Biomedical subjects

A J Smith

Publications and source records attributed to A J Smith.

At least 19 recordsLinked to original sources

PubMed2007

Instabilities in vertically vibrated fluid-grain systems.

When a bed of fluid-immersed fine grains is exposed to vertical vibration a wealth of phenomena may be observed. At low frequencies a horizontal bed geometry is generally unstable and the bed breaks spatial symmetry, acquiring a tilt. At the same time it undergoes asymmetric granular convection. Fine binary mixtures may separate completely into layers or patterns of stripes. The separated regions may exhibit instabilities in which they undergo wave-like motion or exhibit quasi-periodic oscillations. We briefly review these and a number of related behaviours, identifying the physical mechanisms behind each. Finally, we discuss the magneto-vibratory separation of binary mixtures which results from exposing each component to a different effective gravity and describe the influence of a background fluid on this process.

Journal Article↗

PubMed2006

Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium.

Previous studies have tested gene replacement therapy in RPE65-deficient dogs using recombinant adeno-associated virus 2/2 (rAAV2/2), -2/1 or -2/5 mediated delivery of the RPE65 gene. They all documented restoration of dark- and light-adapted electroretinography responses and improved psychophysical outcomes. Use of a specific RPE65 promoter and a rAAV vector that targets transgene expression specifically to the RPE may, however, provide a safer setting for the long-term therapeutic expression of RPE65. Subretinal injection of rAAV2 pseudotyped with serotype 4 (rAAV2/4) specifically targets the RPE. The purpose of our study was to evaluate a rAAV2/4 vector carrying a human RPE65cDNA driven by a human RPE65 promoter, for the ability to restore vision in RPE65-/- purebred Briard dogs and to assess the safety of gene transfer with respect to retinal morphology and function. rAAV2/4 and rAAV2/2 vectors containing similar human RPE65 promoter and cDNA cassettes were generated and administered subretinally in eight affected dogs, ages 8-30 months (n = 6 with rAAV2/4, n = 2 with rAAV2/2). Although fluorescein angiography and optical coherence tomography examinations displayed retinal abnormalities in treated retinas, electrophysiological analysis demonstrated that restoration of rod and cone photoreceptor function started as soon as 15 days post-injection, reaching maximal function at 3 months post-injection, and remaining stable thereafter in all animals treated at 8-11 months of age. As assessed by the ability of these animals to avoid obstacles in both dim and normal light, functional vision was restored in the treated eye, whereas the untreated contralateral eye served as an internal control. The dog treated at a later age (30 months) did not recover retinal function or vision, suggesting that there might be a therapeutic window for the successful treatment of RPE65-/- dogs by gene replacement therapy.

Animals↗

PubMed2006

Postmenopausal hormone therapy and quality of life.

OBJECTIVE: To evaluate whether hormonal therapy (HT) had any significant effect on quality of life (QoL) in a selected group of postmenopausal women. METHODS: The study was conducted in a specialist private practice in Tygerberg, Cape Town, South Africa, over an 18-month period ending in July 2003. A questionnaire using the Utian Quality of Life (UQoL) scale was posted to all women with established postmenopausal status, seen over this period. 541 questionnaires were posted, 421 returned and 398 could be used. Women gave written informed consent. RESULTS: The average age of the women was 60 years. 313 women (78.6%) were using hormone therapy (HT) while 275 women (69.1%) reported concomitant medical problems. HT users had significantly higher scores in three of the four QoL domains, namely, occupational (p=0.046), emotional (p=0.03), and sexual (p=0.009). There was no significant difference in the health domain (p=0.2). CONCLUSION: This study found that post-menopausal South African women experienced that HT had a positive effect on global quality of life.

Emotions↗

PubMed2006

EIAV vector-mediated delivery of endostatin or angiostatin inhibits angiogenesis and vascular hyperpermeability in experimental CNV.

