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M A Smith

Publications and source records attributed to M A Smith.

At least 181 records · Page 10Linked to original sources
PubMed2000

Rapid induction of corticotropin-releasing hormone gene transcription in the paraventricular nucleus of the developing rat.

Neonates from postnatal days (pnd) 4-14 display a minimal pituitary-adrenal response to mild stress, the so-called stress hyporesponsive period (SHRP). However, during the SHRP, maternal deprivation (deprived) alters the pituitary-adrenal system, enabling neonates to become endocrine responsive to specific stimuli. Although neonates do display stress-induced ACTH, there is limited evidence for enhanced CRH gene expression early in development. The present experiment examined whether a mild stimulus (isotonic saline injection) administered to deprived and nondeprived neonates would enhance CRH biosynthesis in the paraventricular nucleus. Using in situ hybridization we measured the time course of CRH heteronuclear RNA (hnRNA) and messenger RNA at 15, 30, and 240 min poststimulus. Pnd 6, 12, and 18 were included to examine the CRH gene response during and outside of the SHRP. Despite the minimal endocrine response of nondeprived pups during the SHRP, CRH hnRNA and messenger RNA were elevated at 15 min (all ages). Both transcripts were enhanced at 15-30 min in deprived (pnd 12 and 18) pups; however, the magnitude of the response was less than that in nondeprived pups. These data indicate that during ontogeny there is a rapid stimulus-induced CRH biosynthesis. Thus, during development, the central components of the hypothalamic-pituitary-adrenal axis may be stress hyperresponsive rather than hyporesponsive.

Adrenocorticotropic Hormone↗
PubMed2000

Histochemical and immunocytochemical approaches to the study of oxidative stress.

We review an array of newly developed in situ detection methods that can be used for the qualitative and semi-quantitative measurement of various indices related to oxidative stress. The importance of in situ methods over bulk analysis cannot be overstated when considering the structural and cellular complexity of tissue and the effects of diseases thereof. Indeed, in situ detection allows detection of specific cell types affected or specific localization such that a process affecting only a small fraction of the tissue or cells can be readily visualized. Consequently, a positive signal in situ indicates real levels that cannot be masked by unrelated or compensatory responses in adjacent cells, and corrections can be easily made for the modifications to long-lived proteins during physiological aging. In fact, the damage to extracellular matrix proteins of major vessels, provides a cumulative record of long-term oxidative insult. Yet the same properties that make vessels ideal markers for aging limits their sensitivity to detect disease-specific changes unless in situ techniques are used.

Alzheimer Disease↗
PubMed2000

Induction of photolyase activity in wood frog (Rana sylvatica) embryos.

Rising ultraviolet-B (UVB, 280-320 nm) radiation has been proposed as a factor which may explain nonnormal amphibian population declines. Accordingly research has been directed toward estimating the photolyase activity of several amphibian species in order to predict a species' resilience to UV damage. Unfortunately, in spite of published research which demonstrated that the activity of one of the principal photorepair enzymes, photolyase, can be induced, these estimates did not address the potential for in vivo induction by environmental factors present in situ. We show here that wood frog (Rana sylvatica) embryos exposed to periods of ambient solar radiation (1) displayed significantly different photolyase activities from embryos exposed to equivalent periods of dark; and (2) were positively correlated with the UVB fluence received in vivo. Such results suggest that previous conclusions regarding the relationship between photorepair and population decline must be reevaluated. Estimating amphibian photorepair is a complicated process, and caution must be exercised when interpreting such data.

Ambystoma↗
PubMed2000

Quantitative comparison of intrabrain diffusion in adults and preterm and term neonates and infants.

