High-dose cytosine arabinoside in the treatment of preleukemic disorders: a leukemia intergroup study

Fifteen patients with myelodysplastic/myeloproliferative disorders were treated with high-dose cytosine arabinoside therapy. While severe toxicity was produced in every patient, only two of the 15 patients entered complete remission and two achieved partial remission status. The therapeutic responses were confined to patients who had severe myelofibrosis of apparently recent onset.     

Observation of own exploration movements impairs haptic spatial perception

The present study was designed to assess whether the visibility of ones’ own exploratory movements impairs or enhances perceptual speed and precision of haptic stimuli with varying complexity. Previous studies have shown that noninformative vision of steady surroundings improves haptic spatial perception. However, due to the serial nature of haptic processing and limited capacity of working memory resources, we hypothesized that noninformative vision of limb movements may impair haptic perception. The study sample consisted of ninety-eight healthy adults who were randomized into two groups, matched for sex and age. Participants were required to explore two-dimensional haptic stimuli with varying complexity and to recognize them visually. The difference between the two experimental groups was a screen that would prevent the participants from viewing their hands during exploration in the nonobservation condition (NonOb). The other half of participants were able to see their hands in the manual movement observation condition (MovOb) thanks to the special design of the stimuli. As hypothesized, the persons in the MovOb condition made significantly more errors. The difference in error frequency between participants of the MovOb and NonOb condition was greater for complex stimuli than for simple ones. These results suggest that incoming visual information about own manual exploration movements increases competitive pressure for limited working memory resources, and therefore, more recognition errors are made. Covering the hands during exploration may constitute a helpful simplification of the task’s demands by supporting the maintenance of information in working memory. Additionally, the relation of haptic complexity and stimulus characteristics was analyzed.     

Clathrin-mediated endocytosis is required for compensatory regulation of GLR-1 glutamate receptors after activity blockade

Chronic changes in neural activity trigger a variety of compensatory homeostatic mechanisms by which neurons maintain a normal level of synaptic input. Here we show that chronic activity blockade triggers a compensatory change in the abundance of GLR-1, a Caenorhabditis elegans glutamate receptor. In mutants lacking a voltage-dependent calcium channel (unc-2) or a vesicular glutamate transporter (VGLUT; eat-4), the abundance of GLR-1 in the ventral nerve cord was increased. Similarly, the amplitude of glutamate-evoked currents in ventral cord interneurons was increased in eat-4 VGLUT mutants compared with wild-type controls. The effects of eat-4 VGLUT mutations on GLR-1 abundance in the ventral cord were eliminated in double mutants lacking both the clathrin adaptin protein unc-11 AP180 and eat-4 VGLUT. In contrast, mutations that decreased ubiquitination of GLR-1 did not prevent increased ventral cord abundance of GLR-1 in eat-4 VGLUT mutants. Taken together, our results suggest that GLR-1 is regulated in a homeostatic manner and that this effect depends on clathrin-mediated endocytosis but does not require ubiquitination of GLR-1.     

Separation of two thyrotropin binding components from porcine thyroid tissue by affinity chromatography: characterization of high and low affinity sites.

Two distinct thyrotropin (TSH) binding species have been separated from solubilized porcine thyroid membranes. Membranes was solubilized with 1% Triton X-100, and the supernatant was recovered by centrifugation at 105,000 X g. Scatchard analysis of thyrotropin binding to solubilized membranes (SM) yielded a nonlinear plot with Kd values for the high and low affinity components similar to those of intact membranes. Chromatography of the SM preparation on concanavalin A-Sepharose 4B resulted in the retention of 10-20% of the binding activity. Upon elution of the column, a peak of binding material (5-7% of total activity) was eluted at 0.3 M alpha-methyl-D-mannoside. This concanavalin A (Con A) bound fraction exhibited a linear Scatchard plot with a Kd value similar to that of the high affinity component of the SM. The protein fraction that did not bind to Con A (Con A unbound) also exhibited a linear Scatchard plot, but with affinity similar to that of the low affinity component of SM. Discontinuous sucrose density gradient ultracentrifugation revealed the presence of two major binding peaks in the solubilized membrane preparation. The slowly sedimenting peak corresponded to that seen in the Con A bound fraction, whereas the rapidly sedimenting peak corresponded to that of the Con A unbound fraction. Sepharose 6B chromatography indicated that in the case of the Con A unbound fraction, a single peak of specific binding activity was eluted in the void volume, and in the case of the Con A bound fraction, one major peak with an approximate Stokes radius of 67 A and several other minor peaks were eluted. These results demonstrate the physical separation of two distinct TSH binding species from thyroid membranes and provide further support for the model of multiple classes of binding sites.     

