Biomedical subjects
Publications and source records attributed to M Murray.
A consortium of eight long-term care facilities in Ontario devised a new instrument to measure patient satisfaction in long-term care settings. A standardized protocol for administration was developed that included a program to train volunteers to conduct in-person interviews. Nine facilities have carried out the survey using the standardized protocol.
This is the second of four articles describing the construction and use of an instrument to evaluate resident and family satisfaction with care provided in long-term care settings. It addresses operational issues that arose in the application of the instrument.
The 5-nitroimidazoles, MK-436 and fexinidazole dissolved in dimethylsulphoxide can be converted by the addition of hydroxypropylcellulose into gels which facilitates the ease and accuracy of administration. When these gels are used in combination with melarsoprol gel they are capable of curing experimental murine CNS-trypanosomiasis with a one-day treatment. The use of melarsoprol/MK-436 was more efficient than melarsoprol/fexinidazole gels. Thus while a single treatment with 0.1 ml 3.6% melarsoprol gel with 0.1 ml (14.3 mumol) fexinidazole gel cured the infected mice, the same dose of melarsoprol gel with 0.1 ml (4.0 mumol) of MK-436 gel was equally effective. It was also possible to prepare a combined melarsoprol/MK-436 gel which cured experimental CNS-trypanosomiasis with a single treatment. Topical treatment with this melarsoprol/MK-436 gel mixture also resolved clinically the hind leg paralysis which is associated with post-treatment reactive encephalopathy caused by non-curative treatment of CNS-trypanosomiasis.
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Learn how one successful manufacturer uses in-house training to cut the time it takes to do things in all areas of the company. Learn basic principles that can be used by anyone to reduce time in their work, no matter what job they do.
This article shows how Baldor Electric Company is using training to build a foundation for improving service in all areas of the business. It covers the background that led to Baldor Electric's decision to develop service training in-house, the steps that Baldor took in putting the course together, and the actual principles taught in the Baldor service course. The Baldor service course teaches basic principles that can be used by all employees to improve customer service, no matter what job they do.
The University of California, San Diego, School of Medicine's Learning Resources Center is developing a prototype next-generation application for anatomy education which combines virtual reality and multimedia curricular resources. The anatomy lesson utilizes polygon-based 3-D models of the hepatobiliary system created by BioGraphics Inc. of Fort Collins, Colorado which were derived from the National Library of Medicine's Visible Human Project Dataset. This article describes the needs assessment, learning objectives, and preliminary design of the current prototype. The multivariate design, the development strategy for implementing functionalities, and the engineering of critical software interface components are also outlined.
Frontotemporal dementia is a behavioral disorder of insidious onset and variable progression. Clinically, its early features reflect frontal lobe dysfunction characterized by personality change, deterioration in memory and executive functions, and stereotypical and perseverative behaviors. Pathologically, there is degeneration of the neocortex and subcortical nuclei, without distinctive features such as plaques, neurofibrillary tangles, or Pick or Lewy bodies. Within-family variation in neuropathology and clinical phenotype is observed. In cases where family aggregation is observed, it is inherited as an autosomal dominant, age-dependent disorder. Family studies recently have identified two dementia loci: chromosome 17 for disinhibition-dementia-parkinsonism-amyotrophic complex and pallido-ponto-nigral degeneration and chromosome 3 for familial nonspecific dementia. We describe a family (DUK1684) with clinically and neuropathologically confirmed, autosomal dominant, non-Alzheimer disease dementia. Linkage analysis of this family showed evidence for linkage to chromosome 17q21, with a multipoint location score (log10) of 5.52. A comparison of the clinical and pathological features in DUK1684 with those of the other chromosome 17-linked families, together with the linkage data, suggests that these families are allelic. These studies emphasize that genetic linkage analysis remains a useful tool for differentiating disease loci in clinically complex traits.
