Biomedical subjects
Publications and source records attributed to P Norris.
A method of surgical compartmentalisation of the neck is reported. This technique can be used in order to maintain suction drainage without compromising the flow of the anastomoses when an end-to-side technique in the internal jugular vein is used.
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BACKGROUND: Photoallergic contact dermatitis can be difficult to diagnose if not appropriately investigated. Currently, the most common U.K. photoallergens appear to be sunscreen chemicals. The investigation of choice is photopatch testing (PPT), which is probably underused. In part, this is due to differences in methodology and results interpretation. OBJECTIVES: To conduct PPT using a group of sunscreen chemicals, defined indications and a standardized methodology including interpretation and relevance of reactions in patients attending for investigation at 17 centres across the U.K., Ireland and the Netherlands. METHODS: Patients (n = 1155) who fulfilled the inclusion criteria were investigated with PPT using sunscreen chemicals in addition to suspected topical products. Readings were taken at 24, 48 and 72 h following standardized ultraviolet A irradiation (5 J cm(-2)). The clinical relevance of any reaction was recorded. RESULTS: Of the 1155, 130 had allergic reactions (11.3%). Of these, 51 had photoallergy (PA) (4.4%), 64 had contact allergy (CA) (5.5%), and 15 patients had combined PA and CA (1.3%). Multiple PA was seen in some. The most common photoallergen was benzophenone-3 (27 reactions; 21%). Most reactions (60%) were clinically relevant. The most common indication for testing in patients found to have PA was a history of reacting to a sunscreen (41%). The other 59% had an exposed-site dermatitis/skin problem or a photodermatosis. Some centres (n = 8) performed readings after the standard 48-h reading, and an extra 32 PA and 22 CA reactions were detected, which were not evident at 48 h. A new photoallergen (octyl triazone) was detected in two patients. CONCLUSIONS: Sunscreen PA and CA are probably equally uncommon. Most reactions, of both reaction types, were relevant clinically. A large proportion of patients (59%) found to have PA was unaware of reacting to a sunscreen chemical, suggesting that PA should be considered as an explanation in any exposed-site dermatitis. Although this study focused on reactions at 48 h postirradiation, readings performed up to 96 h, while inconvenient, add value by detecting additional relevant responses. A previously unknown photoallergen was found, highlighting the need for awareness of novel photoallergens in the marketplace. A standardized PPT method not only encourages more use of this investigation, but also facilitates comparison of results between centres and so will improve our understanding of PA.
The "gold standard" of assessing pathological changes in tissue is currently histopathology. However, the processing of biopsy material and the interpretation of the results inevitably leads to diagnostic delay and the added possibility of taking an unrepresentative sample. Recently, there has been increasing interest in the use of optical spectroscopy systems to be able to provide tissue diagnosis in real-time, non-invasively and in situ. These systems rely on the fact that the optical spectrum derived from any tissue will contain information about the histological and biochemical make up of that tissue. The technique has not only been shown to have a role in the detection of dysplasia and malignancy but also in performing guided biopsies, monitoring of haemoglobin tissue perfusion in free-flaps and therapeutic drug levels during chemo- and photodynamic therapy. The assessment of surgical margins and a role in sentinel node biopsy are also interesting developments. The obvious advantages of being able to accurately diagnose pathology without the need to remove a tissue sample diminish patient trauma as well as having financial implications.
T cell-based HIV vaccine candidates have focused on eliciting both CD4- and CD8-mediated responses. One challenge in vaccine development is the successful introduction and presentation of exogenous antigen to elicit an immune response. Modified bacterial toxins have been studied extensively as intracellular delivery agents because of their unique capability to translocate antigen across the cell membrane without affecting cell viability. Modified anthrax toxin lethal factor (LFn) fusion protein is able to effectively induce anti-HIV cytotoxic T lymphocytes in the absence of protective antigen (PA) and is being evaluated as a vaccine candidate. Here we describe, for the first time, the processing and presentation of LFn fusion proteins by the MHC Class II pathway. The ability of LFn--HIV to induce both CD8- and CD4-mediated responses may have relevance in current approaches to vaccine design. Furthermore, the translocation and presentation of antigens occurs in the absence of PA, which proposes a modified molecular mechanism of antigen presentation by the anthrax toxin model. Additionally, we found that LFn--HIV is specific and sensitive in detecting HIV-specific CD4(+) and CD8(+) T cell responses in T cell assays, further broadening the value of this antigen delivery system as a useful immunologic tool.
