Lipid, sugar and liposaccharide based delivery systems

Although there are formidable barriers to the oral delivery of biologically active drugs, considerable progress in the field has been made, using both physical and chemical strategies of absorption enhancement. A possible method to enhance oral absorption is to exploit the phenomenon of lipophilic modification and mono and oligosaccharide conjugation. Depending on the uptake mechanism targeted, different modifications can be employed. To target passive diffusion, lipid modification has been used, whereas the targeting of sugar transport systems has been achieved through drugs conjugated with sugars. These drug delivery units can be specifically tailored to transport a wide variety of poorly absorbed drugs through the skin, and across the barriers that normally inhibit absorption from the gut or into the brain. The delivery system can be conjugated to the drug in such a way as to release the active compound after it has been absorbed (i.e. the drug becomes a prodrug), or to form a biologically stable and active molecule (i.e. the conjugate becomes a new drug moiety). Examples where lipid, sugar and lipid-sugar conjugates have resulted in enhanced drug delivery will be highlighted in this review.

Ionic strontium fluorescence as a method for flow tagging velocimetry

A flow tagging technique based upon ionic fluorescence in strontium is investigated for applications to velocity measurements in gas flows. The method is based upon a combination of two laser based spectroscopic techniques, i.e. resonantly-enhanced ionisation and laser-induced ionic fluorescence. Strontium is first ionised and then planar laser-induced fluorescence is utilised to give 2D 'bright images' of the ionised region of the flow at a given time delay. The results show that this method can be used for velocity measurements. The velocities were measured in two types of air-acetylene flames - a slot burner and a circular burner yielding velocities of 5.1 +/- 0.1 m/s and 9.3 +/- 0.2 m/s, respectively. The feasibility of the method for the determination of velocities in faster flows than those investigated here is discussed.

Patient based method of assessing adverse events in clinical trials in rheumatology: the revised Stanford Toxicity Index

We describe the progress towards developing a patient rated toxicity index that meets all of the patient-important attributes defined by the OMERACT Drug Safety Working Party, These attributes are frequency, severity. importance to patient, importance to the clinician, impact on economics, impact on activities, and integration of adverse effects with benefits. The Stanford Toxicity Index (STI) has been revised to collect all attributes with the exception of impact on activities. However, since the STI is a part of the Health Assessment Questionnaire (HAQ). impact on activities is collected by the HAQ. In particular, a new question asks patients to rate overall satisfaction, taking into consideration both benefits and adverse effects. The nest step in the development of this tool is to ensure that the STI meets the OMERACT filter of truth, discrimination, and feasibility. Although truth and feasibility have been confirmed by comparisons within the ARAMIS database, discrimination needs to be assessed in clinical trials.

Perceived constraints and social support for active leisure among mothers with young children

Evidence suggests that women who are mothers of young children have lower levels of physical activity than women of similar age who do not have children (Brown, Lee, Mishra, & Bauman, 2000). The purposes of this study were to explore the factors that constrain mothers of young children from being more physically active, and the relationship between physical activity and levels of social support available to the women. The empirical basis for this examination was provided through a study of activity levels and barriers to physical activity experienced by a sample of 543 mothers of young children from differing socioeconomic backgrounds. The data indicate that: (a) more than two-thirds of the mothers were inadequately active in their leisure time for health benefit; (b) while the vast majority of mothers expressed a desire to be more active, they were inhibited in their ability to act out their leisure preferences by a combination of structural (e.g., lack of time, money, energy) and ideological influences (e.g., sense of commitment to others); (c) access to social support (from partners, family, and friends) was seen to place some women in a better position than others to negotiate constraints that inhibit leisure participation; and (d) within groups of varying socioeconomic status (SES) there was wide variation in the amount of time spent each week in active leisure.

A novel method for solid-phase synthesis of oligosaccharides using the N-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) linker

The application of the N-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) linker for the solid-phase synthesis of oligosaccharides is described. The oligosaccharide products can be cleaved from the resin by hydrazine, ammonia or primary amines, but the linker is stable under the conditions of oligosaccharide synthesis. The first sugar can be attached to the resin linker via a vinylogous amide bond, or by ether linkage using a p-aminobenzyl alcohol converter. (C) 2001 Elsevier Science Ltd. All rights reserved.

