Rabbit Erythropoiesis in vitro

The erythropoietin (Ep) dose response of erythroid colony-forming units (CFU-e) and erythroid burst-forming units (BFU-e) from rabbit bone were similar to murine erythroid precursor Ep requirements. Bone marrow and peripheral blood contained a continuum of erythroid precursors at differing stages of maturation. The earliest BFU-e were assayed on day 10. CFU-e were observed in bone marrow, but not in peripheral blood. The most mature erythroid precursors observed in peripheral blood were intermediate BFU-e, assayed on day 5. A linear relationship exists between the number of nucleated bone marrow cells plated and the number of 3 day colonies and 10 day bursts observed. The 10 day bursts were composed of erythroid cells at all stages of maturation and these cells contained normal adult hemoglobins. The methylcellulose assay was then used to characterize the hemopoietic tissue in ossicles induced by demineralized allogeneic bone matrix (DBM) and to investigate the mechanisms of action of burst-promoting activity (BPA). DBM, implanted in muscle, induces the formation of an ossicle within which hemopoietic tissue develops. Analyses of ossicle marrow in vitro demonstrated the presence of committed hemopoietic precursors; colony-forming units in culture (CFU-c), CFU-e and BFU-e by 6 weeks postimplantation. The time courses of colony and burst formation by erythroid precursors in ossicle and femoral marrow were similar. Induction of hemolytic anemia by phenylhydrazine hydrochloride at six weeks post DBM implantation showed that the ossicle marrow was responsive to systemic erythropoietic stimuli The DBM implant is a unique model for studying the development of hemopoietic microenvironments within bone. Rabbit bone marrow conditioned media (BMCM) was found to contain potent erythroid BPA. In order to further characterize the mechanisms of action of BPA and to improve the quantitation or BPA, we studied the effects of BMCM on the number of bursts, cells per burst and 59Fe incorporation into heme. Examination of erythroid precursors at different maturational stages revealed that the sensitivity of erythroid precursors to BPA decreases with maturity. Delayed addition of BMCM to cultures demonstrated a requirement for BPA during the early stages of burst formation. BMCM did not enhance granulocyte/macrophage colony formation. The enhancement of heme synthesis by BMCM was routinely much greater (range, 7- to 109-fold) than the increase in burst number (range, 1- to 2-fold). The latter observation suggested that BPA might increase the size of bursts in addition to augmenting burst number. Simultaneous measurement of cell number and 59Fe incorporation in individual bursts showed a strong correlation between these parameters. In this experiment, the total enhancement of cell number and 59Fe incorporation was 6.6- and 8.0-fold, respectively. These results suggest that a major effect of BMCM BPA is to promote cell division during the early phase of burst formation

Group work and the change of obstacles over time: The influence of learning style and group composition

It is through working in groups that students develop cooperative learning skills and experience. However, group work activity often leads students into a difficult experience, especially for first-year students who are not familiar with group work activities at university. This study explores obstacles faced by first-year students during their group work activities. It investigates whether a group of students with a similar learning style (homogeneous group) experience different obstacles compared to a group of students with a diverse learning style (heterogeneous group). In addition, to identify the difference, if any, between a group formed by a tutor and one where the students form the group themselves, tutor and self-allocated group allocations are explored. This study focuses on obstacles experienced by these students during group work activities. Using a sample of more than 200 students over a period of 3 years, the types and the changes of obstacles in different stages of group life are explored. The findings show that students experience obstacles which can be classified into personal and social, leadership and management, and task-related obstacles. Those obstacles were not static but increased over time. The study also investigates the impact of different methods of forming groups and whether this impacted on obstacles experienced. Overall, different interventions prompted different patterns of obstacle development

Planned delivery to improve postpartum cardiac function in women with preterm pre-eclampsia: the PHOEBE mechanisms of action study within the PHOENIX RCT

