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Biomedical subjects

A J Fischer

Publications and source records attributed to A J Fischer.

At least 19 recordsLinked to original sources
PubMed2004

Comparing estimates of cost effectiveness submitted to the National Institute for Clinical Excellence (NICE) by different organisations: retrospective study.

OBJECTIVE: To assess the association between different types of organisation and the results from economic evaluations. DESIGN: Retrospective pairwise comparison of evidence submitted to the technology appraisal programme of the National Institute for Clinical Excellence (NICE) by manufacturers of the relevant healthcare technologies and by contracted university based assessment groups. DATA SOURCES: Data from the first 62 appraisals. MAIN OUTCOME MEASURE: Incremental cost effectiveness ratios. RESULTS: Data from 27 of the 62 appraisals could be compared. The analysis of 54 pairwise comparisons showed that manufacturers' estimates of incremental cost effectiveness ratios were lower (suggesting a more cost effective use of resources) than those produced by the assessment groups (25 were lower, 29 were the same, none were higher, P < 0.01). Restriction of this dataset to include only one pairwise comparison per appraisal (27 pairs) produced a similar result (21 were lower, two were the same, four were higher, P < 0.001). CONCLUSIONS: The estimated incremental cost effectiveness ratios submitted by manufacturers were on average significantly lower than those submitted by the assessment groups. These results show that an important role of NICE's appraisal committee, and of decision makers in general, is to determine which economic evaluations, or parts of evaluations, should be given more credence.

Academies and Institutes↗
PubMed2004

Mid-ultraviolet light-emitting diode detects dipicolinic acid.

Dipicolinic acid (DPA, 2,6-pyridinedicarboxylic acid) is a substance uniquely present in bacterial spores such as that from anthrax (B. anthracis). It is known that DPA can be detected by the long-lived fluorescence of its terbium chelate; the best limit of detection (LOD) reported thus far using a large benchtop gated fluorescence instrument using a pulsed Xe lamp is 2 nM. We use a novel AlGaN light-emitting diode (LED) fabricated on a sapphire substrate that has peak emission at 291 nm. Although the overlap of the emission band of this LED with the absorption band of Tb-DPA (lambda(max) doublet: 273, 279 nm) is not ideal, we demonstrate that a compact detector based on this LED and an off-the-shelf gated photodetection module can provide an LOD of 0.4 nM, thus providing a basis for convenient early warning detectors.

Aerosols↗
PubMed2003

Is it possible to detect Echinochloa spp. tolerance to ACCase-inhibiting herbicides using a simple quick tolerance test?

The objective of this work was to evaluate the reliability of one quick tolerance test that would enable us, in only six days, to quantify tolerance levels of one biotype to one or more herbicides. For this purpose, we evaluated tolerance levels to cyhalofop-butyl of five Echinochloa spp. biotypes: muricata, crus-galli, crus-pavonis, oryzicola and utilis, with unknown records of herbicide treatment. Moreover, two biotypes of Echinochloa phyllopogon were tested, one of them resistant (R) to fenoxaprop-P-ethyl and the other one susceptible (S). The Oryza sativa Puntal var. and Oryza sativa var. (wild rice) were also checked in order to demonstrate cyhalofop-butyl selectivity profiles. The assays were conducted with petri-dishes where, over the following increasing doses, fifty seeds per biotype and dose, were placed in each one: 0, 3, 6, 12, 18, 24, 48 and 60 ppm of cyhalofop-butyl and codacide oil adjuvant. Six days later, the following parameters were evaluated: plumule length, root length, germination (%) and fresh weight reduction (%). E. muricata germination was reduced by 50% with a 6 ppm dose. A non linear relation dose-germination was observed in the rest of the biotypes. The plumule length permitted the ranking of the biotypes into three groups: (1) resistant (E. phyllopogon R) or very tolerant (Oryza sativa Puntal var. and wild rice), those with a reduction of less than 30%, (2) tolerant, between 30 and 60% (E. oryzicola), and (3) susceptible, with a reduction of over 80% (E. muricata, E. crus-galli, E. crus-pavonis, E. utilis and E. phyllopogon S). Only Oryzo sativa and E. phyllopogon R had a minimal reduction of fresh weight (less than 15%). The assays were repeated with whole plants and we checked the accuracy of this test that indicated the resistance level of one biotype in a quick, reliable and economic way.

