Medicine (RMH) - Research Publications
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ItemEphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract(NATL ACAD SCIENCES, 1998-10-27)Members of the Eph family of tyrosine kinase receptors have been implicated in the regulation of developmental processes and, in particular, axon guidance in the developing nervous system. The function of the EphA4 (Sek1) receptor was explored through creation of a null mutant mouse. Mice with a null mutation in the EphA4 gene are viable and fertile but have a gross motor dysfunction, which is evidenced by a loss of coordination of limb movement and a resultant hopping, kangaroo-like gait. Consistent with the observed phenotype, anatomical studies and anterograde tracing experiments reveal major disruptions of the corticospinal tract within the medulla and spinal cord in the null mutant animals. These results demonstrate a critical role for EphA4 in establishing the corticospinal projection.
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ItemManual dexterity and corticospinal connectivity following unilateral section of the cervical spinal cord in the macaque monkey(WILEY-BLACKWELL, 1997-05-12)The macaque recovers quite rapidly from the immediate severe flaccid hemiparesis that results from unilateral section of the cervical spinal cord (between C3 and C6) and starts to use the impaired hand to pick up objects within about 30 days following the surgery. Within another 60 days, the monkey is quite dexterous; nonetheless, there is a persisting deficit. We used video recording to study the long-term recovery of manual dexterity following unilateral section of the cervical cord in newborn and juvenile monkeys. A reach-and-retrieve manual task was examined. By using a preset oppositional force, opposition of the pads of the index finger and thumb in the vertical plane was needed to retrieve the desired target object. The corticospinal connectivity of each monkey was also examined by using retrograde or anterograde tracers at the end of the experimental period (Galea and Darian-Smith [1997] J. Comp. Neurol., this issue) and was correlated with the manual performance. Manually retrieving an object depends on the coordination of several control processes acting in parallel, including 1) visually guided components, such as directing the arm toward the object, aligning the digits with the target object by pronating the forearm, and preshaping the index/thumb separation to match with the size and shape of the target, and 2) manipulative components that depend on tactual input and that also include independent movements of the digits and the application of the appropriate oppositional forces. The impairment of manual dexterity that persisted after a cervical section, although it was small, involved these processes and was evident in 1) the less direct trajectory used in reaching, 2) the loss of preshaping of the separated index finger and thumb prior to grasping the target object, and 3) a weakening of the oppositional forces that could be developed between the pads of the index finger and thumb. Although, in the accompanying paper, we did not preclude some regeneration of severed corticospinal connections, we did show that, if any such reconstruction occurred, then it was limited. The remarkable but incomplete recovery of dexterity over a period of 6-12 months, therefore, must be achieved by 1) optimizing the transmission of information from the cortex to the spinal cord by the substantially reduced populations of corticospinal neurons and corticobulbospinal projections and/or 2) the effective use of spinal circuitry in regulating the more stereotyped elements of the manual task.
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ItemCorticospinal projection patterns following unilateral section of the cervical spinal cord in the newborn and juvenile macaque monkey(WILEY, 1997-05-12)Immediately following a unilateral section of the midcervical spinal cord that interrupts the dorsolateral, lateral, and ventral columns, the macaque monkey has a severe flaccid paralysis on the side of the lesion. Recovery of hand function is rapid, and, although it is incomplete, within a few months, the monkey uses the initially disabled hand and fingers with considerable skill. We examined the accompanying changes in the pattern of projection of corticospinal neurons to the cervical spinal cord that occurred following such a lesion. Spinal section was done both in newborn and juvenile macaques, and the postlesion period was followed for up to 150 weeks. Corticospinal neuron populations were visualized by using both anterogradely and retrogradely transported labels, and their origins, spinal pathways, and terminations were examined at intervals during the period of recovery of hand function. Immediately following unilateral section of the spinal cord at C3, sampled counts of soma profiles of retrogradely labeled neurons indicated that there was a profound reduction in the corticospinal projection to the hemicord caudal to the lesion. The few labeled corticospinal axons spared by the lesion bypassed the spinal lesion by descending in the contralateral cord and then crossing the midline caudal to the lesion. A few corticospinal axons may also have bypassed the lesion in the ipsilateral ventromedial column when this was not fully interrupted by the lesion. In every monkey, we observed a similar, profound reduction in the corticospinal (and rubrospinal) projections to the hemicord caudal to the lesion: This pattern did not alter significantly over an extended recovery period. An unchanging corticospinal projection to the cervical spinal cord contralateral to the lesion was also visualized in each monkey and resembled that seen in the normal macaque. Although the resolution of the labeling and counting procedures used precluded the identification of small increases in the numbers of corticospinal neurons projecting to the hemicord caudal to the lesion, we concluded that there was no substantial reconstruction of this projection over a recovery period of more than 2 years.
