Design and physicochemical characterisation of a bioadhesive patch for dose-controlled topical delivery of imiquimod

Clinical use of the imidazoquinoline immunomodulator imiquimod for the topical treatment of dysplastic and neoplastic lesions has increased markedly in recent years. However, despite guidance from the manufacturer of the proprietary imiquimod cream, there seems to be little consensus between clinicians as to the topically applied dose. Given that patients often apply the cream themselves at home, further dosing variability is expected and, consequently, accurate comparison of the results of different published studies is dif?cult. This paper describes, for the ?rst time, the formulation and physicochemical characterisation of a bioadhesive patch for dose-controlled topical delivery of imiquimod as well as a new HPLC method for sensitive ?uorescence determination of imiquimod released from such systems. Patches containing imiquimod loadings of 4.75, 9.50 and 12.50 mg cm-2 all released signi?cantly more drug across a model membrane than the proprietary cream over a period of 6 h. Inclusion of imiquimod in patches did not adversely affect their physicochemical properties. Of major importance, patches contained de?ned drug loadings per unit area; therefore, their use could reduce inter-clinician variability. This would make critical comparison of clinical studies and determination of an appropriate imiquimod dose for successful treatment much simpler. Since bioadhesive formulations are capable of adhering to body tissues in moist environments, the use of a bioadhesive patch system may allow extension of the clinical uses of imiquimod to the treatment of neoplastic conditions of the oral cavity and cervix, as well as the vulva. © 2005 Elsevier B.V. All rights reserved.

Wide Variation in Adenoma Detection Rates at Screening Flexible Sigmoidoscopy

Background & Aims: Wide between-center variation in adenoma detection rates (ADRs) was observed in the U.K. Flexible Sigmoidoscopy Screening Trial (overall, 12.1%; range, 8.6%-15.9%; P <0.0001). The aim of this study was to determine whether the observed differences could be attributed to varying performance by endoscopists, to examine the effect of experience on performance, and to identify an attainable, standard ADR to which endoscopists could aspire. 

Methods: Thirteen medical endoscopists, one per trial center, each performed about 3000 examinations (200 per month) using the same equipment and protocol. Overall and monthly ADRs were compared using multivariable logistic regression. 

Results: Differences in ADRs were not explained by patient characteristics, incidence of colorectal cancer in the local population, or the endoscopists' medical specialty or previous experience. Average ADRs increased significantly with screening experience (up to 400 examinations). Endoscopists were classified as higher, intermediate, or lower adenoma detectors, and performance levels were maintained over time. Higher detectors had ADRs of 15% overall (men, 20%; women, 10%) and also detected more adenomas per case (higher/lower detectors, 21.7/10.4 adenomas per :100 examinations). 

Conclusions: The differences in ADRs were due to variation in performance of the endoscopists. Long-term follow-up will determine whether this variation is clinically important. We suggest that the standards in higher detecting centers should be achievable by all endoscopists screening unscreened populations aged older than 55 years. Endoscopists should aim to stay above the lower 95% confidence interval band for 200 examinations (10% overall; 5% in women, 15% in men).

Applications of statistical models in proportioning medium strength self-compacting concrete

Self-compacting concrete (SCC) is generally designed with a relatively higher content of finer, which includes cement, and dosage of superplasticizer than the conventional concrete. The design of the current SCC leads to high compressive strength, which is already used in special applications, where the high cost of materials can be tolerated. Using SCC, which eliminates the need for vibration, leads to increased speed of casting and thus reduces labour requirement, energy consumption, construction time, and cost of equipment. In order to obtain and gain maximum benefit from SCC it has to be used for wider applications. The cost of materials will be decreased by reducing the cement content and using a minimum amount of admixtures. This paper reviews statistical models obtained from a factorial design which was carried out to determine the influence of four key parameters on filling ability, passing ability, segregation and compressive strength. These parameters are important for the successful development of medium strength self-compacting concrete (MS-SCC). The parameters considered in the study were the contents of cement and pulverised fuel ash (PFA), water-to-powder ratio (W/P), and dosage of superplasticizer (SP). The responses of the derived statistical models are slump flow, fluidity loss, rheological parameters, Orimet time, V-funnel time, L-box, JRing combined to Orimet, JRing combined to cone, fresh segregation, and compressive strength at 7, 28 and 90 days. The models are valid for mixes made with 0.38 to 0.72 W/P ratio, 60 to 216 kg/m3 of cement content, 183 to 317 kg/m3 of PFA and 0 to 1% of SP, by mass of powder. The utility of such models to optimize concrete mixes to achieve good balance between filling ability, passing ability, segregation, compressive strength, and cost is discussed. Examples highlighting the usefulness of the models are presented using isoresponse surfaces to demonstrate single and coupled effects of mix parameters on slump flow, loss of fluidity, flow resistance, segregation, JRing combined to Orimet, and compressive strength at 7 and 28 days. Cost analysis is carried out to show trade-offs between cost of materials and specified consistency levels and compressive strength at 7 and 28 days that can be used to identify economic mixes. The paper establishes the usefulness of the mathematical models as a tool to facilitate the test protocol required to optimise medium strength SCC.

