The adenomatous polyposis coli protein unambiguously localizes to microtubule plus ends and is involved in establishing parallel arrays of microtubule bundles in highly polarized epithelial cells

Loss of full-length adenomatous polyposis coli (APC) protein correlates with the development of colon cancers in familial and sporadic cases. In addition to its role in regulating β-catenin levels in the Wnt signaling pathway, the APC protein is implicated in regulating cytoskeletal organization. APC stabilizes microtubules in vivo and in vitro, and this may play a role in cell migration (Näthke, I.S., C.L. Adams, P. Polakis, J.H. Sellin, and W.J. Nelson. 1996. J. Cell Biol. 134:165–179; Mimori-Kiyosue, Y., N. Shiina, and S. Tsukita. 2000. J. Cell Biol. 148:505–517; Zumbrunn, J., K. Inoshita, A.A. Hyman, and I.S. Näthke. 2001. Curr. Biol. 11:44–49) and in the attachment of microtubules to kinetochores during mitosis (Fodde, R., J. Kuipers, C. Rosenberg, R. Smits, M. Kielman, C. Gaspar, J.H. van Es, C. Breukel, J. Wiegant, R.H. Giles, and H. Clevers. 2001. Nat. Cell Biol. 3:433–438; Kaplan, K.B., A. Burds, J.R. Swedlow, S.S. Bekir, P.K. Sorger, and I.S. Näthke. 2001. Nat. Cell Biol. 3:429–432). The localization of endogenous APC protein is complex: actin- and microtubule-dependent pools of APC have been identified in cultured cells (Näthke et al., 1996; Mimori-Kiyosue et al., 2000; Reinacher-Schick, A., and B.M. Gumbiner. 2001. J. Cell Biol. 152:491–502; Rosin-Arbesfeld, R., G. Ihrke, and M. Bienz. 2001. EMBO J. 20:5929–5939). However, the localization of APC in tissues has not been identified at high resolution. Here, we show that in fully polarized epithelial cells from the inner ear, endogenous APC protein associates with the plus ends of microtubules located at the basal plasma membrane. Consistent with a role for APC in supporting the cytoskeletal organization of epithelial cells in vivo, the number of microtubules is significantly reduced in apico-basal arrays of microtubule bundles isolated from mice heterozygous for APC

Functional status in ICU survivors and out of hospital outcomes: a cohort study

OBJECTIVES: Functional status at hospital discharge may be a risk factor for adverse events among survivors of critical illness. We sought to examine the association between functional status at hospital discharge in survivors of critical care and risk of 90-day all-cause mortality after hospital discharge. DESIGN: Single-center retrospective cohort study. SETTING: Academic Medical Center. PATIENTS: Ten thousand three hundred forty-three adults who received critical care from 1997 to 2011 and survived hospitalization. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The exposure of interest was functional status determined at hospital discharge by a licensed physical therapist and rated based on qualitative categories adapted from the Functional Independence Measure. The main outcome was 90-day post hospital discharge all-cause mortality. A categorical risk-prediction score was derived and validated based on a logistic regression model of the function grades for each assessment. In an adjusted logistic regression model, the lowest quartile of functional status at hospital discharge was associated with an increased odds of 90-day postdischarge mortality compared with patients with independent functional status (odds ratio, 7.63 [95% CI, 3.83-15.22; p < 0.001]). In patients who had at least 7 days of physical therapy treatment prior to hospital discharge (n = 2,293), the adjusted odds of 90-day postdischarge mortality in patients with marked improvement in functional status at discharge was 64% less than patients with no change in functional status (odds ratio, 0.36 [95% CI, 0.24-0.53]; p < 0.001). CONCLUSIONS: Lower functional status at hospital discharge in survivors of critical illness is associated with increased postdischarge mortality. Furthermore, patients whose functional status improves before discharge have decreased odds of postdischarge mortality.L30 TR001257 - NCATS NIH HH

Matter-positronium interaction: An exact diagonalization study of the He atom - positronium system

The many-body system comprising a He nucleus, three electrons, and a positron has been studied using the exact diagonalization technique. The purpose has been to clarify to which extent the system can be considered as a distinguishable positronium (Ps) atom interacting with a He atom and, thereby, to pave the way to a practical atomistic modeling of Ps states and annihilation in matter. The maximum value of the distance between the positron and the nucleus is constrained and the Ps atom at different distances from the nucleus is identified from the electron and positron densities, as well as from the electron-positron distance and center-of-mass distributions. The polarization of the Ps atom increases as its distance from the nucleus decreases. A depletion of the He electron density, particularly large at low density values, has been observed. The ortho-Ps pick-off annihilation rate calculated as the overlap of the positron and the free He electron densities has to be corrected for the observed depletion, specially at large pores/voids.Comment: 18 pages, 8 figure

A re-examination of the BEST Trial using composite outcomes, including emergency department visits

Objectives: The influence of choice of endpoint on trial size, duration, and interpretation of results was examined in patients with heart failure who were enrolled in BEST (Beta-blocker Evaluation of Survival Trial). Background: The choice of endpoints in heart failure trials has evolved over the past 3 decades. Methods: In the BEST trial, we used Cox regression analysis to examine the effect of bucindolol on the current standard composite of cardiovascular death or heart failure hospitalization (CVD/HFH) compared with the original primary mortality endpoint and the expanded composite that included emergency department (ED) visits. We also undertook an analysis of recurrent events primarily using the Lin, Wei, Ying, and Yang model. Results: Overall, 448 (33%) patients on placebo and 411 (30%) patients on bucindolol died (hazard ratio [HR]: 0.90; 95% confidence interval [CI]: 0.78 to 1.02; p = 0.11). A total of 730 (54%) patients experienced CVD/HFH on placebo and 624 (46%) on bucindolol (HR: 0.80; 95% CI: 0.72 to 0.89; p &lt; 0.001). Adding ED visits increased these numbers to 768 (57%) and 668 (49%), respectively (HR: 0.81; 95% CI: 0.73 to 0.90; p &lt; 0.001). A total of 568 (42%) patients on placebo experienced HFH compared with 476 (35%) patients on bucindolol (HR: 0.78; 95% CI: 0.69 to 0.89; p &lt; 0.001), with a total of 1,333 and 1,124 admissions, respectively. With the same statistical assumptions, using the composite endpoint instead of all-cause mortality would have reduced the trial size by 40% and follow-up duration by 69%. The rate ratio for recurrent events (CVD/HFH) was 0.83 (95% CI: 0.73 to 0.94; p = 0.003). Conclusions: Choice of endpoint has major implications for trial size and duration, as well as interpretation of results. The value of broader composite endpoints and inclusion of recurrent events needs further investigation. (Beta Blocker Evaluation in Survival Trial [BEST]; NCT00000560

The role of positronium decoherence in the studies of positron annihilation in matter

A small difference between the energy of the para-positronium (p-Ps) and ortho-positronium (o-Ps) states suggests the possibility of superposition of p-Ps and o-Ps during the formation of positronium (Ps) from pre-Ps terminating its migration in the matter in a void ('free volume'). It is shown that such a superposition decohere in the basis of p-Ps and o-Ps and the decoherence time is estimated. The time scale of the decoherence estimated here motivates respective correction in decomposition of the positron annihilation lifetime spectra. The way of the correction is sketched. The timescale of the decoherence suggests a need of awareness when experimental data from positron annihilation techniques are processed. More generally, the superposited state of Ps should contribute to the evolution theory of positronium in matter.Comment: 15 pages, 6 figure