Evidence for somatic selection of natural autoantibodies.

Natural autoantibodies are primarily immunoglobulin M (IgM) antibodies that bind to a variety of self-antigens, including self-IgG. Accounting for a large proportion of the early B cell repertoire, such polyspecific autoantibodies are speculated to contribute to the homeostasis and/or competence of the primary humoral immune system. Recent studies indicate that the leukemia cells from most patients with chronic lymphocytic leukemia (CLL) also express such IgM autoantibodies. Similarly, the leukemia cells from many CLL patients react with murine monoclonal antibodies (mAbs) specific for crossreactive idiotypes (CRIs) associated with human IgM autoantibodies. In particular, leukemic cells frequently react with G6, a mAb specific for an Ig heavy chain (H chain)-associated CRI, and/or with 17.109, a mAb that defines a kappa light chain (L chain)-associated CRI. Generated against IgM rheumatoid factor (RF) paraproteins, G6 and 17.109 each recognize a major CRI that is present in many IgM RF paraproteins. Furthermore, over 90% of the IgM paraproteins found to bear both H and L chain-associated CRIs also are found to have RF activity. Molecular characterization of these CRIs demonstrates that each is a serologic marker for expression of a highly conserved Ig V gene. As such, the frequent production of IgM polyspecific autoantibodies in CLL simply may reflect the frequent use of such highly conserved autoantibody-encoding Ig V genes with little or no somatic mutation. To test this hypothesis, we generated murine transfectomas to pair the 17.109-reactive kappa L chain of SMI, a 17.109/G6-reactive CLL population, with the Ig H chain of SMI or other G6-reactive leukemia cells or tonsillar lymphocytes. Cotransfection of vectors encoding the Ig H and L chains of SMI generated transfectomas that produce IgM kappa RF autoantibodies reactive with human IgG1 and IgG4. In contrast to G6/17.109-reactive IgM kappa RF Waldenstrom's paraproteins, the SMI IgM kappa also reacts with several other self-antigens, including myoglobin, actin, and ssDNA. However, cotransfection of the SMI L chain with a vector encoding any one of 10 different G6-reactive Ig H chains generated transfectomas that produce IgM kappa antibodies without detectable polyspecific autoantibody activity. These results indicate that polyspecific antiself-reactivity of G6/17.019-reactive Ig is dependent on the somatically generated Ig third complementarity determining region. Collectively, these studies imply that selection may be responsible for the frequent expression of polyspecific autoantibodies in CLL and early B cell ontogeny

Evaluation of subcutaneous implantable cardioverter-defibrillator performance in patients with ion channelopathies from the EFFORTLESS cohort and comparison with a meta-analysis of transvenous ICD outcomes

Background: The subcutaneous implantable cardioverter-defibrillator (S-ICD) is an alternative to conventional transvenous ICD (TV-ICD) therapy to reduce lead complications. Objective: To evaluate outcomes in channelopathy vs patients with structural heart disease in the EFFORTLESS-SICD Registry and with a previously reported TV-ICD meta-analysis in channnelopathies. Methods: The EFFORTLESS registry includes 199 patients with channelopathies (Brugada syndrome 83, long QT syndrome 24, idiopathic ventricular fibrillation 78, others 14) and 786 patients with structural heart disease. Results: Channelopathy patients were younger (39 ± 14 years vs 51 ± 17 years; P 200 beats per minute (P = .0002). Annualized appropriate shock, IAS, and complication rates appear to be lower for the S-ICD vs meta-analysis TV-ICD patients, particularly lead complications. Conclusion: EFFORTLESS demonstrates similar S-ICD efficacy and a nonsignificant, lower rate of IAS in channelopathy patients as compared to structural heart disease. Comparable IAS rates were achieved with the device programmed to higher rates for channelopathy patients

Commentary on 'What is the point: will screening mammography save my life?' by Keen and Keen

Commentary on Keen and Keen 'What is the point: will screening mammography save my life?' BMC Medical Informatics and Decision Making, 200

On the elastic moduli of three-dimensional assemblies of spheres: characterization and modeling of fluctuations in the particle displacement and rotation

