their architecture to bring the leaves higher in the vegetation where more light is available than in the lower strata. These architectural responses include accelerated elongation of the hypocotyl, internodes and petioles, upward leaf movement (hyponasty), and reduced shoot branching and are collectively referred to as the shade avoidance syndrome. This review discusses various cues that plants use to detect the presence and proximity of neighbouring competitors and respond to with the shade avoidance syndrome. These cues include light quality and quantity signals, mechanical stimulation, and plant-emitted volatile chemicals. We will outline current knowledge about each of these signals individually and discuss their possible interactions. In conclusion, we will make a case for a whole-plant, ecophysiology approach to identify the relative importance of the various neighbour detection cues and their possible interactions in determining plant performance during competition.

The role of a Mediterranean diet on the risk of oral and pharyngeal cancer.

BACKGROUND: The Mediterranean diet has a beneficial role on various neoplasms, but data are scanty on oral cavity and pharyngeal (OCP) cancer. METHODS: We analysed data from a case-control study carried out between 1997 and 2009 in Italy and Switzerland, including 768 incident, histologically confirmed OCP cancer cases and 2078 hospital controls. Adherence to the Mediterranean diet was measured using the Mediterranean Diet Score (MDS) based on the major characteristics of the Mediterranean diet, and two other scores, the Mediterranean Dietary Pattern Adherence Index (MDP) and the Mediterranean Adequacy Index (MAI). RESULTS: We estimated the odds ratios (ORs), and the corresponding 95% confidence intervals (CI), for increasing levels of the scores (i.e., increasing adherence) using multiple logistic regression models. We found a reduced risk of OCP cancer for increasing levels of the MDS, the ORs for subjects with six or more MDS components compared with two or less being 0.20 (95% CI 0.14-0.28, P-value for trend <0.0001). The ORs for the highest vs the lowest quintile were 0.20 (95% CI 0.14-0.28) for the MDP score (score 66.2 or more vs less than 57.9), and 0.48 (95% CI 0.33-0.69) for the MAI score (score value 2.1 or more vs value less 0.92), with significant trends of decreasing risk for both scores. The favourable effect of the Mediterranean diet was apparently stronger in younger subjects, in those with a higher level of education, and in ex-smokers, although it was observed in other strata as well. CONCLUSIONS: Our study provides strong evidence of a beneficial role of the Mediterranean diet on OCP cancer.

On the Upper Ordovician unconformity in the Pyrenees: New evidence from the La Cerdanya area

In recent years, contradictory reports about whether or not an unconformity exists at the base of the Upper Ordovician succession of the Pyrenees have been made. In the Cerdanya area (Central Pyrenees), good outcrop evidence for this unconformity is displayed at the base of the Rabassa conglomerates. In this area, the Upper Ordovician rocks overlie a tilted Cambro-Ordovician sequence, displaying an angular unconformity and indicating a break in the stratigraphic series. Moreover, the existence of such an unconformity is supported by the distribution of Variscan minor structures, suggesting that the Cambro-Ordovician and the Upper Ordovician strata initially had different orientations before the main Variscan folding.

A global marine sedimentary response to the end-Permian mass extinction: Examples from southern Turkey and the western United States

The end-Permian mass extinction greatly diminished marine diversity and brought about a whole-scale restructuring of marine ecosystems; these ecosystem changes also profoundly affected the sedimentary record. Data presented here, attained through facies analyses of strata deposited during the immediate aftermath of the end-Permian mass extinction (southern Turkey) and at the close of the Early Triassic (southwestern United States), in combination with a literature review, show that sedimentary systems were profoundly affected by: (1) a reduction in biotic diversity and abundance and (2) long-term environmental fluctuations that resulted from the end-Permian crisis. Lower Triassic strata display widespread microbialite and carbonate seafloor fan development and contain indicators of suppressed infaunal bioturbation such as flat-pebble conglomerates and wrinkle structures (facies considered unusual in post-Cambrian subtidal deposits). Our observations suggest that depositional systems, too, respond to biotic crises, and that certain facies may act as barometers of ecologic and environmental change independent of fossil assemblage analyses. Close investigation of facies changes during other critical times in Earth history may serve as an important tool in interpreting the ecology of metazoans and their environment.

Improvement of Granular Base Course Materials with Portland Cement, Special Report, HR-99

A highway base course may be defined as a layer of granular material which lies immediately below the wearing surface of a pavement and must possess high resistance to deformation in order to withstand pressures imposed by traffic. A material commonly used for base course construction is crushed limestone. Sources of limestone, acceptable for highway bases in the state of Iowa, occur almost entirely in the Pennsylvanian, Mississippian and Devonian strata. Performance records of the latter two have been quite good, while material from the Pennsylvanian stratum has failed on numerous occasions. The study reported herein is one segment of an extensive research program on compacted crushed limestone used for flexible highway base courses. The primary goals of the total study are: 1. Determination of a suitable and realistic laboratory method of compaction. 2. Effect of gradation, and mineralogy of the fines, on shearing strength. 3. Possible improvement of the shear strength with organic and inorganic chemical stabilization additives. Although the study reported herein deals primarily with the third goal, information gathered from work on the first two was required for this investigation. The primary goal of this study was the evaluation of various factors of stability of three crushed limestones when treated with small amounts of type I Portland cement. Investigation of the untreated materials has indicated that shear strength alone is not the controlling factor for stability of crushed stone bases. Thus the following observations were made in addition to shear strength parameters, to more adequately ascertain the stability of the cement treated materials: 1. Volume change during consolidation and shear testing. 2. Pore pressure during shear. The consolidated-undrained triaxial shear test was used for determination of the above factors.

HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies.

