Centenarians today: New insights on selection from the 5-COOP study

The number of oldest old grew tremendously over the past few decades. However, recent studies have disclosed that the pace of increase strongly varies among countries. The present study aims to specify the level of mortality selection among the nonagenarians and centenarians living currently in five low mortality countries, Denmark, France, Japan, Switzerland, and Sweden, part of the 5-Country Oldest Old Project (5-COOP). All data come from the Human Mortality Database, except for the number of centenarians living in Japan. We disclosed three levels of mortality selection, a milder level in Japan, a stronger level in Denmark and Sweden and an intermediary level in France and Switzerland. These divergences offer an opportunity to study the existence of a trade-off between the level of mortality selection and the functional health status of the oldest old survivors which will be seized by the 5-COOP project. © 2010 Jean-Marie Robine et al.published_or_final_versio

Optimality of mutation and selection in germinal centers

The population dynamics theory of B cells in a typical germinal center could play an important role in revealing how affinity maturation is achieved. However, the existing models encountered some conflicts with experiments. To resolve these conflicts, we present a coarse-grained model to calculate the B cell population development in affinity maturation, which allows a comprehensive analysis of its parameter space to look for optimal values of mutation rate, selection strength, and initial antibody-antigen binding level that maximize the affinity improvement. With these optimized parameters, the model is compatible with the experimental observations such as the ~100-fold affinity improvements, the number of mutations, the hypermutation rate, and the "all or none" phenomenon. Moreover, we study the reasons behind the optimal parameters. The optimal mutation rate, in agreement with the hypermutation rate in vivo, results from a tradeoff between accumulating enough beneficial mutations and avoiding too many deleterious or lethal mutations. The optimal selection strength evolves as a balance between the need for affinity improvement and the requirement to pass the population bottleneck. These findings point to the conclusion that germinal centers have been optimized by evolution to generate strong affinity antibodies effectively and rapidly. In addition, we study the enhancement of affinity improvement due to B cell migration between germinal centers. These results could enhance our understandings to the functions of germinal centers.Comment: 5 figures in main text, and 4 figures in Supplementary Informatio

Projections of global warming-induced impacts on winter storm losses in the German private household sector

We present projections of winter storm-induced insured losses in the German residential building sector for the 21st century. With this aim, two structurally most independent downscaling methods and one hybrid downscaling method are applied to a 3-member ensemble of ECHAM5/MPI-OM1 A1B scenario simulations. One method uses dynamical downscaling of intense winter storm events in the global model, and a transfer function to relate regional wind speeds to losses. The second method is based on a reshuffling of present day weather situations and sequences taking into account the change of their frequencies according to the linear temperature trends of the global runs. The third method uses statistical-dynamical downscaling, considering frequency changes of the occurrence of storm-prone weather patterns, and translation into loss by using empirical statistical distributions. The A1B scenario ensemble was downscaled by all three methods until 2070, and by the (statistical-) dynamical methods until 2100. Furthermore, all methods assume a constant statistical relationship between meteorology and insured losses and no developments other than climate change, such as in constructions or claims management. The study utilizes data provided by the German Insurance Association encompassing 24 years and with district-scale resolution. Compared to 1971–2000, the downscaling methods indicate an increase of 10-year return values (i.e. loss ratios per return period) of 6–35 % for 2011–2040, of 20–30 % for 2041–2070, and of 40–55 % for 2071–2100, respectively. Convolving various sources of uncertainty in one confidence statement (data-, loss model-, storm realization-, and Pareto fit-uncertainty), the return-level confidence interval for a return period of 15 years expands by more than a factor of two. Finally, we suggest how practitioners can deal with alternative scenarios or possible natural excursions of observed losses

Fibroma of tendon sheath located within the ankle joint capsule

We report a very rare case of fibroma of the tendon sheath arising from the anteromedial ankle joint capsule, with no apparent connection to any tendon in the area, found in a 58-year-old patient complaining of progressive local swelling. This uncommon tumor has its usual localization in tendon sheaths, is extremely rare in joint capsules, and has never been described in this location previously. MRI showed nonuniform low signal intensity in T1- and T2-weighted images and high intensity in STIR images. The mass was completely excised by open surgery. Histopathological analysis later confirmed the diagnosis of a fibroma of the tendon sheath

