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Biomedical subjects

J G Flanagan

Publications and source records attributed to J G Flanagan.

At least 19 recordsLinked to original sources
PubMed1992

Heparin is required for cell-free binding of basic fibroblast growth factor to a soluble receptor and for mitogenesis in whole cells.

Heparin is required for the binding of basic fibroblast growth factor (bFGF) to high-affinity receptors on cells deficient in cell surface heparan sulfate proteoglycan. So that this heparin requirement could be evaluated in the absence of other cell surface molecules, we designed a simple assay based on a genetically engineered soluble form of murine FGF receptor 1 (mFR1) tagged with placental alkaline phosphatase. Using this assay, we showed that FGF-receptor binding has an absolute requirement for heparin. By using a cytokine-dependent lymphoid cell line engineered to express mFR1, we also showed that FGF-induced mitogenic activity is heparin dependent. Furthermore, we tested a series of small heparin oligosaccharides of defined lengths for their abilities to support bFGF-receptor binding and biologic activity. We found that a heparin oligosaccharide with as few as eight sugar residues is sufficient to support these activities. We also demonstrated that heparin facilitates FGF dimerization, a property that may be important for receptor activation.

3T3 Cells↗
PubMed1991

Transmembrane form of the kit ligand growth factor is determined by alternative splicing and is missing in the Sld mutant.

The ligand (KL) for the c-kit receptor is a growth factor encoded at the mouse steel (Sl) locus. KL exists in both cell surface and soluble forms, though little is known of the regulation and functional significance of these forms. We show here that tissue-specific alternative splicing gives two types of KL mRNA. Both encode a transmembrane domain, but in transfected cells one produced the soluble form of KL at relatively high levels, whereas the other preferentially gave the cell surface form. Cell surface KL not only stimulated proliferation, but also mediated cell-cell adhesion. The SId allele, which impairs development of hematopoietic cells, melanocytes, and germ cells, has a deletion in the KL gene removing the transmembrane and intracellular domains. Expression of a corresponding cDNA gave a soluble protein that stimulated cellular proliferation but was not associated with the cell surface. These results provide evidence that cell surface KL has a critical role in the intact organism.

Amino Acid Sequence↗
PubMed1990

The kit ligand: a cell surface molecule altered in steel mutant fibroblasts.

The c-kit proto-oncogene, the gene at the mouse W developmental locus, is one of a substantial group of genes that appear to encode cell surface receptors but for which the ligands are unknown. We have characterized the kit ligand by a generally applicable approach: the receptor extracellular domain was genetically fused to placental alkaline phosphatase, producing a soluble receptor affinity reagent with an enzyme tag that could be easily and sensitively traced. This fusion protein, APtag-KIT, was used to demonstrate a specific binding interaction (KD = 3 x 10(-8) M) with a ligand on 3T3 fibroblast lines. In situ staining showed labeling over the whole surface of the 3T3 cells, but not extending to adjacent nonexpressing cells. These findings provide direct molecular evidence that the kit ligand can exist as a cell surface protein. Binding was not detected on 3T3 fibroblasts carrying the steel (Sl) mutation, confirming the biological significance of the binding activity and demonstrating that mutations at the Sl locus affect the expression or structure of the kit ligand.

Animals↗
PubMed1990

Visual and neural function in Leber's optic neuropathy.

This report details the chronology of vision loss for an 18-year-old Caucasian male with Leber's optic neuropathy. Findings of an oculo-visual assessment with auxiliary in-office tests of visual neural function, results of neurophysiological testing, and rehabilitative therapy with low vision aids are presented. The clinical characteristics of this devastating disorder are reviewed.

Adolescent↗
PubMed1990

Intracranial meningioma: an exercise in differential diagnosis.

A 48-year-old man presented with a unilateral visual disturbance including reduced visual acuity and decreased sensitivity of the temporal visual field. He was initially diagnosed as having optic neuritis. Four months later the condition not only remained unresolved, but showed signs of progression. This presentation was atypical for optic neuritis and further detailed investigation was warranted. The patient's symptoms, along with multi-channel topographic visual evoked potentials and quantitative visual field analysis, were more indicative of a diagnosis of a space occupying lesion. A CT scan confirmed the presence of an intracranial tumour which was surgically excised. Pre- and post-operative visual function are described. The case report highlights the difficulty of differential diagnosis of optic neuritis and the clinical value of the appropriate and judicious use of multi-channel evoked potentials.

Color Perception Tests↗
PubMed1989

Meridional differences in temporal response characteristics.

It is well established that a large variety of psychophysical factors influence the critical flicker fusion frequency (CFF). Several recent studies have examined the relationship between CFF and retinal location with confounding and contradictory results. The aim of this study was to determine the CFF for a number of stimulus sizes and luminances in an attempt to evaluate the interactive effects of these parameters and the quadrantic variation in temporal sensitivity. Retinal sensitivity gradients were measured along the two major oblique meridians out to an eccentricity of 50 degrees. CFF profiles for the 1.724 and 0.431 degree targets were shown to decrease with increasing eccentricity more rapidly in the inferior nasal quadrant (superior temporal retina). No significant difference between superior and inferior visual field temporal processing was evident.

