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Biomedical subjects

J A Sharpe

Publications and source records attributed to J A Sharpe.

At least 19 recordsLinked to original sources
PubMed1992

Regulation of human embryonic globin genes zeta 2 and epsilon in stably transformed mouse erythroleukemia cells.

Previous work has suggested that the promoter regions of the human embryonic zeta 2 and epsilon globin genes contain negative regulatory regions that could play a role in the repression of these genes in postembryonic erythroblasts. We have examined this possibility by studying the expression of these genes in mouse erythroleukemia cells, an adult erythroid cell line that might be expected to contain repressor molecules that would bind to the putative negative regulatory regions. When attached to appropriate upstream regulatory elements (alpha HS-40 and beta HS1,2) both the zeta and epsilon genes were expressed in these cells at a low level, but no increase in expression was observed when similar constructs lacking the proposed negative regulatory sequences were introduced into these cells. These results cast doubt on the possibility that these sequences play a major role in the developmental repression of the embryonic globin genes, unless they function only in a normal chromosomal organization.

Adenine Phosphoribosyltransferase↗
PubMed1992

Paresis of contralateral smooth pursuit and normal vestibular smooth eye movements after unilateral brainstem lesions.

Pursuit and vestibular smooth eye movements were measured in patients with lesions of the caudal brainstem tegmentum identified by magnetic resonance imaging (MRI) and computed tomography (CT), with neuropathological correlation in 1 patient. Contralateral smooth pursuit gain was significantly lower than ipsilateral gain in each patient. Ipsilateral smooth pursuit gain was also subnormal in patients with unilateral pontine damage that caused slowing of ipsilateral saccades. Horizontal vestibulo-ocular reflex gain and phase were normal. These quantitative correlations indicate that lesions of the pontine tegmentum that paralyze ipsilateral saccades can spare the vestibulo-ocular reflex, and that smooth pursuit movement and the vestibulo-ocular reflex can be impaired independently by pontine or medullary lesions. In contrast to lesions at other sites, unilateral lesions of the pontine or medullary tegmentum impair contralateral smooth pursuit more than ipsilateral pursuit movements. These findings provide evidence that a double decussating pathway mediates smooth pursuit; the first decussation is from the pons to the cerebellum, and the second decussation is from the vestibular nucleus to the contralateral abducens nucleus.

Brain Diseases↗
PubMed1992

Motion-defined letter detection and recognition in patients with multiple sclerosis.

Two important distinctions in visual perception are (1) between the detection and recognition of shape (e.g., letters), and (2) between the recognition of shapes defined by a difference in brightness and the recognition of shapes defined by a difference in motion. We report that 6 of 10 patients with multiple sclerosis showed impaired recognition for motion-defined (MD) letters, although the detection of MD letters was normal as were both detection and recognition of luminance-defined letters. We have shown that this was not a function of acuity loss or the loss of ability to detect motion or a general failure of recognition per se, but was confined to a loss of ability to recognize MD letters. The neurological implications of these findings are discussed, and it is suggested that the MD letter test be used by others interested in the central pathology of visual disorders.

Adult↗
PubMed1992

Analysis of the human alpha globin upstream regulatory element (HS-40) in transgenic mice.

We have analysed the effect of a 1.4 kb segment of DNA containing the upstream alpha globin regulatory element (HS-40) on human alpha globin gene expression in fetal mice and lines of transgenic mice. High levels of tissue-specific, human alpha mRNA expression were seen in all transgenic animals and in this sense expression was position independent. However, the level of human alpha mRNA expression per integrated gene copy decreased during development and was inversely related to copy number. The limitation in expression with increasing gene copy number was shown to be in cis since homozygotes for the transgene produced twice as much human alpha mRNA as hemizygotes. In many respects HS -40 appears similar to single elements within the previously described beta globin locus control region and in cross breeding experiments we have shown that HS -40 behaves in a similar manner to such elements in transgenic mice.

Animals↗
PubMed1992

Single fiber EMG in the frontalis muscle in ocular myasthenia: specificity and sensitivity.

