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Biomedical subjects

S Cash

Publications and source records attributed to S Cash.

11 recordsLinked to original sources
PubMed2005

Pseudosyndactyly and musculoskeletal contractures in inherited epidermolysis bullosa: experience of the National Epidermolysis Bullosa Registry, 1986-2002.

Mitten deformities of the hands and feet occur in nearly every patient with the most severe subtype (Hallopeau-Siemens) of recessive dystrophic epidermolysis bullosa, and in at least 40-50% of all other recessive dystrophic epidermolysis bullosa patients. Smaller numbers of patients with dominant dystrophic, junctional, and simplex types of epidermolysis bullosa are also at risk of this complication. Surgical intervention is commonly performed to correct these deformities, but recurrence and the need for repeated surgery are common. Higher numbers of epidermolysis bullosa patients also develop musculoskeletal contractures in other anatomic sites, further impairing overall function. Lifetable analyses not only better project the cumulative risk of mitten deformities and other contractures but also emphasize the need for early surveillance and intervention, since both of these musculoskeletal complications may occur within the first year of life.

Adolescent↗
PubMed1999

Linear summation of excitatory inputs by CA1 pyramidal neurons.

A fundamental problem in neurobiology is understanding the arithmetic that dendrites use to integrate inputs. The impact of dendritic morphology and active conductances on input summation is still unknown. To study this, we use glutamate iontophoresis and synaptic stimulation to position pairs of excitatory inputs throughout the apical, oblique, and basal dendrites of CA1 pyramidal neurons in rat hippocampal slices. Under a variety of stimulation regimes, we find a linear summation of most input combinations that is implemented by a surprising balance of boosting and shunting mechanisms. Active conductances in dendrites paradoxically serve to make summation linear. This "active linearity" can reconcile predictions from cable theory with the observed linear summation in vivo and suggests that a simple arithmetic is used by apparently complex dendritic trees.

Action Potentials↗
PubMed1998

Input summation by cultured pyramidal neurons is linear and position-independent.

The role of dendritic morphology in integration and processing of neuronal inputs is still unknown. Models based on passive cable theory suggest that dendrites serve to isolate synapses from one another. Because of decreases in driving force or resistance, two inputs onto the same dendrite would diminish their joint effect, resulting in sublinear summation. When on different dendrites, however, inputs would not interact and therefore would sum linearly. These predictions have not been rigorously tested experimentally. In addition, recent results indicate that dendrites have voltage-sensitive conductances and are not passive cables. To investigate input integration, we characterized the effects of dendritic morphology on the summation of subthreshold excitatory inputs on cultured hippocampal neurons with pyramidal morphologies. We used microiontophoresis of glutamate to systematically position inputs throughout the dendritic tree and tested the summation of two inputs by measuring their individual and joint effects. We find that summation was surprisingly linear regardless of input position. For small inputs, this linearity arose because no significant shunts or changes in driving force occurred and no voltage-dependent channels were opened. Larger inputs also added linearly, but this linearity was caused by balanced action of NMDA and IA potassium conductances. Therefore, active conductances can maintain, paradoxically, a linear input arithmetic. Furthermore, dendritic morphology does not interfere with this linearity, which may be essential for particular neuronal computations.

2-Amino-5-phosphonovalerate↗
PubMed1996

Spread of synaptic depression mediated by presynaptic cytoplasmic signaling.

Postsynaptic activity may modulate presynaptic functions by transsynaptic retrograde signals. At developing neuromuscular synapses in Xenopus nerve-muscle cultures, a brief increase in the cytosolic calcium ion (Ca2+) concentration in postsynaptic myocytes induced persistent depression of presynaptic transmitter secretion. This depression spread to distant synapses formed by the same neuron. Clearance of extracellular fluid did not prevent the spread of depression, and depression could not be induced by increasing the Ca2+ concentration in a nearby myocyte not in contact with the presynaptic neuron. Thus, the spread of depression is mediated by signaling in the presynaptic cytoplasm, rather than by a retrograde factor in the extracellular space.