Adult↗
PubMed1988

Multi-channel visual evoked potentials in early compressive lesions of the chiasm.

The sensitivity of transient, pattern-reversal visual evoked potentials in the detection of early compressive lesions of the chiasm is controversial in the literature. There have been claims that the technique is capable of detecting an abnormality in the absence of any demonstrable visual field loss, and conversely that VEPs are not reliable for the detection of chiasmal lesions even when a bitemporal hemianopsia is clearly recordable. Using nine patients with pituitary adenoma we attempted to quantify the extent of visual field loss and correlate the diagnostic capabilities of topographically recorded potentials following full- and half-field stimulus presentations of various field and check sizes. Differential light thresholds were measured and quantified according to one investigator's graticule for the neural representation of visual space. Results show a strong correlation between the degree of information loss and the diagnostic value of the visual evoked potential. The technique was, however, capable of detecting abnormality in the absence of recordable field loss when large field and check sizes were used.

Adenoma↗
PubMed1988

Stimulus configuration and the format of the normal sensitivity gradient.

The study investigated the effect of three distinct types of stimulus configuration on the format of the normal sensitivity gradient derived by computer assisted perimetry namely: projected stimuli; light emitting diodes (LED) with the same luminance as the perimeter bowl; and 'black hole' LED stimuli. The study comprised two separate parts: 22 age matched subjects were examined with the Dicon AP3000 and with the Topcon SBP-1000 along the 15 degrees-195 degrees meridian of the visual field of the right eye; a further 22 subjects matched for age and gender were examined along the same meridian in an identical manner with the Dicon AP2025 and with the Humphrey Field Analyser 620. The various stimulus parameters were chosen in order to provide uniformity as far as possible between the instruments. The Topcon evoked greater relative sensitivity than the Dicon at all eccentricities although the rate of change of sensitivity with increase in peripheral angle varied between the two instruments at different locations. Centrally the Dicon profile followed more closely that of Humphrey stimulus size II and beyond 5 degrees that of stimulus size I. The Topcon profile followed that of the Humphrey stimulus size II both centrally and peripherally in spite of being geometrically closer to the size III stimulus. It is proposed that the variations in the sensitivity gradient are not exclusively related to stimulus size and spatial summation; the accommodative stimulus of the 'black hole' LED stimuli, stimulus colour and thresholding strategy may all be contributing factors.

Adult↗
PubMed1988

neu protooncogene fused to an immunoglobulin heavy chain gene requires immunoglobulin light chain for cell surface expression and oncogenic transformation.

The protein encoded by the neu protooncogene (human gene symbol NGL for neuro/glioblastoma-derived) is a member of the surface receptor/tyrosine kinase family. Though its structure suggests that it can transduce a transmembrane signal, neither its extracellular ligand nor its critical intracellular substrates are known. To explore the functional properties of the protein encoded by neu, we created a fusion gene that joins the cytoplasmic domain of neu to the extracellular portion of an immunoglobulin heavy chain. The localization of the fusion polypeptide can then be controlled by coexpression with immunoglobulin light chain. In the absence of light chain, the heavy chain-neu polypeptide is expressed intracellularly and has no transforming activity. By contrast, in the presence of light chain the fusion polypeptide is expressed at the cell surface and produces tumorigenic foci. Thus, transformation apparently requires expression at the cell surface, where the neu intracellular domain can interact with components that are localized to the plasma membrane. The fusion protein is active in cellular transformation when the transmembrane domain is derived either from neu or from immunoglobulin, indicating that the neu transmembrane domain is not specifically required for transformation, although neu activation in tumors is known to result from a point mutation in this region. The extracellular immunoglobulin heavy and light chain domains of the fusion protein form a functional binding site that allows antigen to modulate its activity, reversing the transforming effect.

Animals↗
PubMed1987

Spatial summation and the cortical magnification of perimetric profiles.

M-scaling of the conventional spot targets of clinical perimetry at low photopic adaptation levels, such as that of the Octopus automated perimeter, does not result in the expected isosensitive profile using the current equations for humans. This disparity has been attributed to variations in the ganglion cell characteristics across the retina, most notably that of spatial summation. The hypothesis was further investigated by M-scaling the perimetric sensitivity recorded under conditions favouring reduced spatial summation, namely an increased adaptation level and a longer stimulus duration afforded by the Humphrey Field Analyzer. The M-scaled data exhibited a paracentral reduction in sensitivity relative to the theoretical isosensitive profile and an increased sensitivity beyond an eccentricity of 12 degrees. This indicates that for perimetric spot stimuli, the current human M-scaling equations under represent the fovea at the visual cortex. The implications for the design of perimetric routines are discussed.