Drug Tolerance↗
PubMed2001

Müller glia are a potential source of neural regeneration in the postnatal chicken retina.

The retina of warm-blooded vertebrates is believed to be incapable of neural regeneration. Here we provide evidence that the retina of postnatal chickens has the potential to generate new neurons. In response to acute damage, numerous Müller glia re-entered the cell cycle, and shortly thereafter, expressed CASH-1, Pax6 and Chx10, transcription factors expressed by embryonic retinal progenitors. These progenitor-like cells transiently expressed neurofilament. Newly formed cells became distributed throughout the inner and outer nuclear layers of the retina, and remained for at least three weeks after damage. Some of these newly formed cells differentiated into retinal neurons, a few formed Müller glia, and most remained undifferentiated, with continued expression of Pax6 and Chx10. These cells continued to proliferate when grown in culture, with some differentiating into retinal neurons or Müller glia. We propose that, in response to damage, Müller glia in the retina are a potential source of neural regeneration.

Animals↗
PubMed2001

Transdifferentiation of pigmented epithelial cells: a source of retinal stem cells?

In urodeles, larval anurans, embryonic chicks and rodents, the retinal pigmented epithelium (RPE) is capable of transdifferentiation and generating new neurons. Recent evidence suggests that pigmented cells in the ciliary body of the adult rodent eye are capable of producing new neurons in vitro. Here we provide data to suggest that the pigmented epithelium at the retinal margin of postnatal chickens is similar to that found in the embryonic retina. Pigmented cells at the retinal margin expressed mitf and pax6, transcription factors that are transiently expressed by the developing RPE. Furthermore, these pigment cells at the retinal margin express high levels of proliferating cell nuclear antigen and accumulate bromodeoxyuridine, indicating that they continue to proliferate long after embryonic stages of development. Exogenous fibroblast growth factor-2 (FGF2) or insulin alone did not affect the proliferation of these cells, while FGF2 plus insulin induced their proliferation and loss of pigmentation. We propose that the pigmented cells at the retinal margin of the postnatal chicken are similar to those found in the embryonic eye, and these cells could be a source of neural regeneration under appropriate conditions.

Animals↗
PubMed2001

Stem cells in the vertebrate retina.

The capacity for retinal regeneration in cold-blooded vertebrates has long been recognized. Regeneration occurs, in part, through a population of retinal stem cells residing at the peripheral margin of the retina. It has generally been thought that homeothermic vertebrates, such as birds and mammals, lack this so-called ciliary marginal zone. Recent studies have, however, provided evidence that birds too possess a zone of cells at the retinal margin analogous to the ciliary marginal zone of fish and amphibians. In addition, there is an indication that, under certain conditions, Müller glia of the chicken retina can transdifferentiate into retinal progenitor/stem cells. These progenitor/stem cells then generate certain types of retinal neurons. Taken together, these studies have revealed an unexpected capacity for retinal regeneration in birds.

Animals↗
PubMed2001

Immunocytochemical characterization of cysts in the peripheral retina and pars plana of the adult primate.