Lanczos subspace filter diagonalization: Homogeneous recursive filtering and a low-storage method for the calculation of matrix elements

We develop a new iterative filter diagonalization (FD) scheme based on Lanczos subspaces and demonstrate its application to the calculation of bound-state and resonance eigenvalues. The new scheme combines the Lanczos three-term vector recursion for the generation of a tridiagonal representation of the Hamiltonian with a three-term scalar recursion to generate filtered states within the Lanczos representation. Eigenstates in the energy windows of interest can then be obtained by solving a small generalized eigenvalue problem in the subspace spanned by the filtered states. The scalar filtering recursion is based on the homogeneous eigenvalue equation of the tridiagonal representation of the Hamiltonian, and is simpler and more efficient than our previous quasi-minimum-residual filter diagonalization (QMRFD) scheme (H. G. Yu and S. C. Smith, Chem. Phys. Lett., 1998, 283, 69), which was based on solving for the action of the Green operator via an inhomogeneous equation. A low-storage method for the construction of Hamiltonian and overlap matrix elements in the filtered-basis representation is devised, in which contributions to the matrix elements are computed simultaneously as the recursion proceeds, allowing coefficients of the filtered states to be discarded once their contribution has been evaluated. Application to the HO2 system shows that the new scheme is highly efficient and can generate eigenvalues with the same numerical accuracy as the basic Lanczos algorithm.

An extended interval dosing method for gentamicin in neonates

Traditional gentamicin dosing every 8–24 h depending on age and weight in neonates does not provide the ideal concentration–time profile to both optimize the concentration-dependent killing by aminoglycosides and minimize toxicity. Fifty-three neonates were audited prospectively while receiving gentamicin 2.5 mg/kg every 8–24 h, aiming for peak concentrations (Cmax) of 6–10 mg/L and trough concentrations (Cmin) 10 mg/L after the first dose. The mean area under the concentration versus time curve AUC0–24 was 93 mg•h/L (target = 100 mg•h/L). The extended interval dosing achieved higher Cmax values while ensuring that overall exposure per 24 h was acceptable. Prospective testing of the method demonstrated good predictive ability.

Active site heterogeneity in dimethyl sulfoxide reductase from Rhodobacter capsulatus revealed by raman spectroscopy

Raman spectroscopy has been used to investigate the structure of the molybdenum cofactor in DMSO reductase from Rhodobacter capsulatus. Three oxidized forms of the enzyme, designated 'redox cycled', 'as prepared', and DMSORmodD, have been studied using 752 nm laser excitation. In addition, two reduced forms of DMSO reductase, prepared either anaerobically using DMS or using dithionite, have been characterized. The 'redox cycled' form has a single band in the Mo=O stretching region at 865 cm(-1) consistent with other studies. This oxo ligand is found to be exchangeable directly with (DMSO)-O-18 or by redox cycling. Furthermore, deuteration experiments demonstrate that the oxo ligand in the oxidized enzyme has some hydroxo character, which is ascribed to a hydrogen bonding interaction with Trp 116. There is also evidence from the labeling studies for a modified dithiolene sulfur atom, which could be present as a sulfoxide. In addition to the 865 cm(-1) band, an extra band at 818 cm(-1) is observed in the Mo=O stretching region of the 'as prepared' enzyme which is not present in the 'redox cycled' enzyme. Based on the spectra of unlabeled and labeled DMS reduced enzyme, the band at 818 cm(-1) is assigned to the S=O stretch of a coordinated DMSO molecule. The DMSORmodD form, identified by its characteristic Raman spectrum, is also present in the 'as prepared' enzyme preparation but not after redox cycling. The complex mixture of forms identified in the 'as prepared' enzyme reveals a substantial degree of active site heterogeneity in DMSO reductase.

The reliability of immunohistochemistry as a prescreening method for the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) - Results of an international collaborative study

Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is an autosomal dominant condition accounting for 2–5% of all colorectal carcinomas as well as a small subset of endometrial, upper urinary tract and other gastrointestinal cancers. An assay to detect the underlying defect in HNPCC, inactivation of a DNA mismatch repair enzyme, would be useful in identifying HNPCC probands. Monoclonal antibodies against hMLH1 and hMSH2, two DNA mismatch repair proteins which account for most HNPCC cancers, are commercially available. This study sought to investigate the potential utility of these antibodies in determining the expression status of these proteins in paraffin-embedded formalin-fixed tissue and to identify key technical protocol components associated with successful staining. A set of 20 colorectal carcinoma cases of known hMLH1 and hMSH2 mutation and expression status underwent immunoperoxidase staining at multiple institutions, each of which used their own technical protocol. Staining for hMSH2 was successful in most laboratories while staining for hMLH1 proved problematic in multiple labs. However, a significant minority of laboratories demonstrated excellent results including high discriminatory power with both monoclonal antibodies. These laboratories appropriately identified hMLH1 or hMSH2 inactivation with high sensitivity and specificity. The key protocol point associated with successful staining was an antigen retrieval step involving heat treatment and either EDTA or citrate buffer. This study demonstrates the potential utility of immunohistochemistry in detecting HNPCC probands and identifies key technical components for successful staining.

