Seventy-five genetic loci influencing the human red blood cell.

Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.

A Prognostic Score to Identify Low-risk Outpatients with Acute Deep Vein Thrombosis in the Lower Limbs.

BACKGROUND: No prior studies have identified which patients with deep vein thrombosis in the lower limbs are at a low risk for adverse events within the first week of therapy. METHODS: We used data from the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) to identify patients at low risk for the composite outcome of pulmonary embolism, major bleeding, or death within the first week. We built a prognostic score and compared it with the decision to treat patients at home. RESULTS: As of December 2013, 15,280 outpatients with deep vein thrombosis had been enrolled. Overall, 5164 patients (34%) were treated at home. Of these, 12 (0.23%) had pulmonary embolism, 8 (0.15%) bled, and 4 (0.08%) died. On multivariable analysis, chronic heart failure, recent immobility, recent bleeding, cancer, renal insufficiency, and abnormal platelet count independently predicted the risk for the composite outcome. Among 11,430 patients (75%) considered to be at low risk, 15 (0.13%) suffered pulmonary embolism, 22 (0.19%) bled, and 8 (0.07%) died. The C-statistic was 0.61 (95% confidence interval [CI], 0.57-0.65) for the decision to treat patients at home and 0.76 (95% CI, 0.72-0.79) for the score (P = .003). Net reclassification improvement was 41% (P < .001). Integrated discrimination improvement was 0.034 for the score and 0.015 for the clinical decision (P < .001). CONCLUSIONS: Using 6 easily available variables, we identified outpatients with deep vein thrombosis at low risk for adverse events within the first week. These data may help to safely treat more patients at home. This score, however, should be validated.

Involvement of 4E-BP1 in the protection induced by HDLs on pancreatic beta cells.

High-density lipoproteins (HDLs) protect pancreatic beta cells against apoptosis. This property might relate to the increased risk to develop diabetes in patients with low HDL blood levels. The mechanisms by which HDLs protect beta cells are poorly characterized however. Here we used a transcriptomic approach to identify genes differentially modulated by HDLs in beta cells subjected to apoptotic stimuli. The transcript encoding 4E-BP1 was up-regulated by serum starvation and HDLs blocked this increase. 4E-BP1 inhibits cap-dependent translation in its non- or hypo-phosphorylated state but it looses this ability when hyper-phosphorylated. At the protein level, 4E-BP1 was also up-regulated in response to starvation and IL1beta and this was blunted by HDLs. While an ectopic increase of 4E-BP1 expression induced beta cell death, silencing 4E-BP1 increase with shRNAs inhibited the apoptotic-inducing capacities of starvation. HDLs can therefore protect beta cells by blocking 4E-BP1 protein expression but this is not the sole protective mechanism activated by HDLs. Indeed, HDLs blocked apoptosis induced by ER stress with no associated decrease in total 4E-BP1 induction. Although, HDLs favored the phosphorylation, and hence the inactivation of 4E-BP1 in these conditions, this appeared not to be required for HDL protection. Our results indicate that HDLs can protect beta cells through modulation of 4E-BP1 depending on the type of stress stimuli.

Chromosome localization of microsatellite markers in the shrews of the Sorex araneus group.

The extremely high rate of karyotypic evolution that characterizes the shrews of the Sorex araneus group makes this group an exceptionally interesting model for population genetics and evolutionary studies. Here, we attempted to map 46 microsatellite markers at the chromosome arm level using flow-sorted chromosomes from three karyotypically different taxa of the Sorex araneus group (S. granarius and the chromosome races Cordon and Novosibirsk of S. araneus). The most likely localizations were provided for 35 markers, among which 25 were each unambiguously mapped to a single locus on the corresponding chromosomes in the three taxa, covering the three sexual chromosomes (XY1Y2) and nine of the 18 autosomal arms of the S. araneus group. The results provide further evidence for a high degree of conservation in genome organization in the S. araneus group despite the presence of numerous Robertsonian rearrangements. These markers can therefore be used to compare the genetic structure among taxa of the S. araneus group at the chromosome level and to study the role of chromosomal rearrangements in the genetic diversification and speciation process of this group.

Batalin-Vilkovisky analysis of covariant and noncovariant actions

The equivalence between the covariant and the noncovariant versions of a constrained system is shown to hold after quantization in the framework of the field-antifield formalism. Our study covers the cases of electromagnetism and Yang-Mills fields and sheds light on some aspects of the Faddeev-Popov method, for both the covariant and noncovariant approaches, which have not been fully clarified in the literature.

Common variants in mendelian kidney disease genes and their association with renal function.

Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

Prognostic relevance of Masaoka and Müller-Hermelink classification in patients with thymic tumors.