PURPOSE: To better characterize the cellular constituents of cysts in the peripheral retina and pars plana of the adult monkey. METHODS: Frozen sections of the peripheral retinal margin and pars plana from monkeys (Macaca nemestrina) between 1 and 15 years of age were stained with toluidine blue or immunolabeled with a variety of glia- and neuron-specific antibodies. RESULTS: In animals 1 to 2 years of age, the nonpigmented inner layer of the pars plana is a pseudostratified columnar epithelium. In these young animals, the peripheral retina had distinct layers and did not contain cysts. In animals 6 years of age or older, there were numerous cysts in the pars plana and in the peripheral retina. In the peripheral retina, neurons were randomly distributed and did not have a laminar organization. Cells surrounding cysts were immunoreactive for different types of markers for retinal neurons. Some of the cells surrounding cysts in the pars plana were also unexpectedly immunoreactive for antigens normally expressed only in retinal neurons and glia. CONCLUSIONS: Cysts form in the peripheral retina and pars plana in adult monkeys. The peripheral retinal cysts disrupt the normal lamination of the cells, but all types of retinal neurons are still present in the cysts. In an unexpected finding, cysts in the pars plana also contained cells immunoreactive for a few of the markers of retinal cells, suggesting that neurogenesis may occur in the pars plana of the adult primate.

Aging↗
PubMed2000

Identification of a proliferating marginal zone of retinal progenitors in postnatal chickens.

In warm-blooded vertebrates it is generally accepted that after early stages of development new neurons are not added to the retina. Contrary to this belief, we show here that hatched chickens have a zone of proliferating cells at the peripheral margin of the retina, similar to that of fish and amphibians. We found that cells at the peripheral edge of the retina incorporated the thymidine analog BrdU and expressed the cell cycle regulator proliferating cell nuclear antigen (PCNA). Furthermore, cells in the ciliary epithelium and retinal margin coexpressed the homeodomain transcription factors Pax6 and Chx-10, similar to multipotent progenitors of embryonic retina. Expression of PCNA, Pax6, and Chx-10 in cells at the retinal margin was maintained in adult birds. Double-labeling studies showed that BrdU-labeled cells that were integrated into the retina expressed proteins found only in differentiated neurons. Increased rates of ocular growth, induced by visual deprivation, resulted in increased numbers of BrdU-labeled cells at the retinal margin. Unlike the progenitors in the retinal marginal zone of fish and amphibians, the progenitors of the chick retina do not increase their rate of proliferation in response to acute damage. Furthermore, insulin, insulin-like growth factor-I, and epidermal growth factor increased proliferation of progenitors at the retinal margin, while basic fibroblast growth factor had no effect. These results indicate that the avian retina has a marginal growth zone containing proliferating cells that share similarities with multipotent embryonic retinal progenitors and the retinal stem cells of cold-blooded vertebrates.

Animals↗
PubMed2000

Ambulance economics.

BACKGROUND: Ambulance services produce a large quantity of data, which can yield valuable summary statistics. For strategic planning purposes, an economic framework is proposed, and the following four resource allocation questions are answered, using data from the Surrey Ambulance Service: (1) To satisfy government response time targets, how many additional ambulances will be required, ceteris paribus? (2) To minimize average response time (r*) with given resources, how should ambulances be rostered temporally? (3) Which innovations are worth undertaking? (4) How would an increase in demand affect r*? METHODS: The 'Ambulance Response Curve' --the relation between response time and the number of available but not-in-use ambulances--is used to estimate how much r* will be reduced by deploying an additional ambulance. Estimating the marginal cost of an ambulance allows us to estimate the opportunity cost of each second of response time, and to compare the cost of three 'innovations' with that of increasing resources. The time savings of adding an extra ambulance at each of the 168 h of the week are examined. RESULTS: In 1997-1998, r* was 8 min 52 s. An additional ambulance reduces r* by 8.9 s. Each reduction of 1 s in r* costs 28,000 pounds per year. Fourteen additional ambulances are required to meet response time targets if the 8.9 s reduction per ambulance is maintained. r* reduces by 4.6 s when ambulances are shifted from early mornings to Saturday evenings. Activation time reduces by 38 s when crews sit in their ambulances. A 1 min decrease in overall call time decreases r* by 1.1 s. Answering only 10 per cent of all calls reduces r* by 63 s. An increase of demand of 10 per cent increases r* by 7.8 s. CONCLUSIONS: Ambulance services will be better able to determine which innovations are worth undertaking. Policy makers will be better placed to determine funding levels to achieve response time targets.