Synthesis, Kinetic Evaluation and Utilization of a Biotinylated Dipeptide Proline Diphenyl Phosphonate for the Disclosure of Dipeptidyl Peptidase IV-like Serine Proteases

In this study, we report on the synthesis, kinetic characterisation, and application of a novel biotinylated and active site-directed inactivator of dipeptidyl peptidase IV (DPP-IV). Thus, the dipeptide-derived proline diphenyl phosphonate NH(2)-Glu(biotinyl-PEG)-Pro(P)(OPh)(2) has been prepared by a combination of classical solution- and solid-phase methodologies and has been shown to be an irreversible inhibitor of porcine DPP-IV, exhibiting an over all second-order rate constant (k(i)/K(i)) for inhibition of 1.57 x 10(3) M(-1) min(-1). This value compares favourably with previously reported rates of inactivation of DPP-IV by dipeptides containing a P(1) proline diphenyl phosphonate grouping [B. Boduszek, J. Oleksyszyn, C.M. Kam, J. Selzler, R.E. Smith, J.C. Powers, Dipeptide phophonates as inhibitors of dipeptidyl peptidase IV, J. Med. Chem. 37 (1994) 3969-3976; B.F. Gilmore, J.F. Lynas, C.J. Scott, C. McGoohan, L. Martin, B. Walker, Dipeptide proline diphenyl phosphonates are potent, irreversible inhibitors of seprase (FAPalpha), Biochem, Biophys. Res. Commun. 346 (2006) 436-446.], thus demonstrating that the incorporation of the side-chain modified (N-biotinyl-3-(2-(2-(3-aminopropyloxy)-ethoxy)-ethoxy)-propyl) glutamic acid residue at the P(2) position is compatible with inhibitor efficacy. The utilisation of this probe for the detection of both purified dipeptidyl peptidase IV and the disclosure of a dipeptidyl peptidase IV-like activity from a clinical isolate of Porphyromonas gingivalis, using established electrophoretic and Western blotting techniques previously developed by our group, is also demonstrated.

Parameter sensitivity for optimal design of 65 nm node SOI transistors

Mixed-mode simulation, where device simulation is embedded directly within a circuit simulator, is used for the first time to provide scaling guidelines to achieve optimal digital circuit performance for double gate SOI MOSFETs. This significant advance overcomes the lack of availability of SPICE model parameters. The sensitivity of the gate delay and on-off current ratio to each of the key geometric and technological parameters of the transistor is quantified. The impact of the source-drain doping profile on circuit performance is comprehensively investigated.

Making 'party identification' more versatile: operationalising the concept for the multiparty setting

The conventional operationalisation of the concept of party identification is not appropriate for the multiparty setting. I offer new measures that facilitate multiple, and negative as well as positive, identities. Using survey evidence from Northern Ireland, these new measures are validated in a number of ways and their role in a comprehensive model of voting is illustrated.

The Tragedy of Darfur and the Limits of the Responsibility to Protect

The view that states which claim sovereign status must comply with the responsibility to protect their own citizens is gaining ground in international politics. When a state is unable or unwilling to meet this responsibility, the international community is justified in intervening militarily to end widespread human rights violations. This article argues that a diffuse responsibility to protect, as currently conceived, may have important negative consequences. By using the ongoing tragedy of Darfur as an example, the article argues that the responsibility to protect is reactive and focused on the short term, contributes to the outbreak of violence and perversely provides repressed groups with a further incentive to continue their armed struggle after war breaks out. The tragedy of Darfur shows that effective protection requires case-specific policies aimed at prevention, democratization and economic and political development.

