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Biomedical subjects

A W Clark

Publications and source records attributed to A W Clark.

15 recordsLinked to original sources
PubMed1992

GAP-43 gene expression is increased in anterior horn cells of amyotrophic lateral sclerosis.

In amyotrophic lateral sclerosis (ALS), neuronal loss and axonal degeneration occur in motor neurons. Although there is limited axonal regeneration, surviving motor neurons send collateral sprouts to denervated muscle fibers. GAP-43, a protein enriched in growth cones and synaptic terminals, is thought to have a role in axonal elongation and synaptogenesis. GAP-43 messenger RNA (mRNA) expression was evaluated in ALS spinal cords using Northern blot analysis and in situ hybridization to assess whether surviving neurons can mount an appropriate response to injury. There was a two- to four-fold increase in GAP-43 mRNA in ALS that localized to the anterior horn cells. The increase in GAP-43 mRNA indicates that the mechanism which leads to degeneration in ALS does not compromise the neuron's capacity for vigorous expression of growth-associated proteins.

Amyotrophic Lateral Sclerosis↗
PubMed1991

Beta-amyloid precursor protein gene is differentially expressed in axotomized sensory and motor systems.

The beta-amyloid precursor protein (APP) is involved in the degenerative and regenerative neural changes associated with aging and Alzheimer's disease. We studied the regulation of APP gene expression in a paradigm of degeneration and regeneration, the axotomized rat sciatic system. The sciatic nerves of rats were crushed and at intervals between 4 and 60 days, the affected dorsal root ganglia and spinal cord segments were processed for Northern analysis and in situ hybridization to evaluate various APP mRNA species. After nerve crush, dorsal root ganglia APP mRNA levels are increased for both APP695 (695 amino acids) and APPKPI (Kunitz protease inhibitor). Following reinnervation, APP695 returns to baseline but APPKPI remains elevated. In spinal cord there is a decrease of APP695, which returns to baseline following reinnervation. If regeneration is prevented, the initial phase of post-axotomy response for all APP forms persists for at least 60 days in both dorsal root ganglia and spinal cord. In situ hybridization confirms that the changes are referable to neurons. These findings indicate that neuron-target interactions are important in APP gene regulation; that the APP695 and APPKPI transcripts are differentially regulated following neuronal injury; and that different neuronal populations regulate APP expression in a cell-type specific manner.

Amyloid beta-Protein Precursor↗
PubMed1991

Multi-joint reaching movements and eye-hand tracking in cerebellar incoordination: investigation of a patient with complete loss of Purkinje cells.

Performance on an eye-hand tracking task and a multi-joint reaching movement to a visual target was studied in a patient with stable cerebellar ataxia and in control subjects. The patient subsequently died and a full neuropathological examination was performed. The neuropathological findings were similar to those seen in patients with paraneoplastic cerebellar degeneration, but no tumor was found at autopsy eight years after onset of the patient's cerebellar syndrome. A severe cerebellar cortical degeneration with complete Purkinje cell loss was demonstrated, whereas cerebellar nuclei and brainstem structures showed no neuronal loss. Tracking performance by the patient was characterized by abnormally large numbers of high velocity movements and hand direction reversals, and by excessive lagging of the hand behind the target in time. In the multi-joint reaching movement, the patient showed a delay in movement onset at the elbow joint compared to movement onset at the shoulder joint. The velocity profile of the movement at the shoulder joint was abnormal. The duration of the acceleration phase was poorly correlated with both peak angular velocity and the duration of the deceleration phase. One of the most striking findings was the inability of the patient to consistently produce the same movement direction from trial to trial while reaching to the same target. Our data suggests that the cerebellar cortex is involved in multiple aspects of motor control including visuomotor integration mechanisms.

Adult↗
PubMed1978

Slow axonal transport of neurofilament proteins: impairment of beta,beta'-iminodipropionitrile administration.

beta,beta'-Iminodipropionitrile (IDPN) administration prevented normal slow axonal transport of [35S]methionine- or [3H]leucine-labeled proteins in rat sciatic motor axons. Ultrastructural and electrophoretic studies showed that the neurofilament triplet proteins in particular were retained within the initial 5 millimeters of the axons, resulting in neurofilament-filled axonal swellings. Fast anterograde and retrograde axonal transport were not affected. The IDPN thus selectively impaired slow axonal transport. The neurofibrillary pathology in this model is the result of the defective slow transport of neurofilaments.

Axonal Transport↗
PubMed1977

Suppression by elevated calcium of black widow spider venom activity at frog neuromuscular junctions.

