Long-term follow-up of cognitive function and activities of daily living in older people: a feasibility study in the PROSPER cohort

<p>Background: The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) considered the benefits of pravastatin therapy and provided insights into cognitive decline/disability in older people but follow-up was short.</p> <p>Methods: We performed a feasibility study of 300 PROSPER recruits, 7 years after the trial finished. The subject’s general practitioner provided basic follow-up data. Telephone contact with participants established cognition/functional level. Relatives of those unsuitable for contact were asked to complete postal questionnaires.</p> <p>Results: Of 300 participants we established 132 were alive, 135 dead and 33 lost to follow-up. Of 132 survivors data were obtained for 78 participants by telephone, 10 participants with GP diagnosis of dementia, and 3 participants whose relative provided information. Therefore cognitive function was determined in 69% of survivors and functional ability in 61%.</p> <p>Conclusions: It was feasible to perform long-term follow-up of cognition/functional ability in the majority of survivors from a large randomised controlled trial.</p&gt

The V_H gene repertoire of splenic B cells and somatic hypermutation in systemic lupus erythematosus

In systemic lupus erythematosus (SLE) it has been hypothesized that self-reactive B cells arise from virgin B cells that express low-affinity, nonpathogenic germline V genes that are cross-reactive for self and microbial antigens, which convert to high-affinity autoantibodies via somatic hypermutation. The aim of the present study was to determine whether the V<sub>H</sub> family repertoire and pattern of somatic hypermutation in germinal centre (GC) B cells deviates from normal in SLE. Rearranged immunoglobulin V<sub>H</sub> genes were cloned and sequenced from GCs of a SLE patient's spleen. From these data the GC V gene repertoire and the pattern of somatic mutation during the proliferation of B-cell clones were determined. The results highlighted a bias in V<sub>H</sub>5 gene family usage, previously unreported in SLE, and under-representation of the V<sub>H</sub>1 family, which is expressed in 20–30% of IgM+ B cells of healthy adults and confirmed a defect in negative selection. This is the first study of the splenic GC response in human SLE

Hypothesis exploration with visualization of variance.

BackgroundThe Consortium for Neuropsychiatric Phenomics (CNP) at UCLA was an investigation into the biological bases of traits such as memory and response inhibition phenotypes-to explore whether they are linked to syndromes including ADHD, Bipolar disorder, and Schizophrenia. An aim of the consortium was in moving from traditional categorical approaches for psychiatric syndromes towards more quantitative approaches based on large-scale analysis of the space of human variation. It represented an application of phenomics-wide-scale, systematic study of phenotypes-to neuropsychiatry research.ResultsThis paper reports on a system for exploration of hypotheses in data obtained from the LA2K, LA3C, and LA5C studies in CNP. ViVA is a system for exploratory data analysis using novel mathematical models and methods for visualization of variance. An example of these methods is called VISOVA, a combination of visualization and analysis of variance, with the flavor of exploration associated with ANOVA in biomedical hypothesis generation. It permits visual identification of phenotype profiles-patterns of values across phenotypes-that characterize groups. Visualization enables screening and refinement of hypotheses about variance structure of sets of phenotypes.ConclusionsThe ViVA system was designed for exploration of neuropsychiatric hypotheses by interdisciplinary teams. Automated visualization in ViVA supports 'natural selection' on a pool of hypotheses, and permits deeper understanding of the statistical architecture of the data. Large-scale perspective of this kind could lead to better neuropsychiatric diagnostics

Interplay between the ionic and electronic density profiles in liquid metal surfaces

First principles molecular dynamics simulations have been performed for the liquid-vapor interfaces of liquid Li, Mg, Al and Si. We analize the oscillatory ionic and valence electronic density profiles obtained, their wavelengths and the mechanisms behind their relative phase-shift.Comment: Accepted for publication in Journal of Chemical Physic

Hemostatic function and progressing ischemic stroke: D-dimer predicts early clinical progression

<p><b>Background and Purpose:</b> Early clinical progression of ischemic stroke is common and is associated with increased risk of death and dependency. We hypothesized that activation of the coagulation system is an important contributor in some cases of deterioration. We aimed to characterize alterations in circulating hemostatic markers in patients with progressing stroke.</p> <p><b>Methods:</b> Consecutive acute ischemic stroke admissions were recruited. Progressing stroke was defined by deterioration in components of the Scandinavian Stroke Scale. Hemostatic markers (coagulation factors VIIc, VIIIc, and IXc, prothrombin fragments 1+2 [F1+2], thrombin-antithrombin complexes [TAT], D- dimer, fibrinogen, von Willebrand factor [vWF] and tissue plasminogen activator) were measured within 24 hours of symptom recognition.</p> <p><b>Results:</b> Fifty-four (25%) of the 219 patients met criteria for progressing stroke. F1+2 (median 1.28 versus 1.06 nmol/L, P=0.01), TAT (5.28 versus 4.07 mug/L, P lt 0.01), D-dimer ( 443 versus 194 ng/mL, P lt 0.001) and vWF (216 versus 198 IU/dL, P lt 0.05) levels were higher in these patients than in stable/improving patients. In logistic regression analysis, with all important clinical and laboratory variables included, only natural log D-dimer (odds ratio [OR]: 1.87; 95% confidence interval [CI]: 1.38 to 2.54; P=0.0001) and mean arterial blood pressure (OR: 1.26 per 10 mm Hg change; 95% CI: 1.05 to 1.51; P=0.01) remained independent predictors of progressing stroke.</p> <p><b>Conclusions:</b> There is evidence of excess thrombin generation and fibrin turnover in patients with progressing ischemic stroke. Measurement of D-dimer levels can identify patients at high risk for stroke progression. Further research is required to determine whether such patients benefit from acute interventions aimed at modifying hemostatic function.</p&gt