Pharmacokinetic drug interactions involving the calcium channel blocker diltiazem (DTZ) have been attributed to inhibition of microsomal cytochrome P450 (P450)-mediated drug oxidation. Accumulation of certain DTZ metabolites during dosage with the drug, as well as dose-related differences in DTZ pharmacokinetics, suggests that DTZ metabolites may also participate in P450 inhibition. The present study evaluated a series of putative DTZ metabolites as inhibitors of major constitutive P450s in rat liver in vitro, in relation to DTZ biotransformation. The principal finding to emerge was that the N-demethylated metabolite of DTZ was a more potent competitive inhibitor than DTZ of CYP3A2-dependent testosterone 6 beta-hydroxylation. This P450 appeared to be the preferred target for inhibition, because the observed K/K(m) ratio for inhibition of CYP3A2-dependent steroid hydroxylation was approximately 4- and 100-fold lower than those for CYP2C11 and CYP2A1-dependent pathways, respectively. It was also established that N-desmethyl-DTZ was a major metabolite formed during microsomal DTZ biotransformation in rat liver in vitro. The other primary metabolites, desacetyl-DTZ and O-desmethyl-DTZ, were ineffective inhibitors of any pathways of steroid oxidation by P450s, but several other potential metabolites, which were not detected in microsomal incubations, also inhibited P450 activity. Consistent with previous reports, there was no evidence of P450 inactivation or complexation by DTZ, but the drug and its N-desmethyl metabolite generated binding interactions with ferric P450 in rat hepatic microsomes. Considered together, the findings of the present study establish that N-desmethyl-DTZ is a preferential inhibitor of CYP3A2 in rat hepatic microsomes, with greater potency than the parent drug. This is consistent with clinical reports in which this metabolite accumulates during multiple-dose therapy with DTZ. The competitive nature of the inhibitory interaction suggests that the eventual elimination of N-desmethyl-DTZ should restore normal hepatic oxidation capacity.
Following surgical deafferentation of the spinal cord, cut dorsal roots degenerate, and spared projections compensate for this loss by collateral sprouting (reactive reinnervation). Light microscopic immunocytochemistry has shown sprouting by selected undamaged intraspinal projections, including those that express the transmitters substance P and serotonin. Quantitative immunoelectron microscopy supports these results by demonstrating loss and subsequent recovery of substance P-containing terminals and an increase in serotonin-containing terminals. To test the hypothesis that changes in afferent innervation modulate neurotransmitter receptors on second-order neurons, we used receptor binding autoradiography in this model. Adult rats were subjected to L1-S2 unilateral dorsal rhizotomy and killed at 1, 2, 6, or > 20 weeks after surgery. Receptor binding densities of tachykinin (neurokinins-1 and -3), glutamate (N-methyl-D-aspartate), and serotonin (serotonin-1a) receptors were assayed in the lumbar dorsal horn. Neurokinin-1 binding density was increased in lamina II of the deafferented side by 1 week after surgery, remained elevated at 2 weeks, and returned to control values by 6 weeks. Neurokinin 3 binding density was elevated at 2 weeks and then returned to control levels. N-methyl-D-aspartate receptor binding showed slight but not statistically significant increased binding density at 6 and at > 20 weeks. No significant changes were found in serotonin-1a receptor binding density. The elevations in tachykinin receptor binding density occur when afferents in the dorsal horn are degenerating and suggest reactive up-regulation of the receptor. The return to normal levels coincides with reactive reinnervation in the spinal cord, which restores synaptic numbers. Changes in N-methyl-D-aspartate binding occur much later than the restitution of synaptic numbers but may indicate a role for this receptor in synaptic stabilization following reactive reinnervation.