OBJECTIVE: Quantitative measurements of mean water diffusivity (D(av)) were made in human neonates, infants, and adults to assess changes in brain tissue that occur with maturation. SUBJECTS AND METHODS: Values of D(av) were obtained by calculating the average of the diffusion measurements made with diffusion-sensitizing gradients placed along three orthogonal directions. The mean diffusivity, a rotationally invariant determination of apparent diffusion coefficient, was measured in five healthy prematurely born neonates and infants, in 10 healthy term neonates and infants, and in five adults. RESULTS: Values of D(av) were found to decrease with maturation in most parts of the brain. In prematurely born neonates and infants with a postmenstrual age (postgestastional age + postnatal age) under 36 weeks, the average value of D(av) in frontal white matter was 1.90 x 10(-3) mm2 sec(-1). The corresponding value was measured as 1.62 x 10(-3) mm2 sec(-1) in neonates and infants born at term with a postnatal age of no more than 43 days and 0.79 x 10(-3) mm2 sec(-1) in the adult brain. CONCLUSION: Values of D(av) are known to decrease in neonates and young infants in the period immediately after ischemic insult. This decrease and the associated increase in signal intensity seen on diffusion-weighted imaging have been used to monitor ischemic brain injury in neonates and infants. Therefore, the decrease in D(av) that occurs with maturation, which we report in this study, must be considered if quantitative diffusion measurements are used to assess ischemic neonatal brain injury.

Adult↗
PubMed2000

The role of metals in neurodegenerative diseases.

There is increasing evidence in a number of neurodegenerative diseases that transition metal-mediated abnormalities play a crucial role in disease pathogenesis. In this treatise, we review the role of metal homeostasis as it pertains to alterations in brain function in neurodegenerative diseases. In fact, while there is documented evidence for alterations in transition metal homeostasis, redox-activity and localization, it is also important to realize that alterations in specific copper- and iron-containing metalloenzymes also appear to play a crucial role in the neurodegenerative process.

Alzheimer Disease↗
PubMed2000

Intravascular ultrasound-guided interventions in coronary artery disease: a systematic literature review, with decision-analytic modelling, of outcomes and cost-effectiveness.

BACKGROUND: Intravascular ultrasound (IVUS) is the generic name for any ultrasound technology used in vivo within the blood vessels. More specifically, intracoronary ultrasound enables imaging of the coronary arteries from within the lumen. This review concentrates on the role of intracoronary ultrasound as an adjunct to interventional cardiology. OBJECTIVES: (1) To identify the literature on IVUS for guiding coronary interventions, and to synthesise evidence about outcomes compared with outcomes when IVUS guidance has not been used. (2) To use this evidence, together with other information about costs and outcomes, to model the cost effectiveness of IVUS guidance. (3) To synthesise the evidence on the reproducibility of measurements of cross-sectional area made using IVUS. METHODS DATA SOURCES: (1) Electronic searches of MEDLINE, EMBASE, Science Citation Index, Index to Scientific and Technical Proceedings, Engineering Compendex, Engineering Page One, Cochrane Library, Inside (British Library), 1990-98. (2) Contacting experts and centres of expertise, 1990-99. (3) Internet search, 1990-99. METHODS STUDY SELECTION: Studies of IVUS-guided coronary interventions performed on humans were included in the review. Non-English language studies were also included when they covered IVUS-guided stenting or angioplasty. Control evidence regarding outcomes without IVUS guidance was sought only from randomised controlled trials (RCTs). Studies investigating the reproducibility of measurements of cross-sectional area were included only if the results were expressed in terms of the mean and standard deviation of paired differences. METHODS DATA EXTRACTION: Checklists that covered study details, patient characteristics and results were completed independently by three reviewers. Consensus was reached on any disagreements. Local data were gathered on the costs of IVUS-guided stenting. METHODS DATA SYNTHESIS: Overall event rates were calculated by pooling patient results from the included studies. A decision-analytic model was used to combine information from the literature with cost estimates, in order to predict cost-effectiveness in terms of cost per restenosis event avoided by the use of IVUS guidance. The analysis was performed from the perspective of the healthcare provider. Sensitivity analysis was undertaken. A simple extrapolation was made to long-term outcome so that cost-utility (using quality-adjusted life years (QALYs)) could be estimated. The minimum detectable change in cross-sectional area was estimated from the reproducibility results. RESULTS: Only one study on IVUS-guided angioplasty satisfied the inclusion criteria, and there were no studies on IVUS-guided atherectomy or other IVUS-guided interventions that satisfied the inclusion criteria. Of the 15 articles on IVUS-guided stenting that satisfied the inclusion criteria, seven presented data on outcomes at 6 months post-intervention. The angiographic restenosis rate was 16 +/- 1%. This compared with 24 +/- 2% derived from five articles on stenting without IVUS guidance. Data for follow-up periods longer than 6 months were presented in only two studies. Data from a total of five studies were included in the decision-analytic model. The cost per restenosis event avoided was 1545 pound sterling. After extrapolation to long-term outcome, the calculated cost per QALY was 6438 pound sterling. The baseline QALY gain was only 0.03 years. Sensitivity analysis resulted in large differences between the best- and worst-case scenarios, for example, from a saving of 5000 pound sterling to a cost of 24,000 pound sterling restenosis event avoided. The smallest changes in cross-sectional area that could be measured were 1.6 mm2 by a single observer and 1.9 mm2 by different observers. CONCLUSIONS: Implications for healthcare: The evidence available is too weak for there to be any reliable implications for clinical practice. (ABSTRACT TRUNCATED)

