The expression of SLAMF7 levels in malignant B cells: a novel therapeutic pathway for patients with CLL

Signalling lymphocyte activation molecule (SLAM) F7 is found on the surface of some immune cells including B-lymphocytes. Its activation leads to the proliferation or differentiation of immune cells. The objectives of the study were to measure SLAMF7 expression levels on B-CLL cells, and to upregulate the expression of SLAMF7 with phorbol myristate acetate (PMA) and Bryostatin. The levels of expression of SLAMF7 receptors of B-CLL cells from patients were measured; using immunofluorescence, flow cytometry, confocal microscopy and reverse transcriptase polymerase chain reaction (RT-PCR). The effects of treatments with PMA and Bryostatin were determined from different patients. Different levels of SLAMF7 expression were found to be associated with B-CLL cells from different patients. PMA treatment of B-CLL cells showed more positive SLAMF7 staining with the majority of the extracted B-CLL cell cases, while less positive results were associated with Bryostatin treatment. The study has shown that both PMA and Bryostatin could upregulate SLAMF7. Successful modulation of SLAMF7 expression may provide a novel target for the treatment of patients with CLL.Keywords: SLAMF7, RT PCR, Elotuzumab, Bryostatin, PM

Lithium isotope evidence for enhanced weathering and erosion during the Paleocene-Eocene Thermal Maximum

The Paleocene-Eocene Thermal Maximum (PETM; ~55.9 Ma) was a geologically rapid warming period associated with carbon release, which caused a marked increase in the hydrological cycle. Here, we use lithium (Li) isotopes to assess the global change in weathering regime, a critical carbon drawdown mechanism, across the PETM. We find a negative Li isotope excursion of ~3‰ in both global seawater (marine carbonates) and in local weathering inputs (detrital shales). This is consistent with a very large delivery of clays to the oceans or a shift in the weathering regime toward higher physical erosion rates and sediment fluxes. Our seawater records are best explained by increases in global erosion rates of ~2× to 3× over 100 ka, combined with model-derived weathering increases of 50 to 60% compared to prewarming values. Such increases in weathering and erosion would have supported enhanced carbon burial, as both carbonate and organic carbon, thereby stabilizing climate

Thin current sheets in the deep geomagnetic tail

The ISEE‐3 magnetic field and plasma electron data from Jan ‐ March 1983 have been searched to study thin current sheets in the deep tail region. 33 events were selected where the spacecraft crossed through the current sheet from lobe to lobe within 15 minutes. The average thickness of the observed current sheets was 2.45R_{E}, and in 24 cases the current sheet was thinner than 3.0R_{E}; 6 very thin current sheets (thickness λ < 0.5R_{E}) were found. The electron data show that the very thin current sheets are associated with considerable temperature anisotropy. On average, the electron gradient current was ∼ 17% of the total current, whereas the current arising from the electron temperature anisotropy varied between 8 – 45% of the total current determined from the lobe field magnitude

The Response of Electron Pitch Angle Distributions to the Upper Limit on Stably Trapped Particles

We use Van Allen Probes electron data during 70 geomagnetic storms to examine the response of equatorial pitch angle distributions (PADs) at L* = 4.0–4.5 to a theoretical upper limit on stably trapped particle fluxes. Of the energies examined, 54 and 108 keV electron PADs isotropize to a previously assumed level within 6 hr of reaching the limit, near-identically across all 70 storms, consistent with rapid pitch angle scattering due to chorus wave interactions. In around 30% of events, 54 keV electrons completely exceed the KP limit, before being quickly subdued. 470 and 749 keV PADs show clear indications of an upper limit, though less aligned with the calculated limit used here. The consistency of an absolute upper limit shown across all events demonstrates the importance of this phenomena in both the limiting effect on electron flux and consistently influencing electron PAD evolution during geomagnetic storms. These results also highlight the need for further investigation, particularly related to the limiting of higher energy electrons

Developing conceptual models for the recognition of coseismic landslides hazard for shallow crustal and megathrust earthquakes in different mountain environments – an example from the Chilean Andes