Animals↗
PubMed1996

Postsynaptic elevation of calcium induces persistent depression of developing neuromuscular synapses.

Synaptic activity is known to modulate neuronal connectivity in the nervous system. At developing Xenopus neuromuscular synapses in culture, repetitive postsynaptic application of ACh near the synapse leads to immediate and persistent synaptic depression, which was shown to be caused by reduction of presynaptic evoked transmitter release. However, little depression was found when ACh was applied to the muscle 20 microns or further from the synapse. Fluorescence imaging of cytosolic Ca2+ ([Ca2+]i) showed that each ACh pulse induced a transient elevation of myocyte [Ca2+]i that spread approximately 20 microns. Local photoactivated release of Ca2+ from the caged Ca2+ chelators nitr-5 or nitrophen in the postsynaptic cell was sufficient to induce persistent synaptic depression. These results support a model in which localized Ca2+ influx into the postsynaptic myocyte initiates transsynaptic retrograde modulation of presynaptic secretion mechanisms.

Acetylcholine↗
PubMed1994

Role change after traumatic brain injury in adults.

OBJECTIVES: The purpose of this study was to gather information regarding changes in adult life roles following severe traumatic brain injury. METHOD: The Role Checklist and a semistructured interview were administered to 28 adults with traumatic brain injury who had been in the community for at least 8 months prior to the study. All 28 subjects reported role changes in their lives. RESULTS: The majority of the role changes were losses (71%). More than 64% percent of the subjects reported three or four role losses. The losses were in major organizing roles such as worker, hobbyist, and friend. Most role gains were seen in the roles of home maintainer, family member, and religious participant. Almost 40% of all roles were reported as changed (loss or gain), while more than 60% of roles were reported as unchanged (continuous or absent). The participants' subjective impressions concerning the role changes and why they occurred were elicited. CONCLUSION: With a better understanding of possible role change after traumatic brain injury, rehabilitation professionals can target the development of specific skills necessary for the continuation of valued roles.

Adult↗
PubMed1993

Cellular mechanisms governing synaptic development in Drosophila melanogaster.

The neuromuscular connections of Drosophila are ideally suited for studying synaptic function and development. Hypotheses about cell recognition can be tested in a simple array of pre- and postsynaptic elements. Drosophila muscle fibers are multiply innervated by individually identifiable motoneurons. The neurons express several synaptic cotransmitters, including glutamate, proctolin, and octopamine, and are specialized by their synaptic morphology, neurotransmitters, and connectivity. During larval development the initial motoneuron endings grow extensively over the surface of the muscle fibers, and differentiate synaptic boutons of characteristic morphology. While considerable growth occurs postembryonically, the initial wiring of motoneurons to muscle fibers is accomplished during mid-to-late embryogenesis (stages 15-17). Efferent growth cones sample multiple muscle fibers with rapidly moving filopodia. Upon reaching their target muscle fibers, the growth cones rapidly differentiate into synaptic contacts whose morphology prefigures that of the larval junction. Mismatch experiments show that growth cones recognize specific muscle fibers, and can do so when the surrounding musculature is radically altered. However, when denied their normal targets, motoneurons can establish functional synapses on alternate muscle fibers. Blocking synaptic activity with either injected toxins or ion channel mutants does not derange synaptogenesis, but may influence the number of motor ending processes. The molecular mechanisms governing cellular recognition during synaptogenesis remain to be identified. However, several cell surface glycoproteins known to mediate cellular adhesion events in vitro are expressed by the developing synapses. Furthermore, enhancer detector lines have identified genes with expression restricted to small subsets of muscle fibers and/or motoneurons during the period of synaptogenesis. These observations suggest that in Drosophila a mechanism of target chemoaffinity may be involved in the genesis of stereotypic synaptic wiring.