Safety and Effectiveness of Drug-Eluting Versus Bare-Metal Stents in Saphenous Vein Bypass Graft Percutaneous Coronary Interventions : Insights From the Veterans Affairs CART Program

Background

Stenosis of saphenous vein grafts (SVGs) after coronary artery bypass grafting (CABG) is common and often requires percutaneous coronary interventions (PCI) for treatment. However, data for the effectiveness of drug-eluting stents (DES) versus bare-metal stents (BMS) in SVG-PCI are unclear.

Objectives

This study sought to examine the association between DES versus BMS used during SVG PCI and clinical outcomes in the national Veterans Affairs integrated healthcare system.

Methods

We studied a national cohort of 2,471 post-CABG veterans undergoing SVG-PCI between 2008 and 2011 at all Veterans Affairs hospitals and compared clinical outcomes of between those receiving DES and BMS. Clinical outcomes included procedural complications, myocardial infarction (MI), and all-cause mortality. Comparisons were made in a propensity-matched cohort using Cox proportional hazards regression models.

Results

DES were used in 1,549 SVG-PCI patients (63%) and the use of DES increased progressively with each calendar year (50% in 2008 to 69% in 2011). Incidence of procedural complications was low and comparable in both groups (2.8% among BMS vs. 2.3% among DES patients; p = 0.54). During long-term (>2 years) follow-up, use of DES was associated with lower mortality than BMS (hazard ratio [HR]: 0.72; 95% confidence interval [CI]: 0.57 to 0.89) and similar rates of MI (HR: 0.94; 95% CI: 0.71 to 1.24) in the propensity-matched cohort.

Conclusions

In a national cohort of veterans, we observed widespread and increasing use of DES during SVG-PCI. In long-term follow-up, compared with BMS, DES use was safe and effective in SVG-PCI patients.     

Regression calibration for models with two predictor variables measured with error and their interaction,using instrumental variables and longitudinal data

Regression calibration provides a way to obtain unbiased estimators of fixed effects in regression models when one or more predictors are measured with error. Recent development of measurement error methods has focused on models that include interaction terms between measured‐with‐error predictors, and separately, methods for estimation in models that account for correlated data. In this work, we derive explicit and novel forms of regression calibration estimators and associated asymptotic variances for longitudinal models that include interaction terms, when data from instrumental and unbiased surrogate variables are available but not the actual predictors of interest. The longitudinal data are fit using linear mixed models that contain random intercepts and account for serial correlation and unequally spaced observations. The motivating application involves a longitudinal study of exposure to two pollutants (predictors) – outdoor fine particulate matter and cigarette smoke – and their association in interactive form with levels of a biomarker of inflammation, leukotriene E4 (LTE ₄, outcome) in asthmatic children. Because the exposure concentrations could not be directly observed, we used measurements from a fixed outdoor monitor and urinary cotinine concentrations as instrumental variables, and we used concentrations of fine ambient particulate matter and cigarette smoke measured with error by personal monitors as unbiased surrogate variables. We applied the derived regression calibration methods to estimate coefficients of the unobserved predictors and their interaction, allowing for direct comparison of toxicity of the different pollutants. We used simulations to verify accuracy of inferential methods based on asymptotic theory. Copyright © 2013 John Wiley & Sons, Ltd.