A 10-year follow-up of the European multicenter trial of interferon ß-1b in secondary-progressive multiple sclerosis.

OBJECTIVES: To explore long-term effects of treatment and prognostic relevance of variables assessed at baseline and during the European secondary progressive multiple sclerosis (SPMS) trial of interferon beta 1b (IFNB-1b). METHODS: We assessed 362 patients (60% female; median age 41 years; Expanded Disability Status Scale (EDSS): 5.5; 51% randomized to IFNB-1b) for their EDSS and treatment history after 10 years. Non-parametric analysis of covariance (ANCOVA) and multivariate linear regression models were applied. RESULTS: Median EDSS was 6.0 at the end of the randomized controlled trial (RCT), in the IFNB-1b and placebo groups, and 7.0 in long-term follow-up patients (those receiving IFNB-1b in the RCT were 6.5 and those receiving placebo in the RCT were 7.0; p = 0.086). 24 patients (6.6%) were deceased. The EDSS at baseline and the EDSS change during the RCT were the most important predictors of the EDSS 10 years later (partial R(2): 0.47). The ability to predict changes in EDSS 10 years after the RCT was limited (R(2): 0.12). Magnetic resonance imaging (MRI) measures remained in the predictive models, but explained < 5% of the variability. CONCLUSIONS: The results from this analysis did not provide convincing evidence to support a favorable long-term outcome in those patients allocated IFNB-1b during the RCT, in our SPMS cohort. The progressive stage of the disease remains largely unpredictable by clinical and conventional MRI measures, so better prognostic markers are needed.

Impact of laser-contaminant interaction on the performance of the protective capping layer of 1 ω high-reflection mirror coatings.

High dielectric constant multilayer coatings are commonly used on high-reflection mirrors for high-peak-power laser systems because of their high laser-damage resistance. However, surface contaminants often lead to damage upon laser exposure, thus limiting the mirror's lifetime and performance. One plausible approach to improve the overall mirror resistance against laser damage, including that induced by laser-contaminant coupling, is to coat the multilayers with a thin protective capping (absentee) layer on top of the multilayer coatings. An understanding of the underlying mechanism by which laser-particle interaction leads to capping layer damage is important for the rational design and selection of capping materials of high-reflection multilayer coatings. In this paper, we examine the responses of two candidate capping layer materials, made of SiO2 and Al2O3, over silica-hafnia multilayer coatings. These are exposed to a single oblique shot of a 1053 nm laser beam (fluence ∼10 J/cm2, pulse length 14 ns), in the presence of Ti particles on the surface. We find that the two capping layers show markedly different responses to the laser-particle interaction. The Al2O3 cap layer exhibits severe damage, with the capping layer becoming completely delaminated at the particle locations. The SiO2 capping layer, on the other hand, is only mildly modified by a shallow depression. Combining the observations with optical modeling and thermal/mechanical calculations, we argue that a high-temperature thermal field from plasma generated by the laser-particle interaction above a critical fluence is responsible for the surface modification of each capping layer. The great difference in damage behavior is mainly attributed to the large disparity in the thermal expansion coefficient of the two capping materials, with that of Al2O3 layer being about 15 times greater than that of SiO2.

Exploring Adult Care Experiences and Barriers to Transition in Adult Patients with Sickle Cell Disease.

BACKGROUND: Young adults with sickle cell anemia are at high risk for increased hospitalization and death at the time of transition to adult care. This may be related to failure of the transition system to prepare young adults for the adult healthcare system. This qualitative study was designed to identify factors related to transition that may affect the health of adults with sickle cell anemia. PROCEDURE: Ten patients currently treated in an adult hematology clinic participated in semi-structured qualitative interviews to describe their experience transitioning from pediatric to adult care and differences in adult and pediatric healthcare systems. RESULTS: Participants were generally unprepared for the adult healthcare system. Negative issues experienced by participants included physician mistrust, difficulty with employers, keeping insurance, and stress in personal relationships. Positive issues experienced by participants included improved self efficacy with improved self care and autonomy. CONCLUSIONS: In the absence of a formalized transition program, adults with sickle cell anemia experience significant barriers to adult care. In addition to medical history review and identification of an adult provider, transition programs should incorporate strategies to navigate the adult medical system, insurance and relationships as well as encouraging self efficacy.

Safety and pharmacokinetics of p792, a new blood-pool agent: results of clinical testing in nonpatient volunteers.