Ambulances↗
PubMed1999

Nitric oxide synthase-containing cells in the retina, pigmented epithelium, choroid, and sclera of the chick eye.

Nitric oxide is a nonconventional neurotransmitter that is produced as needed by the enzyme nitric oxide synthase (NOS). NOS has been detected in numerous neural structures, including distinct populations of retinal neurons in a variety of vertebrate species. The purpose of this study was to identify NOS-containing cells in the retina and extraretinal ocular tissues of hatched chicks. NOS was detected in frozen sections by using nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase histochemistry and antisera to neuronal NOS. In the retina, NADPH-diaphorase and NOS immunolabelling were present in four subtypes of amacrine cells, some ganglion cells, efferent fibers, efferent target cells, and neuronal processes in both plexiform layers, whereas diaphorase alone was detected in photoreceptor ellipsoids and Müller cells. In addition, NADPH-diaphorase and immunoreactive NOS were detected in axon bundles and innervation to vascular smooth muscle in the choroid, whereas stromal and endothelial cells in the choroid, scleral chondrocytes, and the retinal pigmented epithelium contained only NADPH-diaphorase. The excitotoxin quisqualate destroyed all but one subtype of NOS-immunoreactive amacrine cell and caused increased NADPH-diaphorase activity in Müller cells. We conclude that nitric oxide is produced by many different cells in the chick eye, including retinal amacrine and ganglion cells, Müller cells, retinal pigmented epithelium, and cells in the choroid, and likely has a broad range of visual and regulatory functions.

Animals↗
PubMed1999

Colchicine causes excessive ocular growth and myopia in chicks.

Colchicine has been reported to destroy ganglion cells (GCs) in the retina of hatchling chicks. We tested whether colchicine influences normal ocular growth and form-deprivation myopia, and whether it affects cells other than GCs. Colchicine greatly increased axial length, equatorial diameter, eye weight, and myopic refractive error, while reducing corneal curvature. Colchicine caused DNA fragmentation in many GCs and some amacrine cells and photoreceptors, ultimately leading to the destruction of most GCs and particular sub-sets of amacrine cells. Colchicine-induced ocular growth may result from the destruction of amacrine cells that normally suppress ocular growth, and corneal flattening may result from the destruction of GCs whose central pathway normally plays a role in shaping the cornea.

Animals↗
PubMed1999

Localization of retinoid binding proteins, retinoid receptors, and retinaldehyde dehydrogenase in the chick eye.

Retinoids have many functions in the eye, including, perhaps, the visual guidance of ocular growth. Therefore, we identified where retinoid receptors, binding proteins, and biosynthetic enzymes are located in the ocular tissues of the chick as a step toward discovering where retinoids are generated and where they act. Using antibodies to interphotoreceptor retinoid binding protein (IRBP), cellular retinol binding protein (CRBP), cellular retinoic acid binding protein (CRABP), cellular retinaldehyde binding protein (CRALBP), retinaldehyde dehydrogenase (RALDH), and retinoic acid receptors (RAR and RXR), we localized these proteins to cells in the retina, retinal pigmented epithelium, choroid and sclera of the chick eye. IRBP was detected in the photoreceptor layer and pigmented epithelium; CRBP was in the pigmented epithelium; CRABP was in amacrine and bipolar cells in the retina; CRALBP was in Müller cells, pigmented epithelium, choroid, and fibrous sclera; RALDH was in retinal amacrine cells, pigmented epithelium, and choroid; RAR was in amacrine cells, choroid, and chondrocytes and fibroblasts in the sclera; and RXR was in amacrine and ganglion cells, bipolar cell nuclei, choroid, and chondrocytes. We also found that the growth-modulating toxins colchicine and quisqualate destroyed selectively different subsets of CRABP-containing amacrine cells. We conclude that the distribution of proteins involved in retinoid metabolism is consistent with a role of retinoids not only in phototransduction, but also in maintenance of cellular phenotype and visual guidance of ocular growth.

