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Biomedical subjects

A B Fulton

Publications and source records attributed to A B Fulton.

At least 37 records · Page 2Linked to original sources
PubMed1998

Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis.

RPE65 is a protein of unknown function expressed specifically by the retinal pigment epithelium. We examined all 14 exons of this gene in 147 unrelated patients with autosomal recessive retinitis pigmentosa (RP), in 15 patients with isolate RP, and in 45 patients with Leber congenital amaurosis (LCA). Sequence anomalies that were likely to be pathogenic were found in two patients with recessive RP, in one patient with isolate RP recategorized as recessive, and in seven patients with LCA. Cosegregation analysis in each available family showed that all affected individuals were either homozygotes or compound heterozygotes and that all unaffected individuals were either heterozygote carriers or homozygous wild type. In one family, there was one instance of a new mutation not present in either parent of the affected individual. In another family, affected members with recessive RP in three branches (i.e., three distinct pairs of parents) were compound heterozygotes for the same two mutations or homozygous for one of them. Based on our results, mutations in the RPE65 gene appear to account for approximately 2% of cases of recessive RP and approximately 16% of cases of LCA.

Blindness↗
PubMed1998

Assembly of tropomyosin isoforms into the cytoskeleton of avian muscle cells.

Tropomyosin (TM) is a component of microfilaments of most eukaryotic cells. In striated muscle, TM helps confer calcium sensitivity to the actin-myosin interaction. TM is a fibrillar, self-associating protein that binds to the extended actin filament system. We hypothesized that these structural features would permit TM to undergo assembly into the cytoskeleton during translation, or cotranslational assembly. Pulse-chase experiments with [35S]methionine and pulse experiments with [3H]puromycin followed by extraction and immunoprecipitation of TM were performed to examine the mechanism of assembly of TM into the cytoskeleton in cultured avian muscle cells. Pulse-chase experiments provide kinetic evidence for cotranslational assembly of TM in skeletal and cardiac muscle. Demonstration of a large majority of completed TM on purified skeletal muscle microfilaments after a short labeling period confirms that these kinetic data are not related to trapping of TM within the actin network of the cytoskeleton. Nascent TM peptides are demonstrated on the cytoskeleton of muscle cells after a short metabolic pulse followed by puromycin treatment to release nascent peptides from ribosomes or after labeling with [3H]puromycin. Nascent chain localization to the cytoskeleton independent of ribosomal attachment further confirms the high degree of cotranslational assembly of this protein. The extent of cotranslational assembly is similar before and after the formation of significant myofibril in myotubes, suggesting that cotranslational assembly of TM is active during contractile apparatus assembly in muscle differentiation. This is the first report where assembly mechanism has been predicted to be cotranslational based upon structural features of a cytoskeletal protein.

Animals↗
PubMed1997

Organization of protein and mRNA for titin and other myofibril components during myofibrillogenesis in cultured chicken skeletal muscle.

Myofibril assembly requires the cell to join diverse components, correctly oriented to the rest of the cell. Titin, a huge elastic protein with a role in myogenesis, assembles during translation in vivo and may require spatially organized mRNA to allow assembly. By immunofluorescence, we examined titin and myosin protein organization early in skeletal muscle development in vitro; titin was the first organized, initially as spots, then as periodically spaced lines, and later as doublets. Titin mRNA organization during development was detected by fluorescent in situ hybridization. Only titin mRNA was seen in mononucleated myoblasts. Shortly after fusion, both titin protein and mRNA were diffuse. Titin mRNA remained diffuse when titin protein formed cables. Where titin protein formed linear arrays of spots, titin mRNA showed a colinear, continuous array. Titin mRNA remained in arrays colinear with young myofibrils until several slender myofibrils aligned laterally; then, titin mRNA formed periodic arrays. The titin probe encodes peptide sequence in the A band, where this region of titin mRNA is detected in the most organized cells. Nebulin undergoes a similar progression slightly later in development. This pattern, of narrowly spaced stripes, is too closely spaced to function in the soluble phase. Titin mRNA is the earliest mRNA to become so highly organized in muscle; it does so earlier and at a different location than do mRNAs for costamere proteins. These results, taken with earlier ones, suggest mRNA localization may be as key to somatic cell differentiation as it is to embryonic development.

