Freeze-dried, mucoadhesive system for vaginal delivery of the HIV microbicide, dapivirine: Optimisation by an artificial neural network

Dapivirine mucoadhesive gels and freeze-dried tablets were prepared using a 3 x 3 x 2 factorial design. An artificial neural network (ANN) with multi-layer perception was used to investigate the effect of hydroxypropyl-methylcellulose (HPMC): polyvinylpyrrolidone (PVP) ratio (XI), mucoadhesive concentration (X2) and delivery system (gel or freeze-dried mucoadhesive tablet, X3) on response variables; cumulative release of dapivirine at 24 h (Q(24)), mucoadhesive force (F-max) and zero-rate viscosity. Optimisation was performed by minimising the error between the experimental and predicted values of responses by ANN. The method was validated using check point analysis by preparing six formulations of gels and their corresponding freeze-dried tablets randomly selected from within the design space of contour plots. Experimental and predicted values of response variables were not significantly different (p > 0.05, two-sided paired t-test). For gels, Q(24) values were higher than their corresponding freeze-dried tablets. F-max values for freeze-dried tablets were significantly different (2-4 times greater, p > 0.05, two-sided paired t-test) compared to equivalent gets. Freeze-dried tablets having lower values for X1 and higher values for X2 components offered the best compromise between effective dapivirine release, mucoadhesion and viscosity such that increased vaginal residence time was likely to be achieved. (C) 2009 Elsevier B.V. All rights reserved.

PS1-10afx at z = 1.388: Pan-STARRS1 Discovery of a New Type of Superluminous Supernova

We present the Pan-STARRS1 discovery of PS1-10afx, a unique hydrogen-deficient superluminous supernova (SLSN) at redshift z = 1.388. The light curve peaked at z P1 = 21.7 mag, making PS1-10afx comparable to the most luminous known SNe, with Mu = -22.3 mag. Our extensive optical and near-infrared observations indicate that the bolometric light curve of PS1-10afx rose on the unusually fast timescale of ~12 days to the extraordinary peak luminosity of 4.1 × 1044 erg s-1 (M bol = -22.8 mag) and subsequently faded rapidly. Equally important, the spectral energy distribution is unusually red for an SLSN, with a color temperature of ~6800 K near maximum light, in contrast to previous hydrogen-poor SLSNe, which are bright in the ultraviolet (UV). The spectra more closely resemble those of a normal SN Ic than any known SLSN, with a photospheric velocity of ~11, 000 km s-1 and evidence for line blanketing in the rest-frame UV. Despite the fast rise, these parameters imply a very large emitting radius (gsim 5 × 1015 cm). We demonstrate that no existing theoretical model can satisfactorily explain this combination of properties: (1) a nickel-powered light curve cannot match the combination of high peak luminosity with the fast timescale; (2) models powered by the spindown energy of a rapidly rotating magnetar predict significantly hotter and faster ejecta; and (3) models invoking shock breakout through a dense circumstellar medium cannot explain the observed spectra or color evolution. The host galaxy is well detected in pre-explosion imaging with a luminosity near L*, a star formation rate of ~15 M ⊙ yr-1, and is fairly massive (~2 × 1010 M ⊙), with a stellar population age of ~108 yr, also in contrast to the young dwarf hosts of known hydrogen-poor SLSNe. PS1-10afx is distinct from known examples of SLSNe in its spectra, colors, light-curve shape, and host galaxy properties, suggesting that it resulted from a different channel than other hydrogen-poor SLSNe.

Late referral for assessment of renal failure

It has been recommended that adult patients with a serum creatinine above 150 µmol/l should be referred to a nephrologist for specialist assessment. This study ascertained all patients in Northern Ireland with creatinine above this concentration in 2001 (n?=?19 286 ) to see if this triggered referral within the subsequent year. After exclusion of those who were already known to a nephrologist and those who had acute renal failure, it was found that younger patients and diabetic patients were more likely to be referred. There was no difference in referral rates between male and female patients. However, only 6.5% of all non-diabetic subjects and 19% of diabetic patients were referred within 12 months after a first increased serum creatinine test.

Performance analysis of a feasible air-cycle refrigeration system for road transport

The performance of an air-cycle refrigeration unit for road transport, which had been previously reported, was analysed in detail and compared with the original design model and an equivalent Thermo King SL200 vapour-cycle refrigeration unit. Poor heat exchanger performance was found to be the major contributor to low coefficient of performance values. Using state-of-the-art, but achievable performance levels for turbomachinery and heat exchangers, the performance of an optimised air-cycle refrigeration unit for the same application was predicted. The power requirement of the optimised air-cycle unit was 7% greater than the equivalent vapour-cycle unit at full-load operation. However, at part-load operation the air-cycle unit was estimated to absorb 35% less power than the vapour-cycle unit. The analysis demonstrated that the air-cycle system could potentially match the overall fuel consumption of the vapour-cycle transport refrigeration unit, while delivering the benefit of a completely refrigerant free system.