Landslides represent the most frequent geological hazard in mountainous environments. Most notably, landslides are a major source of fatalities and damage related with strong earthquakes. The main aim of this research is to show through three-dimensional engineer-friendly computer drawings, different mountain environments where coseismic landslides could be generated during shallow crustal and megathrust earthquakes in the Andes of Central Chile. From the comparison of local earthquake-induced landslide inventories in Chile, from the Mw 6.2, shallow crustal Aysén earthquake in 2007 (45.3° S) and the Mw 8.8, megathrust Maule earthquake in 2010 (32.5°S - 38.5°S), with others from abroad, as well as analysis of large, prehistoric landslide inventories proposed as likely induced by seismic activity, we have determined topographic, geomorphological, geological and seismic controlling factors in the occurrence of earthquake-triggered landslides. With these results, we have built four representative geomodels of coseismic landslide geomorphological environments in the Andes of central Chile. Each one represents the possible landslide types to be generated by a shallow crustal earthquake versus those likely to be generated by an megathrust earthquake. Additionally, the associated hazards and suggested mitigation measures are expressed in each scenario. These geomodels are a powerful tool for earthquake-induced landslide hazard assessment

Defining clinically important perioperative blood loss and transfusion for the Standardised Endpoints for Perioperative Medicine (StEP) collaborative: a protocol for a scoping review

INTRODUCTION: 'Standardised Endpoints for Perioperative Medicine' (StEP) is an international collaboration undertaking development of consensus-based consistent definitions for endpoints in perioperative clinical trials. Inconsistency in endpoint definitions can make interpretation of trial results more difficult, especially if conflicting evidence is present. Furthermore, this inconsistency impedes evidence synthesis and meta-analyses. The goals of StEP are to harmonise definitions for clinically meaningful endpoints and specify standards for endpoint reporting in clinical trials. To help inform this endeavour, we aim to conduct a scoping review to systematically characterise the definitions of clinically important endpoints in the existing published literature on perioperative blood loss and transfusion. METHODS AND ANALYSIS: The scoping review will be conducted using the widely adopted framework developed by Arksey and O'Malley, with modifications from Levac. We refined our methods with guidance from research librarians as well as researchers and clinicians with content expertise. The electronic literature search will involve several databases including Medline, PubMed-not-Medline and Embase. Our review has three objectives, namely to (1) identify definitions of significant blood loss and transfusion used in previously published large perioperative randomised trials; (2) identify previously developed consensus-based definitions for significant blood loss and transfusion in perioperative medicine and related fields; and (3) describe the association between different magnitudes of blood loss and transfusion with postoperative outcomes. The multistage review process for each question will involve two reviewers screening abstracts, reading full-text articles and performing data extraction. The abstracted data will be organised and subsequently analysed in an iterative process. ETHICS AND DISSEMINATION: This scoping review of the previously published literature does not require research ethics approval. The results will be used to inform a consensus-based process to develop definitions of clinically important perioperative blood loss and transfusion. The results of the scoping review will be published in a peer-reviewed scientific journal

Decision for reconstructive interventions of the upper limb in individuals with tetraplegia: the effect of treatment characteristics

Objective: To determine the effect of treatment characteristics on the\ud decision for reconstructive interventions for the upper extremities (UE) in\ud subjects with tetraplegia. - \ud Setting: Seven specialized spinal cord injury centres in the Netherlands. - \ud Method: Treatment characteristics for UE reconstructive interventions were\ud determined. Conjoint analysis (CA) was used to determine the contribution\ud and the relative importance of the treatment characteristics on the decision\ud for therapy. Therefore, a number of different treatment scenarios using these\ud characteristics were established. Different pairs of scenarios were presented\ud to subjects who were asked to choose the preferred scenario of each set. - \ud Results: forty nine subjects with tetraplegia with a stable C5, C6 or C7\ud lesion were selected. All treatment characteristics significantly influenced\ud the choice for treatment. Relative importance of treatment characteristics\ud were: intervention type (surgery or surgery with FES implant) 13%, number\ud of operations 15%, in patient rehabilitation period 22%, ambulant\ud rehabilitation period 9%, complication rate 15%, improvement of elbow\ud function 10%, improvement of hand function 15%. In deciding for therapy\ud 40% of the subjects focused on one characteristic. - \ud Conclusion: CA is applicable in Spinal Cord Injury medicine to study the\ud effect of health outcomes and non-health outcomes on the decision for\ud treatment. Non-health outcomes which relate to the intensity of treatment\ud are equally important or even more important than functional outcome in the\ud decision for reconstructive UE surgery in subjects with tetraplegia