Does Preexisting Antiplatelet Treatment Influence Postthrombolysis Intracranial Hemorrhage in Community‐treated Ischemic Stroke Patients? An Observational Study

Objectives Intracranial hemorrhage ( ICH ) after acute stroke thrombolysis is associated with poor outcomes. Previous investigations of the relationship between preexisting antiplatelet use and the safety of intravenous ( IV ) thrombolysis have been limited by low event rates. The objective of this study was to determine whether preexisting antiplatelet therapy increased the risk of ICH following acute stroke thrombolysis. The primary hypothesis was that antiplatelet use would not be associated with radiographic evidence of ICH after controlling for relevant confounders. Methods Consecutive cases of thrombolysis patients treated in the emergency department (ED) were identified using multiple methods. Retrospective data were collected from four hospitals from 1996 to 2004 and 24 other hospitals from 2007 to 2010 as part of a cluster‐randomized trial. The same chart abstraction tool was used during both time periods, and data were subjected to numerous quality control checks. Hemorrhages were classified using a prespecified methodology: ICH was defined as presence of hemorrhage in radiographic interpretations of follow‐up imaging (primary outcome). Symptomatic ICH ( sICH ) was defined as radiographic ICH with associated clinical worsening. A multivariable logistic regression model was constructed to adjust for clinical factors previously identified to be related to postthrombolysis ICH. Sensitivity analyses were conducted where the unadjusted and adjusted results from this study were combined with those of previously published external studies on this topic via meta‐analytic techniques. Results There were 830 patients included, with 47% having documented preexisting antiplatelet treatment. The mean (± standard deviation [SD]) age was 69 (±15) years, and the cohort was 53% male. The unadjusted proportion of patients with any ICH was 15.1% without antiplatelet use and 19.3% with antiplatelet use (absolute risk difference = 4.2%, 95% confidence interval [CI] = −1.2% to 9.6%); for sICH this was 6.1% without antiplatelet use and 9% with antiplatelet use (absolute risk difference = 3.1%, 95% CI = −1% to 6.7%). After adjusting for confounders, antiplatelet use was not significantly associated with radiographic ICH (odds ratio [OR] = 1.1, 95% CI = 0.8 to 1.7) or sICH (OR = 1.3, 95% CI = 0.7 to 2.2). In patients 81 years and older, there was a higher risk of radiographic ICH (absolute risk difference = 11.9%, 95% CI = 0.1% to 23.6%). The meta‐analyses combined the findings of this investigation with previous similar work and found increased unadjusted risks of radiographic ICH (absolute risk difference = 4.9%, 95% CI = 0.7% to 9%) and sICH (absolute risk difference = 4%, 95% CI = 2.3% to 5.6%). The meta‐analytic adjusted OR of sICH for antiplatelet use was 1.6 (95% CI = 1.1 to 2.4). Conclusions The authors did not find that preexisting antiplatelet use was associated with postthrombolysis ICH or sICH in this cohort of community treated patients. Preexisting tobacco use, younger age, and lower severity were associated with lower odds of sICH . The meta‐analyses demonstrated small, but statistically significant increases in the absolute risk of radiographic ICH and sICH , along with increased odds of sICH in patients with preexisting antiplatelet use. Resumen ¿Influye el Tratamiento Antiagregante Previo en la Hemorragia Intracraneal tras la Trombolisis en los Pacientes con Ictus Isquémicos Tratados en la Comunidad? Un Estudio Observacional Objetivos La hemorragia intracraneal ( HIC ) tras la trombolisis de un ictus agudo se asocia con malos resultados. Los estudios previos de la relación entre el uso de antiagregantes y la seguridad de la trombolisis intravenosa ( IV ) han estado limitados por los porcentajes bajos de sucesos. El objetivo de este estudio fue determinar si el tratamiento antiagregante previo está asociado con la evidencia radiológica de HIC tras el control por los factores de confusión relevantes. Metodología Se identificaron los casos consecutivos de pacientes tratados con trombolisis en el SU de múltiples formas. Se recogieron los datos de forma retrospectiva de cuatro hospitales de 1996 a 2004 y de 24 hospitales distintos de 2007 a 2010 como parte de un ensayo clínico aleatorizado en racimos. Se utilizó la misma tabla resumen de historia clínica durante ambos periodos de tiempo y los datos fueron sometidos a numerosos controles de calidad. Las hemorragias se clasificaron siguiendo una metodología preestablecida: la HIC se definió como la presencia de hemorragia en las interpretaciones radiológicas de las imágenes de seguimiento (resultado primario); y la HIC sintomática ( HIC s) se definió como la HIC radiológica asociada con un empeoramiento clínico. Se construyó un modelo multivariable de regresión logística para ajustar los factores clínicos previamente identificados como relacionados con un la HIC tras la trombolisis. Los análisis de sensibilidad se realizaron mediante técnicas de metanálisis y se combinaron los resultados ajustados y no ajustados de esta investigación con los estudios externos previamente publicados en este tema. Resultados Se incluyeron 830 pacientes, de los cuales el 47% tenía documentado tratamiento antiagregante previo. La media de edad fue de 69 años, y el 53% eran varones. La proporción no ajustada de pacientes con cualquier tipo de HIC fue del 15,1% sin toma de antiagregante y del 19,3% con la toma de antiagregante (diferencia del riesgo absoluto 4,2%, IC 95% = −1,2% a 9,6%); y para las HIC s fue del 6,1% sin toma de antiagregantes y del 9% con la toma de antiagregantes (diferencia absoluta del riesgo 3,1%, IC 95% = −1% a 6,7%). Tras ajustar por los factores de confusión, la toma de antiagregantes no se asoció de forma significativa con la HIC radiológica ( OR 1,1, IC 95% = 0,8 a 1,7]) o HIC s ( OR 1,3, IC 95% = 0,7 a 2,2). En los pacientes de 81 años o más, hubo mayor riesgo de HIC radiológica (diferencia de riesgo absoluta 11,9%, IC 95% = 0,1% a 23,6%). El metanálisis que combinó los hallazgos de esta investigación con los trabajos similares previos encontró un riesgo no ajustado incrementado para la HIC radiológica (diferencia absoluta del riesgo 4,9%, IC 95% = 0,7% a 9%) y de HIC s (diferencia absoluta del riesgo 4%, IC 95% = 2,3% a 5,6%). La odds ratio ajustada del metanálisis de HIC s para los pacientes con tratamiento de antigregantes fue de 1,6 ( IC 95% = 1,1 a 2,4). Conclusiones Los autores no encontraron que la toma previa de antigregantes se asocie con la HIC o la HIC s tras la trombolisis en esta cohorte de pacientes tratados en la comunidad. El consumo previo de tabaco, la edad más joven y la menor gravedad se asociaron con odds ratio menores de HIC s. El metanálisis demostró un incremento bajo, aunque estadísticamente significativo, de riesgo absoluto de HIC radiológica o de HIC s, con una odds ratio aumentada de HIC s en los pacientes con toma previa de antiagregantes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96759/1/acem12077.pd