We evaluated the efficacy of equine infectious anaemia virus (EIAV)-based lentiviral vectors encoding endostatin (EIAV.endostatin) or angiostatin (EIAV.angiostatin) in inhibiting angiogenesis and vascular hyperpermeability in the laser-induced model of choroidal neovascularisation (CNV). Equine infectious anaemia virus.endostatin, EIAV.angiostatin or control (EIAV.null) vectors were administered into the subretinal space of C57Bl/6J mice. Two weeks after laser injury CNV areas and the degree of vascular hyperpermeability were measured by image analysis of in vivo fluorescein angiograms. Compared with EIAV.null-injected eyes, EIAV.endostatin resulted in a 59.5% (P<0.001) reduction in CNV area and a reduction in hyperpermeability of 25.6% (P<0.05). Equine infectious anaemia virus.angiostatin resulted in a 50.0% (P<0.05) reduction in CNV area and a 23.9% (P<0.05) reduction in hyperpermeability. Equine infectious anaemia virus.endostatin, but not EIAV.angiostatin significantly augmented the frequency of apoptosis within the induced CNV as compared with injected controls. TdT-dUTP terminal nick end labeling analysis 5 weeks post-injection, and histological and retinal flatmount analysis 12 months post-injection revealed no evidence of vector- or transgene expression-related deleterious effects on neurosensory retinal cells, or mature retinal vasculature in non-lasered eyes. Highly expressing EIAV-based vectors encoding endostatin or angiostatin effectively control angiogenesis and hyperpermeability in experimental CNV without long-term deleterious effects, supporting the use of such a strategy in the management of patients with exudative age-related macular degeneration.

Angiogenesis Inhibitors↗

PubMed2006

Differential sensitivity of flounder (Platichthys flesus) in response to oestrogenic chemical exposure: an issue for design and interpretation of monitoring and research programmes.

This study was conducted as an initial investigation of 'differential response' in one of the main sentinel organisms used for monitoring programmes in United Kingdom estuaries, the flounder Platichthys flesus. It has been hypothesised that monitoring using species with a wide geographical spread and limited migration, such as flounder, might result in the comparison of different genetic stocks and certainly of populations with differing early life stage contaminant exposure histories. Furthermore, it is probable that these pre-exposure and genetic differences could manifest themselves in an ability to respond differently to contaminant exposure, so-called 'differential response'. It is important that the extent and nature of this response is understood, if we want to be able to fully interpret the monitoring data from such programmes. During this study, flounder were collected from four separate sources; wild caught fish from the estuaries of the Rivers Alde, Mersey and Tyne, and farmed flounder from Port Erin Farm, Isle of Man. Under controlled laboratory conditions, groups of fish from each source were exposed to water-borne concentrations of the synthetic oestrogen ethynylestradiol (EE2) at a nominal concentration of 50 ng/l. Plasma was taken from each male fish after 6 and 10 days exposure and analysed for the presence of vitellogenin (VTG) using an ELISA technique. Significant levels of VTG induction were evident in fish from all sources after both 6 and 10 days exposure. Flounder from the Mersey were the only fish with significantly elevated initial background levels of VTG (day 0) and this appeared to be reflected in that these specimens showed the highest induction response after day 6. However, after day 10, fish from all other sites had a slightly higher mean VTG than those from the Mersey which showed significantly (p < 0.05) lower mean plasma VTG. It is suggested that other differential responses may have been masked by the use of a high dose of EE2 which produced maximum induction in nearly all fish. The findings of the study are discussed in terms of implications for further research into the differential response issue and how the initial plasma VTG figures contribute to a time-series from the Mersey, Tyne and Alde estuaries.

Animals↗

PubMed2006

Exploring the use of caged Nucella lapillus to monitor changes to TBT hotspot areas: a trial in the River Tyne estuary (UK).

Caged dogwhelks (Nucella lapillus) and mussels (Mytilus edulis) were placed in situ at sites along the River Tyne (UK) in order to investigate the potential for monitoring any change in tributyltin (TBT) mediated effects. After 6 months the development of imposex was investigated in the dogwhelks and concentrations of TBT were determined in the whole tissues of both species. Sites within the estuary showed a high degree of imposex, whilst those at sites North and South of the estuary mouth exhibited significantly lower induction. Concentrations of TBT measured in the dogwhelk and mussel tissues showed the same pattern. The success of the caging technique, occurrence of imposex at other UK sites and the need for further monitoring at TBT impacted locations in the light of current international controls on the use of TBT-based antifouling paints on sea-going vessels are discussed.

Animals↗

PubMed2006

The JAK3 inhibitor WHI-P154 prevents PDGF-evoked process outgrowth in human neural precursor cells.

The prospect of manipulating endogenous neural stem cells to replace damaged tissue and correct functional deficits offers a novel mechanism for treating a variety of CNS disorders. The aim of this study was to investigate pathways controlling neurite outgrowth in human neural precursor cells, in particular in response to platelet-derived growth factor (PDGF). PDGF-AA, -AB and -BB were found to initiate calcium signalling and produce robust increases in neurite outgrowth. PDGF-induced outgrowth of Tuj1-positive precursors was abolished by the addition of EGTA, suggesting that calcium entry is a critical part of the signalling pathway. Wortmannin and PD098059 failed to inhibit PDGF-induced outgrowth. Clostridium Toxin B increased the amount of PDGF-induced neurite branching but had no effect on basal levels. In contrast, WHI-P154, an inhibitor of Janus protein tyrosine kinase (JAK3), Hck and Syk, prevented PDGF-induced neurite outgrowth. PDGF activates multiple signalling pathways with considerable potential for cross-talk. This study has highlighted the complexity of the pathways leading to neurite outgrowth in human neural precursors, and provided initial evidence to suggest that calcium entry is critical in producing the morphological changes observed.

