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Biomedical subjects

M J Ford

Publications and source records attributed to M J Ford.

At least 19 recordsLinked to original sources
PubMed2006

Effect of composition and packing configuration on the dichroic optical properties of coinage metal nanorods.

When nanorods of Au, Ag and some other elements are aligned with a preferred orientation with respect to light, their optical extinction characteristics become dependent on the polarization and angle of incidence of the light. This effect is explored here and it is shown that it could potentially be exploited to produce a 'colour-change coating'. However, particle-particle interactions are also likely to occur in such coatings, with red shifting of extinction spectra occurring for end-on-end configurations of monodisperse rods, and blue shifting for side-by-side configurations. Surprisingly, the particle-particle interactions are attenuated if they are between rods of differing aspect ratios, and this offers a useful new means of control of the optical properties of coatings of nanorods.

Circular Dichroism↗
PubMed2005

Theoretical study of ethynylbenzene adsorption on Au(111) and implications for a new class of self-assembled monolayer.

Density functional calculations of the adsorption of ethynylbenzene on the Au(111) surface show that, after cleavage of the C-H bond, the terminal carbon makes a strong covalent bond to the surface. The bond energy is shown to be about 70 kcal.mol(-1) with the fcc hollow site being most stable and the molecule oriented perpendicular to the surface. Adsorption without elimination of hydrogen is also possible via a hydrogen 1,2 shift to form a vinylidene surface-bound species, or opening of the C-C triple bond and adsorption through the two carbon atoms in a flat conformation. The reaction energy for formation of the surface-bound vinylidene is estimated to be 5 kcal.mol(-1) exothermic relative to the isolated ethynylbenzene and gold substrate.

Journal Article↗
PubMed2002

A marked disparity between the expression of prion protein and its message by neurones of the CNS.

Expression of the normal cellular form of prion protein is both necessary and rate-limiting in the spread of prion disease, yet its cellular expression in vivo is poorly understood. To optimise immunohistochemical labelling of this protein in mouse brain, we have developed novel antibodies that recognise cellular prion protein in glutaraldehyde-fixed tissue. Expression was found to be predominantly neuronal, and to differ between different classes of neurone. Thus, neurones immunoreactive for GABA expressed very high levels of normal prion protein; most projection neurones expressed much lower levels, particularly on their axons in the major fibre tracts, and some neurones (e.g. those positive for dopamine) displayed no detectable prion protein. In marked contrast, all neurones, even those that were immunonegative, expressed high levels of message for prion protein, shown by non-radioactive in situ hybridisation. Glia expressed very low levels of message, and undetectable levels of prion protein. We conclude that the steady-state level of prion protein, which differs so markedly between different neuronal types, is primarily controlled post-transcriptionally, possibly by differences in protein trafficking or degradation. These marked differences in the way different neurones produce and/or degrade their normal cellular prion protein may influence the selective spread and neurotoxic targeting of prion diseases within the CNS.

Animals↗
PubMed2002

Selective expression of prion protein in peripheral tissues of the adult mouse.

The level of expression of normal cellular prion protein, PrP(c) (cellular prion protein), controls both the rate and the route of neuroinvasive infection, from peripheral entry portal to the CNS. Paradoxically, an overview of the distribution of PrP(c) within tissues outside the CNS is lacking. We have used novel antibodies that recognise cellular prion protein in glutaraldehyde-fixed tissue (in order to optimise immunohistochemical labelling of this conformationally labile protein), in combination with in situ hybridisation, to examine the expression of PrP(c) in peripheral tissues of the adult mouse. We found that although prion protein is expressed in many tissues, it is expressed at high levels only in discrete subpopulations of cells. Prominent amongst these are elements of the "hardwired neuroimmune network" that integrate the body's immune defence and neuroendocrine systems under CNS control. These prion protein-expressing elements include small diameter afferent nerves in the skin and the lamina propria of the aerodigestive tract, sympathetic ganglia and nerves, antigen presenting and processing cells (both follicular and non-follicular dendritic cells) and sub-populations of lymphocytes particularly in skin, gut- and bronchus-associated lymphoid tissues. Prion protein is also expressed in the parasympathetic and enteric nervous systems, in the dispersed neuroendocrine system, and in peripheral nervous system axons and their associated Schwann cells. This selective expression of cellular prion protein provides a variety of alternative routes for the propagation and transport of prion infection entering from peripheral sites, either naturally (via the aerodigestive tract or abraded skin) or experimentally (by intraperitoneal injection) to the brain. Key regulatory cells that express prion protein, and in particular enteroendocrine cells in the mucosal wall of the gut, and dendritic cells that convey pathogens from epithelial layers to secondary lymphoid organs, may be particularly important in the transmission of infection in the periphery.

Animals↗
PubMed2002

The effect of dietary selenium source and level on the uptake of selenium by developing chick embryos.

