Biomedical subjects
H Durham
Publications and source records attributed to H Durham.
Internal migration and urban change in Poland.
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Cell culture models of interspecies selectivity to organophosphorous insecticides.
In toxicology, the need to reduce uncertainties in human risk assessment is met by understanding why species and individuals within that species respond differently to chemical exposure. This kind of information is needed when extrapolating data from experimental (i.e., whole animal) systems to the human condition in terms of risk assessment. In 1993 the Neurotoxicology Division of the Environmental Protection Agency funded several investigators to examine this phenomenon (i.e., interspecies selectivity) using cell culture models. Organophosphorous (OP) insecticides were examined since they are characterized by an extremely divergent interspecies response. In 1995, a symposium entitled Novel Insights into Chemical Neurotoxicity, sponsored by the Society for In Vitro Biology featured this research. In it, a historical overview of the phenomenon of interspecies selectivity to OP insecticides was given, current explanations for it were discussed and contemporary in vitro models being used to explain it, were described. Data from these studies have helped to redefine the underlying mechanisms that characterize and influence the cross-species response to insecticides. These experiments have refocused the explanation of this phenomenon to include cellular metabolism, target enzyme baseline activities, and receptor-mediated electrophysiological and second-messenger events. Several investigators on this panel also reported on the use of subcellular markers (e.g., target esterases, second messengers, ionic fluxes) to differentiate neuropathy-causing OP compounds from acetylcholinesterase inhibitors. After these presentations, technical considerations used in the designed of in vitro neurotoxicity studies were discussed.
The principles of gene therapy for the nervous system.
Research pertaining to gene transfer into cells of the nervous system is one of the fastest growing fields in neuroscience. An important application of gene transfer is gene therapy, which is based on introducing therapeutic genes into cells of the nervous system by ex vivo or in vivo techniques. With the eventual development of efficient and safe vectors, therapeutic genes, under the control of a suitable promoter, can be targeted to the appropriate neurons or glial cells. Gene therapy is not only applicable to the treatment of genetic diseases of the nervous system and the control of malignant neoplasia, but it also has therapeutic potential for acquired degenerative encephalopathies (Alzheimer's disease, Parkinson's disease), as well as for promoting neuronal survival and regeneration in various pathological states.
Assessment of the neurotoxicity of styrene, styrene oxide, and styrene glycol in primary cultures of motor and sensory neurons.
The neurotoxicity of styrene and its major metabolites, styrene oxide and styrene glycol, was investigated in dissociated primary cultures of murine spinal cord-dorsal root ganglia (DRG)-skeletal muscle using morphological and electrophysiological endpoints. Styrene and styrene oxide (but not styrene glycol) were acutely cytotoxic to both neuronal and non-neuronal cells in the cultures; concentrations in excess of 2 and 0.2 mM, respectively, induced blebbing, vacuolation, detachment from the substratum and cell death in neuronal and non-neuronal cells within 4 days. No effects on neuronal morphology were observed in cultures treated with sublethal concentrations of styrene or styrene oxide for up to 3 weeks. The results suggest that oxidation of multiple cellular macromolecules that underlies the toxicity of styrene in other organ systems may also be responsible for damage to cells in the nervous system. No changes in action potential production indicative of a 'solvent effect' on membrane electrical properties was apparent in cultures treated with up to 8 mM styrene or 10 mM styrene glycol.
A hypothesis for the pathogenesis of amyotrophic lateral sclerosis.
The microscopic pathology of spinal cord and brain in ALS has suggested that the earliest abnormality is a progressive depletion of dendritic neurofilaments leading to dendritic atrophy, vulnerability to breakage and attrition. We hypothesize that this in turn will lead to shrinkage and eventual death of the perikaryon. This hypothesis could explain the preferential vulnerability of the spinal, corticospinal and cortico-bulbar neurons to damage and death in ALS because only these neurons contain conspicuous bundles of neurofilaments in dendrites. Agents or factors that could subvert the transport or the integrity of dendritic neurofilaments should be sought in ALS.
Early Delaware physicians. Another early Delaware physician: Dr. John S. Hill.
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Early Delware physicians. Another early Delaware physician: Dr. William Thornton.
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Christmas and the M.D.'s wife--or pay as you mend.
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Modulation of monoamine oxidase activity in different brain regions and platelets following exposure of rats to methylmercury.
Monoamine oxidase (MAO; EC 1.4.3.4) is known to have an important role in the regulation of biogenic amines in the brain and peripheral tissues. It is also known that circulating platelets represent an excellent model for an easy assessment of the effect of MAO-B inhibitors in extracerebral tissue. The present study was carried out to determine the effects of methylmercury (MeHg) on the activity of MAO in synaptosomes of different brain regions of male Sprague-Dawley rats as well as in rat blood platelets both in vitro and in vivo. MeHg pretreatment inhibited the activity of MAO in the synaptosomes of the cortex, hypothalamus, hippocampus, striatum, cerebellum, and brain stem in a concentration-dependent (0-10 microM) manner. The threshold concentration of MeHg for such inhibition in different brain synaptosomes was found to be the same (i.e., 1 microM) except for in the rat striatum it was 2.5 microM, and the IC50 value for MeHg was found to be around 2.1 microM. Significant inhibition of the MAO activity was also observed in synaptosomes of the cortex, cerebellum, hypothalamus, and hippocampus as well as in platelets of rats 24 h after treatment by gavage with a total cumulative dose of 35 mg/kg (5 mg/kg/day for 7 days). The decrease of such activity was found to be at maximum in different brain synaptosomes and platelets 24 h following treatment with a cumulative total dose of 75 mg/kg (7.5 mg/kg/day for 10 days); the treated animals showed signs of ataxia under these conditions. The data have further shown that methylmercury is capable of inhibiting the MAO activity in different brain synaptosomes to different degrees but without showing any specificity towards any specific brain region. The present in vivo results suggest that the platelet MAO activity may be used as a potential biomarker of early neurotoxicity due to repeated exposure to MeHg in rats.