Antigen-driven clonal proliferation of B cells within the target tissue of an autoimmune disease: the salivary glands of patients with Sjögren's syndrome

Structures resembling germinal centers are seen in the salivary glands of patients with Sjögren's syndrome, but it is not known whether the microenvironment of these cell clusters is sufficient for the induction of a germinal center response. Therefore, we cloned and sequenced rearranged Ig V genes expressed by B cells isolated from sections of labial salivary gland biopsies from two Sjögren's syndrome patients. Rearranged V genes from B cells within one cell cluster were polyclonal and most had few somatic mutations. Two adjacent clusters from another patient each contained one dominant B cell clone expressing hypermutated V genes. None of the rearranged V genes was found in both clusters, suggesting that cells are unable to migrate out into the surrounding tissue and seed new clusters. The ratios of replacement to silent mutations in the framework and complementarity determining regions suggest antigen selection of high-affinity mutants. These results show that an antigen-driven, germinal center-type B cell response is taking place within the salivary glands of Sjögren's syndrome patients. In view of the recent demonstration of a germinal center response within the rheumatoid synovial membrane and the existence of similar structures in the target tissues of other autoimmune. diseases, we propose that germinal center- type responses can be induced in the nonlymphoid target tissues of a variety of autoimmune diseases

Orbital-Free Molecular Dynamics Simulations of Melting in Na8 and Na20: Melting in Steps

The melting-like transitions of Na8 and Na20 are investigated by ab initio constant energy molecular dynamics simulations, using a variant of the Car-Parrinello method which employs an explicit electronic kinetic energy functional of the density, thus avoiding the use of one-particle orbitals. Several melting indicators are evaluated in order to determine the nature of the various transitions, and compared with other simulations. Both Na8 and Na20 melt over a wide temperature range. For Na8, a transition is observed to begin at approx. 110 K, between a rigid phase and a phase involving isomerizations between the different permutational isomers of the ground state structure. The ``liquid'' phase is completely established at approx. 220 K. For Na20, two transitions are observed: the first, at approx. 110 K, is associated with isomerization transitions between those permutational isomers of the ground state structure which are obtained by interchanging the positions of the surface-like atoms; the second, at approx. 160 K, involves a structural transition from the ground state isomer to a new set of isomers with the surface molten. The cluster is completely ``liquid'' at approx. 220 K.Comment: Revised version, accepted for publication in J. Chem. Phys. The changes include longer simulations for the Na20 microcluster, a more complete comparison to previous theoretical results, and the discussion of some technical details of the method applie

Allosteric p97 inhibitors can overcome resistance to ATP-competitive p97 inhibitors for potential anti-cancer therapy

A major challenge of targeted cancer therapy is the selection for drug‐resistant mutations in tumor cells leading to loss of treatment effectiveness. p97/VCP is a central regulator of protein homeostasis and a promising anti‐cancer target because of its vital role in cell growth and survival. One ATP‐competitive p97 inhibitor, CB‐5083, has entered clinical trials. Selective pressure on HCT116 cells treated with CB‐5083 identified 5 different resistant mutants. Identification of p97 inhibitors with different mechanisms of action would offer the potential to overcome this class of resistance mutations. Our results demonstrate that two CB‐5083 resistant p97 mutants, N660K and T688A, were also resistant to several other ATP‐competitive p97 inhibitors, whereas inhibition by two allosteric p97 inhibitors NMS‐873 and UPCDC‐30245 were unaffected by these mutations. We also established a CB‐5083 resistant cell line that harbors a new p97 double mutation (D649A/T688A). While CB‐5083, NMS‐873, and UPCDC‐30245 all effectively inhibited proliferation of the parental HCT116 cell line, NMS‐873 and UPCDC‐30245 were 30‐fold more potent than CB‐5083 in inhibiting the CB‐5083 resistant D649A/T688A double mutant. Our results suggest that allosteric p97 inhibitors are promising alternatives when resistance to ATP‐competitive p97 inhibitors arises during anti‐cancer treatment