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Biomedical subjects

A W Clark

Publications and source records attributed to A W Clark.

At least 19 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↗
PubMed1990

Neuronal gene expression in amyotrophic lateral sclerosis.

To characterize neuronal gene expression in amyotrophic lateral sclerosis (ALS), we quantitated one glial and three neuronal mRNAs in spinal cords of 7 subjects with ALS and 11 controls. The ALS cases showed no loss of mRNA for the neurofilament light subunit when assessed with in situ hybridization. Northern analysis, and RNase protection assay; and no loss of mRNA for amyloid precursor protein or a growth-associated protein (GAP-43/B-50) on Northern analysis. ALS cords also showed no significant change in glial mRNA. Our findings indicate that expression of these neuronal mRNAs is well maintained in ALS-afflicted spinal cord. They do not support the hypothesis of a generalized impairment of neuronal gene transcription in the pathogenesis of this disorder.

Adult↗
PubMed1989

Altered expression of genes for amyloid and cytoskeletal proteins in Alzheimer cortex.

Recent studies have indicated a normal gene dose for the amyloid precursor protein (APP) in Alzheimer's disease (AD). These findings leave open the possibility that elevated levels of messenger RNA (mRNA) for this protein may contribute to the pathogenesis of AD. Using Northern analysis, we compared the levels of mRNA for the APP and 3 cytoskeletal proteins in parietal cortex of 6 brains having marked AD-type degeneration with the levels of these mRNAs in 6 control samples. The cytoskeletal mRNAs studied were those for the human neurofilament 68-kDa subunit (HNFL), for alpha-tubulin, and for glial fibrillary acidic protein (GFAP). A ribonuclease (RNase) protection assay was also used to compare AD and control HNFL mRNA levels. The mRNAs for APP, HNFL, and alpha-tubulin were diminished in AD cortex. The decrement for APP mRNA was less than that for HNFL or alpha-tubulin. The message for GFAP in AD cortex showed no loss. The findings support a general deficit in neuronal mRNAs, including that for APP. They do not exclude the possibility of elevated levels of the message for the APP in small neuronal subsets, in subcortical neurons projecting to cortex, or as a generalized phenomenon in earlier stages of the disease.

Alzheimer Disease↗
PubMed1989

Expression of neuronal mRNAs in Alzheimer type degeneration of the nervous system.

There is extensive evidence for decrements of gene expression in AD, at several levels in the process. There is also evidence for increments of expression of some genes. Message for the amyloid precursor protein (APP), for example, is elevated in surviving neurons of certain subcortical populations in AD. We evaluated expression of message for APP as well as for certain neuronal and glial cytoskeletal proteins in the cortex of six cases of AD. Neuronal mRNAs, including that for APP, were significantly decreased when compared with control cortex, whereas the glial mRNA was increased. We have projected studies to determine the evolution of these mRNA decrements in Alzheimer-type degeneration. The rationale for these studies and preliminary findings are discussed.

Alzheimer Disease↗
PubMed1988

Neurofilament gene expression following beta,beta'-iminodipropionitrile (IDPN) intoxication.

beta,beta'-Iminodipropionitrile (IDPN) is an agent that produces a disorganization of the axonal cytoskeleton with massive accumulation of neurofilaments in the proximal axon. Abnormalities in axonal transport of neurofilament proteins and in their phosphorylation occur in this model. In this study we evaluated the gene expression of neurofilament and other cytoskeletal components at an early, intermediate and late stage of intoxication to determine whether this neuropathy is directly due to or secondarily affects the expression of these components. Specific cytoskeletal mRNA expression was evaluated in the spinal cords of rats treated with IDPN for varying durations using Northern analysis and in situ hybridization. Our results show no qualitative or quantitative alteration in the mRNA expression of the neurofilament triplet, alpha-tubulin, alpha-actin or glial fibrillary acidic protein. We conclude that abnormalities at various stages of cytoskeletal processing such as the early disorganization of the cytoskeleton, the impairment of neurofilament transport, and the long-term redistribution of neurofilaments along the axon are not directly due to, nor do they affect the gene expression of cytoskeletal components in IDPN neuropathy.