We studied the effect of dietary source (organic or inorganic) and level of Se on the Se uptake of chick embryos. After receiving a low-Se diet for 16 wk, 126 Leghorn laying hens were randomly assigned to one of seven dietary treatments. Treatments consisted of feeding a low-Se basal diet alone or with one of three levels of added Se (0.1,0.2, or 0.3 mg/kg Se) supplied by sodium selenite or Se-enriched yeast. Fertile eggs were collected after 33 d of feeding the experimental diets. Eggs were subjected to no incubation or incubation for 5, 10, 15, or 20 d. Non-incubated eggs were separated, and the yolk and albumen were assayed separately for Se. Incubated eggs were separated into the embryo and extra-embryonic portions, which were assayed separately for Se. Se concentrations of the yolk and albumen were significantly different among dietary treatments. Compared with eggs from hens fed sodium selenite, yolk and albumen Se concentrations were higher in eggs from hens fed Se yeast. Embryonic and extra-embryonic Se concentrations were higher in eggs from hens fed Se yeast than eggs from hens fed sodium selenite. The largest increase in embryonic Se concentration was observed during Days 10 to 15 of incubation. It was concluded that Se source and dietary inclusion level influenced the Se concentration of portions of developing embryonated eggs and that embryonic Se concentration changed during incubation.

Animals↗
PubMed2001

Hepatic intra-arterial delivery of a retroviral vector expressing the cytosine deaminase gene, controlled by the CEA promoter and intraperitoneal treatment with 5-fluorocytosine suppresses growth of colorectal liver metastases.

Targeting of colorectal liver metastases by regional gene therapy was tested in a clinically relevant syngeneic model. First, the CEA-CD-113 retroviral vector containing the cytosine deaminase gene controlled by the CEA specific tumour cell promoter, was shown in vitro to convert 5-fluorocytosine to 5-fluorouracil, resulting in cancer cell killing with a large bystander effect. Second, 10 days after the establishment of liver metastases, retroviral vectors were delivered to the liver by hepatic artery injection. After 5-fluorocytosine administration for 7 days, most surface metastases disappeared and tumour volumes were suppressed up to 8.2-fold. The results support the development of this approach for patient treatment.

Animals↗
PubMed2001

Molecular evolution of transferrin: evidence for positive selection in salmonids.

Transferrins are iron-binding proteins that are involved in iron storage and resistance to bacterial disease. Previous work has shown that nonsynonymous-to-synonymous-site substitution ratios (d(n)/d(s) ratios) between transferrin genes from some salmonid species were significantly greater than 1.0, providing evidence for positive selection at the transferrin gene. The purpose of the current study was to put these earlier results in a broader evolutionary context by examining variation among 25 previously published transferrin sequences from fish, amphibians, and mammals. The results of the study show that evidence for positive selection at transferrin is limited to salmonids-d(n)/d(s) ratios estimated for nonsalmonid lineages were generally less than 1.0. Within the salmonids, approximately 13% of the transferrin codon sites are estimated to be subject to positive selection, with an estimated d(n)/d(s) ratio of approximately 7. The three- dimensional locations of some of the selected sites were inferred by comparing these sites to homologous sites in the bovine lactoferrin crystallographic structure. The selected sites generally fall on the outside of the molecule, within and near areas that are bound by transferrin-binding proteins from human pathogenic bacteria. The physical locations of sites estimated to be subject to positive selection support previous speculation that competition for iron from pathogenic bacteria could be the source of positive selection.

Amino Acid Substitution↗
PubMed2000

Effects of natural selection on patterns of DNA sequence variation at the transferrin, somatolactin, and p53 genes within and among chinook salmon (Oncorhynchus tshawytscha) populations.

This paper describes DNA sequence variation within and among four populations of chinook salmon (Oncorhynchus tshawytscha) at the transferrin, somatolactin and p53 genes. Patterns of variation among salmon species at the transferrin gene have been hypothesized to be shaped by positive natural selection for new alleles because the rate of nonsynonymous substitution is significantly greater than the rate of synonymous substitution. The twin goals of this study were to determine if the history of selection among salmon species at the transferrin gene is also reflected in patterns of intraspecific variation in chinook salmon, and to look for evidence of local adaptation at the transferrin gene by comparing patterns of nonsynonymous and synonymous variation among chinook salmon populations. The analyses presented here show that unlike patterns of variation between species, there is no evidence of greater differentiation among chinook salmon populations at nonsynonymous compared to synonymous sites. There is also no evidence of a reduction of within-species variation due to the hitchhiking effect at the transferrin gene, although in some populations nonsynonymous and synonymous derived mutations are both at higher frequencies than expected under a simple neutral model. Population size weighted selection coefficients (4Ns) that are consistent with both the inter and intraspecific data range from approximately 10 to approximately 235, and imply that between 1 and 40% of new nonsynonymous mutations at the transferrin gene have been beneficial.

Alleles↗
PubMed1999

The human eukaryotic initiation factor 4AI gene (EIF4A1) contains multiple regulatory elements that direct high-level reporter gene expression in mammalian cell lines.

