Controlled release of a model antibacterial drug from a novel self-lubricating silicone biomaterial

Abstract There is considerable interest in developing medical devices that provide controlled delivery of biologically active agents, for example, to reduce the incidence of device-related infection. Silicone elastomers are one of the commonest biomaterials used in medical device production. However, they have a relatively high coefficient of friction and the resulting lack of lubricity can cause pain and tissue damage on device insertion and removal. Novel silicone cross-linking agents have recently been reported that produce inherently ‘self-lubricating’ silicone elastomers with very low coefficients of friction. In this study, the model antibacterial drug metronidazole has been incorporated into these self-lubricating silicone elastomers to produce a novel bioactive biomaterial. The in vitro release characteristics of the bioactive component were evaluated as a function of cross-linker composition and drug loading. Although conventional matrix-type release kinetics were observed for metronidazole from the silicone systems, it was also observed that increasing the concentration of the cross-linking agent responsible for the lubricious character (tetra(oleyloxy)silane) relative to that of the standard non-lubricious cross-linking agent (tetrapropoxysilane) produced an increase in the metronidazole flux rate by up to 65% for a specified drug loading. The results highlight the potential for developing lubricious silicone medical devices with enhanced drug release characteristics.

The spectrum of endogenous human chromogranin A-derived peptides identified using a modified proteomic strategy.

The hypothesis that chromogranin A (CgA), a protein of neuroendocrine cell secretory granules, may be a precursor of biologically active peptides, rests on observed activities of peptide fragments largely produced by exogenous protease digestion of the bovine protein. Here we have adopted a modified proteomic strategy to isolate and characterise human CgA-derived peptides produced by endogenous prohormone convertases. Initial focus was on an insulinoma as previous studies have shown that CgA is rapidly processed in pancreatic beta cells and that tumours arising from these express appropriate prohormone convertases. Eleven novel peptides were identified arising from processing at both monobasic and dibasic sites and processing was most evident in the C-terminal domain of the protein. Some of these peptides were identified in endocrine tumours, such as mid-gut carcinoid and phaeochromocytoma, which arise from endocrine cells of different phenotype and in different anatomical sites. Two of the most interesting peptides, GR-44 and ER-37, representing the C-terminal region of CgA, were found to be amidated. These data would imply that the intact protein is C-terminally amidated and that these peptides are probably biologically active. The spectrum of novel CgA-derived peptides, described in the present study, should provide a basis for biological evaluation of authentic entities.

What Have We Learned in Five Decades of Neutralization Research?

Neutralization theory, though a popular framework for understanding deviant behavior, remains badly underdeveloped. Few attempts have been made to connect it to narrative and sociocognitive research in psychology and related fields. From this wider perspective, one reason neutralization theory has received only mixed empirical support is that it has been understood as a theory of criminal etiology. This makes little sense (how can one neutralize something before they have done it?) and makes the theory difficult to test. Neutralization should instead be seen as playing a role in persistence in or desistance from criminal behavior. The theory's central premises need to be substantially complicated. The notions that all excuses or justifications are "bad" and that reform involves "accepting complete responsibility" for one's actions are not tenable.

The role of BRCA1 in transcriptional regulation and cell cycle control

The exact functions of BRCA1 have not been fully described but it now seems apparent that it has roles in DNA damage repair, transcriptional regulation, cell cycle control and most recently in ubiquitylation. These functions of BRCA1 are most likely interdependent but this review will focus on the role of BRCA1 in relation to transcriptional regulation and in particular how this impacts upon cell cycle control. We will (i) describe the structure of BRCA1 and how it may contribute to its transcription function; (ii) describe the interaction of BRCA1 with the core transcriptional machinery (RNA polII); (iii) describe how BRCA1 may regulate transcription at an epigenetic level through chromatin modification; (iv) discuss the role of BRCA1 in modulating transcription through its association with sequence-specific transcription factors. Finally, we will discuss the possible effects of BRCA1 transcriptional regulation on downstream targets with known roles in cell cycle control.

Effect of a COL1A1 Sp1 Binding Site Polymorphism on Arterial Pulse Wave Velocity: An Index of Compliance.

Reduced arterial compliance precedes changes in blood pressure, which may be mediated through alterations in vessel wall matrix composition. We investigated the effect of the collagen type I-1 gene (COL1A1) +2046G>T polymorphism on arterial compliance in healthy individuals. We recruited 489 subjects (251 men and 238 women; mean age, 22.6±1.6 years). COL1A1 genotypes were determined using polymerase chain reaction and digestion by restriction enzyme Bal1. Arterial pulse wave velocities were measured in 3 segments, aortoiliac (PWVA), aortoradial (PWVB), and aorto-dorsalis-pedis (PWVF), as an index of compliance using a noninvasive optical method. Data were available for 455 subjects. The sample was in Hardy-Weinberg equilibrium with genotype distributions and allele frequencies that were not significantly different from those reported previously. The T allele frequency was 0.22 (95% confidence interval, 0.19 to 0.24). Two hundred eighty-three (62.2%) subjects were genotype GG, 148 (35.5%) subjects were genotype GT, and 24 (5.3%) subjects were genotype TT. A comparison of GG homozygotes with GT and TT individuals demonstrated a statistically significant association with arterial compliance: PWVF 4.92±0.03 versus 5.06±0.05 m/s (ANOVA, P=0.009), PWVB 4.20±0.03 versus 4.32±0.04 m/s (ANOVA, P=0.036), and PWVA 3.07±0.03 versus 3.15±0.03 m/s (ANOVA, P=0.045). The effects of genotype were independent of age, gender, smoking, mean arterial pressure, body mass index, family history of hypertension, and activity scores. We report an association between the COL1A1 gene polymorphism and arterial compliance. Alterations in arterial collagen type 1A deposition may play a role in the regulation of arterial compliance