RATIONALE AND OBJECTIVES: To evaluate the safety and pharmacokinetics of P792, a new macromolecular blood-pool agent for magnetic resonance imaging (MRI), in nonpatient volunteers. METHODS: This was a single blind, placebo-controlled, ascending-dose study in 32 healthy male volunteers, randomized to receive a single intravenous dose of P792 (0.0065, 0.013, 0.026, and 0.039 mmol/kg). The safety controls consisted of complete pre- and postdose physical examinations, measurement of vital signs, clinical laboratory investigations, and monitoring of adverse events (up to 22 days after injection). For pharmacokinetic analysis, the determination of P792 was performed using the ICP-MS technique for blood and urine samples up to 22 days. RESULTS: No serious adverse events occurred during the study. There were no clinically significant changes in vital signs, or clinical laboratory findings. P792 blood half-life, distribution volume, and renal clearance are consistent with the definition of a rapid clearance blood-pool agent (RCBPA) as defined previously. CONCLUSION: P792 appeared to be a safe and well-tolerated RCBPA in nonpatient subjects. Phase II studies will be conducted to evaluate the efficacy of the blood-pool agent for vascular, perfusion, and permeability imaging in MRI.

Growth and cellular differentiation: a physico-biochemical conundrum? The example of the hand.

Currently, the predominant hypothesis explains cellular differentiation as an essentially genetic intracellular process. The goal of this paper is to suggest that cell growth and differentiation may be, simply, the result of physical and chemical constraints. Bone growth occurs at the level of cartilage conjunction (growth plate) in a zone of lesser constrain. It appears that this growth also induces muscle, tendon, nerve and skin elongation. This cartilage growth by itself seems to explain the elongation of the hand. Growth stops at puberty likely because of feed-back from an increasing muscle load. The ossification (that is differentiation of cartilage into bone) appears to result from the shear stress induced. The study of bone age, obtained by X-ray picture of the hand, shows that ossification of epiphyses is very precise both in time and space. Computer modelization suggests that this ossification occurs where shear stress is greatest. The cartilage which does not ossify (joint, nose, larynx, ear, bronchus, etc.) is not exposed to high shear. Shear stress induces the secretion of extracellular matrix and a change of the biochemical environment of the cell. Precipitation of calcium phosphate, as in ossification, seems related to the alkalosis induced by shear stress. To speak in more general terms, loss of cellular differentiation, as occurs with cancer, can result from a change in the physical-chemical environments.

Implementation of high-resolution diffractive optical elements on coupled phase and amplitude spatial light modulators.

We propose the optical implementation of diffractive optical elements onto electrically addressed liquid-crystal spatial light modulators. We compare the classic implementations onto amplitude-only or phase-only domains with the implementations onto coupled phase and amplitude (spiral) domains. We demonstrate that the coupling between amplitude and phase provides a trade-off between diffraction efficiency and the signal-to-noise ratio in the reconstruction. Furthermore, when investigating the influence of the maximum dephasing on phase domains and spiral domains through the use of optimal trade-off design, we show that phase-only domains with limited maximum dephasing can provide satisfactory performance. Finally, optical implementations are provided.

The effect of valerian extract on sleep polygraphy in poor sleepers: a pilot study.

The effect of acute and repeated treatment (seven days) with a valerian extract (Valdispert forte, 405 mg t.i.d.) on objective and subjective measures of sleep was studied. Polysomnography was conducted in 14 elderly poor sleepers on three nights, at one-week intervals (N0, N1, N2). N0 was an adaptation night, N1 and N2 the first and last night under treatment. Six subjects received placebo and eight subjects valerian. Subjects in the valerian group showed an increase in slow-wave sleep (SWS) and a decrease in sleep stage 1. Density of K-complexes was increased under active treatment. There was no effect on sleep onset time or time awake after sleep onset. REM sleep was unaltered. There was also no effect on self-rated sleep quality. We hypothesize that valerian increases SWS in subjects with low baseline values.

Damage threshold prediction of hafnia-silica multilayer coatings by nondestructive evaluation of fluence-limiting defects.