Patients (n = 41) with isolated weakness of the eyelids or extraocular muscles, who had been referred for single fiber electromyography (SFEMG), were followed up after 4 to 24 months, At follow-up the patients were classified as "definite ocular myasthenia gravis" (MG), "definite other diagnosis," or "no definite diagnosis" on the basis of the completed investigations and subsequent course. The original SFEMG findings in the frontalis muscle were then reviewed. The specificity and sensitivity of SFEMG for "definite ocular MG" could be maximized by using as criteria for abnormality greater than 8/20 pairs with jitter greater than 45 microseconds, or a mean jitter of 20 pairs of greater than 50 microseconds. Patients with abnormal SFEMG according to these criteria have MG, and are likely to require treatment in the immediate future. Patients who have normal SFEMG according to these criteria (and no other demonstrated disorder) may have MG, but it is so mild that they are unlikely to require treatment. Two patients whose final diagnosis was progressive external ophthalmoplegia had normal SFEMG according to these criteria.

Adult↗
PubMed1992

Spasm of fixation: a quantitative study.

Spasm of fixation, consisting of impaired initiation of saccades in the presence of fixation target, but normal initiation in the absence of a fixation target, was measured in a patient with cerebral hemispheric damage. When a central target was constantly present, the patient made horizontal saccades to the sudden appearance of a second target at very prolonged latencies (mean 369 ms). In the absence of a central fixation target, saccadic latency decreased to normal (197 ms). Extinction of a target for a gap interval elicited very short latency movements (122 ms), termed express saccades. The intervals between self-paced horizontal refixation saccades with the head immobile were prolonged, whereas voluntary refixation saccades with the head free to move occurred at shorter intervals. We postulate that cerebral hemispheric damage may cause spasm of visual fixation by disinhibiting the substantia nigra pars reticulata, thereby inhibiting the superior colliculus.

Adult↗
PubMed1992

A single beta-globin locus control region element (5' hypersensitive site 2) is sufficient for developmental regulation of human globin genes in transgenic mice.

The beta-globin gene complex is regulated by an upstream locus control region (LCR) which is responsible for high-level, position-independent, erythroid-cell-specific expression of the genes in the cluster. Its role in the developmental regulation of beta-like globin gene transcription remains to be established. We have examined the effect of a single LCR element, hypersensitive site 2 (HS2), on the developmental regulation of the human fetal gamma and adult beta genes in transgenic mice. In mice bearing HS2A gamma beta and HS2G gamma A gamma-117 delta beta human globin gene constructs, switching from gamma- to beta-gene expression begins at about day 13.5 of gestation and is largely completed shortly after birth. The larger construct also demonstrates a switch in G gamma- to A gamma-gene expression during the gamma-to-beta switch similar to that observed during normal human development. We conclude that HS2 alone is sufficient for developmental regulation of the human beta-globin genes.

Aging↗
PubMed1992

Visual processing of motion-defined form: selective failure in patients with parietotemporal lesions.

The following psychophysical data were obtained from 13 patients with unilateral cerebral hemispheric lesions and 20 control subjects: speed thresholds for detecting and for recognizing motion-defined letters, speed thresholds for detecting coherent motion and for discriminating its direction, and visual acuity for recognizing letters of 96% and 11% contrast. Acuity was between 6/6 and 6/3 for all patients. Four patients showed a selective loss of ability to recognize motion-defined letters, while the ability to detect those same letters was spared, as was the ability to detect coherent motion and discriminate its direction (type I loss). Three patients showed a loss of ability both to recognize and to detect motion-defined letters, while the ability to detect coherent motion and discriminate its direction was spared (type II loss). All seven patients who failed to recognize motion-defined letters had extensive lesions in parietotemporal white matter underlying Brodmann cortical areas 18, 19, 37, 39, 21, and 22. The lesion was in the left hemisphere for three patients and in the right hemisphere for the remaining four. The region of overlap in these seven patients was not invaded by the lesion in any of the other six patients, and none of these six patients showed a loss of ability to recognize motion-defined letters. Three patients showed selective loss of acuity for low-contrast letters with normal Snellen acuity. The lesions in these three patients extended more posteriorly than in any other patient, and their region of overlap was in white matter underlying areas 18 and 19. We conclude that (1) the loss of ability to recognize letters in seven patients was specific to motion-defined letters rather than being a general loss of letter-recognition ability, (2) this visual loss was specific to motion-defined form rather than being a general failure of motion processing, and (3) the visual loss was not produced by lesions that did not involve the localized cerebral region specified above. To explain the existence of type I and of type II loss with sparing of the detection and discrimination of coherent motion, we propose that motion information is processed hierarchically. We further suggest that homologs of the socalled motion and color/form pathways (i.e., areas V1/MT/MST/7a and areas V1/V4/IT) are interconnected to form a distributed system that is important for the recognition of motion-defined form.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1991