Calcium↗

PubMed2006

Qualitative assessment of patient experiences related to extended pelvic resection for rectal cancer.

BACKGROUND: Patients with locally advanced rectal cancer (LARC) and locally recurrent rectal cancer (LRRC) represent a complex management challenge. While there is potential for cure in a subset of patients, the cost in terms of morbidity can be high. Few descriptions of the physical, psychological, social, and emotional experiences of these patients exist. METHODS: Face-to-face interviews were completed with ten LARC and LRRC patients treated with multimodal therapy that included surgery. Patient opinions and experiences were explored in depth until information redundancy and common themes were delineated using qualitative research methods. Clinical information was obtained from the database. RESULTS: Nine of the ten patients were male, seven had LARC, and the median age was 71. Six themes were identified from the patient interviews. Themes reflected patients' highly focused desire to seek wellness and cure, but also revealed misunderstanding of their disease biology, probability of cure, therapeutic options, and treatment morbidity. CONCLUSIONS: Patient experiences confirm that this is challenging treatment to complete, and that patient understanding of pre-operative information is incomplete. Our findings underscore the need for a multidisciplinary approach when managing this patient population, with emphasis on both supportive care needs and the technically skilled delivery of surgery, chemotherapy, and radiotherapy.

Adult↗

PubMed2006

Distribution of epidemic antibiotic-resistant pneumococcal clones in Scottish pneumococcal isolates analysed by multilocus sequence typing.

Sequence types of pneumococci isolated in Scotland between 1996 and 2003 were compared with those of globally prevalent antibiotic-resistant clones. Multilocus sequence typing was performed on 252 invasive pneumococcal isolates referred to the Scottish Meningococcus and Pneumococcus Reference Laboratory. Isolates were not preselected for antimicrobial resistance, patient age or disease caused. Sequence types were compared with globally significant antimicrobial-resistant clones identified by the Pneumococcal Molecular Epidemiology Network (PMEN). Sequence types identical with three of the 26 PMEN clones were present in the Scottish collection; the clones were the Spain(9V)-3 clone (sequence type 156, seven isolates), the England(14)-9 clone (sequence type 9, eight isolates) and the Utah(35B)-24 clone (sequence type 377, one isolate). Many Scottish isolates related to PMEN clones had lower antimicrobial MICs than those described for the corresponding PMEN type strain. A number of single- (SLVs) and double-locus variants (DLVs) were present. Fifteen SLVs related to PMEN sequence types 37, 67, 90, 81, 156, 236 and 377 were detected. The collection contained 10 DLVs related to PMEN sequence types 37, 156, 173 and 338. The majority of SLVs and DLVs were penicillin- or erythromycin-sensitive variants of the resistant PMEN type strains. Capsule switching in isolates related to the PMEN clones was also detected. The highest levels of penicillin resistance were detected in sequence type 320 (serotype 19F), which is not a PMEN clone. These data suggest that PMEN clones are not widely distributed in disease-causing isolates in Scotland.

Anti-Bacterial Agents↗

PubMed2006

Dental follicle infection following a dog bite.

Animal bite wounds and their subsequent infection are relatively common. Incidence rates for dog bites are significantly higher among children aged 0-9 years, especially among boys. Although bite wounds may initially look innocuous, they frequently lead to serious infection with a potential for life-threatening complications. The microbiology of dog bite wounds is usually polymicrobial, typically including anaerobes, Staphylococcus aureus and Pasteurella species. A case is described of a 22-month-old boy who, subsequent to a dog bite over the left maxilla, suffered infection of the dental follicle of the primary maxillary canine with Pasteurella multocida. The infection proved difficult to treat, requiring several attempts at incision and drainage of the abscess together with systemic antibiotics, and resulted in the eventual loss of the tooth.

Animals↗

PubMed2006

Reactionary dentinogenesis after applying restorative materials and bioactive dentin matrix molecules as liners in deep cavities prepared in nonhuman primate teeth.

