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We present a unique matter-wave interferometer whose phase scales with the cube of the time the atom spends in the interferometer. Our scheme is based on a full-loop Stern-Gerlach interferometer incorporating four magnetic field gradient pulses to create a state-dependent force. In contrast to typical atom interferometers that make use of laser light for the splitting and recombination of the wave packets, this realization uses no light and can therefore serve as a high-precision surface probe at very close distances.

Anti-inflammatory and Analgesic Activities of Topical Formulations of Pterocarpus Santalinus Powder in Rat Model of Chronic Inflammation.

INTRODUCTION: The incidence of arthritis is quite high and there is a need for the search of natural products to halt the progression of disease or provide symptomatic relief without significant adverse effects. AIM: This study aimed at evaluating the anti-inflammatory and analgesic activities of topical Pterocarpus santalinus in an animal model of chronic inflammation. MATERIALS AND METHODS: Albino rats of either sex were divided into five groups of six rats each (Group I - Control, Group II -Gel base, Group III -P. santalinus paste, Group IV -P. santalinus gel, Group V- Diclofenac gel). Chronic inflammation was induced on day 0 by injecting 0.1 ml Complete Freund's Adjuvant (CFA) in sub-plantar tissue of left hind paw of the rats. Topical treatment was started from day 12 till day 28. Body weight and paw volume (Plethysmometer) were assessed on day 0, 12 and 28. Pain assessment was done using Randall and Selitto paw withdrawal method. Data was analysed using GraphPad Prism version 5. Unpaired students t-test and ANOVA followed by Tukey's test was used for comparison among groups. RESULTS: Only topical P.santalinus gel significantly reduced the body weight (p=0.02) due to reduction in inflammatory oedema of the left limb. P. santalinus gel also showed significant reduction (p=0.03) in paw volume of rats compared to the other groups. There was significant reduction in pain threshold (gm/sec) due to chronic inflammation, with all the study drugs (p<0.05) but with P. santalinus gel, this reduction was less (p<0.001). CONCLUSION: Gel showed significant anti-inflammatory and mild analgesic activity on topical application in rat model of chronic inflammation.

Evaluation of discordance measures in oncology studies with blinded independent central review of progression-free survival using an observational error model.

To confirm results obtained from local evaluation at investigational centers, many oncology studies utilize blinded independent central review (BICR) to make assessments of the primary endpoint, progression-free survival (PFS). The comparison of data often leads to large discordances between these observations, casting doubt on the reliability of the estimated treatment effects from these trials. Here we propose new statistics to measure discordance and evaluate their utility to detect bias in the local evaluation of progression relative to the standard measures of discordance. A new observational error model is proposed that can be used to describe the discordance in patient assessments between multiple readers.

Blinded independent central review of progression in cancer clinical trials: results from a meta-analysis.

PURPOSE: Progression free survival (PFS) is increasingly used as a primary end-point in oncology clinical trials. This paper provides observations and recommendations on the use of a blinded independent central review (BICR) for progression. PATIENTS AND METHODS: The findings and recommendations are based on extensive simulations and a meta-analysis based on 27 previously conducted randomised phase III trials with BICR performed by the Pharmaceutical Research and Manufacturers Association (PhRMA) sponsored PFS Independent Review Working Group. RESULTS: Results of the meta-analysis demonstrate a strong correlation between LE and BICR estimates of treatment effect (R=0.947). Further, differences between treatment groups in discordance rates predict the differences between LE and BICR estimates of treatment effect supporting the use of a sample-based BICR on a subgroup of patients. CONCLUSION: The meta-analysis demonstrates that local evaluation (LE) provides a reliable estimate of the treatment effect with little evidence for systematic evaluation bias. Therefore, when a trial is blinded or a large effect on PFS is observed a BICR may not be warranted. When a BICR is warranted, a sample-based BICR may provide a reduction in operational complexity without compromising the credibility of trial results. While for large trials that are not adequately blinded a sample-based BICR may be recommended. A full BICR should be considered in the case of smaller trials or in situations in which there is a particular need to increase the confidence in the LE results.

Research outcomes and recommendations for the assessment of progression in cancer clinical trials from a PhRMA working group.

PURPOSE: Progression free survival (PFS) is increasingly used as a primary end-point in oncology clinical trials. This paper provides recommendations for optimal trial design, conduct and analysis in situations where PFS has the potential to be an acceptable end-point for regulatory approval. PATIENTS AND METHODS: These recommendations are based on research performed by the Pharmaceutical Research and Manufacturers Association (PhRMA) sponsored PFS Working Group, including the re-analysis of 28 randomised Phase III trials from 12 companies/institutions. RESULTS: (1) In the assessment of PFS, there is a critical distinction between measurement error that results from random variation, which by itself tends to attenuate treatment effect, versus bias which increases the probability of a false negative or false positive finding. Investigator bias can be detected by auditing a random sample of patients by blinded, independent, central review (BICR). (2) ITT analyses generally resulted in smaller treatment effects (HRs closer to 1) than analyses that censor patients for potentially informative events (such as starting other anti-cancer therapy). (3) Interval censored analyses (ICA) are more robust to time-evaluation bias than the log-rank test. CONCLUSION: A sample based BICR audit may be employed in open or partially blinded trials and should not be required in true double-blind trials. Patients should be followed until progression even if they have discontinued treatment to be consistent with the ITT principle. ICAs should be a standard sensitivity analysis to assess time-evaluation bias. Implementation of these recommendations would standardize and in many cases simplify phase III oncology clinical trials that use a PFS primary end-point.