Nystagmus of Pelizaeus-Merzbacher disease. A magnetic search-coil study.

Magnetic search-coil oculography of three brothers with clinically diagnosed Pelizaeus-Merzbacher disease disclosed the presence of binocular elliptical pendular nystagmus in two patients in whom the waveform of the nystagmus was not obvious on inspection. This study, the first reported application of high-resolution oculography to Pelizaeus-Merzbacher disease, also demonstrated primary position upbeat nystagmus in all three patients. The importance of finding this combination of elliptical pendular and upbeat nystagmus is that it is not described in any other childhood neurodegenerative states and, in combination with supportive clinical history and magnetic resonance imaging, may be so characteristic of Pelizaeus-Merzbacher disease that a strong presumptive diagnosis can be made.

Adult↗
PubMed1991

Upbeat nystagmus: clinicopathological and pathophysiological considerations.

We describe an electro-oculographic study of upbeat nystagmus in 4 patients, with neuropathological correlation in one. All patients had lesions in the pontine tegmentum. The electro-oculographic data may be explained by imbalanced vertical vestibular or smooth pursuit eye movement control. The nystagmus stopped or reversed direction during convergence or in supine head positions. We propose that changes in the intensity or direction of upbeat nystagmus that are induced by convergence or changes in head position, are caused by vertical imbalance in the otolithic-ocular reflex, when superimposed on an imbalanced vestibulo-ocular reflex (VOR). Imbalance of the otolithic-ocular reflex and the vertical VOR are caused by damage in the pontomedullary tegmentum.

Adult↗
PubMed1991

Recognition of motion-defined shapes in patients with multiple sclerosis and optic neuritis.

We have developed a simple procedure for assessing the ability of the visual pathway to extract a two-dimensional shape from motion. The test requires a patient to read motion-defined (MD) letters. These letters differ physically from the familiar contrast-defined (CD) letters that are dimmer or brighter than their surroundings in that the boundaries of MD letters are rendered visible exclusively by a step in velocity while the boundaries of CD letters are rendered visible by a step in luminance. Subjects viewed a random pattern of bright dots containing a perfectly camouflaged letter. Then the letter was revealed by moving dots within and outside the letter at equal speeds in opposite directions. Letter reading scores for 50 eyes of 25 patients with multiple sclerosis (MS) or optic neuritis were compared with norms based on 50 control subjects. When tested with large (50 arc min, i.e., 6/60) MD letters, 34/50 eyes of patients required abnormally high dot speeds to read letters, visual loss being sufficiently selective in 10 eyes that contrast sensitivity, Snellen acuity, 11%-contrast and 4%-contrast acuity were all spared. Four eyes were effectively motion blind in the sense that they could not read large letters even at our highest relative speed of 0.9 deg/s and the failure could not be attributed to reduced Snellen acuity. Our normal limit was 2.5 SD from the control mean and there were 1/50 false positives. Of the 34/50 eyes with elevated speed thresholds, 23 had normal Snellen acuities. The number of eyes abnormal for intermediate (11%) contrast CD letters, was 19/50 of which 8 had normal Snellen acuity, confirming our previous finding that MS can degrade the ability to see low-contrast objects while sparing Snellen acuity. We conclude that MD test letters can detect lesions that are not picked up by testing with CD test letters of high or low contrast. We suggest that the MD letter test can detect dysfunction in the human equivalent of a pathway in monkey brain that originates in large retinal ganglion cells, passes through the magnocellular layers of the lateral geniculate body, includes cortical area MT, and is involved in processing motion.