Contradictions and institutional convergences: Genre as method

My purpose here is to put forward a conception of genre as a way to conduct Futures Studies. To demonstrate the method, I present some examples of contemporary political and corporate discourses and contextualise them in broader institutional and historical settings. I elaborate the method further by giving examples of ‘genre chaining’ and ‘genre hybridity’ (Fairclough 1992 2000) to show how past, present, and future change can be viewed through the lens of genre.

Expression and purification of enzymatically active recombinant RNA-dependent RNA polymerase (NS5) of the flavivirus Kunjin

The NS5 protein of the flavivirus Kunjin (KUN) contains conserved sequence motifs characteristic of RNA-dependent RNA polymerase (RdRp) activity. To investigate this activity in vitro, recombinant NS5 proteins with C-terminal (NS5CHis) and N-terminal (NS5NHis) hexahistidine tags were produced in baculovirus-infected insect cells and purified to near homogeneity by nickel affinity chromatography. Purified NS5CHis exhibited RdRp activity with both specific (9 kb KUN replicon) and non-specific (8.3 kb Semliki Forest virus replicon) RNA templates; this activity did not require the presence of additional viral and/or cellular cofactors. RdRp activity of purified NS5NHis protein was reduced in comparison to NS5CHis, while purified NS5NHis incorporating a GDD -> GVD mutation within the polymerase active site (NS5GVD) lacked RdRp activity. RNase A digestion of the RdRp reaction products indicated that they were double-stranded and of a similar size to the KUN replicative form produced in Vero cells, thus demonstrating that the KUN NS5 protein has an intrinsic, albeit low and non-specific RdRp activity in vitro, similar to that reported for recombinant RdRp of other flaviviruses. However, in contrast to RNA polymerases of other Flavivirus species, purified KUN NS5 polymerase produced a single, full-length replicon RNA product, thus demonstrating efficient processivity. (C) 2001 Elsevier Science B.V. All rights reserved.

Characterization of pore structure and coordination of titanium in TiO2 and SiO2-TiO2 sol-pillared clays

Titania sol-pillared clay (TiO2 PILC) and silica-titania sol-pillared clay (SiO2-TiO2 PILC) were synthesized by the sol-gel method. Supercritical drying (SCD) and treatment with quaternary ammonium surfactants were used to tailor the pore structure of the resulting clay. It was found that SCD approach increased the external surface area of the PILCs dramatically and that treatment with surfactants could be used to tailor pore size because the mesopore formation in the galleries between the clay layers follows the templating mechanism as observed in the synthesis of MCM-41 materials. Highly mesoporous solids were thus obtained. In calcined TiO2 PILC, ultrafine crystallites in anatase phase, which are active for photocatalytic oxidation of organics, were observed. In SiO2-TiO2 PILCs and their derivatives, titanium was highly dispersed in the matrix of silica and no crystal phase was observed. The highly dispersed titanium sites are good catalytic centers for selective oxidation of organic compounds. (C) 2001 Academic Press.

A Ku-band active transmit-array module with a horn or patch array as a signal launching/receiving device

This paper is concerned with the design of a Ku-band active transmit-array module of transistor amplifiers excited by either a pyramidal horn or a patch array Optimal distances between the active transmit array and the signal-launching:receiving device, which is either a passive corporate-fed array or a horn, are determined to maximise the power gain at a design frequency: Having established these conditions, the complete structure is investigated in terms of operational bandwidth and near-field and far-field distributions measured at the output side of the transmit array, The experimental results show that the use of a corporate-fed array as an illuminating/receiving device gives higher gain and significantly larger operational bandwidth, An explanation for this behavior is sought.

Olfaction in the Queensland fruit fly, Bactrocera tryoni. I: Identification of olfactory receptor neuron types responding to environmental odors

The electroantennogram method was used to investigate the number of distinct olfactory receptor neuron types responding to a range of behaviorally active volatile chemicals in gravid Queensland fruit flies, Bactrocera tryoni. Three receptor neuron types were identified. One type responds to methyl butyrate, 2-butanone, farnesene, and carbon dioxide; a second to ethanol; and a third to n-butyric acid and ammonia. The receptor neuron type responding to methyl butyrate, 2-butanone, farnesene, and carbon dioxide consists of three subtypes. The presence of a limited number of receptor neuron types responding to a diverse set of chemicals and the reception of carbon dioxide by a receptor neuron type that responds to other odorants are novel aspects of the peripheral olfactory discrimination process.