The diversity of neuronal morphology and function is correlated with specific expression of various microtubule associated proteins (MAPs). One of the major neuronal MAPs, tau, has multiple isoforms formed as a result of alternative splicing and phosphorylation that are differentially expressed during development. Big tau is a high molecular weight isoform that contains an additional large exon (4a) and is expressed primarily by neurons in the peripheral nervous system (PNS). We cloned the complete 4a exon in an expression vector, isolated the recombinant protein and produced antibodies specific to Big tau that were used to localize Big tau in the developing spinal cord and in the adult central nervous system (CNS). In developing spinal cord, Big tau is first expressed in the central projections of the dorsal root ganglia neurons and in motor neurons at embryonic day 18 and postnatal day 2, respectively. In the adult rat CNS, almost all neurons that extend processes into the PNS express Big tau, including all cranial nerve motor nuclei and central processes of most sensory ganglia; of these ganglia, only the bipolar neurons of the olfactory, vestibular and spiral ganglia did not express Big tau. Retinal ganglion cells are the only CNS neurons, whose processes remain entirely within the CNS, that express high levels of Big tau. The limited and specific distribution of Big tau is consistent with a role in stabilizing microtubules in axons that are subjected to great shear forces.
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Following peripheral trochlear nerve axotomy in the cat, the normal number of myelinated axons is restored despite significant motor neuron death, suggesting regulation of the number of myelinated axons in the regenerated nerve. In this study we used light and electron microscopy to examine the production and maintenance of axonal sprouts at different locations in the nerve and at different postoperative intervals. Despite proliferative sprouting and an overproduction of nonmyelinated axons in the regenerating trochlear nerve, the number of myelinated axons was strictly regulated. Only approximately 1,000 regenerated axons were eventually remyelinated, but many nonmyelinated axons were still present 6-8 months postaxotomy. Regenerated axons were remyelinated in a proximal-to-distal direction between 3 and 4 weeks postaxotomy. We also examined the maturation of regenerated myelinated axons by measuring axon diameter and myelin index (an expression of myelin thickness). Mean myelinated axon diameter remained significantly below normal in long-term regenerated nerves. Mean myelin index was not different from normal at 4 weeks postaxotomy but was significantly decreased at long postoperative intervals, reflecting a slightly thicker myelin sheath relative to the axon diameter. This relative increase in mean myelin thickness could serve to restore normal conduction velocity despite the decrease in mean axon diameter. We suggest that the regulation of the number of myelinated axons at the normal number despite cell death and the increase in mean myelin thickness may both be compensatory mechanisms that function to restore preoperative conditions and maximize functional recovery.
Several matrix and adhesion molecules in fish optic nerve, which are constitutively expressed, are increased during axonal regeneration and are primarily associated with nonneuronal cells (W.P. Battisti, Y. Shinar, M. Schwartz, P. Levitt, and M. Murray [1992] J. Neurocytol. 21:557-573). The current study examines the reactions of specific cell types to optic nerve crush and axonal regeneration. The goldfish optic nerve contains macroglia and microglia as well as a population of monocyte-derived cells (granular macrophages) unique to goldfish. Two cell types were OX-42 positive (granular macrophages and microglia), indicating monocyte lineage, each with a distinct morphology and distribution within the nerve. Within hours of the optic nerve crush, the number of OX-42-labeled cell profiles increased near the crush site, remained elevated during the time axons were elongating, and then declined. Microglia, but not granular macrophages, were phagocytically active. Astrocytes are readily identified in the normal optic nerve, but they exhibited marked morphologic changes within hours of injury, which is consistent with the contribution these cells make to the altered environment. Oligodendroglia could not be reliably identified in regenerating optic nerves until myelin was formed. A comparison of the distribution of OX-42-labeled cells with that of transforming growth factor beta-1 (TGF-beta 1) and tenascin suggests that these molecules are expressed by granular macrophages. Tenascin staining may be additionally associated with astrocytes and/or microglia. The rapid response of these nonneuronal cells to injury, their rapid phagocytic activity, and the secretion of growth-promoting factors by these cells likely contributes to the environment that supports robust regeneration by optic axons in the goldfish.