Aldehyde Oxidoreductases↗
PubMed1999

Light- and focus-dependent expression of the transcription factor ZENK in the chick retina.

Ocular growth and refraction are regulated by visual processing in the retina. We identified candidate regulatory neurons by immunocytochemistry for immediate-early gene products, ZENK (zif268, Egr-1) and Fos, after appropriate visual stimulation. ZENK synthesis was enhanced by conditions that suppress ocular elongation (plus defocus, termination of form deprivation) and suppressed by conditions that enhance ocular elongation (minus defocus, form deprivation), particularly in glucagon-containing amacrine cells. Fos synthesis was enhanced by termination of visual deprivation, but not by defocus and not in glucagon-containing amacrine cells. We conclude that glucagon-containing amacrine cells respond differentially to the sign of defocus and may mediate lens-induced changes in ocular growth and refraction.

Adaptation, Ocular↗
PubMed1998

Cholinergic amacrine cells are not required for the progression and atropine-mediated suppression of form-deprivation myopia.

Muscarinic cholinergic pathways have been implicated in the visual control of ocular growth. However, the source(s) of acetylcholine and the tissue(s) which regulate ocular growth via muscarinic acetylcholine receptors (mAChRs) remain unknown. We sought to determine whether retinal sources of acetylcholine and mAChRs contribute to visually guided ocular growth in the chick. Cholinergic amacrine cells were ablated by intraocular injections of either ethylcholine mustard aziridinium ion (ECMA; a selective cholinotoxin) or quisqualic acid (QA; an excitotoxin that destroys many amacrine cells, including those that release acetylcholine). Disruption of cholinergic pathways was assessed immunocytochemically with antibodies to the acetylcholine-synthesizing enzyme choline acetyltransferase (ChAT) and three different isoforms of mAChR, and by biochemical assay for ChAT activity. ECMA (25 nmol) destroyed two of the four subtypes of cholinergic amacrine cells and attenuated retinal ChAT activity, but left retinal mAChR-immunoreactivity intact. QA (200 nmol) destroyed the majority of all four subtypes of cholinergic amacrine cells, and ablated most mAChR-immunoreactivity and ChAT activity in the retina. ECMA and QA had no apparent effect on mAChRs or cholinergic fibres in the choroid, only marginally reduced choroidal ChAT activity, and had little effect on ChAT activity in the anterior segment. Toxin-treated eyes remained emmetropic and responded to form-deprivation by growing excessively and becoming myopic. Furthermore, daily intravitreal injection of 40 microg atropine for 6 days into form-deprived toxin-treated eyes completely prevented ocular elongation and myopia. We conclude that neither cholinergic amacrine cells nor mAChRs in the retina are required for visual regulation of ocular growth, and that atropine may exert its growth-suppressing influence by acting upon extraretinal mAChRs, possibly in the choroid, retinal pigmented epithelium, or sclera.

Animals↗
PubMed1998

Immunocytochemical characterization of quisqualic acid- and N-methyl-D-aspartate-induced excitotoxicity in the retina of chicks.