The elastic moduli of four numerical random isotropic packings of Hertzian spheres are studied. The four samples are assembled with different preparation procedures, two of which aim to reproduce experimental compaction by vibration and lubrication. The mechanical properties of the samples are found to change with the preparation history, and to depend much more on coordination number than on density. Secondly, the fluctuations in the particle displacements from the average strain are analysed, and the way they affect the macroscopic behavior analyzed. It is found that only the average over equally oriented contacts of the relative displacement these fluctuations induce is relevant at the macroscopic scale. This average depends on coordination number, average geometry of the contact network and average contact stiffness. As far as the separate contributions from particle displacements and rotations are concerned, the former is found to counteract the average strain along the contact normal, while the latter do in the tangential plane. Conversely, the tangential components of the center displacements mainly arise to enforce local equilibrium, and have a small, and generally stiffening effect at the macro-scale. Finally, the fluctuations and the shear modulus that result from two approaches available in the literature are estimated numerically. These approaches are both based on the equilibrium of a small-sized representative assembly. The improvement of these estimate with respect to the average strain assumption indicates that the fluctuations relevant to the macroscopic behavior occur with short correlation length.Comment: Submitted to IJS

Standardising definitions for the pre-eclampsia core outcome set: A consensus development study

Objectives To develop consensus definitions for the core outcome set for pre-eclampsia. Study design Potential definitions for individual core outcomes were identified across four formal definition development initiatives, nine national and international guidelines, 12 Cochrane systematic reviews, and 79 randomised trials. Eighty-six definitions were entered into the consensus development meeting. Ten healthcare professionals and three researchers, including six participants who had experience of conducting research in low- and middle-income countries, participated in the consensus development process. The final core outcome set was approved by an international steering group. Results Consensus definitions were developed for all core outcomes. When considering stroke, pulmonary oedema, acute kidney injury, raised liver enzymes, low platelets, birth weight, and neonatal seizures, consensus definitions were developed specifically for low- and middle-income countries because of the limited availability of diagnostic interventions including computerised tomography, chest x-ray, laboratory tests, equipment, and electroencephalogram monitoring. Conclusions Consensus on measurements for the pre-eclampsia core outcome set will help to ensure consistency across future randomised trials and systematic reviews. Such standardization should make research evidence more accessible and facilitate the translation of research into clinical practice

Drop Traffic in Microfluidic Ladder Networks with Fore-Aft Structural Asymmetry

We investigate the dynamics of pairs of drops in microfluidic ladder networks with slanted bypasses, which break the fore-aft structural symmetry. Our analytical results indicate that unlike symmetric ladder networks, structural asymmetry introduced by a single slanted bypass can be used to modulate the relative drop spacing, enabling them to contract, synchronize, expand, or even flip at the ladder exit. Our experiments confirm all these behaviors predicted by theory. Numerical analysis further shows that while ladder networks containing several identical bypasses are limited to nearly linear transformation of input delay between drops, mixed combination of bypasses can cause significant non-linear transformation enabling coding and decoding of input delays.Comment: 4 pages, 5 figure

Confirmation of low genetic diversity and multiple breeding females in a social group of Eurasian badgers from microsatellite and field data

The Eurasian badger ( Meles meles ) is a facultatively social carnivore that shows only rudimentary co-operative behaviour and a poorly defined social hierarchy. Behavioural evidence and limited genetic data have suggested that more than one female may breed in a social group. We combine pregnancy detection by ultrasound and microsatellite locus scores from a well-studied badger population from Wytham Woods, Oxfordshire, UK, to demonstrate that multiple females reproduce within a social group. We found that at least three of seven potential mothers reproduced in a group that contained 11 reproductive age females and nine offspring. Twelve primers showed variability across the species range and only five of these were variable in Wytham. The microsatellites showed a reduced repeat number, a significantly higher number of nonperfect repeats, and moderate heterozygosity levels in Wytham. The high frequency of imperfect repeats and demographic phenomena might be responsible for the reduced levels of variability observed in the badger

Characterization of Tunable Poly-ε-Lysine-Based Hydrogels for Corneal Tissue Engineering

A family of poly-ε-lysine hydrogels can be synthesized by crosslinking with bis-carboxylic acids using carbodiimide chemistry. In addition to creating hydrogels using a simple cast method, a fragmented method is used to introduce increased porosity within the hydrogel structure. Both methods have created tunable characteristics ranging in their mechanical properties, transparency, and water content, which is of interest to corneal tissue engineering and can be tailored to specific cellular needs and applications. With a worldwide shortage of cornea donor tissue available for transplant and limitations including rejection and potential infection, a synthetic material that can be used as a graft, or a partial thickness corneal replacement, would be an advantageous treatment method. These hydrogels can be tuned to have similar mechanical and transparency properties to the human cornea. They also support the attachment and growth of corneal epithelial cells and the integration of corneal stromal cells