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ItemMaximum voluntary weight-bearing by the affected and unaffected legs in standing following stroke(Elsevier, 1996-09-01)Objective. To compare stroke patients to control subjects for ability to transfer body weight onto the affected and unaffected leg in standing; to investigate intra-session reliability. Design. Comparative clinical study conducted within a single session. Background. There is a paucity of quantitative data about maximum voluntary weight-bearing in patients during rehabilitation following stroke. Methods. A Kistler force platform was used to quantify maximum amount of body weight transferred to a single limb in the lateral and forward directions during weight-shifting. Twelve control subjects matched by gender and age (median 64 years) were compared to 12 inpatient stroke patients after a median of 37 days post-onset. Results. The median score for control subjects was approximately 95% of body weight to each leg in both directions. In contrast, stroke patients transferred less body weight (P < 0.01) to the affected leg (65.5% lateral; 54.9% forward) and also to the unaffected leg (85.0% lateral; 80.1% forward). For the stroke patients, transfer of body weight was more challenging in the forward direction than the lateral direction on the affected leg (P < 0.05). Relative to individual differences in the stroke group, error due to the repeated measurement process was low. Conclusion. The testing procedure was found to discriminate between stroke patients and control patients and had high retest reliability within a single session.
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ItemPostnatal maturation of the direct corticospinal projections in the macaque monkey(Oxford University Press, 1995-11-01)Postnatal changes in the topography of the multiple corticospinal projections in the macaque monkey were followed using retrogradely transported fluorescent tracers, and related to the monkey's acquisition of manual dexterity; both behavioral and anatomical maturation were completed by about 8 postnatal months. Cortical origins of the corticospinal projections were examined by constructing planar projection maps of the distributions of labeled corticospinal neuron somas; these somas were found only in lamina V. At birth elaborate somatotopically organized corticospinal projections from primary motor cortex (area 4), the mesial supplementary motor area and cingulate areas 23 and 24, area 12, dorsolateral area 6a beta, the dorsolateral and ventral area 6a alpha (area F4), parietal areas 2/5, 7b and the peri-insular cortex (including area SII), were clearly defined, with axons extending to all spinal cord segments. While this pattern of regional projections broadly resembled that of the mature macaque, there were, however, substantial maturational changes during the 8 months after birth. These included (1) a halving of the area of cerebral cortex from which the contralateral corticospinal projection originated and (2) a threefold reduction in the number of labeled corticospinal neurons projecting to all segments of the cord. Collateral elimination rather than neuronal cell death was the likely mechanism for this reduction in the population and areal extent of corticospinal neurons in the maturing macaque. The surviving corticospinal axon terminals also developed substantially during the postnatal period. At birth some terminals had invaded the intermediate zone in each spinal segment, but few had penetrated the dorsal and ventral horns. By 6 postnatal months, however, many corticospinal neurons were retrogradely labeled following the injection of fluorescent labels into each of these spinal zones in cervical and lumbar spinal segments. These data demonstrate a considerable postnatal reduction in corticospinal neurons projecting to the contralateral spinal cord, and imply that many of the axons that are eliminated never synapse on spinal neurons. It is suggested that during the middle fetal period the axons of many of the cortical neurons in lamina V that in the mature monkey will terminate on particular neuron populations in the thalamus, brainstem, or spinal cord, traverse a common pathway down through the internal capsule into the spinal cord, passing close to these successive targets, and possibly forming collaterals at these levels. In the postnatal period each such neuron establishes a stable, effective synaptic input to only one or a few of these subcortical target populations, and the remaining collateral branches regress. The postnatal maturation of corticospinal neurons, examined in this study, is compatible with such a model.
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ItemCHONDROITIN SULFATE A IS A CELL-SURFACE RECEPTOR FOR PLASMODIUM-FALCIPARUM-INFECTED ERYTHROCYTES(ROCKEFELLER UNIV PRESS, 1995-07-01)Adherence of Plasmodium falciparum-infected erythrocytes to cerebral postcapillary venular endothelium is believed to be a critical step in the development of cerebral malaria. Some of the possible receptors mediating adherence have been identified, but the process of adherence in vivo is poorly understood. We investigated the role of carbohydrate ligands in adherence, and we identified chondroitin sulfate (CS) as a specific receptor for P. falciparum-infected erythrocytes. Parasitized cells bound to Chinese hamster ovary (CHO) cells and C32 melanoma cells in a chondroitin sulfate-dependent manner, whereas glycosylation mutants lacking chondroitin sulfate A (CSA) supported little or no binding. Chondroitinase treatment of wild-type CHO cells reduced binding by up to 90%. Soluble CSA inhibited binding to CHO cells by 99.2 +/- 0.2% at 10 mg/ml and by 72.5 +/- 3.8% at 1 mg/ml, whereas a range of other glycosaminoglycans such as heparan sulfate had no effect. Parasite lines selected for increased binding to CHO cells and most patient isolates bound specifically to immobilized CSA. We conclude that P. falciparum can express or expose proteins at the surface of the infected erythrocyte that mediate specific binding to CSA. This mechanism of adherence may contribute to the pathogenesis of P. falciparum malaria, but has wider implications as an example of an infectious agent with the capacity to bind specifically to cell-associated or immobilized CS.