We have recently reported that disease-specific differential alterations in the hepatic expression of xenobiotic-metabolizing cytochrome P450 (CYP P450) enzymes occur in patients with advanced liver disease. In order to determine whether the observed changes in CYP proteins are modulated at pre- or post-translational levels, we have now examined the hepatic levels of mRNA for CYPs 1A2, 2C9, 2E1 and 3A4 by solution hybridization in the same livers of 20 controls (surgical waste from histologically normal livers), 32 cases of hepatocellular and 18 of cholestatic severe chronic liver disease. CYP1A2 mRNA and CYP1A immunoreactive protein were both reduced in livers with hepatocellular and cholestatic types of cirrhosis. In contrast, CYP3A4 mRNA and protein were reduced only in livers from patients with hepatocellular diseases. For 1A2 and 3A4 there were significant correlations between mRNA species and the respective protein contents (rS1A2 = 0.74, rS3A4 = 0.64, P < 0.0001). CYP2C9 mRNA was reduced in patients with both cholestatic and hepatocellular types of liver disease, but 2C protein was reduced only in patients with cholestatic dysfunction. The correlation between CYP2C9 mRNA and protein, was also significant (rs = 0.36, P < 0.005) but mRNA levels accounted for only 13% of the variability in protein rankings. This is probably a consequence of other CYP2C proteins apart from 2C9 being detected by the anti-2C antibody. CYP2E1 mRNA and protein were reduced in patients with cholestatic liver disease, but in hepatocellular disease the expression of only CYP2E1 mRNA was decreased. CYP2E1 mRNA was significantly correlated with CYP2E1 protein but accounted for only 18% of the variability in protein rankings (rs = 0.43, P < 0.0005). Taken collectively these data indicate that the disease-specific alterations of xenobiotic-metabolizing CYP enzymes among patients with cirrhosis is due, at least in part, to pre-translational mechanisms. The lack of a strong correlation between CYP2E1 mRNA and protein suggests that this gene, like its rat orthologue, may be subject to pre-translational as well as translational and/or post-translational regulation.
In the optic tectum of goldfish, the outer, middle and inner layers of the endomeninx were evident in animals ranging in age from 1 month to several years. The outer layer in young animals consisted of closely overlapping cells with intertwined processes, whereas in the older animals it contained large extracellular spaces. The intermediate layer cells were always arranged in a single continuous layer, but in young animals they overlapped extensively with one another toward their edges whereas in the oldest animals they became extremely flat and non-overlapping. The inner layer included an outer tier of cells with their bases adhering to the intermediate layer, and an inner tier of cells detached from both the intermediate layer and the basal lamina overlying the brain parenchyma. Inner layer cells contained many large vacuoles that were in continuity with the extracellular space. With age, the extracellular space and the vacuolar system expanded, and the inner layer evolved into a meshwork of attenuated cytoplasmic processes embedded in the granular extracellular matrix. Another age-related feature was the accumulation adjacent to the basal lamina of uniform disc-shaped membranous structures, resembling multilamellar bodies of lung surfactant. These "disc bodies" were apparently generated by the coalescence of vesicles formed at the surface of the inner layer cells, possibly as a by-product of protein secretion by these cells.
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Projections to the dorsal horn change in adult mammals in response to complete or partial deafferentation. The number of synaptic terminals remains constant after complete lumbosacral deafferentation, indicating replacement of lost dorsal root terminals by newly formed terminals from spared intrinsic systems. The density of a spared central projection of a dorsal root is increased in dorsal horn after partial deafferentation, consistent with sprouting by the axons in the spared root. In this study, we have used electron microscopy to study morphological changes in a specific class of terminals in the dorsal horn induced by partial deafferentation. Complex terminals (CTs) in the dorsal horn originate exclusively from dorsal roots and are readily distinguished morphologically. The CTs and the postsynaptic densities (PSDs) associated with CTs were measured in lamina II at L5 and L6 in cats subjected to unilateral spared root (L6) dorsal rhizotomies and compared to CTs in the control side. Acutely following partial deafferentation, the number of CT profiles decreased. At more chronic survivals, the number of CT profiles were restored to normal levels, and both the number and the length of PSDs were increased. The changes in CTs and PSDs suggest sprouting and synaptogenesis by the spared dorsal root fibers that produce changes in the postsynaptic neuron. Spared root deafferentation thus elicits compensatory changes in presynaptic terminals of the spared root and also in their postsynaptic target neurons.