Animals↗
PubMed1997

Dark-adapted thresholds in children with histories of mild retinopathy of prematurity.

PURPOSE: To test the hypothesis that rod-mediated visual thresholds at 10 degrees eccentricity are elevated in children with histories of mild retinopathy of prematurity (ROP). METHODS: Dark-adapted thresholds for detection of 50 msec, 2 degrees diameter spots at a 10 degrees eccentric site, and at a peripheral reference site, 30 degrees eccentric, were measured in 20 children with a history of mild ROP and known courses of refractive development. Ten myopic control subjects also were tested. The thresholds of the ROP and control subjects were compared. RESULTS: Six of the subjects with ROP had elevated thresholds at the 10 degrees site. High myopia had been present since age 18 months or younger in each of the six. The thresholds of all other subjects with ROP, whose courses of refractive development had been toward emmetropia, and the control subjects with myopia were normal. In subjects with ROP, the association of early, persistent high myopia and an elevated threshold at 10 degrees was significant (chi 2 = 20; P < 0.01). Among the subjects with ROP, refractive error and axial length were correlated. CONCLUSIONS: ROP or factors causing ROP appear to alter rod-mediated retinal function. The association of abnormal rod-mediated sensitivity and refractive development suggests that rod-mediated retinal function is involved in the regulation of eye growth in children with a history of mild ROP.

Adolescent↗
PubMed1996

Vision in Leber congenital amaurosis.

OBJECTIVE: To determine if vision changed with age in infants and children with Leber congenital amaurosis. PATIENTS: Grating acuity and dark-adapted visual thresholds were tested in 36 patients with Leber congenital amaurosis. Longitudinal assessments were obtained for 24 patients and analyzed for significant changes over time. Visual acuity and threshold and the courses of visual acuity and threshold were examined for significant associations with hyperopia, fundus appearance, and complicated vs uncomplicated status. RESULTS: Measurable grating acuities ranged from 0.16 to 6 cycles per degree (median, 1.27 cycles per degree or about 20/500), and dark-adapted visual thresholds were elevated 1.0 to 5.6 log units (median, 2.33 log units). Eighteen patients never had demonstrable grating acuity, and 12 had no light perception. Among those with serial tests, visual acuity improved or remained stable in 10 patients and declined in 4. Dark-adapted visual thresholds were stable in those with improving or stable visual acuities but worsened in 5 patients, including the 4 whose visual acuity worsened. No significant associations of visual acuity, dark-adapted visual threshold, the course of visual acuity, or the course of dark-adapted visual threshold with hyperopia, fundus appearance, or complicated vs uncomplicated status were found. CONCLUSIONS: Visual capabilities varied widely. Vision was stable in the majority by longitudinal measures but increased in a few and deteriorated in others. Neither ocular characteristics nor complicated vs uncomplicated status predicted visual function. Thus, if vision and its course are to be known in a patient with Leber congenital amaurosis, it must be tested.

Aging↗
PubMed1996

Photoreceptor function in infants and children with a history of mild retinopathy of prematurity.

Five infants and children with a history of mild retinopathy of prematurity (ROP) were tested for postulated alterations in rod photoreceptor function. The photoreceptor responses were derived from the electroretinographic alpha waves. Postreceptoral components, the beta wave and the oscillatory potentials, were also examined. The saturated amplitude and sensitivity of the rod photoreceptor responses were low, except for the sensitivity in one patient. The beta-wave sensitivity was low, but saturated amplitudes were within the 95% prediction interval for normal. The amplitudes of the oscillatory-potential responses were also attenuated. The results indicate that retinal dysfunction may be present in patients with a history of mild ROP long after the ROP has completely resolved. Additionally, the data suggest that the photoreceptors are the primary site of retinal dysfunction in mild ROP.