Indwelling prostheses and subcutaneous delivery devices are now routinely and indispensably employed in medical practice. However, these same devices often provide a highly suitable surface for bacterial adhesion and colonization, resulting in the formation of complex, differentiated, and structured communities known as biofilms. The University of Washington Engineered Biomaterials group has developed a novel drug delivery polymer matrix consisting of a poly(2-hydroxyethyl methacrylate) hydrogel coated with ordered methylene chains that form an ultrasound-responsive coating. This system was able to retain the drug ciprofloxacin inside the polymer in the absence of ultrasound but showed significant drug release when low-intensity ultrasound was applied. To assess the potential of this controlled drug delivery system for the targeting of infectious biofilms, we monitored the accumulation of Pseudomonas aeruginosa biofilms grown on hydrogels with and without ciprofloxacin and with and without exposure to ultrasound (a 43-kHz ultrasonic bath for 20 min daily) in an in vitro flow cell study. Biofilm accumulation from confocal images was quantified and statistically compared by using COMSTAT biofilm analysis software. Biofilm accumulation on ciprofloxacin-loaded hydrogels with ultrasound-induced drug delivery was significantly reduced compared to the accumulation of biofilms grown in control experiments. The results of these studies may ultimately facilitate the future development of medical devices sensitive to external ultrasonic impulses and capable of treating or preventing biofilm growth via "on-demand" drug release.
In modern medicine, artificial devices are used for repair or replacement of damaged parts of the body, delivery of drugs, and monitoring the status of critically ill patients. However, artificial surfaces are often susceptible to colonization by bacteria and fungi. Once microorganisms have adhered to the surface, they can form biofilms, resulting in highly resistant local or systemic infections. At this time, the evidence suggests that (+)-usnic acid, a secondary lichen metabolite, possesses antimicrobial activity against a number of planktonic gram-positive bacteria, including Staphylococcus aureus, Enterococcus faecalis, and Enterococcus faecium. Since lichens are surface-attached communities that produce antibiotics, including usnic acid, to protect themselves from colonization by other bacteria, we hypothesized that the mode of action of usnic acid may be utilized in the control of medical biofilms. We loaded (+)-usnic acid into modified polyurethane and quantitatively assessed the capacity of (+)-usnic acid to control biofilm formation by either S. aureus or Pseudomonas aeruginosa under laminar flow conditions by using image analysis. (+)-Usnic acid-loaded polymers did not inhibit the initial attachment of S. aureus cells, but killing the attached cells resulted in the inhibition of biofilm. Interestingly, although P. aeruginosa biofilms did form on the surface of (+)-usnic acid-loaded polymer, the morphology of the biofilm was altered, possibly indicating that (+)-usnic acid interfered with signaling pathways.
This paper reports the use of improved numerical approaches to modelling extraction profiles, and shows that the approach substantially reduces statistical prediction uncertainties compared to those obtained on the basis of a three-point extrapolation from the later part of the extraction curve. Numerical fitting of manually obtained polycyclic aromatic hydrocarbon extraction data to a spherical particle diffusion model showed uncertainties typically reduced by a factor of three (with extremes at 1.02 and 770). Application to pressurised fluid extraction study of pelletised poly(vinylchloride) containing 30 mass% di(2-ethylhexyl)phthalate also showed good improvements. However, this high precision data showed small but significant lack of fit resulting in residual correlation and visibly biased prediction (more so than simple extrapolation). Re-fitting and uncertainty estimation using a first-order autoregression approximation to the covariance matrix produced more realistic uncertainty estimates and closer parameter estimates and is accordingly recommended for treating residual correlation from other causes, but did not entirely alleviate the problem. Different shape models (spherical, plane sheet and cylindrical) were applied without accounting fully for fitting error, and particle size effects were eliminated by modelling a simple size distribution. However, an approximate model based on linearly concentration-dependent diffusion coefficient showed excellent fit, confirming concentration-dependence as the most likely cause. This semiempirical model led to an uncertainty in total extractable material, at 0.2% of the total extractable value (with allowance for correlation). This is potentially good enough for recovery estimation and correction in certification of reference materials for validation purposes.
AIMS: To examine changes in the prescribing of anti-depressants in New Zealand from 1993-1997, in terms of expenditure, the number of dispensings and days of therapy supplied. METHOD: Data on subsidised dispensings of anti-depressant drugs during 1993 to 1997 were obtained from PHARMAC and analysed using SAS. RESULTS: The overall size of the anti-depressant market increased considerably over the study period. Government expenditure rose 2.25 times, and 1.65 times as many days of anti-depressant medication were supplied in 1997 as in 1993. Most of this was due to the growth in prescribing of newer anti-depressants, but the use of older drugs remained constant. CONCLUSIONS: In common with other countries, the use of newer agents is contributing to increased overall use of anti-depressant medication and government expenditure in New Zealand. Use of older drugs has not diminished substantially.