Animals↗
PubMed1988

Patterns of psychoactive drug prescriptions by house officers for nonpatients.

Substance abuse may be an occupational hazard for physicians, yet the mechanisms of this hazard remain obscure. The present authors tested the hypothesis that a potential source of psychoactive drugs for the physician trainees and other health professionals is prescription writing by house officers. Furthermore, the hypothesis was advanced that house officers may write significant numbers of psychoactive prescriptions for their family members and friends. Of 565 house officers at a medical center, 339 responded to a questionnaire designed to determine the number of prescriptions each had written for nonpatients in the previous eight months for several categories of psychoactive drugs. The largest number of such prescriptions was written for family members and friends, and the second largest number was for fellow house officers. Narcotics were the most frequently prescribed psychoactive drugs. When compared with their representation in the sample, first-year residents and residents in surgery and surgical subspecialties wrote significantly more psychoactive drug prescriptions than other residents. Implications of these findings for residents are discussed.

Academic Medical Centers↗
PubMed1988

Late appearance of a radiodense lesion at the site of an irradiated metastasis: neuropathological findings.

The appearance of contrast-enhancing computed tomographic (CT) lesions at the site of an irradiated brain tumor often has sinister implications. We present the case of a 43-year-old woman who received cranial irradiation as treatment for cerebral metastases from lung cancer. Follow-up radiographic studies revealed complete tumor regression; however, 26 months after treatment, enhanced CT scanning showed a radiodense nodule at the site of one of the previous metastatic deposits. Neuropathological examination of the surgically excised tissue identified benign reactive changes only. The natural history of irradiated brain lesions is discussed.

Adenocarcinoma↗
PubMed1987

Role of the heavy and light chains of botulinum neurotoxin in neuromuscular paralysis.

Botulinum neurotoxin (NT) is synthesized by Clostridium botulinum in any of seven antigenically distinct forms called types A-G. NT, when fully active, is a dichain protein, composed of two polypeptides, a heavy (H) and a light (L) chain (approximately 100,000 and approximately 50,000 Da, respectively) that are held together by noncovalent bonds and at least one disulfide bond. Two types of dichain NT, A and B, and their respective H and L chains were applied to nerve-muscle (NM) preparations (phrenic nerve-hemidiaphragm of the mouse), in order to develop a broader, comparative understanding of the neuroparalytic actions of NT types. It was found that the paralysis induced by dichain NT was delayed or antagonized if NM preparations were incubated with isolated and purified H chain prior to, or during, incubation with the parent, dichain NT. NM preparations preincubated with H chain and then washed free of unbound H chain became paralyzed after subsequent incubation with L chain. Paralysis did not occur if NM preparations were incubated first with L chain, washed, and then incubated with H chain. These observations suggest that the H chain binds with specific sites on the nerve terminal. This binding appears to permit the L chain, or some combination of the L and H chain, to bring about neuroparalysis through a mechanism very similar to that of the parent, dichain NT.

Animals↗
PubMed1987

The plantar nerves-lumbrical muscles: a useful nerve-muscle preparation for assaying the effects of botulinum neurotoxin.

The plantar nerves-lumbrical muscles (PL) of the hindpaw of the mouse is a preparation that is particularly useful for assaying the effects of botulinum neurotoxin (NT) on the mammalian neuromuscular junction. Each mouse provides a minimum of 4 and a maximum of 8 such preparations. The muscles are thin enough so that neuromuscular junctions can be easily located with Nomarski interference contrast optics for impaling with microelectrodes. The preparations are small enough so they can be sectioned transversely or longitudinally, in their entirety, for light and electron microscopy, or just the regions containing end-plates can be used. An examination of the responses of this preparation to types A and E NT reveal its exceptional suitability for experiments with NT. The small number of fibers and their arrangement permit assays of low concentrations of NT to proceed to complete and total paralysis in a convenient period of time.

