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Biomedical subjects

A C Mitchell

Publications and source records attributed to A C Mitchell.

At least 19 recordsLinked to original sources

Prospects for applications of lanthanide-based upconverting surfaces to bioassay and detection.

Biological assays to detect binding interactions are often conducted using fluorescence resonance energy transfer (FRET) but this has several disadvantages that markedly reduce the dynamic range of measurements. The very short range of FRET interactions also causes difficulties when large analytes such as viruses or spores are to be detected. Conventional FRET-based assays can in principle be improved using infrared-excited upconverting lanthanide-based energy donors but this does not address the short range of the FRET process. Here we investigate an alternative mode of energy transfer based on evanescent wave coupling from an erbium-doped waveguide to an absorbed fluorophore and characterise the luminescence from the dopant. The upconverted erbium emission is highly structured with well-separated bands in the violet, green and red spectral regions and very little detectable signal between the peaks. The relative intensity of these bands depends on power-density of infrared excitation. Green emission predominates at low power-density and red emission increases more rapidly as power-density increases, with a smaller violet peak also emerging. The temporal response of the upconverting material to pulsed infrared excitation was investigated and was shown to vary markedly with emission wavelength with the red component being particularly sensitive to the duration of the excitation pulse. A surface monolayer of the fluorescent protein R-phycoerythrin was very easily detected on binding to an upconverting waveguide. The potential advantages and limitations of the evanescent wave excitation technique for fluorescence detection are discussed and avenues for further development are considered.

Biological Assay↗

Total internal reflection fluorescence imaging using an upconverting cover slip for multicolour evanescent excitation.

Total internal reflection fluorescence microscopy is well known as a means of studying surface-bound structures in cell biology. It is usually measured either by coupling a light source to the sample using a prism or with a special objective where light passing through the periphery of the lens illuminates the contact region beyond the critical angle. In this study we present a new and simple approach to total internal reflection fluorescence microscopy where the sample is mounted on a cover slip prepared from a high-index upconverting glass-ceramic. Excitation of the cover slip with a low-cost near-infrared laser diode generates intense narrow-band visible emission within the cover slip, some of which is totally internally reflected. This emission gives rise to an evanescent wave at the interface and hence can excite surface-bound fluorescent species. Depending on the excitation conditions the cover slip can generate violet, green and red emission and hence can excite a wide range of fluorescent labels. Fluorescence emission from the sample can be detected in spectral regions where the direct emission from the cover slip is very weak. The advantages and limitations of the technique are discussed in comparison with conventional total internal reflection fluorescence microscopy measurements and prospects for novel total internal reflection fluorescence microscopy geometries are considered.

Journal Article↗

Metallization of fluid nitrogen and the mott transition in highly compressed low-Z fluids.

Electrical conductivities are reported for degenerate fluid nitrogen at pressures up to 180 GPa (1.8 Mbar) and temperatures of approximately 7000 K. These extreme quasi-isentropic conditions were achieved with multiple-shock compression generated with a two-stage light-gas gun. Nitrogen undergoes a nonmetal-metal transition at 120 GPa, probably in the monatomic state. These N data and previous conductivity data for H, O, Cs, and Rb are used to develop a general picture of the systematics of the nonmetal-metal transition in these fluids. Specifically, the density dependences of electrical conductivities in the semiconducting fluid are well correlated with the radial extent of the electronic charge-density distributions of H, N, O, Cs, and Rb atoms. These new data for N scale with previous data for O, as expected from their similar charge-density distributions.

Journal Article↗

Direct modulation of the effective sensitivity of a CCD detector: a new approach to time-resolved fluorescence imaging.

In this paper a novel approach to frequency-domain fluorescence lifetime imaging (FLIM) is described. In a CCD camera a single pixel is defined by a charge pattern on a group of electrodes. By modulation of the pattern of voltages defining the pixel structure it is possible to modulate the sensitivity of the CCD at radio frequency. The modulation enhances the noise performance of the CCD, in contrast to the deterioration in performance seen when an intensifier stage is similarly modulated. The new technology has potential applications to a wide range of assays as well as in conventional FLIM applications. Unlike intensifier-based systems, the directly modulated CCD is physically small, inexpensive, robust and offers superior resolution and noise performance.

Journal Article↗

Measurement of nanosecond time-resolved fluorescence with a directly gated interline CCD camera.