OBJECTIVE: The aim of this in vivo study was to evaluate the response of the pulp-dentin complex following application of resin-modified glass-ionomer cement, calcium hydroxide hard-setting cement and EDTA-soluble preparation of dentine matrix proteins (ESDP) in deep cavities prepared in non-human primate teeth. METHODS: Eighteen deep Class V buccal cavities were prepared in premolars of four capuccin monkeys. In Groups 1 and 2, the cavity floor was lined with ESDP or a resin-modified glass-ionomer cement (Vitrebond - 3M ESPE), respectively. In Group 3 (control), the cavity was lined with a hard setting calcium hydroxide cement (Dycal - Dentsply). The cavities were subsequently filled with amalgam. After 6 months, the animals were sacrificed and the teeth were prepared for microscopic assessment. Six-micron thick serial sections were stained with H/E, Masson's trichrome and Brown & Brenn techniques. RESULTS: No inflammatory pulpal response was observed for all experimental and control Groups. However, the amount of reactionary dentin deposition differed between groups in the rank order ESDP (Group 1) > calcium hydroxide (Group 3) > resin-modified glass-ionomer (Group 2). These differences were statistically significant. CONCLUSIONS: All materials were biocompatible when applied in deep cavities. ESDP stimulated higher deposition of reactionary dentin matrix than Vitrebond and Dycal.

Animals↗

PubMed2006

Guidelines for health and welfare monitoring of fish used in research.

The aim of this paper is to provide background material necessary for the development of international guidelines for the health and welfare monitoring of fish used in research. It provides an overview of present guidelines and discusses why more detailed and species-specific guidelines are needed. A major issue within fish research is to document the situation today and point out areas where improvements are needed.

Animal Welfare↗

PubMed2005

Evidence for TeV gamma-ray emission from a region of the galactic plane.

Gamma-ray emission from a narrow band at the galactic equator has previously been detected up to 30 GeV. We report evidence for a TeV gamma-ray signal from a region of the galactic plane by Milagro, a large-field-of-view water Cherenkov detector for extensive air showers. An excess with a significance of 4.5 standard deviations has been observed from the region of galactic longitude l E (40 degrees, 100 degrees) and latitude /b/ < 5 degrees. Under the assumption of a simple power law spectrum, with no cutoff in the EGRET-Milagro energy range, the measured integral flux is phi gamma(>3.5 TeV) = (6.4 +/- 1.4 +/- 2.1) x 10(-11) cm(-2) s(-1) sr(-1). This flux is consistent with an extrapolation of the EGRET spectrum between 1 and 30 GeV in this galactic region.

Journal Article↗

PubMed2005

An inverse agonist selective for alpha5 subunit-containing GABAA receptors enhances cognition.

Alpha5IA is a compound that binds with equivalent subnanomolar affinity to the benzodiazepine (BZ) site of GABA(A) receptors containing an alpha1, alpha2, alpha3, or alpha5 subunit but has inverse agonist efficacy selective for the alpha5 subtype. As a consequence, the in vitro and in vivo effects of this compound are mediated primarily via GABA(A) receptors containing an alpha5 subunit. In a mouse hippocampal slice model, alpha5IA significantly enhanced the burst-induced long-term potentiation of the excitatory postsynaptic potential in the CA1 region but did not cause an increase in the paroxysmal burst discharges that are characteristic of convulsant and proconvulsant drugs. These in vitro data suggesting that alpha5IA may enhance cognition without being proconvulsant were confirmed in in vivo rodent models. Hence, alpha5IA significantly enhanced performance in a rat hippocampal-dependent test of learning and memory, the delayed-matching-to-position version of the Morris water maze, with a minimum effective oral dose of 0.3 mg/kg, which corresponded to a BZ site occupancy of 25%. However, in mice alpha5IA was not convulsant in its own right nor did it potentiate the effects of pentylenetetrazole acutely or produce kindling upon chronic dosing even at doses producing greater than 90% occupancy. Finally, alpha5IA was not anxiogenic-like in the rat elevated plus maze nor did it impair performance in the mouse rotarod assay. Together, these data suggest that the GABA(A) alpha5-subtype provides a novel target for the development of selective inverse agonists with utility in the treatment of disorders associated with a cognitive deficit.

Animals↗

PubMed2005

A study of visual and blood contamination on reprocessed endodontic files from general dental practice.