Animals↗
PubMed1987

Major E. coli heat-stress protein do not translocate: implications for cell survival.

When Escherichia coli are exposed to heat stress, the majority of proteins in the process of synthesis at the time of heat stress are rapidly translocated to the outer membrane of the bacterium. The synthesis of most of these proteins appears to take place on membrane-bound polyribosomes. With the temperature shift, overall protein synthesis is inhibited while the synthesis of a small group of proteins is initiated. These proteins are not translocated, but remain in the cytosolic compartment, and they are identifiable as heat-stress proteins. Both the translocation phenomenon and the retention of heat-stress proteins in the cytosolic compartment in proximity to the nucleoid could counteract the effects of heat stress. The translocated proteins may operate by stabilizing the outer membrane prior to the induction of heat-stress proteins and the latter, which are confined to the cytoplasmic compartment, may serve to protect the integrity of the nucleoid structures.

Bacterial Proteins↗
PubMed1987

Effect of changes in neurofilament content on caliber of small axons: the beta,beta'-iminodipropionitrile model.

The structural role of neurofilaments in the normal axon and the consequences of altered axonal transport of neurofilaments have been extensively studied in large axons. These studies suggest that neurofilament numbers and interneurofilament spacing are major determinants of axonal cross-sectional area. In contrast, in small axons and dendrites, microtubules and membranous organelles appear to be the most closely correlated with size and shape of the cell process. In this study we have examined the effect of impairment in neurofilament transport on small axons, typical of most CNS pathways. Neurofilament transport was impaired by administration of beta,beta'-iminodipropionitrile (IDPN), resulting in proximal accumulation and distal depletion of neurofilaments. The evolution of these changes was studied in the optic nerves of guinea pigs treated with IDPN, 1-35 weeks following intoxication. The effect of this redistribution of neurofilaments on cross-sectional area of small axons was evaluated using quantitative ultrastructural methods. Our results show that with the alteration in neurofilament transport seen with IDPN intoxication, there is a wide spectrum of neurofilament densities, ranging from a 5-fold increase above normal in the proximal axon, to a 5-fold decrease below normal in the distal axon. Although the optic nerve fibers enlarge with the increase in neurofilament content, they do not atrophy significantly with the continued loss of neurofilaments. We conclude that factors other than neurofilament content are capable of maintaining size and shape of these small axons. Candidate organelles include microtubules and membranous organelles and possibly other axonal elements.

Animals↗
PubMed1986

Primary degenerative dementia without Alzheimer pathology.

To define the pathology in cases of non-Alzheimer primary degenerative dementia (non-AD PDD), we have studied autopsies from four medical centres accessioned in consecutive years since 1976. Neurochemical studies of the basal forebrain-cortical (BF-C) cholinergic system have been conducted in cases from which frozen tissue was available. Twenty-two cases (mean age 70 years, range 47-86) in which the history was consistent with PDD, but which did not meet anatomic criteria for AD, were selected. Approximately 70 cases of PDD, which were accessioned in the same years and met the anatomic criteria for AD, were excluded. The pathologic findings permitted a classification into six groups: Lewy body disease (LBD), 4 cases; Pick's disease, 6 cases: cortical degeneration with motor neuron disease (CDmnd), 2 cases; hippocampal and temporal lobe sclerosis, 3 cases; few or nonspecific abnormalities, 5 cases; other disorders, 2 cases. Our findings suggest that LBD and Pick's disease account for a large proportion of cases of non-AD PDD in the presenile age group, but that a large number of other disorders occasionally present as PDD. Careful examination of the motor systems, as well as cerebral structures relate to cognitive function, is important in the neuropathologic evaluation. Lesions of the BF-C cholinergic system have been most consistent and severe in LBD, and have not been identified in CDmnd.

Aged↗