CCD cameras coupled optically to gated image intensifiers have been used for fast time-resolved measurements for some years. Image intensifiers have disadvantages, however, and for some applications it would be better if the image sensor could be gated directly at high speed. Control of the 'charge drain' function on an interline-transfer CCD allows the sensor to be switched rapidly from an insensitive state. The temporal and spatial properties of the charge drain are explored in the present paper and it is shown that nanosecond time resolution with acceptable spatial uniformity can be achieved for a small commercial sensor. A fluorescence lifetime imaging system is demonstrated, based on a repetitively pulsed laser excitation source synchronized to the CCD control circuitry via a programmable delay unit.

Journal Article↗

High pressure insulator-metal transition in molecular fluid oxygen.

We report the first experimental evidence for a metallic phase in fluid molecular oxygen. Our electrical conductivity measurements of fluid oxygen under dynamic quasi-isentropic compression show that a nonmetal-metal transition occurs at 3.4 fold compression, 4500 K, and 1.2 Mbar. We discuss the main features of the electrical conductivity dependence on density and temperature and give an interpretation of the nature of the electrical transport mechanisms in fluid oxygen at these extreme conditions.

Journal Article↗

An unusual case of chronic neuropathic pain responds to an optimum frequency of intravenous ketamine infusions.

The effective treatment of patients suffering from a variety of difficult pain syndromes, including phantom pain and other neuropathic pains, remains a clinical challenge. Neuropathic pain has been shown to respond to drugs that block the N-methyl-D-aspartate (NMDA) receptor, such as ketamine and amantidine. A 44-year-old woman with a previous right-sided forequarter amputation presented to the Palliative Medicine Team complaining of neuropathic pain in her left arm, which was neurologically intact. The pain was treated with repeated infusions of intravenous ketamine. Twenty-one infusions were given over a period of four months. The pain intensity experienced by the patient lessened as the frequency of the ketamine infusions increased. This finding has not been described previously and supports the theory that there may be an optimum frequency of ketamine infusions to achieve adequate pain control.

Adult↗

Fast laser-induced solute release from liposomes sensitized with photochromic lipid: effects of temperature, lipid host, and sensitizer concentration.

Liposomes of gel-phase phospholipid have been prepared containing a photochromic lipid sensitizer. A fast UV laser pulse isomerizes the sensitizer destabilizing the lipid bilayer structure and causing release of trapped solute. The kinetics of solute release have been investigated as a function of host lipid chain length, sensitizer concentration, and temperature, and the limits of liposome stability have been established. At low concentrations of sensitizer, pulsed laser irradiation induces some solute release when continuous UV illumination is ineffective. Although rates of solute release usually increase with temperature, at low sensitizer concentration in a rigid host, leakage at first increases but then decreases rapidly above a threshold temperature. The results presented are relevant to the design of photostimulated drug delivery systems and to potential applications of photosensitive liposomes as caging agents for biological effectors.

Dose-Response Relationship, Radiation↗

Metallization and electrical conductivity of hydrogen in Jupiter.

Electrical conductivities of molecular hydrogen in Jupiter were calculated by scaling electrical conductivities measured at shock pressures in the range of 10 to 180 gigapascals (0.1 to 1.8 megabars) and temperatures to 4000 kelvin, representative of conditions inside Jupiter. Jupiter's magnetic field is caused by convective dynamo motion of electrically conducting fluid hydrogen. The data imply that Jupiter should become metallic at 140 gigapascals in the fluid, and the electrical conductivity in the jovian molecular envelope at pressures up to metallization is about an order of magnitude larger than expected previously. The large magnetic field is produced in the molecular envelope closer to the surface than previously thought.

Electric Conductivity↗

Fluorescence lifetime imaging: an emerging technique in fluorescence microscopy.

Fluorescence microscopy is an important tool for biological research, in part because of the extremely high detection sensitivity that can be achieved, but also because fluorescent molecules can be used as probes on account of their environmental responsiveness, for example to measure intracellular pH or metal ion concentration. Unfortunately, the environmental sensitivity can sometimes be a source of problems because of enhancement or 'quenching', which can make it very difficult to relate emission intensity to the amount of fluorophore present. The measured intensity is essentially proportional to the product of the amount of fluorophore present in the sample and the local quantum yield of the fluorophore (the quantum yield can be thought of as the probability that an excited molecule decays by fluorescence emission rather than by other non-radiative processes). This is a particular difficulty in an environment such as a cell or tissue slice in which quantum yield and flurophore concentration can both vary within the sample. Ideally we would wish to be able to measure the quantum yield of fluorescence as well as the fluorescence intensity, as this would allow environmental effects to be compensated for. Unfortunately, this is not at all easy, and indirect means to achieve the same goal are more appropriate. A recently introduced technique, fluorescence lifetime imaging (Morgan et al. 1992, Wang et al. 1992), offers one such means to improve quantification of fluorescence microscopy. In addition, as will be explained, the technique offers the prospect of significantly improving detection sensitivity in appropriate circumstances.