Adult↗
PubMed1996

Rhodopsin in immature rod outer segments.

PURPOSE: To test the hypothesis that rhodopsin concentration is low in immature rat rod outer segments (ROS). METHODS: Microspectrophotometry (MSP) was used to assess rhodopsin absorbances in localized regions of isolated ROS from dark-adapted 13-, 19-, and 34-day-old and adult rats. Photopigment was extracted from the retinas of paired eyes in dark-adapted and light-adapted rats. One retina of each pair was treated with 9-cis retinal before extraction of photopigment. Rhodopsin with native 11-cis retinal was extracted from the fellow retina. RESULTS: By MSP, rhodopsin absorbance was low in the short ROS of 13-day-old rats. In 19-day-old rats with ROS lengths approximately equal to those of adults, absorbance was low at the tip, but at the base, it was equal to the high absorbance at both the tip and the base in adults. The 9-cis retinal did not add absorbance to the photopigment extracts of dark-adapted retinas at any age, but it did add absorbance to extracts of the light-adapted retinas at every age. CONCLUSIONS: The MSP results show that the accumulation of rhodopsin in developing rat rods depends on increasing concentrations in localized regions. No evidence of apo-opsin is found in immature rat rods. Thus, in immature ROS regions, the low rhodopsin absorbances suggest that the amount of opsin is also low. Greater disk-to-disk spacing in immature ROS regions than in mature regions could account for these findings.

Aging↗
PubMed1995

Transdifferentiation of chicken embryonic cells into muscle cells by the 3' untranslated region of muscle tropomyosin.

Transfection with a plasmid encoding the 3' untranslated region (3' UTR) of skeletal muscle tropomyosin induces chicken embryonic fibroblasts to express skeletal tropomyosin. Such cells become spindle shaped, fuse, and express titin, a marker of striated muscle differentiation. Skeletal muscle tropomyosin and titin organize in sarcomeric arrays. When the tropomyosin 3' UTR is expressed in osteoblasts, less skeletal muscle tropomyosin is expressed, and titin expression is delayed. Some transfected osteoblasts become spindle shaped but do not fuse nor organize these proteins into sarcomeres. Transfected cells expressing muscle tropomyosin organize muscle and nonmuscle isoforms into the same structures. Thus, the skeletal muscle tropomyosin 3' UTR induces transdifferentiation into a striated muscle phenotype in a cell-type-specific context.

Animals↗
PubMed1995

Identical twins with Cohen syndrome.

We report the first case of identical female twins who satisfy the proposed diagnostic criteria for Cohen syndrome. The sisters presented with retinal degeneration, obesity and mental retardation, and had the characteristic facial appearance. The manifestations of previously reported cases of Cohen syndrome are reviewed. Unusual changes in our patients include tall stature, macrocephaly, and transient cardiomyopathy during the first year of life. These anomalies have been reported previously in other patients with Cohen syndrome, and suggest that the disorder is phenotypically heterogeneous. Precocious puberty was present in both girls; the latter findings have not been reported previously in the Cohen syndrome. Detailed metabolic and cytogenetic analysis demonstrated no abnormalities.

Child↗
PubMed1995

The course of myopia in children with mild retinopathy of prematurity.

The courses of spherical equivalent in patients (n = 62) who had mild, non-cicatricial retinopathy of prematurity (ROP), and in those without a history of ROP (n = 25) were modeled as a linear function of age; an exponential model was also considered. A few (n = 5) without ROP have abnormal courses characterized by hyperopia in early infancy; none have poor acuity. Although the majority of patients with ROP have courses indistinguishable from those of term born controls, 27 (43.5%) have abnormal courses, most of which are toward myopia. Optotype acuities were significantly poorer among the ROP patients with abnormal than normal refractive courses. Thus abnormal refractive development and acuity deficits are associated in eyes that have had mild ROP.

Adolescent↗
PubMed1995

Effect of prior oxygen exposure on the electroretinographic responses of infant rats.