The gene encoding human eukaryotic initiation factor 4A (EIF4A1) is located on chromosome 17p13, 667 bp upstream from the gene encoding the macrophage endosomal protein CD68. The EIF4AI gene contains 10 intervening sequences with the 1397-bp first intron containing a CpG-rich methylation-free island. Sequences capable of enhancing gene expression reside between positions -69 and -371 and positions -504 and -1100 of the EIF4AI 5' flanking sequence and within introns 1, 2, 3, 7, and 9. In macrophage cell lines, EIF4A1 expression vectors give sustained high-level reporter gene expression to levels 10 times higher than that obtained using the human cytomegalovirus immediate-early gene promoter/enhancer. Sequences of the human EIF4AI gene may find application in the development of new vectors for gene therapy and genetic vaccination.

5' Untranslated Regions↗
PubMed1999

Natural selection promotes divergence of transferrin among salmonid species.

Transferrin is an iron-binding protein that plays an important role in iron metabolism and resistance to bacterial infection in a variety of organisms. A comparison of transferrin coding sequences from four salmonid species shows that the rate of evolution at nonsynonymous sites is significantly higher than the rate at synonymous sites, suggesting that positive natural selection for new alleles has played an important role in the evolution of transferrin in some salmon species. We hypothesize that the selective agent driving rapid divergence is interactions between host transferrin and the iron-scavenging proteins of pathogenic bacteria.

Alleles↗
PubMed1999

Can general practitioner referral letters for acute medical admissions be improved?

BACKGROUND: General practitioner (GP) referral letters for emergency medical admissions should contain enough information to ensure that patients are managed safely and effectively. AIM: Our aim was to assess the quality of referral letters for acute medical admissions. METHOD: GP letters from 300 consecutive acute medical admissions were prospectively assessed by the admitting doctor and then independently assessed by a senior house officer (SHO), and a senior registrar. A random sample of 25 were assessed by a general practitioner. Content and legibility were evaluated for demographic details, current history, past history, social history, drugs and allergies, in order to grade the overall quality as "excellent", "good", "adequate" or "inadequate". RESULTS: Two hundred and ninety one letters were received, of which 208 (71%) were from the patients' own GP practice and 83 (28%) from a co-operative or deputising service. The admitting doctor rated 38 (13%) as excellent, 108 (37%) as good, 96 (33%) as adequate and 49 (17%) as inadequate. Kappa values for overall quality between the admitting doctors and the other doctors (senior house officer, senior registrar and our general practitioner) were 0.32, 0.26 and 0.44 respectively, representing fair to moderate interobserver agreement. Co-operatives or deputising services used proformas more often than GP practices (65/83, 78% and 17/208, 8% respectively, p < 0.01). There was no significant difference in overall quality between GP practices and co-operatives or deputising services, or between letters received on headed note paper or proformas. CONCLUSION: Most letters are satisfactory for the individual management of acutely ill patients, but collaborative work could usefully be undertaken to address the factors which result in the production of sub-optimal referral letters.

Acute Disease↗
PubMed1999

Hypersensitivity reactions to parenteral vitamin K.

Cutaneous hypersensitivity reactions to vitamin K are rare. They occur almost exclusively with fat-soluble vitamin K (K1). The lesion is most commonly a pruritic, indurated plaque at the site where the vitamin was injected. Most plaques resolve within 4 to 8 week without sequelae, but some progress to produce scar-like changes that may last for years.

Adult↗
PubMed1998

Virus directed enzyme prodrug therapy for ovarian and pancreatic cancer using retrovirally delivered E. coli nitroreductase and CB1954.

Expression of the E. coli enzyme nitroreductase (NTR) in tumour cells enables them to activate the prodrug CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide), leading to interstrand DNA crosslinking and cell death. Using transfected or retrovirally transduced SKOV3 ovarian carcinoma cell clones, we show a strong correlation between sensitivity to CB1954 and level of NTR enzyme activity. Importantly for clinical application in ovarian cancer, a cisplatin-resistant ovarian tumour cell line remains as susceptible to the NTR-dependent cytotoxicity of CB1954 as parental cells. In mixed populations of NTR-expressing and non-expressing cells, we observe a marked 'bystander killing' effect with this system. The use of NTR-encoding retroviruses from clonal producer cell lines at titres of 5 x 10(5) c.f.u./ml to transduce either established or low passage primary ovarian carcinoma lines only achieves an average 10-fold sensitisation of the cultures at gene transfer efficiencies of 15-25%. Concentration of the retrovirus to 3 x 10(7) c.f.u./ml elevates gene transfer to 80-90% in a single exposure to target cells, resulting in up to 500-fold sensitisation of the entire, unselected SKOV3 population to CB1954. In an initial investigation of NTR/CB1954 for the treatment of tumours in vivo, we observe regression of tumours expressing NTR following administration of CB1954, resulting in significantly increased median survival.

Animals↗