Energy Transfer↗

Fast solute release from photosensitive liposomes: an alternative to 'caged' reagents for use in biological systems.

The kinetics of release of soluble marker trapped in liposomes of gel phase phospholipid containing a photoisomerisable phospholipid analogue have been investigated. Marker release is triggered by UV laser flash photolysis at 355 nm. A markedly temperature-dependent release rate is seen, and above 25 degrees C millisecond release kinetics can be achieved. These results suggest that such liposomes might find application as an alternative to conventional 'caged' reagents for photo-triggered reagent release in biological research.

1,2-Dipalmitoylphosphatidylcholine↗

Liposome fusion and lipid exchange on ultraviolet irradiation of liposomes containing a photochromic phospholipid.

A photochromic phospholipid, 1,2-bis[4-4(4-n-butylphenylazo) phenylbutyroyl] phosphatidylcholine (Bis-Azo PC) has been incorporated into liposomes of gel- and liquid-crystalline- phase phospholipids. Liposomes of gel-phase phospholipid are stable in the presence of the trans photostationary state Bis-Azo PC and can encapsulate fluorescent marker dye. On photoisomerization to the cis photostationary state, trapped marker is rapidly released. Liposomes containing Bis-Azo PC can rapidly fuse together after UV isomerization, this process continuing in the dark. Exposure to white light causes reversion of Bis-Azo Pc to the trans form and halts dye leakage and vesicle fusion. Both unilamellar and multilamellar liposomes are able to fuse together on UV exposure. On UV photolysis, liposomes containing Bis-Azo PC do not fuse with a large excess of unlabeled liposomes, but transfer of Bis-Azo PC can be demonstrated spectrophotometrically. Vesicles of pure gel-phase lipid containing trapped marker dye but initially no Bis-Azo PC become leaky as a result of this lipid transfer. Liposomes composed of liquid-crystalline-phase phosphatidylcholine- containing Bis-Azo PC neither leak trapped marker no fuse together on photolysis, nor do liquid-crystalline-phase liposomes fuse with gel-phase liposomes under these conditions. These results are discussed together with some possible applications of liposome photodestabilization.

Fluorescent Dyes↗

Education of nursing students with special needs.

Recent legislation such as the Americans with Disabilities Act will have a significant impact on higher education in nursing. A survey was conducted to describe the extent to which BSN and ADN nursing programs in the United States admit and graduate special needs and chronically ill students, and to identify the accommodations which have been successful in providing nursing education to these students. Responses received from 86 schools of nursing in 44 states indicated that most schools have had contact with students with special needs such as visual, hearing, or mobility impairments, learning disabilities, and mental or chronic illnesses. Learning disabilities and mental impairment were cited most frequently as having been present among the student population. Few programs have had experience with students with vision problems. While most programs responding had little experience with providing special accommodations to special needs students, most were aware of accessibility on their campuses. Recent legislation aimed at creating opportunities for disabled individuals to successfully enter the work force creates challenges for schools of nursing in education of students with special needs. Issues are raised that must be addressed to meet this important challenge.

Persons with Disabilities↗

Light-induced fusion of liposomes with release of trapped marker dye is sensitised by photochromic phospholipid.

Liposomes have been prepared from dipalmitoylphosphatidylcholine containing small amounts of a synthetic photochromic phospholipid, 'Bis-Azo PC'. In the dark, these are stable at room temperature, and contents do not significantly leak over weeks. Photoisomerisation results in immediate release of trapped marker, and in liposome fusion to form larger structures. Fusion has been detected using a fluorescence polarisation assay, and confirmed by electron microscopy. In mixtures, fusion occurs between 'photochromic' liposomes and those of pure lipid. Bis-Azo PC contains two photochromic acyl chains; analogues bearing a single photochromic chain appear to have little effect on bilayer permeability after isomerisation. Photo-induced leakage and liposome fusion suggest possible applications for localised drug delivery as an adjunct to phototherapy. The ability to non-invasively trigger fusion processes should be useful in fundamental studies of membrane interactions. We believe this to be the first report of photo-induced fusion to date.

1,2-Dipalmitoylphosphatidylcholine↗