Background Women whose pregnancies are affected by hypertensive disorders of pregnancy, in particular preterm pre-eclampsia, are at increased risk of long-term cardiovascular morbidity and mortality. Objectives To investigate the hypothesis that prolongation of a pregnancy affected by preterm pre-eclampsia managed by expectant management compared with planned early delivery would result in worse cardiovascular function 6 months postpartum. Design A randomised controlled trial. Setting 28 maternity hospitals in England and Wales. Participants Women who were eligible for the Pre-eclampsia in HOspital: Early iNductIon or eXpectant management (PHOENIX) study were approached and recruited for the PHOEBE study. The PHOENIX (Pre-eclampsia in HOspital: Early iNductIon or eXpectant management) study was a parallel-group, non-masked, multicentre, randomised controlled trial that was carried out in 46 maternity units across England and Wales. This study compared planned early delivery with expectant management (usual care) with individual randomisation in women with late preterm pre-eclampsia who were 34 weeks’ gestation to less than 37 weeks’ gestation and having a singleton or dichorionic diamniotic twin pregnancy. Interventions Postpartum follow-up included medical history, blood pressure assessment and echocardiography. All women had blood sampling performed on at least two time points from recruitment to the 6-month follow-up for assessment of cardiac necrosis markers. Main outcome measures Primary outcome was a composite of systolic and/or diastolic dysfunction (originally by 2009 guidelines then updated by 2016 guidelines, with an amended definition of diastolic dysfunction). Analyses were by intention to treat, together with a per-protocol analysis for the primary and secondary outcomes. Results Between 27 April 2016 and 30 November 2018, 623 women were found to be eligible, of whom 420 (67%) were recruited across 28 maternity units in England and Wales. A total of 133 women were allocated to planned delivery, 137 women were allocated to expectant management and a further 150 received non-randomised expectant management within usual care. The mean time from enrolment to delivery was 2.5 (standard deviation 1.9) days in the planned delivery group compared with 6.8 (standard deviation 5.3) days in the expectant management group. There were no differences in the primary outcome between women in the planned delivery group and those in the expectant management group using either the 2009 (risk ratio 1.06, 95% confidence interval 0.80 to 1.40) or the 2016 definition (risk ratio 0.78, 95% confidence interval 0.33 to 1.86). Overall, 10% (31/321) of women had a left ventricular ejection fraction < 55% and 71% of the cohort remained hypertensive at 6 months postpartum. No differences were observed between groups in cardiorespiratory outcomes prior to discharge from hospital or in systolic or diastolic blood pressure measurements. Variables associated with the primary outcome (2009 definition) at 6 months postpartum were maternal body mass index (adjusted odds ratio 1.33 per 5 kg/m2, 95% confidence interval 1.12 to 1.59 per 5 kg/m2) and maternal age (adjusted odds ratio 2.16, 95% confidence interval 1.44 to 3.22 per 10 years). Limitations include changing definitions regarding systolic and/or diastolic dysfunction. Conclusions Preterm pre-eclampsia results in persistence of hypertension in the majority of women with late preterm pre-eclampsia at 6 months postpartum and systolic dysfunction in 10%. Pre-eclampsia should not be considered a self-limiting disease of pregnancy alone. Future work Interventions aimed at reducing cardiovascular dysfunction. Trial registration Current Controlled Trials ISRCTN01879376. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 12. See the NIHR Journals Library website for further project information

Stresses in silos: Comparison between theoretical models and new experiments

We present precise and reproducible mean pressure measurements at the bottom of a cylindrical granular column. If a constant overload is added, the pressure is linear in overload and nonmonotonic in the column height. The results are {\em quantitatively} consistent with a local, linear relation between stress components, as was recently proposed by some of us. They contradict the simplest classical (Janssen) approximation, and may pose a rather severe test of competing models.Comment: 4 pages, 2 figures, final version to appear in Phys. Rev. Let

Stress in frictionless granular material: Adaptive Network Simulations

We present a minimalistic approach to simulations of force transmission through granular systems. We start from a configuration containing cohesive (tensile) contact forces and use an adaptive procedure to find the stable configuration with no tensile contact forces. The procedure works by sequentially removing and adding individual contacts between adjacent beads, while the bead positions are not modified. In a series of two-dimensional realizations, the resulting force networks are shown to satisfy a linear constraint among the three components of average stress, as anticipated by recent theories. The coefficients in the linear constraint remain nearly constant for a range of shear loadings up to about .6 of the normal loading. The spatial distribution of contact forces shows strong concentration along ``force chains". The probability of contact forces of magnitude f shows an exponential falloff with f. The response to a local perturbing force is concentrated along two characteristic rays directed downward and laterally.Comment: 8 pages, 8 figure