OBJECTIVE: To evaluate deaths from AIDS-defining malignancies (ADM) and non-AIDS-defining malignancies (nADM) in the D:A:D Study and to investigate the relationship between these deaths and immunodeficiency. DESIGN: Observational cohort study. METHODS: Patients (23 437) were followed prospectively for 104 921 person-years. We used Poisson regression models to identify factors independently associated with deaths from ADM and nADM. Analyses of factors associated with mortality due to nADM were repeated after excluding nADM known to be associated with a specific risk factor. RESULTS: Three hundred five patients died due to a malignancy, 298 prior to the cutoff for this analysis (ADM: n = 110; nADM: n = 188). The mortality rate due to ADM decreased from 20.1/1000 person-years of follow-up [95% confidence interval (CI) 14.4, 25.9] when the most recent CD4 cell count was <50 cells/microl to 0.1 (0.03, 0.3)/1000 person-years of follow-up when the CD4 cell count was more than 500 cells/microl; the mortality rate from nADM decreased from 6.0 (95% CI 3.3, 10.1) to 0.6 (0.4, 0.8) per 1000 person-years of follow-up between these two CD4 cell count strata. In multivariable regression analyses, a two-fold higher latest CD4 cell count was associated with a halving of the risk of ADM mortality. Other predictors of an increased risk of ADM mortality were homosexual risk group, older age, a previous (non-malignancy) AIDS diagnosis and earlier calendar years. Predictors of an increased risk of nADM mortality included lower CD4 cell count, older age, current/ex-smoking status, longer cumulative exposure to combination antiretroviral therapy, active hepatitis B infection and earlier calendar year. CONCLUSION: The severity of immunosuppression is predictive of death from both ADM and nADM in HIV-infected populations.

High constant incidence of second primary colorectal cancer.

Patients who had a colorectal cancer have a 1.5- to 2-fold excess risk of a second colorectal cancer as compared to the general population, the excess being higher at younger age at diagnosis. To further investigate the risk and the age-relation of the incidence of second primary colorectal cancer, we considered 9,389 first colon and rectal cancers registered in the Vaud Cancer Registry, Switzerland, between 1974 and 2008, and followed-up to the end of 2008 for a total of 44,113 person-years. There were 136 second colorectal cancers versus 90.5 expected, corresponding to a standardized incidence ratio (SIR) of 1.5 (95% confidence interval, CI, 1.3-1.8). The SIRs were not heterogeneous between men and women, and in strata of calendar year at diagnosis, duration of follow-up, and subsite. However, the SIR was 7.5 (95% CI 4.2-12.4) for subjects diagnosed below age 50 and declined thereafter to reach 1.0 (95% CI 0.6-1.6) at age 80 or over. Consequently, the incidence of second primary colorectal cancer was stable, and exceedingly high, around 300-400/100,000 between age 30-39 and 70 or over. This age pattern is consistent with the existence of a single mutational event in a population of highly susceptible individuals.

Status Epilepticus Severity Score (STESS): a tool to orient early treatment strategy

BACKGROUND : Status epilepticus (SE) treatment ranges from small benzodiazepine doses to coma induction. For some SE subgroups, it is unclear how the risk of an aggressive therapeutic approach balances with outcome improvement. We recently developed a prognostic score (Status Epilepticus Severity Score, STESS), relying on four outcome predictors (age, history of seizures, seizure type and extent of consciousness impairment), determined before treatment institution. Our aim was to assess whether the score might have a role in the treatment strategy choice. METHODS : This cohort study involved adult patients in three centers. For each patient, the STESS was calculated before primary outcome assessment: survival vs. death at discharge. Its ability to predict survival was estimated through the negative predictive value for mortality (NPV). Stratified odds ratios (OR) for mortality were calculated considering coma induction as exposure; strata were defined by the STESS level. RESULTS : In the observed 154 patients, the STESS had an excellent negative predictive value (0.97). A favorable STESS was highly related to survival (P < 0.001), and to return to baseline clinical condition in survivors (P < 0.001). The combined Mantel-Haenszel OR for mortality in patients stratified after coma induction and their STESS was 1.5 (95 % CI: 0.59-3.83). CONCLUSION : The STESS reliably identifies SE patients who will survive. Early aggressive treatment could not be routinely warranted in patients with a favorable STESS, who will almost certainly survive their SE episode. A randomized trial using this score would be needed to confirm this hypothesis.

Geological structure, recharge processes and underground drainage of a glacierised karst aquifer system, Tsanfleuron-Sanetsch, Swiss Alps

The relationships between stratigraphic and tectonic setting, recharge processes and underground drainage of the glacierised karst aquifer system `Tsanfleuron-Sanetsch' in the Swiss Alps have been studied by means of various methods, particularly tracer tests (19 injections). The area belongs to the Helvetic nappes and consists of Jurassic to Palaeogene sedimentary rocks. Strata are folded and form a regional anticlinorium. Cretaceous Urgonian limestone constitutes the main karst aquifer, overlain by a retreating glacier in its upper part. Polished limestone surfaces are exposed between the glacier front and the end moraine of 1855/1860 (Little Ice Age); typical alpine karrenfields can be observed further below. Results show that (1) large parts of the area are drained by the Glarey spring, which is used as a drinking water source, while marginal parts belong to the catchments of other springs; (2) groundwater flow towards the Glarey spring occurs in the main aquifer, parallel to stratification, while flow towards another spring crosses the entire stratigraphic sequence, consisting of about 800 m of marl and limestone, along deep faults that were probably enlarged by mass movements; (3) the variability of glacial meltwater production influences the shape of the tracer breakthrough curves and, consequently, flow and transport in the aquifer.