A variety of microscopic techniques were employed to characterize fluence-limiting defects in hafnia-silica multilayer coatings manufactured for the National Ignition Facility, a fusion laser with a wavelength of 1.053 mum and a pulse width of 3 ns. Photothermal microscopy, with the surface thermal lens effect, was used to map the absorption and thermal characteristics of 3 mm x 3 mm areas of the coatings. High-resolution subaperture scans, with a 1-mum step size and a 3-mum pump-beam diameter, were conducted on the defects to characterize their photothermal properties. Optical and atomic force microscopy were used to identify defects and characterize their topography. The defects were then irradiated by a damage testing laser (1.06 mum and 3 ns) in single-shot mode until damage occurred. The results were analyzed to determine the role of nodular and nonnodular defects in limiting the damage thresholds of the multilayer coatings. It was found that, although different types of defect were present in these coatings, the fluence-limiting ones had the highest photothermal signals (up to 126x over the host coating). The implication of this study is that coating process improvements for hafnia-silica multilayer coatings should have a broader focus than just elimination of source ejection, since high photothermal signals frequently occur at nodule-free regions. The study also demonstrates that, for optics subject to absorption-induced thermal damage, photothermal microscopy is an appropriate tool for nondestructive identification of fluence-limiting defects.

Effects of vacuum exposure on stress and spectral shift of high reflective coatings.

Coating stress and spectral shift are affected by changing from ambient to vacuum environments. This change can affect optical systems that are aligned in air and used in a vacuum or in a dry environment. Spectral shifts up to 3% and reflected wave-front changes up to 0.35 waves peak to valley are reported for conventional electron-beam deposition and ion-assisted deposition. Alternatively, ion-beam sputtered coatings have virtually no changes between different pressure environments.

Reactive evaporation of low-defect density hafnia.

Motivation for this work includes observations at Lawrence Livermore National Laboratory of a correlation between laser damage thresholds and both the absorption and the nodular-defect density of coatings. Activated oxygen is used to increase the metal-oxidation kinetics at the coated surface during electron-beam deposition. A series of hafnia layers are made with various conditions: two µ-wave configuations, two sources (hafnium and hafnia), and two reactive oxygen pressures. Laser damage thresholds (1064-nm, 10-ns pulses), absorption (at 511 nm), and nodular-defect densities from these coatings are reported. The damage thresholds are observed to increase as the absorption of the coatings decreases. However, no significant increase in damage thresholds are observed with the coatings made from a low nodular-defect density source material (hafnium). Hafnia coatings can be made from hafnium sources that have lower nodular-defect densities, lower absorption, and damage thresholds thatare comparable with coatings made from a conventional hafnia source.

Increased calcium sensitivity of chemically skinned human atria by myosin light chain kinase.

We investigated the influence of myosin P-LC phosphorylation catalysed by calcium/calmodulin-dependent myosin light chain kinase (MLCK) on the tension-pCa relation of chemically skinned human atrial fibres. MLCK-induced increased myosin P-LC phosphorylation sensitized human atrial skinned fibres for calcium by 0.11 pCa-units in patients with valvular heart disease, and by 0.05 to 0.07 pCa-units in patients with coronary heart disease. The MLCK effect could be antagonized by a light chain phosphatase. The protein phosphatase ocadaic acid (OA) had no influence on the tension-pCa relation of skinned human atrial fibres and had no potentiating effect together with MLCK. The MLCK preparation used in this study was from bovine ventricle and revealed a KM of 1.8 x 10(-5) M and a Vmax of 822 nmol Pi/min/mg using purified bovine ventricular myosin-LCs as substrate.

Further studies on the effects of myosin P-light chain phosphorylation on contractile properties of skinned cardiac fibres.

We investigated the influence of myosin P-light chain phosphorylation by Ca2+-calmodulin dependent myosin light chain kinase (MLCK) on the sensitivity of the tension-pCa relation and maximum unloaded shortening velocity (Vmax) of chemically skinned heart fibres of the pig. Submaximum Ca2+ stimulation (pCa 5.5) induced 20 +/- 5% of the isometric tension achieved at maximum Ca2+ activation (pCa 4.3). MLCK-induced myosin P-light chain phosphorylation increased the isometric force development at pCa 5.5 by 40% whereas maximum tension at pCa 4.3 was not affected. Unloaded shortening velocity (Vmax) was not altered by myosin P-light chain phosphorylation either at maximum or at submaximum Ca2+ concentration, being c. 1.2 muscle length/s at pCa 5.5 and 2.2 muscle length/s at pCa 4.3. The MLCK-induced increase of the myosin P-light chain phosphorylation level was evaluated by determination of 32P-incorporation. Two phosphorylatable myosin P-light chains could be demonstrated.