Stress Propagation through Frictionless Granular Material

We examine the network of forces to be expected in a static assembly of hard, frictionless spherical beads of random sizes, such as a colloidal glass. Such an assembly is minimally connected: the ratio of constraint equations to contact forces approaches unity for a large assembly. However, the bead positions in a finite subregion of the assembly are underdetermined. Thus to maintain equilibrium, half of the exterior contact forces are determined by the other half. We argue that the transmission of force may be regarded as unidirectional, in contrast to the transmission of force in an elastic material. Specializing to sequentially deposited beads, we show that forces on a given buried bead can be uniquely specified in terms of forces involving more recently added beads. We derive equations for the transmission of stress averaged over scales much larger than a single bead. This derivation requires the Ansatz that statistical fluctuations of the forces are independent of fluctuations of the contact geometry. Under this Ansatz, the $d(d+1)/2$-component stress field can be expressed in terms of a d-component vector field. The procedure may be generalized to non-sequential packings. In two dimensions, the stress propagates according to a wave equation, as postulated in recent work elsewhere. We demonstrate similar wave-like propagation in higher dimensions, assuming that the packing geometry has uniaxial symmetry. In macroscopic granular materials we argue that our approach may be useful even though grains have friction and are not packed sequentially.=17Comment: 15 pages, 4 figures, revised vertion for Phys. Rev.

Jamming and Stress Propagation in Granular Materials

We have recently developed some simple continuum models of static granular media which display "fragile" behaviour: they predict that the medium is unable to support certain types of infinitesimal load (which we call "incompatible" loads) without plastic rearrangement. We argue that a fragile description may be appropriate when the mechanical integrity of the medium arises adaptively, in response to a load, through an internal jamming process. We hypothesize that a network of force chains (or "granular skeleton") evolves until it can just support the applied load, at which point it comes to rest; it then remains intact so long as no incompatible load is applied. Our fragile models exhibits unusual mechanical responses involving hyperbolic equations for stress propagation along fixed characteristics through the material. These characteristics represent force chains; their arrangement expressly depends on the construction history. Thus, for example, we predict a large difference in the stress pattern beneath two conical piles of sand, one poured from a point source and one created by sieving.Comment: 40 pages, 9 figures, LATE

Characterization of disease course and remission in early seropositive rheumatoid arthritis: results from the TACERA longitudinal cohort study

Background: To characterise disease course and remission in a longitudinal observational study of newly diagnosed, initially treatment-naïve patients with seropositive rheumatoid arthritis (RA). Methods: Patients with early untreated seropositive RA were recruited from 28 UK centres. Multiple clinical and laboratory measures were collected every 3 months for up to 18 months. Disease activity was measured using the 28-joint Disease Activity Score with C-reactive protein (DAS28-CRP) and Simplified Disease Activity Index (SDAI). Logistic regression models examined clinical predictors of 6-month remission and latent class mixed models characterised disease course. Results: We enrolled 275 patients of whom 267 met full eligibility and provided baseline data. According to SDAI definition, 24.3% attained 6-month remission. Lower baseline Health Assessment Questionnaire (HAQ) and SDAI predicted 6-month remission (p = 0.013 and 0.011). Alcohol intake and baseline prescribing of methotrexate with a second disease-modifying antirheumatic drug (DMARD; vs monotherapy without glucocorticoids) were also predictive. Three distinct SDAI trajectory subpopulations emerged; corresponding to an inadequate responder group (6.5%), and higher and lower baseline activity responder groups (22.4% and 71.1%). Baseline HAQ and Short Form-36 Health Survey – Mental Component Score (SF-36 MCS) distinguished these groups. In addition, a number of baseline clinical predictors correlated with disease activity severity within subpopulations. Beneficial effects of alcohol intake were found across subpopulations. Conclusion: Three distinct disease trajectory subpopulations were identified. Differential effects of functional and mental well-being, alcohol consumption, and baseline RA medication prescribing on disease activity severity were found across subpopulations. Heterogeneity across trajectories cannot be fully explained by baseline clinical predictors. We hypothesise that biological markers collected early in disease course (within 6 months) may help patient management and better targeting of existing and novel therapies