AIMS: To examine regional differences in the prescribing of anti-depressants in New Zealand from 1993 to 1997, and to examine the composition and dynamics of these differences. METHODS: Data on every subsidised dispensing of anti-depressant drugs 1993 to 1997 were obtained from PHARMAC and analysed using SAS. Each dispensing was allocated to a regional council area on the basis of the location of the dispensing pharmacy. RESULTS: Prescribing of anti-depressants increased with time in all regions. However, there was substantial regional variation in prescribing rates per-capita, the highest being 2.28 to 2.49 times the lowest in every year. Regions also varied substantially in the mix of newer and older drugs used, although newer drugs became increasingly important in every region. CONCLUSIONS: Regional differences in anti-depressant prescribing are large. Further research with different data sources is required to explore the reasons for this variation.
Photodynamic Therapy (PDT), with topically applied 5-aminolaevulinic acid as the photosensitiser, is an effective treatment for various malignant and pre-malignant skin conditions. Several studies have shown the importance of fluence rate as well as fluence in the efficacy of PDT. We propose a measure of PDT efficacy, Photodynamic Damage Dose (PDD), which uses the product of instantaneous fluence rates, photosensitiser concentrations and oxygen concentrations in its calculation. We derive a qualitative numerical model of PDT and verify it by demonstrating an inverse fluence rate effect, increased efficacy of fractionated PDT, PDT induced hypoxia, and the dependence of photobleaching on fluence rate under certain circumstances. We recommend that fluence, fluence rate and any fractionation regime used should be detailed when reporting a trial as altering any of these has significant effects on PDT efficacy. The model predicts that low fluence rate irradiations should be as effective as high fluence rate irradiations if carried out over the same length of time. To test this we build a light emitting diode-based lamp (fluence rate of 7 mW cm(-2) at 635 nm) and used it to treat 32 superficial basal cell carcinomas on 22 patients (30 min treatment time, fluence 12.6 J cm(-2)). The complete response rate at one year was 84%, which is comparable to that achieved using higher fluence rate sources for similar treatment times. We conclude that this robust, inexpensive light source is effective for topical PDT.
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Treating partially protected sugar hemiacetals with triphosgene in THF results in the formation of glycosyl chlorides. The method is compatible with acid-sensitive isopropylidene protecting groups in the hemiacetal substrates.
The two photodermatoses, polymorphic light eruption (PLE) and chronic actinic dermatitis (CAD), are characterized by lymphocyte-rich inflammatory infiltrates, the pathogeneses of which are not fully understood. We have therefore studied suction blister fluid (SBF) samples from patients with these conditions before and at two time points after the induction of experimental lesions by means of a solar simulator; this SBF was then tested for the presence of selected cytokines known to induce peripheral blood lymphocyte (PBL) migration in vitro. A specific EL-4 NOB-1 bioassay was used to detect interleukin (IL)-1 activity, which has already been noted in normal skin and this was found in pre-irradiation control samples as well as 1-3 h and 24 h post-irradiation in both patient groups, but at levels not significantly different from those of controls. Use of a B9 cell proliferation assay showed no detectable IL-6-like activity pre-irradiation, but there was substantial activity in samples at both post-irradiation time points in both patient groups. Further, in other experiments, retained SBF samples were tested in an in vitro PBL migration assay in the presence and absence of neutralizing antibodies against IL-1 alpha, IL-1 beta, IL-6 and IL-8; considerable PBL attractant activity was noted in the pre-irradiation SBF from both patient groups; a finding consistent with previous reports of such activity in samples from normal skin, and at least in CAD patients, a proportion of this activity appeared to be due to IL-1, pre-incubation of SBF with neutralizing antibodies against IL-1 alpha and IL-1 beta reducing the effect significantly. Substantial PBL attractant activity was present also in the SBF from 1-3 h and 24 h post-irradiation samples in both patient groups and again, IL-1 neutralizing antibodies reduced this in the 1-3 h and 24 h CAD samples. In addition, neutralizing antibodies against IL-6 and IL-8 reduced the activity in the 24 h PLE samples significantly and although not fully conclusive in the case of IL-1, these data suggest that IL-6, IL-8 and possibly IL-1 may be involved in the induction of PBL infiltrates, and perhaps other events, in both PLE and CAD.
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Although not a member of the European Union (EU), Norway is part of the European internal market as a result of the European economic area (EEA) agreement. Before 1994, Norway had a distinctive set of arrangements for the licensing and distribution of medicines. Many of these have undergone considerable change as a result of European harmonisation. This paper describes the previous arrangements and the impact of European harmonisation on them. Significant changes have been made to the Norwegian marketing authorisation system because of the loss of the 'need clause' and changes in price control. These are described and an attempt is made to evaluate their impact. The development of parallel importing and the introduction of private wholesaling companies have led to the development of new players in the Norwegian drug market and an increase in competition both within and between levels of the pharmaceutical distribution chain. New co-operatives have also arisen to increase the negotiating power of purchasers, particularly hospitals. Further significant changes are likely to occur in the Norwegian pharmaceutical sector in the future. The Norwegian case study provides an opportunity to look at the impact of European harmonisation on a particular set of regulatory arrangements and sheds light on the difficulty of implementing European policy in a national setting.