Polymorphims in the Interferon-y/Interleukin 26 Gene Region Contribute to Sex Bias in Susceptibility to Rheumatoid Arthritis

Objective:

To determine whether polymorphisms in the interferon-? (IFN?)/interleukin-26 (IL-26; formerly, AK155) gene cluster contribute to sex-based differential susceptibility to rheumatoid arthritis (RA).

Methods:

Four microsatellite markers, located in a 118-kb interval that contains both the IFN? and IL-26 genes on chromosome 12q15, were typed in 251 patients with RA and 198 unrelated healthy controls (all of whom lived in Northern Ireland) by means of polymerase chain reaction–based fragment analysis.

Results:

Marker D12S2510, which is located 3 kb 3' from the IL-26 gene, was significantly associated with RA in women (corrected P [Pcorr] = 0.008, 2 degrees of freedom [2 df]) but not in men (P = 0.99, 2 df). A 3-marker haplotype, IFNGCA*13;D12S2510*8;D12S2511*9, was inferred that showed significant underrepresentation in women with RA (odds ratio 0.50, 95% confidence interval 0.32–0.78; P = 0.002, Pcorr = 0.03) but not in men with RA.

Conclusion:

Our results demonstrate that common polymorphisms in the IFN?/IL-26 gene region may contribute to sex bias in susceptibility to RA, by distorting the propensity of female carriers versus male carriers to contract this disease. These results conform to our recent observations of a role for this gene cluster in sex-based differential susceptibility to another Th1-type inflammatory disease, multiple sclerosis.

Fe XIII emission lines in active region spectra obtained with the Solar Extreme-Ultraviolet Research Telescope and Spectrograph

Recent fully relativistic calculations of radiative rates and electron impact excitation cross-sections for FeXIII are used to generate emission-line ratios involving 3s23p2-3s3p3 and 3s23p2-3s23p3d transitions in the 170-225 and 235-450 Å wavelength ranges covered by the Solar Extreme-Ultraviolet Research Telescope and Spectrograph (SERTS). A comparison of these line ratios with SERTS active region observations from rocket flights in 1989 and 1995 reveals generally very good agreement between theory and experiment. Several new FeXIII emission features are identified, at wavelengths of 203.79, 259.94, 288.56 and 290.81 Å. However, major discrepancies between theory and observation remain for several FeXIII transitions, as previously found by Landi and others, which cannot be explained by blending. Errors in the adopted atomic data appear to be the most likely explanation, in particular for transitions which have 3s23p3d1D2 as their upper level. The most useful FeXIII electron-density diagnostics in the SERTS spectral regions are assessed, in terms of the line pairs involved being (i) apparently free of atomic physics problems and blends, (ii) close in wavelength to reduce the effects of possible errors in the instrumental intensity calibration, and (iii) very sensitive to changes in Ne over the range 108-1011cm-3. It is concluded that the ratios which best satisfy these conditions are 200.03/202.04 and 203.17/202.04 for the 170-225 Å wavelength region, and 348.18/320.80, 348.18/368.16, 359.64/348.18 and 359.83/368.16 for 235-450 Å.

A comparison of theoretical Si VIII emission line ratios with observations from SERTS

Recent R-matrix calculations of electron impact excitation rates in N-like Si VIII are used to derive theoretical emission line intensity ratios involving 2s(2)2p(3)-2s2p(4) transitions in the 216 -320 Angstrom wavelength range. A comparison of these with an extensive dataset of solar active region, quiet- Sun, sub-flare and off-limb observations, obtained during rocket flights of the Solar EUV Research Telescope and Spectrograph (SERTS), indicates that the ratio R-1 = I(216.94 Angstrom)/I(319.84 Angstrom) may provide a usable electron density diagnostic for coronal plasmas. The ratio involves two lines of comparable intensity, and varies by a factor of about 5 over the useful density range of 10(8)-10(11) cm(-3). However R-2 = I(276.85 Angstrom)/I(319.84 Angstrom) and R-3 = I(277.05 Angstrom)/I(319.84 Angstrom) show very poor agreement between theory and observation, due to the severe blending of the 276.85 and 277.05 Angstrom lines with Si VII and Mg VII transitions, respectively, making the ratios unsuitable as density diagnostics. The 314.35 Angstrom feature of Si VIII also appears to be blended, with the other species contributing around 20% to the total line flux.