PURPOSE: To study electroretinographic responses of infant rats with a history of exposure to high-ambient oxygen. METHODS: Electroretinographic responses to a range of full-field stimuli were recorded from 13-day-old (n = 8) and 18-day-old (n = 10) rats with a history of intermittent exposure to 80% oxygen and age-matched controls. The a-waves were fitted with a model of rod cell sensitivity and saturated response amplitude. The amplitudes and implicit times of the b-wave and oscillatory wavelets were examined as a function of stimulus energy. Response parameters in oxygen-exposed rats were compared to those in controls. RESULTS: The amplitude of the saturated rod response was reduced in oxygen-exposed 13-day-old but not 18-day-old rats. The sensitivity of the rod response was reduced in both 13- and 18-day-old oxygen-exposed rats. The saturated amplitude and sensitivity of the b-wave did not differ significantly between oxygen-exposed and control rats age 13 days, but both amplitude and sensitivity were significantly decreased in 18-day-old oxygen-exposed rats. Oscillatory potentials, which could be investigated only in 18-day-old rats, showed significant attenuation of OP3 but not OP4 amplitudes in the oxygen-exposed rats. The sensitivity of OP2 did not differ significantly between oxygen-exposed and control rats. The avascular area in the oxygen-exposed rats was not correlated with any of the rod cell, b-wave, or oscillatory potential response parameters. CONCLUSION: The function of the rod photoreceptors, as well as the inner retina, is altered in infant rats with a history of oxygen exposure.

Aerobiosis↗
PubMed1995

The effects of acetazolamide on the electroretinographic responses in rats.

PURPOSE: To study the mechanisms and sites of action of the carbonic anhydrase inhibitor, acetazolamide (AZM), on the rod- and cone-mediated electroretinogram (ERG) of the dark-adapted rat. METHODS: After a within-subjects design, ERG responses to brief, full-field flashes were recorded from adult (60 to 90 days old) albino rats, with and without AZM (5 mg/100 g, intraperitoneally). Flickering stimuli (6 and 26 Hz) were used to study rod- and cone-mediated responses. Aspartate-isolated responses of the isolated retina were recorded with and without AZM in the superfusate. The a-wave and PIII responses were fitted with a model of the rod's response by estimating the maximum response (Rmp3), sensitivity (S), and delay td. The b-wave response amplitude and implicit time were examined as a function of stimulus energy. The parameters obtained in the AZM-treated and untreated conditions were compared. RESULTS: Acetazolamide causes a significant decrease in saturated rod response, b-wave amplitude, aspartate-isolated PIII, and the rod- and cone-mediated responses to flickering light. The estimated sensitivity of the rod response (S), b-wave sensitivity, and b-wave implicit time are not altered significantly by AZM. CONCLUSION: Acetazolamide, probably through mechanisms that acidify the retina, attenuates the amplitudes of the retinal responses without significant effect on sensitivity.

Acetazolamide↗
PubMed1995

The development of the rod photoresponse from dark-adapted rats.

PURPOSE: To study electroretinographic a- and b-wave responses of rats at the ages during which rod outer segment length (ROS) and rhodopsin content increase. METHODS: Electroretinographic responses to brief, full-field stimuli were recorded from dark-adapted young (ages 12 to 30 days) and adult rats. The amplitude of the a-wave and the amplitude and implicit time of the b-wave were examined as a function of stimulus intensity. Sensitivity (S), saturated amplitude (RmP3), and delay (td) of the rod cell responses were calculated from the a-waves. RESULTS: The developmental increase in saturated a-wave amplitude parallels, but lags behind, growth of outer segment length, whereas the saturated b-wave amplitude increases with about the same course as rhodopsin content of the retina. The sensitivity, S, depends on rhodopsin content, and the developmental decrease in the flash energy required to produce a half-maximum b-wave amplitude is inversely proportional to the developmental increase in rhodopsin content. No significant age-dependent variation in td can be detected. CONCLUSION: During development, ROS length and rhodopsin content of the retina are significant determinants of a- and b-wave response parameters.