Adult↗
PubMed1991

Characterization of the major regulatory element upstream of the human alpha-globin gene cluster.

The major positive regulatory activity of the human alpha-globin gene complex has been localized to an element associated with a strong erythroid-specific DNase I hypersensitive site (HS -40) located 40 kb upstream of the zeta 2-globin mRNA cap site. Footprint and gel shift analyses of the element have demonstrated the presence of four binding sites for the nuclear factor GATA-1 and two sites corresponding to the AP-1 consensus binding sequence. This region resembles one of the major elements of the beta-globin locus control region in its constitution and characteristics; this together with evidence from expression studies suggests that HS -40 is a primary element controlling alpha-globin gene expression.

Base Sequence↗
PubMed1991

Vertical vestibulo-ocular reflex control after supranuclear midbrain damage.

The vertical vestibulo-ocular reflex (VOR) and its visual enhancement and cancellation were measured in patients with focal midbrain lesions that caused paralysis of upward, or upward and downward saccades. VOR gain was reduced in darkness during active vertical head pitch at frequencies from 0.25 to 2 Hz. Visual enhancement of the reflex by fixating a stationary target was subnormal upward and downward. Cancellation of the VOR was defective in both vertical directions during eye-head tracking. The VOR showed abnormal phase lead of the eyes in darkness, indicating that pretectal midbrain damage impairs the integration of eye velocity commands.

Brain Injuries↗
PubMed1991

Primary position upbeat nystagmus. Clinicopathologic study of four patients.

We report an electro-oculographic study (EOG) of upbeat nystagmus and neuroradiological correlations in 4 patients and neuropathological findings in 1 patient. All 4 patients revealed responsible lesions in the lower pontine tegmentum. The EOG data suggest that our patients had a deficit in vertical smooth eye movement balance. The nystagmus stopped or reversed direction during convergence or changes of head position. These EOG findings might be caused by vertical imbalance in the otolithic ocular reflex, superimposed on an imbalanced vestibulo-ocular reflex (VOR), secondary to a damage to the pontomedullary tegmentum.

Adult↗
PubMed1990

End-point nystagmus and ocular drift: an experimental and theoretical study.

End-point nystagmus (EPN) and ocular drift during eccentric fixation were investigated in five normal subjects. All had EPN during prolonged eccentric fixation, two had sustained EPN within a few seconds of fixating an eccentric target. Our data show that the occurrence of EPN was determined by the velocity of slow phase ocular drift. Drift velocities greater than 1 deg/sec elicited sustained EPN or fatigue EPN while drift velocities lower than 0.3 deg/sec did not elicit EPN. Slow phase drift velocity increased with eccentricity and fixation duration and decreased with visual feedback. Computer simulations and theoretical analysis suggest that the reduction in drift eye movement velocity during fixation of a visible target, as compared to drift eye movement velocity during attempted fixation of a remembered target in darkness, is mainly due to the smooth pursuit system.

Adult↗
PubMed1990

Cerebral hemispheric localization of smooth pursuit asymmetry.

We recorded horizontal smooth pursuit in 23 patients with discrete unilateral cerebral hemispheric lesions and in 12 normal subjects. Most patients had bidirectional reduction of smooth pursuit gain, indicating that each cerebral hemisphere participates in smooth pursuit in both directions. Pursuit gain fell proportionately more with increasing target acceleration in patients than in normals. A normal phase relationship between eye and target motion in patients indicated an intact predictor mechanism for smooth pursuit. Ten patients had pursuit asymmetry with lower gain when tracking toward the side of cerebral damage; none had lower gain when tracking away. Two patients with lower ipsilateral gain had frontal lobe lesions. Areas of anatomic overlap of lesions associated with asymmetric pursuit in 8 patients provide evidence for a pursuit pathway that originates from Brodmann areas 19 and 39 and descends to the brainstem through the posterior limb of the internal capsule.

Adolescent↗