Adult↗
PubMed1986

The interpretation of the differential threshold in the central visual field.

Computer assisted perimetry has revolutionised the investigation of the visual field. Experience of central field assessment with the Octopus Automated Perimeter shows that sensitivity recorded with target size 3 across all age groups can frequently be greater than the published normative values. Use of the latter values can therefore provide a serious underestimation of field loss. Inter-individual variation in sensitivity is found within and between age groups. The limitations associated with the use of the measurement error to define abnormality and the additional problems of hypernormal thresholds and resolution of the blind spot are discussed. It is suggested that methods should be developed to evaluate sensitivity on an intra-individual basis.

Adolescent↗
PubMed1986

Source derivation of the visually evoked potential.

There has been much recent conjecture over the apparent source location of the visually evoked potential, particularly in considering the lateralization found in halffield pattern reversal stimulation. This paper presents an alternative by directly identifying the sinks or sources present in the scalp current flow as these correspond to the maximal current flow into or out of the cortex (Nunez, 1981). Hjorth (1975) introduced a practical procedure for source derivation which has proved useful in the interpretation of the electroencephalogram (Wallin and Stalberg, 1980). We have applied source derivaton to cortical evoked potentials and present results obtained from right and left half-field stimulation, (Clement, Flanagan and Harding, 1985) and upper and lower field stimulation in normal subjects and patients with visual deficits.

Cerebral Cortex↗
PubMed1985

Manipulation of sensitivity in visual field investigation.

Sophistication of computer software and flexibility of stimulus and background luminance parameters in static perimeter design offer the opportunity for increased information in the assessment of the visual field. Relationships between dynamic ranges and resulting sensitivity gradients in a group of 10 normal 21 year old subjects using the Octopus automated perimeter, the Dicon Autoperimeter 2000 and the Friedmann VFA II are assessed. Inadequacies in the use of normative data to assess the visual field are noted. Implications for the use of dynamic range/sensitivity gradient relationships in visual field assessment without reliance on normative data are discussed.

Adult↗
PubMed1984

The qualitative comparative analysis of the visual field using computer assisted, semi-automated and manual instrumentation: I. Scoring system.

Previous methods for the qualitative evaluation of visual field instruments are subject to certain limitations. A system is proposed to overcome these deficiencies. It has been developed from experiences of a clinical study involving 5 different visual field instruments. The method uses 4 levels of analysis and permits separate appraisals of diagnostic potential and detailed inter-instrument comparative evaluation.

Computers↗
PubMed1984

The qualitative comparative analysis of the visual field using computer assisted, semi-automated and manual instrumentation: II. Statistical analysis.

A comparative evaluation of the Octopus automated perimeter (Programmes 21 and 31), the Goldmann Bowl perimeter, the Bjerrum Screen and the Friedmann VFAs MkI and MkII was carried out on a heterogeneous sample of 75 patients. The results for the sample as a whole were analysed statistically in terms of the scoring system developed by Flanagan, Wild, Barnes, Gilmartin, Good and Crews (1984a). Statistically significant differences between the instruments were found at each of the 4 levels of analysis.

Adolescent↗
PubMed1984

The qualitative comparative analysis of the visual field using computer assisted, semi-automated and manual instrumentation: III. Clinical analysis.

A comparative evaluation of the Octopus automated perimeter (Programmes 21 and 31), the Goldmann Bowl perimeter, the Bjerrum Screen and the Friedmann VFAs Mk I and Mk II was carried out on a heterogeneous sample of 75 patients. Field loss was categorized using a modification of the classifications proposed by Greve (1982). The results were analysed using the Level 4 analysis developed by Flanagan, Wild, Barnes, Gilmartin, Good and Crews (1984a). The performance of the various test logics was found to differ between the categories of field defect.

Computers↗
PubMed1984

Mechanisms of divergence and convergence of the human immunoglobulin alpha 1 and alpha 2 constant region gene sequences.

Nucleotide sequences of the human alpha 1 and two allelic alpha 2 immunoglobulin heavy chain constant region genes are presented. The genes contain three exons, each encoding a single constant region protein domain. The protein hinge region is encoded at the 5' end of the second exon, and the rapid evolutionary changes in length of the hinge correspond to duplications or deletions within the hinge-coding region, probably facilitated by repeats in the DNA sequence. Alignment of the alpha 1 and alpha 2 gene sequences reveals an unusual coupled deletion-duplication in the 5'-flanking region, which can be explained in terms of a slipped-strand mispairing model. Comparison of nucleotide sequences of the alpha 1 gene and two alleles of the alpha 2 gene indicates a localized transfer of genetic information from the 3' end of the alpha 1 gene to one of the alpha 2 alleles, probably by a gene conversion. At one end of the region within which conversion apparently occurred, there is a 40 bp sequence of the type that can form Z-DNA.

Base Sequence↗