Inheritance of an Epigenetic Mark: The CpG DNA Methyltransferase 1 Is Required for De Novo Establishment of a Complex Pattern of Non-CpG Methylation

Site-specific methylation of cytosines is a key epigenetic mark of vertebrate DNA. While a majority of the methylated residues are in the symmetrical (meC)pG:Gp(meC) configuration, a smaller, but significant fraction is found in the CpA, CpT and CpC asymmetric (non-CpG) dinucleotides. CpG methylation is reproducibly maintained by the activity of the DNA methyltransferase 1 (Dnmt1) on the newly replicated hemimethylated substrates (meC)pG:GpC. On the other hand, establishment and hereditary maintenance of non-CpG methylation patterns have not been analyzed in detail. We previously reported the occurrence of site- and allele-specific methylation at both CpG and non-CpG sites. Here we characterize a hereditary complex of non-CpG methylation, with the transgenerational maintenance of three distinct profiles in a constant ratio, associated with extensive CpG methylation. These observations raised the question of the signal leading to the maintenance of the pattern of asymmetric methylation. The complete non-CpG pattern was reinstated at each generation in spite of the fact that the majority of the sperm genomes contained either none or only one methylated non-CpG site. This observation led us to the hypothesis that the stable CpG patterns might act as blueprints for the maintenance of non-CpG DNA methylation. As predicted, non-CpG DNA methylation profiles were abrogated in a mutant lacking Dnmt1, the enzymes responsible for CpG methylation, but not in mutants defective for either Dnmt3a or Dnmt2