Animals↗
PubMed1993

Growth cone choices of Drosophila motoneurons in response to muscle fiber mismatch.

In Drosophila embryos, each motoneuron is accurately matched to one or more singly identifiable muscle fibers. In this article we altered the number and pattern of the embryonic muscle fibers using genetic, heat shock, and laser ablation methods to test whether motoneuron growth cones are able to recognize specific targets. The choices made by two motoneurons were assayed using both intracellular dye fills and immunocytochemistry. The motoneurons RP1 and RP3 have nearly identical central and peripheral axonal trajectories. However, RP3 innervates the two most ventral longitudinal muscle fibers, 7 and 6, while RP1 grows past these fibers to innervate only muscle fiber 13. In rhomboid mutants muscle fiber 7 does not develop. Despite the loss of one of its targets, RP3 faithfully innervated the remaining muscle fiber 6 in over 80% of the observed cases. Furthermore, neuron RP1 accurately innervated muscle fiber 13, although it traversed one fiber fewer to reach it. Laser ablation of muscle fiber 7 confirmed the target choices shown by the motoneurons. In numb mutants, multiple muscle fibers, including 7, 13, and 12, fail to develop. This allowed us to test whether fibers distal to the target are involved in muscle fiber recognition, possibly by halting the growth cone advance. In mutant embryos, RP3 innervated muscle fiber 6 at the same frequency regardless of the absence of the distal muscle fiber 13. By contrast, RP1, which had lost its target entirely, frequently failed to innervate any muscle fiber during the period examined. Finally, muscle fiber 13 can be duplicated in wild-type embryos by means of a brief heat pulse during myogenesis. Presented with two targets, RP1 innervated both fibers in each case examined, while RP3 synapsed with muscle fibers 7 and 6 normally. Neuron-specific antibodies revealed that the embryonic growth cone choices were not transient, but persisted into the larval neuromuscular projections. These results indicate that each motoneuron growth cone has a primary target preference, which is retained even when the numbers of the muscle fibers, and therefore their relative positions, are altered. We therefore suggest that synaptic recognition by Drosophila motoneuron growth cones relies on unique features of the individual muscle fibers.

Animals↗
PubMed1992

Alternate neuromuscular target selection following the loss of single muscle fibers in Drosophila.

The Drosophila embryonic and larval body wall consists of a simple array of segmental muscle fibers, innervated in a precise manner by identified neurons. During development motoneurons were forced to find alternate targets following the selective deletion of a single muscle fiber, the pleural internal oblique #5. We used backfills, intracellular dyefills, and immunocytochemistry in embryos and larvae to characterize the normal motoneurons to the fiber. Deleting the fiber using either a genetic or laser lesioning method yielded essentially the same result. In nearly half the cases examined, an ectopically placed neuromuscular projection was found on either of two neighboring muscle fibers, with one favored eight times more than the other. The ectopic projection derived from the nerve branch that normally supplied the deleted muscle fiber 5. Motoneuronal endings on undeleted muscle fibers elsewhere in the body wall had normal morphology. The ectopically placed motor terminals accumulated glutamate in normally sized synaptic boutons, beneath which transmitter sensitivity was localized. The number of boutons and branches at the ectopic endings did not differ significantly from those on intact muscle fiber 5s. Also, the native motoneurons did not alter their arborization sizes in response to a supernumerary ectopically placed contact. While the orientation of the individual ectopically placed branches was variable, the ectopic endings occupied a predictable site on the surrogate muscle fibers. The results suggest that Drosophila motoneurons can project to body wall destinations in the absence of their muscle fiber targets, and that alternate muscle fibers are selected by their proximity. The muscle fibers will support apparently stable and functional supernumerary motor endings on ectopic sites, and these inputs do not significantly influence the behavior of the native motoneurons. The data suggest that Drosophila motoneurons may behave autonomously when making synapses, and that competition does not play a major role in the matching of motoneuron to muscle fiber.

Animals↗