OBJECTIVE: This study examined methods used for reprocessing endodontic instruments in general dental practice and determined the degree of residual visual contamination and blood contamination on 250 reprocessed files collected from 25 general dental practices. MATERIALS AND METHODS: A questionnaire was administered to 25 general dental practitioners to obtain information on the re-processing of used endodontic files. Ten files which had been used and reprocessed were also collected from each practice. These were examined visually under a dissecting light microscope for residual contamination and then tested for blood deposits using the Kastle-Meyer test. RESULTS: Nineteen of the 25 practices used stainless steel hand files. No practitioners used endodontic files as single use devices. Ninety-two per cent of the practitioners discarded and replaced files when they were bent or damaged. Several decontamination methods were reported. The two combinations employed most frequently were manual cleaning and autoclaving or manual cleaning, followed by ultrasonic cleaning and autoclaving. Of the 250 files, 75% showed some degree of visual contamination and seven percent tested positive for residual blood. Blood contaminated files were significantly more heavily contaminated when examined visually. Large variations were found in residual contamination of files collected from practices using the same methods of decontamination. CONCLUSIONS: While all practitioners re-used endodontic files, the variations in decontamination methods reported indicate a lack of clarity on best practice. This study demonstrates that endodontic files are not reliably decontaminated by methods currently employed in dental practice.

Blood↗

PubMed2005

Antimicrobial susceptibility testing of Actinomyces species with 12 antimicrobial agents.

OBJECTIVE: This study was conducted to assess the susceptibility of human clinical isolates of Actinomyces species to 12 antimicrobial agents. METHODS: Human clinical isolates of Actinomyces spp. were collected from stored collections held at the Microbiology Department, Edinburgh University, Anaerobe Reference Laboratory, Cardiff, Glasgow Dental Hospital and Glasgow Royal Infirmary. Each isolate was identified by restriction analysis of amplified 16S ribosomal DNA. MICs of 12 antibiotics comprising benzyl penicillin, amoxicillin, ceftriaxone, linezolid, tetracycline, deoxycycline, clindamycin, erythromycin, clarithromycin, ciprofloxacin, meropenem and piperacillin/tazobactam for 87 strains of Actinomyces species were obtained by Etest methodology. RESULTS: The Actinomyces species identified for this study comprised: Actinomyces israelii, Actinomyces gerencseriae, Actinomyces turicensis, Actinomyces funkei, Actinomyces graevenitzii and Actinomyces europaeus. All isolates were susceptible to penicillin and amoxicillin. All but one strain of A. turicensis was susceptible to linezolid. A number of A. europaeus and A. graevenitzii isolates were resistant to ceftriaxone and piperacillin/tazobactam. A number of isolates of A. turicensis and A. europaeus also demonstrated resistance to erythromycin. All Actinomyces species tested appeared resistant to ciprofloxacin. CONCLUSIONS: Actinomyces species appear to be susceptible to a wide range of beta-lactam agents and these, when combined with beta-lactamase inhibitors, should be regarded as agents of first choice. Ciprofloxacin performed poorly. Tetracyclines also demonstrated poor performance. This is the first study of antimicrobial susceptibilities for a number of accurately identified clinical isolates of Actinomyces spp. There are a number of species differences in susceptibility profiles to the antimicrobials tested, suggesting that accurate identification and speciation may have an impact on clinical outcome.

Actinomyces↗

PubMed2005

Traveling waves in a water-immersed binary granular system vibrated within an annular cell.

It has been known since the time of Faraday that vertically vibrated fine grains may spontaneously form piles through their interaction with a fluid. More recently, it has been observed that a fine binary mixture may separate under vertical vibration through the differential influence of the fluid on the two granular components. Here, we report a detailed study of a system of water-immersed bronze and glass grains held between two coaxial cylinders. Under vertical vibration, the bronze separates to form a layer above the glass, which itself breaks symmetry to form a pile. Symmetry is broken a second time by the bronze forming layers of different thicknesses upon the two slopes of the glass pile. The pile then travels as a wave with the thicker bronze layer upon its leading surface. We examine the conditions for these traveling waves and determine how their speed varies with particle size, frequency, and amplitude of vibration. A model is developed which provides a semiquantitative account of the wave motion.

Journal Article↗

PubMed2005

RNA polymerase mutants defective in the initiation of transcription-coupled DNA repair.

The bacterial Mfd protein is a transcription-repair coupling factor that performs two key functions during transcription-coupled DNA repair. The first is to remove RNA polymerase (RNAP) complexes that have been stalled by a DNA lesion from the site of damage, and the second is to mediate the recruitment of DNA repair proteins. Mfd also displaces transcription complexes that have been stalled by protein roadblocks, and catalyses the reactivation of transcription complexes that have become 'backtracked'. We have identified amino acid substitutions in the beta subunit of Escherichia coli RNAP that disrupt a direct interaction between Mfd and RNAP. These substitutions prevent Mfd displacing stalled RNAP from DNA in vivo and in vitro. They define a highly conserved surface-exposed patch on the beta1 domain of RNAP that is required by Mfd for the initial step of transcription-coupled repair, the enhancement of roadblock repression and the reactivation of backtracked transcription complexes.

Amino Acid Sequence↗