A single, large dose of N-methyl-D-aspartate (NMDA) or quisqualic acid (QA) injected into the chick eye has been shown previously to destroy many retinal amacrine cells and to induce excessive ocular growth accompanied by myopia. The purpose of this study was to identify distinct populations of retinal cells, particularly those believed to be involved in regulating ocular growth, that are sensitive to NMDA or QA. Two pmol of NMDA or 0.2 micromol of QA were injected unilaterally into eyes of 7-day-old chicks, and retinas were prepared for observation 1, 3, or 7 days later. Retinal neurons were identified by using immunocytochemistry, and cells containing fragmented DNA were identified by 3'-nick-end labelling in frozen sections. NMDA and QA destroyed many amacrine cells, including those immunoreactive for vasoactive intestinal polypeptide, Met-enkephalin, and choline acetyltransferase, but they had little effect upon tyrosine hydroxylase-immunoreactive cells. Other cells affected by both QA and NMDA included those immunoreactive for glutamic acid decarboxylase, gamma-aminobutyric acid, parvalbumin, serotonin, and aminohydroxy methylisoxazole propionic acid (AMPA) receptor subunits GluR1 and GluR2/3. Cells largely unaffected by QA or NMDA included bipolar cells immunoreactive for protein kinase C (alpha and beta isoforms) and amacrine cells immunoreactive for glucagon. DNA fragmentation was detected maximally in many amacrine cells and in some bipolar cells 1 day after exposure to QA or NMDA. We propose that excitotoxicity caused by QA and NMDA induces apoptosis in specific populations of amacrine cells and that these actions are responsible for the ocular growth-specific effects of QA and NMDA reported elsewhere.

Animals↗
PubMed1998

Identification and localization of muscarinic acetylcholine receptors in the ocular tissues of the chick.

The purpose of this study was to characterize the distribution of muscarinic acetylcholine receptors (mAChRs) in the ocular tissues of hatched chicks. In the chick, different isoforms of these receptors have been detected in the brain, heart, and retina, and mAChRs in ocular tissues have been implicated in the pathogenesis of form-deprivation myopia. However, the precise anatomical distribution of mAChRs within the retina, retinal pigment epithelium, choroid, ciliary body, and ciliary ganglion remains unknown. We used affinity-purified, type-specific antibodies directed to three different chick mAChR subtypes (cm2, cm3, and cm4) to detect receptor immunoreactivity in sections and extracts of these ocular tissues. We found cm2, cm3, and cm4 in the retina, retinal pigment epithelium, choroid, and ciliary body. Within the retina, cm2 was expressed in numerous amacrine and ganglion cells; cm3 was expressed in many bipolar cells and small subsets of amacrine cells; and cm4 was found in most, if not all, amacrine and ganglion cells. Each mAChR was localized to distinct strata within the inner plexiform layer that cumulatively form three broad bands that closely match previously described localizations of subtype-nonspecific muscarinic ligand binding. Only cm3 was detected in the outer plexiform layer, and only cm4 was detected in the ciliary ganglion. We propose that each mAChR subtype has unique functions in each ocular tissue.

Animals↗
PubMed1997

Light-modulated release of RFamide-like neuropeptides from nervus terminalis axon terminals in the retina of goldfish.

The nervus terminalis of teleosts, a cranial nerve anatomically associated with the olfactory system, projects to visual system targets including retina and optic tectum. It is known to contain gonadotropin-releasing hormone and RFamide-like peptides, but its function remains unknown. We have probed nervus terminalis function in goldfish by measuring peptide content in retina and tectum with a radioimmunoassay for A18Famide (neuropeptide AF; bovine morphine-modulating peptide). We found that retinal peptide content increased in the dark and decreased in the light, whereas tectal peptide content decreased in the dark and increased in the light. In addition, RFamide-like peptide content in the retina was transiently decreased by severing both olfactory tracts, increased in light-adapted eyes treated with a GABAergic agonist (isoguvacine), and decreased in dark-adapted eyes treated with GABAergic antagonists (bicuculline and picrotoxin). We also found that RFamide-like peptide release could be induced in dark-adapted isolated-superfused retinas by exposure to light or a high concentration (102.5 mM) of potassium ions. We interpret the increase and decrease in peptide content as reflecting a decrease and increase, respectively, in rate of peptide release. We propose that the release and accumulation of RFamide-like peptides in axon terminals of nervus terminalis processes in the retina are modulated primarily by neurons intrinsic to the retina and regulated by light. Peptide release appears to be inhibited tonically in the dark by GABA acting through GABAA receptors; light facilitates peptide release by disinhibition due to a reduction in GABA release. In addition, we propose that electrical signals originating outside the retina can override these intrinsic release-modulating influences.

Adaptation, Ocular↗