Biomechanical evaluation of a novel fenestrated pedicle screw augmented with bone cement in osteoporotic spines.

STUDY DESIGN: Comparative biomechanical study was conducted in osteoporotic human cadaveric spines. OBJECTIVE: Determine the influence of the volume of polymethyl methacrylate injected through a fenestrated pedicle screw on the pullout strength and on the ability to safely remove the implant. SUMMARY OF BACKGROUND DATA: Pedicle screw fixation in the osteoporotic spine can be improved by the addition of bone cement. Various injection techniques have been used. While improvement has been shown for the pullout strength, the optimal volume of cement to inject has not been previously studied. METHODS: Seven osteoporotic spines were instrumented with a standard and a fenestrated pedicle screw augmented with polymethyl methacrylate at each level (T7-L5). Three volumes of bone cement were randomly injected and stratified to the thoracic (0.5 cc, 1.0 cc, and 1.5 cc) and lumbar spine (1.5 cc, 2.0 cc, and 2.5 cc). Axial pullout strength and removal torque of the pedicle screws were quantified. RESULTS: The pullout strength of the fenestrated screw was normalized with respect to its contralateral control. Student paired t tests were conducted and a statistically significant increase was noted for 1.0 cc (186 ± 45%) and 1.5 cc (158 ± 46%) in the thoracic spine and for 1.5 cc (264 ± 193%), 2.0 cc (221 ± 93%), and 2.5 cc (198 ± 42%) in the lumbar spine. There was no significant difference with higher volumes of cement. The median removal torque was 0.34 Nm for the standard and 1.83 Nm for the augmented screws. When the augmented implants were removed, the bone cement sheared completely off at the fenestrations in 15 of the 17 cases. CONCLUSION: Significant increases in pullout strength can be accomplished by injecting a limited quantity of bone cement through a fenestrated screw while minimizing the risks associated with higher volume. The majority of implants were removed without damaging the vertebra as the bone cement sheared off at the fenestrations.

Structure of the central RNA recognition motif of human TIA-1 at 1.95A resolution.

T-cell-restricted intracellular antigen-1 (TIA-1) regulates alternative pre-mRNA splicing in the nucleus, and mRNA translation in the cytoplasm, by recognizing uridine-rich sequences of RNAs. As a step towards understanding RNA recognition by this regulatory factor, the X-ray structure of the central RNA recognition motif (RRM2) of human TIA-1 is presented at 1.95A resolution. Comparison with structurally homologous RRM-RNA complexes identifies residues at the RNA interfaces that are conserved in TIA-1-RRM2. The versatile capability of RNP motifs to interact with either proteins or RNA is reinforced by symmetry-related protein-protein interactions mediated by the RNP motifs of TIA-1-RRM2. Importantly, the TIA-1-RRM2 structure reveals the locations of mutations responsible for inhibiting nuclear import. In contrast with previous assumptions, the mutated residues are buried within the hydrophobic interior of the domain, where they would be likely to destabilize the RRM fold rather than directly inhibit RNA binding.

Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common, progressive respiratory disease that causes great morbidity and mortality despite treatment. There is evidence for airway inflammation in COPD. Cilomilast is an orally active, potent, selective phosphodiesterase type 4 inhibitor, which in vitro can affect cells thought to be of clinical importance in COPD. Our aim was to assess the safety, efficacy, and dose response of cilomilast in the treatment of patients with this disease. METHODS: We did a 6-week, randomised, dose-ranging study in 424 patients with COPD (forced expiratory volume in 1 s [FEV(1)] 46.8% of predicted, FEV(1)/forced vital capacity [FVC] 54.6%, and postsalbutamol reversibility 5.4%). We randomly assigned individuals at 60 European centres to receive cilomilast 5 (n=109), 10 (n=102), or 15 (n=107) mg twice daily, or placebo (n=106). The main outcome measure was trough FEV(1) before and after use of a bronchodilator. Analyses were by intention to treat. FINDINGS: Cilomilast 15 mg twice daily significantly improved FEV(1) compared with placebo (mean 130 mL vs -30 mL [95% CI 90-240] at week 6, p<0.0001). FVC and peak expiratory flow were also improved (p=0.001 and p<0.0001, respectively). Quality of life measures did not differ significantly between the groups. There were no significant differences in serious adverse events between the groups. INTERPRETATION: Cilomilast 15 mg twice daily might be an effective maintenance treatment for COPD. Further clinical studies are underway.

DuP 532, an angiotensin II receptor antagonist: first administration and comparison with losartan.

We investigated the tolerability and angiotensin II antagonist activity of oral DuP 532 in healthy male subjects. DuP 532 (1 to 200 mg) was well tolerated, with no effect on blood pressure or heart rate. Compared with losartan (100 mg), DuP 532 (200 mg) was a weak antagonist of pressor responses to intravenous angiotensin II. Maximum inhibition of diastolic pressor response was 86% (95% confidence interval [CI], 84%, 88%) approximately 4.6 hours after losartan and 48% (95% CI, 38%, 56%) 8.7 hours after DuP 532. Twenty-four hours after dosing, inhibition by losartan and DuP 532 was similar (40% to 45%). DUP 532 is extensively bound in human plasma, with an in vitro free fraction of 0.06. Although DuP 532 and EXP3174 (losartan's active metabolite) have similar AT1-receptor potency, and plasma concentrations of DuP 532 were much greater than losartan/EXP3174, the level of antagonism was much less for DuP 532. These results indicate that multiple factors determine the in vivo potency of angiotensin II antagonists, including affinity for and distribution to the receptor as modulated by plasma binding.