BACKGROUND: To compare the prognostic relevance of Masaoka and Müller-Hermelink classifications. METHODS: We treated 71 patients with thymic tumors at our institution between 1980 and 1997. Complete follow-up was achieved in 69 patients (97%) with a mean follow up-time of 8.3 years (range, 9 months to 17 years). RESULTS: Masaoka stage I was found in 31 patients (44.9%), stage II in 17 (24.6%), stage III in 19 (27.6%), and stage IV in 2 (2.9%). The 10-year overall survival rate was 83.5% for stage I, 100% for stage IIa, 58% for stage IIb, 44% for stage III, and 0% for stage IV. The disease-free survival rates were 100%, 70%, 40%, 38%, and 0%, respectively. Histologic classification according to Müller-Hermelink found medullary tumors in 7 patients (10.1%), mixed in 18 (26.1%), organoid in 14 (20.3%), cortical in 11 (15.9%), well-differentiated thymic carcinoma in 14 (20.3%), and endocrine carcinoma in 5 (7.3%), with 10-year overall survival rates of 100%, 75%, 92%, 87.5%, 30%, and 0%, respectively, and 10-year disease-free survival rates of 100%, 100%, 77%, 75%, 37%, and 0%, respectively. Medullary, mixed, and well-differentiated organoid tumors were correlated with stage I and II, and well-differentiated thymic carcinoma and endocrine carcinoma with stage III and IV (p < 0.001). Multivariate analysis showed age, gender, myasthenia gravis, and postoperative adjuvant therapy not to be significant predictors of overall and disease-free survival after complete resection, whereas the Müller-Hermelink and Masaoka classifications were independent significant predictors for overall (p < 0.05) and disease-free survival (p < 0.004; p < 0.0001). CONCLUSIONS: The consideration of staging and histology in thymic tumors has the potential to improve recurrence prediction and patient selection for combined treatment modalities.

Cherenkov mesons as in-medium quark energy loss

We recently showed that a heavy quark moving su ciently fast through a quark-gluon plasma may lose energy by Cherenkov-radiating mesons [1]. Here we review our previous holographic calculation of the energy loss in N = 4 Super Yang-Mills and extend it to longitudinal vector mesons and scalar mesons. We also discuss phenomenological implications for heavy-ion collision experiments. Although the Cherenkov energy loss is an O(1=Nc) effect, a ballpark estimate yields a value of dE/dx for Nc = 3 which is comparable to that of other mechanisms.

Quantitative Assessment of Soil Physical Quality in Northern China Based on S-theory

ABSTRACT Quantitative assessment of soil physical quality is of great importance for eco-environmental pollution and soil quality studies. In this paper, based on the S-theory, data from 16 collection sites in the Haihe River Basin in northern China were used, and the effects of soil particle size distribution and bulk density on three important indices of theS-theory were investigated on a regional scale. The relationships between unsaturated hydraulic conductivityKi at the inflection point and S values (S/hi) were also studied using two different types of fitting equations. The results showed that the polynomial equation was better than the linear equation for describing the relationships between -log Ki and -logS, and -log Kiand -log (S/hi)2; and clay content was the most important factor affecting the soil physical quality index (S). The variation in the S index according to soil clay content was able to be fitted using a double-linear-line approach, with decrease in the S index being much faster for clay content less than 20 %. In contrast, the bulk density index was found to be less important than clay content. The average S index was 0.077, indicating that soil physical quality in the Haihe River Basin was good.

Risk of falls and major bleeds in patients on oral anticoagulation therapy.

BACKGROUND: The risk of falls is the most commonly cited reason for not providing oral anticoagulation, although the risk of bleeding associated with falls on oral anticoagulants is still debated. We aimed to evaluate whether patients on oral anticoagulation with high falls risk have an increased risk of major bleeding. METHODS: We prospectively studied consecutive adult medical patients who were discharged on oral anticoagulants. The outcome was the time to a first major bleed within a 12-month follow-up period adjusted for age, sex, alcohol abuse, number of drugs, concomitant treatment with antiplatelet agents, and history of stroke or transient ischemic attack. RESULTS: Among the 515 enrolled patients, 35 patients had a first major bleed during follow-up (incidence rate: 7.5 per 100 patient-years). Overall, 308 patients (59.8%) were at high risk of falls, and these patients had a nonsignificantly higher crude incidence rate of major bleeding than patients at low risk of falls (8.0 vs 6.8 per 100 patient-years, P=.64). In multivariate analysis, a high falls risk was not statistically significantly associated with the risk of a major bleed (hazard ratio 1.09; 95% confidence interval, 0.54-2.21). Overall, only 3 major bleeds occurred directly after a fall (incidence rate: 0.6 per 100 patient-years). CONCLUSIONS: In this prospective cohort, patients on oral anticoagulants at high risk of falls did not have a significantly increased risk of major bleeds. These findings suggest that being at risk of falls is not a valid reason to avoid oral anticoagulants in medical patients.

Riesenzellarteriitis : Ätiologische Erkenntnisse und diagnostische Herausforderung für den Pathologen [Giant cell arteritis : Etiological knowledge and diagnostic challenge for pathologists].

Giant cell arteritis is a potentially systemic disease of medium-sized and large caliber arteries, showing a preferential manifestation in the extracranial branches of the carotid artery. The diagnosis is oriented to clinical and histomorphological criteria which will be critically reviewed. Particular emphasis is placed on the differentiation from normal aging processes and from healing stages under steroid therapy. In addition, the advances in our understanding of the disease pathomechanism during the last 10 years will be briefly presented as the basis for the hitherto empiric steroid treatment.