CaII K interstellar observations towards early-type disc and halo stars

We present high-resolution (R = lambda/Deltalambda similar to 40 000) Ca II K interstellar observations (lambda(air) = 3933.66Angstrom) towards 88 mainly B-type stars, of which 74 are taken from the Edinburgh-Cape or Palomar-Green surveys, and 81 have > 25degrees. The majority of the data come from previously existing spectroscopy, although also included are 18 new observations of stars with echelle spectra taken with UVES on the Very Large Telescope UT2 (Kueyen). Some 49 of the sample stars have distance estimates above the Galactic plane (z) greater than or equal to 1 kpc, and are thus good probes of the halo interstellar medium. Of the 362 interstellar Ca K components that we detect, 75 (21 per cent) have absolute values of their LSR velocity values exceeding 40 km s(-1). In terms of the deviation velocity for the sightlines with distance estimates, 46/273 (17 per cent) of components have velocity values exceeding those predicted by standard Galactic rotation by more than 40 km s(-1). Combining this data set with previous observations, we find that the median value of the reduced equivalent width (REW) of stars with z greater than or equal to 1 kpc (EW x sin ) is similar to 115 mAngstrom (n = 80), similar to that observed in extragalactic sightlines by Bowen. Using data of all z distances, the REW at infinity is found to be similar to 130 mAngstrom, with the scaleheight (1) of the Ca II K column density distribution being;z 800 pc (n = 196) and reduced column density at infinity of log[N(Ca II K) cm(-2)] similar to 12.24. This implies that similar to30 per cent of Ca II K absorption occurs at distances exceeding similar to1 kpc. For nine sightlines, with distance exceeding 1 kpc and with a companion object within 5degrees, we find that all but two have values of Ca II reduced equivalent width the same to within similar to20 per cent, when the REW of the nearest object is extrapolated to the distance of the further of the pair, and assuming 1 = 800 pc. For 29 of our sightlines with z greater than or equal to 1 kpc and a H I detection from the Leiden-Dwingeloo survey (beamsize of 0.5degrees), we find log(N(Ca II K)IN(H I)) ranging from -7.4 to - 8.4. Values of the Ca II K abundance relative to neutral hydrogen (log[N(Ca II K) cm(-2)] - log[N(H I) cm(-2)]) are found to be more than similar to0.5 dex higher in stars with distances exceeding approximate to100 pc, when compared with the (log[N(Ca II K) cm(-2)] -log[N(H-tot) cm(-2)]) values found in nearby sightlines such as those in Wakker & Mathis (2000). Finally, stellar Ca II K equivalent widths of the sample are determined for 26 objects.

A non-LTE analysis of the spectra of two narrow lined main sequence stars in the SMC

An analysis of high-resolution VLT/UVES spectra of two B-type main sequence stars, NGC 346-11 and AV 304, in the Small Magellanic Cloud (SMC), has been undertaken, using the non-LTE tlusty model atmospheres to derive the stellar parameters and chemical compositions of each star. The chemical compositions of the two stars are in reasonable agreement. Moreover, our stellar analysis agrees well with earlier analyses of H II regions. The results derived here should be representative of the current base-line chemical composition of the SMC interstellar medium as derived from B-type stars.

Cross-Kerr-based information transfer processes

The realization of nonclassical states is an important task for many applications of quantum information processing. Usually, properly tailored interactions, different from goal to goal, are considered in order to accomplish specific tasks within the general framework of quantum state engineering. In this paper, we remark on the flexibility of a cross-Kerr nonlinear coupling in hybrid systems as an important ingredient in the engineering of nonclassical states. The general scenario we consider is the implementation of high cross-Kerr nonlinearity in cavity-quantum electrodynamics. In this context, we discuss the possibility of performing entanglement transfer and swapping between matter qubits and light fields initially prepared in separable coherent states. The recently introduced concept of entanglement reciprocation is also considered and shown to be possible with our scheme. We reinterpret some of our results in terms of applications of a generalized Ising interaction to systems of different nature.