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Biomedical subjects

J A Sharpe

Publications and source records attributed to J A Sharpe.

15 recordsLinked to original sources

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

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

Cerebral and retinal vascular complications of inflammatory bowel disease.

Recurrent retinal branch artery occlusions, carotid thromboembolism, cerebral venous thrombosis, transient brainstem ischemia, and massive brainstem and cerebral infarction complicated the course of inflammatory bowel disease in 5 patients. Three patients had ulcerative colitis and 2 had regional enteritis. The usual risk factors for stroke were absent. Neuropathological examination in 1 patient showed in situ thrombosis of small cerebral and brainstem arteries and veins. Coagulation studies showed thrombocytosis, short partial thromboplastin times, and elevation of fibrinogen and Factor VIII levels. Platelet counts and coagulation factors returned toward normal after control of intestinal inflammation in each of the 4 surviving patients. Inflammatory bowel disease can be accompanied by a hypercoagulable state that predisposes to stroke.

Adult

Midbrain asterixis.

Asterixis is usually a manifestation of metabolic encephalopathy. It was the only skeletal motor sign in a patient with ophthalmoplegia caused by midbrain infarction; no metabolic abnormality was present. The asterixis was accompanied by signs of damage to the mesencephalic reticular formation. We propose that episodic lapses of postural control by the reticular formation are responsible for midbrain asterixis and suggest that this asterixis is a segmental form of drop attack.

Aged

Control of the saccadic and smooth pursuit systems after cerebral hemidecortication.

Saccadic and smooth pursuit eye movements were analysed in 5 patients eight to twelve years after cerebral hemidecortication. Saccadic peak velocities were mildly reduced and saccadic durations were prolonged in both horizontal directions. Slowing of saccades may signify a loss of cerebral modulation of the discharge frequency and duration of brain-stem burst units or a less specific susceptibility of the hemidecorticate brain to fatigue. Symmetrical latencies of saccades to 20- and 40-degree target steps into the hemianopic and intact visual fields provided evidence for brain-stem processing of retinal signals from the hemianopic field. Latencies of saccades to 5-degree target steps into the blind hemifield were significantly longer than to 5-degree steps into the intact field. Disparity between saccadic latencies to parafoveal (5 degrees) and peripheral (20- and 40-degrees) targets indicated that such visual capacity in the hemianopic field is dependent upon target eccentricity.

Adult

Beneficial effect of operation-day blood-transfusions on human renal-allograft survival.

In 56 patients 1-year renal-graft survival was significantly better (71% vs 40%) in those who had received blood before operation, confirming previous observations. In addition, transfusion on the day of operation proved to have been beneficial, both in those previously transfused (82% vs 64%) and in those never previously transfused (71% vs 28%). Irrespective of pretransplant transfusion, 1-year graft survival was significantly better (79% vs 44%) in those transfused on the day of operation.

Blood Transfusion

Destruction of the internal sagittal stratum and normal smooth pursuit.

Analysis of smooth pursuit by infrared oculography showed normal horizontal smooth eye movement gain in a patient with a unilateral parietooccipital hematoma that involved the internal sagittal stratum and the adjacent tapetum and visual radiation. Normal pursuit toward the lesion is attributed to commissural transfer of visual information from the normal cerebral hemisphere to the intact extrastriate cortex of the visually deprived hemisphere. This pathophysiological correlation indicates that the occiptiomesencephalic projections of the internal sagittal stratum and the peristriate interhemispheric connections of the tapetum are not necessary for smooth pursuit system function.

Aged

Effect of aging on horizontal smooth pursuit.

Quantitative infrared oculographic study of horizontal pursuit in young and elderly normal subjects showed significantly lower smooth pursuit velocities in the elderly when tracking triangular waveform targets of 20 degrees amplitude at velocities of 10 degrees/sec and over. Latencies for initiation of smooth eye movements were significantly prolonged in older subjects. The reduced velocity responses of the pursuit system indicate that the diagnosis of abnormal pursuit must be qualified by the age of the patient. Smooth pursuit is an age-dependent motor system.

Adult

The ocular tilt reaction. A paroxysmal dyskinesia associated with elliptical nystagmus.

The ocular tilt reaction, a synkinesis of ocular torsion, skew deviation, and head tilting, was a paroxysmal disorder in a patient with multiple sclerosis. In this distinctive pattern of eye and head motion, the 12 o'clock corneal meridians of both eyes are rotated conjugately in the direction of the lower skewed eye and the head is inclined laterally in the same direction. Paroxysmal activation of brain stem otolithic vestibular projections is proposed responsible for the dyskinesia. Coincident attacks of vertical and horizontal low amplitude pendular oscillation of the eyes produced elliptical nystagmus. This ocular motor disorder was treated effectively with carbamazepine.

Adult

Neuroepithelial cyst of the fourth ventricle. Case report.

Developmental cysts lined by neuroepithelium are a distinctive form of neural tube dysgenesis. Neuropathological study of fourth ventricular cysts that caused symptomatic hydrocephalus indicated its neuroepithelial origin. The cyst arose from the ventral surface of cerebellar vermis. Evagination of the rhombencephalic roof and entrapment of a ventricular diverticulum beneath the cerebellar anlagen is proposed as a mechanism responsible for the extraordinary occurrence of neuroepithelial cysts within the fourth ventricle.

Adolescent

Convergence-evoked nystagmus. Congenital and acquired forms.

Pendular nystagmus occurring during binocualr fixation and pursuit of near objects is true convergence-evoked nystagmus. Two forms of this nystagmus are described, one congenital and the other acquired in the course of multiple sclerosis. The congenital form was conjugate and the acquired form disjunctive. Neuropathological examination provided no morphological explanation for the congenital pattern. These two unique forms of nystagmus are induced by one of the visuomotor subsystems controlling convergence.

Adult

Atrophy of myelinated nerve fibres in the retina in optic neuritis.

Atrophy of the nerve fibres in the retina visible by direct ophthalmoscopy using red-free illumination, together with corresponding scotomata in the visual fields, signified retrograde degeneration of retinal nerve fibres from multiple sclerosis. Defects in medullated retinal nerve fibres were continous with arcuate nerve fibre bundle defects. These myelin defects exemplify secondary demyelination of optic axons.

Adult

Familial paralysis of horizontal gaze. Associated with pendular nystagmus, progressive scoliosis, and facial contraction with myokymia.

Paralysis of horizontal gaze, pendular nystagmus, and progressive scoliosis were manifestations of an autosomal recessive genetic disease in four siblings. Bilateral facial myokymia with continuous facial contraction developed in the oldest patient. Electromyographic examination of his facial muscles after facial nerve block at the stylomastoid foramen showed absence of all muscle potentials, consistent with a supranuclear origin of the myokymia. Normality of convergence, vertical gaze, and pupillary constrictor reflex activity assured integrity of midbrain ocular motor function. Absence of horizontal vestibulo-ocular reflexes signified involvement of the pontine tegmentum in this distinctive heredofamilial syndrome.

Adolescent

Comparative velocities of different types of fast eye movements in man.

The peak velocity-amplitude characteristics of voluntary saccades and the fast phases of caloric, rotational, and optokinetic (OKN) nystagmus were compared in ten human subjects in both light and, except for OKN, darkness. All these fast eye movements had similar velocities and all slowed in darkness. This study supports the presumption that the identical brainstem firing patterns found in monkeys for all fast eye movements also occur in man.

Adult