Emerging technologies for the management of Type 1 diabetes in pregnancy

Purpose of Review: The purpose of the study is to discuss emerging technologies available in the management of type 1 diabetes in pregnancy. Recent Findings: The latest evidence suggests that continuous glucose monitoring (CGM) should be offered to all women on intensive insulin therapy in early pregnancy. Studies have additionally demonstrated the ability of CGM to help gain insight into specific glucose profiles as they relate to glycaemic targets and pregnancy outcomes. Despite new studies comparing insulin pump therapy to multiple daily injections, its effectiveness in improving glucose and pregnancy outcomes remains unclear. Sensor-integrated insulin delivery (also called artificial pancreas or closed-loop insulin delivery) in pregnancy has been demonstrated to improve time in target and performs well despite the changing insulin demands of pregnancy. Summary: Emerging technologies show promise in the management of type 1 diabetes in pregnancy; however, research must continue to keep up as technology advances. Further research is needed to clarify the role technology can play in optimising glucose control before and during pregnancy as well as to understand which women are candidates for sensor-integrated insulin delivery

Discovery of a polyomavirus in European badgers (Meles meles) and the evolution of host range in the family Polyomaviridae.

Polyomaviruses infect a diverse range of mammalian and avian hosts, and are associated with a variety of symptoms. However, it is unknown whether the viruses are found in all mammalian families and the evolutionary history of the polyomaviruses is still unclear. Here, we report the discovery of a novel polyomavirus in the European badger (Meles meles), which to our knowledge represents the first polyomavirus to be characterized in the family Mustelidae, and within a European carnivoran. Although the virus was discovered serendipitously in the supernatant of a cell culture inoculated with badger material, we subsequently confirmed its presence in wild badgers. The European badger polyomavirus was tentatively named Meles meles polyomavirus 1 (MmelPyV1). The genome is 5187 bp long and encodes proteins typical of polyomaviruses. Phylogenetic analyses including all known polyomavirus genomes consistently group MmelPyV1 with California sea lion polyomavirus 1 across all regions of the genome. Further evolutionary analyses revealed phylogenetic discordance amongst polyomavirus genome regions, possibly arising from evolutionary rate heterogeneity, and a complex association between polyomavirus phylogeny and host taxonomic groups

Network model of immune responses reveals key effectors to single and co-infection dynamics by a respiratory bacterium and a gastrointestinal helminth

Co-infections alter the host immune response but how the systemic and local processes at the site of infection interact is still unclear. The majority of studies on co-infections concentrate on one of the infecting species, an immune function or group of cells and often focus on the initial phase of the infection. Here, we used a combination of experiments and mathematical modelling to investigate the network of immune responses against single and co-infections with the respiratory bacterium Bordetella bronchiseptica and the gastrointestinal helminth Trichostrongylus retortaeformis. Our goal was to identify representative mediators and functions that could capture the essence of the host immune response as a whole, and to assess how their relative contribution dynamically changed over time and between single and co-infected individuals. Network-based discrete dynamic models of single infections were built using current knowledge of bacterial and helminth immunology; the two single infection models were combined into a co-infection model that was then verified by our empirical findings. Simulations showed that a T helper cell mediated antibody and neutrophil response led to phagocytosis and clearance of B. bronchiseptica from the lungs. This was consistent in single and co-infection with no significant delay induced by the helminth. In contrast, T. retortaeformis intensity decreased faster when co-infected with the bacterium. Simulations suggested that the robust recruitment of neutrophils in the co-infection, added to the activation of IgG and eosinophil driven reduction of larvae, which also played an important role in single infection, contributed to this fast clearance. Perturbation analysis of the models, through the knockout of individual nodes (immune cells), identified the cells critical to parasite persistence and clearance both in single and co-infections. Our integrated approach captured the within-host immuno-dynamics of bacteria-helminth infection and identified key components that can be crucial for explaining individual variability between single and co-infections in natural populations