Observation of a J^PC = 1-+ exotic resonance in diffractive dissociation of 190 GeV/c pi- into pi- pi- pi+

The COMPASS experiment at the CERN SPS has studied the diffractive dissociation of negative pions into the pi- pi- pi+ final state using a 190 GeV/c pion beam hitting a lead target. A partial wave analysis has been performed on a sample of 420000 events taken at values of the squared 4-momentum transfer t' between 0.1 and 1 GeV^2/c^2. The well-known resonances a1(1260), a2(1320), and pi2(1670) are clearly observed. In addition, the data show a significant natural parity exchange production of a resonance with spin-exotic quantum numbers J^PC = 1-+ at 1.66 GeV/c^2 decaying to rho pi. The resonant nature of this wave is evident from the mass-dependent phase differences to the J^PC = 2-+ and 1++ waves. From a mass-dependent fit a resonance mass of 1660 +- 10+0-64 MeV/c^2 and a width of 269+-21+42-64 MeV/c^2 is deduced.Comment: 7 page, 3 figures; version 2 gives some more details, data unchanged; version 3 updated authors, text shortened, data unchange

Six sequence variants on chromosome 9p21.3 are associated with a positive family history of myocardial infarction: a multicenter registry

<p>Abstract</p> <p>Background</p> <p>Recent genome-wide association studies have identified several genetic loci linked to coronary artery disease (CAD) and myocardial infarction (MI). The 9p21.3 locus was verified by numerous replication studies to be the first common locus for CAD and MI. In the present study, we investigated whether six single nucleotide polymorphisms (SNP) rs1333049, rs1333040, rs10757274, rs2383206, rs10757278, and rs2383207 representing the 9p21.3 locus were associated with the incidence of an acute MI in patients with the main focus on the familial aggregation of the disease.</p> <p>Methods</p> <p>The overall cohort consisted of 976 unrelated male patients presenting with an acute coronary syndrome (ACS) with ST-elevated (STEMI) as well as non-ST-elevated myocardial infarction (NSTEMI). Genotyping data of the investigated SNPs were generated and statistically analyzed in comparison to previously published findings of matchable control cohorts.</p> <p>Results</p> <p>Statistical evaluation confirmed a highly significant association of all analyzed SNP's with the occurrence of MI (p < 0.0001; OR: 1.621-2.039). When only MI patients with a positive family disposition were comprised in the analysis a much stronger association of the accordant risk alleles with incident disease was found with odds ratios up to 2.769.</p> <p>Conclusions</p> <p>The findings in the present study confirmed a strong association of the 9p21.3 locus with MI particularly in patients with a positive family history thereby, emphasizing the pathogenic relevance of this locus as a common genetic cardiovascular risk factor.</p

Assessing the Role of CD103 in Immunity to an Intestinal Helminth Parasite

In the intestine, the integrin CD103 is expressed on a subset of T regulatory (T(reg)) cells and a population of dendritic cells (DCs) that produce retinoic acid and promote immune homeostasis. However, the role of CD103 during intestinal helminth infection has not been tested.We demonstrate that CD103 is dispensable for the development of protective immunity to the helminth parasite Trichuris muris. While we observed an increase in the frequency of CD103(+) DCs in the lamina propria (LP) following acute high-dose infection with Trichuris, lack of CD103 had no effect on the frequency of CD11c(+) DCs in the LP or mesenteric lymph nodes (mLN). CD103-deficient (CD103(-/-)) mice develop a slightly increased and earlier T cell response but resolve infection with similar kinetics to control mice. Similarly, low-dose chronic infection of CD103(-/-) mice with Trichuris resulted in no significant difference in immunity or parasite burden. Absence of CD103 also had no effect on the frequency of CD4(+)CD25(+)Foxp3(+) T(reg) cells in the mLN or LP.These results suggest that CD103 is dispensable for intestinal immunity during helminth infection. Furthermore, lack of CD103 had no effect on DC or T(reg) recruitment or retention within the large intestine