Frog neuromuscular junctions were treated with both concentrated black widow spider venom (BWSV) and elevated extracellular calcium (5-50 mM). This procedure causes a dramatic increase in the frequency of spontaneous miniature endplate potentials (mepps) which persists for only a few minutes. In contrast, BWSV-induced mepp activity, the venom effect (VE), continues for 20 min-1 h at junctions in elevated calcium Ringer solutions treated with doses of dilute venom or at junctions in normal calcium (1.91 mM) Ringer solution treated with concentrated venom. Following the disappearance of the VE in elevated extracellular calcium, only a few normal amplitude mepps and a few giant amplitude mepps are observed. The disappearance of the VE in these preparations is irreversible and occurs whether exposure to elevated extracellular calcium precedes or follows exposure to BWSV. Electron microscopy indicates that the major structural alterations produced by exposure to concentrated BWSV and 20 mM calcium Ringer solution are the swelling of nerve terminal mitochondria and the clumping of synaptic vesicles, large numbers of which remain in the terminals. Exposure to 20 mM calcium Ringer solution alone produces no ultrastructural modifications in these preparations. These observations can best be explained if one of the effects of BWSV is to increase the permeability of the nerve terminal membrane to calcium. Only doses of concentrated venom can sufficiently elevate intracellular calcium to a concentration at which synaptic vesicles clump together, thus interruping the transmitter release process.

Action Potentials↗
PubMed1976

Regulation of purine metabolism. Adenylosuccinate synthetase from Novikoff ascites tumor cells.

Adenylosuccinate synthetase has been partially purified from Novikoff ascites tumor cells. The properties of the protein are quite different from the enzyme from rat liver in that the Km for asparate is higher and the K1 for the feedback inhibitor AMP is also higher. The antibiotic hadacidin has a preferential inhibitory effect on the tumor enzyme. These results suggest that the Novikoff ascites tumor enzyme is less sensitive to normal feedback controls but may be more sensitive to specific antitumor drugs.

Adenosine Monophosphate↗
PubMed1976

Changes in the structure of neuromuscular junctions caused by variations in osmotic pressure.

Neuromuscular junctions of the frog, Rana pipiens, were examined for structural modifications produced by exposure to increased and reduced osmotic pressure (pi). Preparations exposed to increased pi for varying lengths of time were fixed with either OSO4-Veronal with and without calcium, glutaraldehyde-phosphate, or glutaraldehyde-formaldehyde-phosphate as primary fixatives. The greatest difference between the fixatives was seen in preparations exposed to increased pi for 5 min, corresponding to the time when miniature endplate potential frequency is highest. The 5-min OSO4 calcium-free preparations appeared comparatively normal, while those fixed with OSO4 and 2 mM CaCl2 or aldehyde-phosphate had wide infoldings of the presynaptic membrane and a reduced number of synaptic vesicles. Aldehyde-phosphate had the same effect on mouse diaphragm. Another series of frog preparations were conditioned to elevated pi and then returned to normal Ringer's for varying times before fixation in OSO4-phosphate. Preparations fixed 2 min after their return to normal Ringer's showed marked disruption of the presynaptic membrane as well as apparently rupturing vesicles. If fixed after 10 min, terminals were depleted of vesicles although the presynaptic membrane had returned to its normal position and appearance.

Animals↗
PubMed1976

Possible active enhancement of a human cadaver renal allograft with antilymphocyte serum (ALS) and donor bone marrow: case report of an initial attempt.

Nonspecific immunosuppression of transplant patients frequently leads to complications which might be circumvented by inducing donor-specific immune unresponsiveness. Such specific immunosuppression has been produced experimentally, with use of donor antigen and antilymphocyte serum (ALS) for active enhancement. A case is presented in which the recipient of a cadaveric renal allograft (zero antigen match, cross-match negative) was given ALS (first 14 days after operation) and 11 X 10(9) donor bone marrow cells (twenty-fifth postoperative day) along with conventional doses of prednisone and Imuran in an attempt to produce donor-specific immune unresponsiveness. There were no rejection episodes, and serum creatinine remained less than 1.0 mg. per 100 ml. By the second month after transplantation there was no evidence for the persistence of donor erythrocytes or white cells. The conventional immunosuppressive agents were tapered and renal function was normal 8 months after transplantation, when the patient developed fatal peritonitis secondary to perforated sigmoid diverticulitis. At autopsy the renal allograft showed only minimal evidence of rejection. The present case illustrates an attempt to use ALS and donor bone marrow cells for active enhancement of a human cadaveric renal allograft. The infusion of stored donor marrow cells after transplantation is a particularly applicable technique for human cadaveric organ transplantation. The rejection-free course of this patient suggests that attempts to produce active enhancement clinically deserve further trial.

Adult↗