Aging↗
PubMed1994

Scotopic center surround organization in 10-week-old infants.

The large critical areas for complete spatial summation in infants may be due to immaturities of receptive field organization in both dark and light adapted scotopic conditions. Scotopic lateral excitatory/inhibitory interactions have been previously studied in adults using Westheimer's [(1965) Journal of Physiology, London, 181, 881-894] paradigm. We modified this paradigm to investigate scotopic receptive field organization in infants. Detection thresholds for probe flashes of constant diameter and duration presented on steady backgrounds of various diameters were determined for 10-week-old infants and adults. Infants' thresholds increased up to background diameters of 3 degrees to 3.5 degrees and then decreased at greater background diameters. Adults' thresholds increased for backgrounds up to about 0.75 degrees diameter and then decreased at greater background diameters. These results suggest that the excitatory, central receptive field size is larger in infants than adults, and that a balanced center-surround mechanism is operative.

Adult↗
PubMed1994

Rearrangement of mRNAs for costamere proteins during costamere development in cultured skeletal muscle from chicken.

Mature skeletal myofibrils are surrounded by costameres, ribs of metavinculin, vinculin, intermediate filaments, and other proteins that connect the myofibril to the extracellular matrix. Costameres have recently been shown to be the sites at which the forces generated by the myofibril are transduced laterally into the extracellular matrix. We observed costameres developing in cultured skeletal muscles, grown in micromass culture from cells taken from embryonic chicken leg. We detected proteins by immunofluorescence and mRNA by in situ hybridization. Antibody and probe signals were imaged by laser scanning confocal microscopy. Antibody to vimentin protein is first detected in stripes in register with the Z line of the myofibril, at approximately day 12 after fusion; soon thereafter probe to vimentin mRNA is also detected in the same stripes. Optical sections indicate that vimentin mRNA and protein are very close, no more than 0.1 mm apart and possibly in immediate contact. Antibody to vimentin is detected in stripes only in cells that twitch spontaneously. Antibodies and probes to desmin and vinculin protein and mRNA are next detected in stripes of the same periodicity, at approximately day 17 after fusion. Vinculin protein (but not mRNA) is detected at focal contacts much earlier in development. Controls for bleed through of fluorescence, RNase H sensitivity, hybridization without probe, and binding to the myofibril all gave appropriate results. Probes to glyceraldehyde-3-phosphate dehydrogenase, a glycolytic enzyme, stained diffusely and did not associate with the myofibril. These results show that components of the costamere arrive at the structure in a defined sequence, and that mRNA organization is a conspicuous, precise and temporally controlled aspect of costamere development. These results may have wider implications. In these cells, some mRNAs are positioned with submicrometer precision in space and differentially over time. Particular mRNAs differ in the time and place of such positioning. This implies both that cellular structures provide physical cues for such positioning and that mRNA contains information that interacts with such cues in a message-specific manner. If such precision in mRNA location is found in other somatic cells, it could have significant implications for the ways in which cells generate and maintain cellular structures.

Animals↗
PubMed1994

Scotopic optokinetic nystagmus thresholds in 10-week-old infants.

PURPOSE: To compare psychophysical and reflexive optokinetic nystagmus (OKN) estimates of dark-adapted scotopic thresholds mediated by the posterior retina in 10-week-old infants and adults. METHODS: A staircase procedure was used to determine the stimulus intensity needed to produce an OKN response to a moving 19 degrees x 19 degrees grating. In the same subjects, a two-alternative, forced-choice procedure was used to obtain thresholds for detecting 10 degrees diameter, 50 ms duration stimuli. RESULTS: Both OKN and psychophysical thresholds of infants are 0.9 log unit higher than those of adults. CONCLUSION: The infant-adult difference in thresholds mediated by retina at the posterior pole is greater than the infant-adult difference in thresholds for full-field stimuli. It is possible that delayed maturation of the posterior retina is the primary determinant of infants' high OKN and psychophysical thresholds.

Adolescent↗