N-terminal His(7)-modification of glucagon-like peptide-1(7-36) amide generates dipeptidyl peptidase IV-stable analogues with potent antihyperglycaemic activity

Glucagon-like peptide-1(7-36)amide (GLP-1) possesses several unique and beneficial effects for the potential treatment of type 2 diabetes. However, the rapid in-activation of GLP-1 by dipeptidyl peptidase IV (DPP IV) results in a short half-life in vivo (less than 2 min) hindering therapeutic development. In the present study, a novel His(7)-modified analogue of GLP-1, N-pyroglutamyl-GLP-1, as well as N-acetyl-GLP-1 were synthesised and tested for DPP IV stability and biological activity. Incubation of GLP-1 with either DPP IV or human plasma resulted in rapid degradation of native GLP-1 to GLP-1 (9-36),amide, while N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 were completely resistant to degradation. N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 bound to the GLP-1 receptor but had reduced affinities (IC50 values 32(.)9 and 6(.)7 nM, respectively) compared with native GLP-1 (IC50 0(.)37 nM). Similarly, both analogues stimulated cAMP production with EC50 values of 16(.)3 and 27 nM respectively compared with GLP-1 (EC50 4(.)7 nM). However, N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 exhibited potent insulinotropic activity in vitro at 5(.)6 mM glucose (P

Advanced glycation end products induce blood-retinal barrier dysfunction in normoglycemic rats

Advanced glycation end products (AGEs) have been implicated in the progressive vascular dysfunction which occurs during diabetic retinopathy. In the current study we have examined the role of these adducts in blood-retinal barrier (BRB) breakdown and investigated expression of the vasopermeabilizing agent vascular endothelial growth factor (VEGF) in the retina. When normoglycemic rats were injected with AGE-modified albumin daily for up to 10 days there was widespread leakage of FITC-dextran and serum albumin from the retinal vasculature when compared to control animals treated with nonmodified albumin. Ultrastructural examination of the vasculature revealed areas of attenuation of the retinal vascular endothelium and increased vesicular organelles only in the AGE-exposed rats. Quantitative RT-PCR and in situ hybridization demonstrated a significant increase in retinal VEGF mRNA expression (P <0.05). These results suggest that AGEs can initiate BRB dysfunction in nondiabetic rats and a concomitant increase in retinal VEGF expression. These findings may have implications for the role of AGEs in the pathogenesis of diabetic retinopathy.

Development of a technique to measure the residual strength of woodworm infested timber

This paper presents a study of the residual strength of Pinus sylvestris, which has been subject to attack by the furniture beetle (Anobium punctatum). It is relatively easy to stop the infestation, but difficult to assess the structural soundness of the remaining timber. Removal and replacement of affected structural elements is usually difficult and expensive, particularly in buildings of historic interest. Current on-site assessment procedures are limited. The main object of the study was to develop an on-site test of timber quality: a test which can be carried out on the surface and also at varying depths into the timber. It is based on a probe pull-out technique using a portable load-measuring device. Pull-out force values have been correlated with both strength and energy absorbed as measured by compression testing on laboratory samples of both sound and infested timber. These two relationships are significant and could be used to assess whether remedial work is needed. In addition, work on the use of artificial borings to simulate the natural worming of timber is presented and the findings discussed.

Glucose-potentiated chemotaxis in human vascular smooth muscle is dependent on cross-talk between the P13K and MAPK signalling pathways

Atheroma formation involves the movement of vascular smooth muscle cells (VSMC) into the subendothelial space. The aim of this study was to determine the involvement of PI3K and MAPK pathways and the importance of cross-talk between these pathways, in glucose-potentiated VSMC chemotaxis to serum factors. VSMC chemotaxis occurred in a serum gradient in 25 mmol/L glucose (but not in 5 mmol/L glucose) in association with increased phosphorylation (activation) of Akt and ERK1/2 in PI3K and MAPK pathways, respectively. Inhibitors of these pathways blocked chemotaxis, as did an mTOR inhibitor. VSMC expressed all class IA PI3K isoforms, but microinjection experiments demonstrated that only the p110beta isoform was involved in chemotaxis. ERK1/2 phosphorylation was reduced not only by MAPK pathway inhibitors but also by PI3K and mTOR inhibitors; when PI3K was inhibited, ERK phosphorylation could be induced by microinjected activated Akt, indicating important cross-talk between the PI3K and ERK1/2 pathways. Glucose-potentiated phosphorylation of molecules in the p38 and JNK MAPK pathways inhibited these pathways but did not affect chemotaxis. The statin, mevinolin, blocked chemotaxis through its effects on the MAPK pathway. Mevinolin-inhibited chemotaxis was restored by farnesylpyrophosphate but not by geranylgeranylpyrophosphate; in the absence of mevinolin, inhibition of farnesyltransferase reduced ERK phosphorylation and blocked chemotaxis, indicating a role for the Ras family of GTPases (MAPK pathway) under these conditions. In conclusion, glucose sensitizes VSMC to serum, inducing chemotaxis via pathways involving p110beta-PI3K, Akt, mTOR, and ERK1/2 MAPK. Cross-talk between the PI3K and MAPK pathways is necessary for VSMC chemotaxis under these conditions.

Characterisation of two calmodulin-like proteins from the liver fluke, Fasciola hepatica.

Calmodulin is a calcium ion-sensing signalling protein found in eukaryotics. Two calmodulin-like gene sequences were identified in an EST library from adult liver flukes. One codes for a protein (FhCaM1) homologous to mammalian calmodulins (98% identity), whereas the other protein (FhCaM2) has only 41% identity. These genes were cloned into expression vectors and the recombinant proteins were expressed in Escherichia coli. Gel shift assays showed that both proteins bind to calcium, magnesium and zinc ions. Homology models have been built for both proteins. As expected, FhCaM1 has a highly similar structure to other calmodulins. Although FhCaM2 has a similar fold, its surface charge is higher than FhCaM1. One of the potential metal ion-binding sites has lower metal-ion co-ordination capability, while another has an adjacent lysine residue, both of which may decrease the metal-binding affinity. These differences may reflect a specialised role for FhCaM2 in the liver fluke.