Algorithms↗
PubMed1999

Prion protein glycosylation is sensitive to redox change.

The conversion of soluble prion protein into an insoluble, pathogenic, protease-resistant isoform is a key event in the development of prion diseases. Although the mechanism by which the conversion engenders a pathogenic event is unclear, there is increasing evidence to suggest that this may depend on the function of the prion protein in preventing oxidative damage. Therefore, in this study, we assessed the interrelationship between redox-sensitive cysteine, glycosylation, and prion metabolism. Cells were treated with a thioreductant, dithiothreitol, to assess the effect of the cellular oxidation state on the synthesis of the prion protein. This change in redox balance affected the glycosylation of the prion protein, resulting in the sole production of glycosylated forms. The role of the single disulfide bridge in mediating this effect within the prion protein was confirmed by mutating the cysteine residues involved in its formation. These data suggest that conditions that increase the rate of formation of the disulfide bridge favor formation of the unglycosylated prion protein. Thus, since the presence of glycans on the prion protein is protective against its pathogenic conversion, a change in the redox status of the cell would increase the risk of developing a prion disease by favoring the production of the unglycosylated form.

Cysteine↗
PubMed1999

The ontogeny of the neuroendocrine response to endotoxin.

During development, the hypothalamic-pituitary-adrenal (HPA) axis is normally hyporesponsive between postnatal days (pnd) 4 and 14. This interval has been designated as the stress-hyporesponsive period (SHRP). Recent evidence indicates that the neonate can respond to selective stimuli, i.e., exposure to immune signals. The purpose of this study was to investigate the neural correlates of the neonatal stress axis in response to a stimulus that activates the pituitary-adrenal hormones. Thus, lipopolysaccharide (LPS) was administered to neonates at three ages (pnd 6, 12, and 18) during or after the SHRP. In an effort to understand the neonatal hypothalamic paraventricular nucleus (PVN) response to an endotoxin, we measured c-fos immunoreactivity and corticotrophin-releasing hormone (CRH) gene expression. At all ages tested, there was an increase in ACTH and corticosterone (CORT) following LPS compared to controls. During the SHRP, LPS treatment resulted in a marked increase in Fos-positive cells in the PVN, whereas a saline injection had no effect. However, at pnd 18, both LPS and a saline injection elicited equivalent PVN Fos expression. In contrast to the effect on Fos, LPS and a saline injection decreased CRH mRNA at pnd 6 and 12. Outside the SHRP, LPS resulted in an increase in CRH gene expression relative to saline-injected controls. Thus, while the LPS-induced activation of Fos protein and plasma hormones were concordant, CRH mRNA did not positively correlate with the peripheral response. This suggests that the SHRP is not absolute, and the brain is responsive to some stimuli during this period.

Adrenocorticotropic Hormone↗
PubMed1999

Serum amyloid P is not present in amyloid beta deposits of a transgenic animal model.

Serum amyloid P component (SAP) is associated with amyloid beta (A beta) deposition in Alzheimer disease (AD). Since SAP is exclusively synthesized by peripheral organs, its presence in the brain of AD suggests impairment of the blood-brain barrier (BBB). We studied the association of SAP with A beta deposits in a transgenic mouse model overexpressing beta-protein precursor (betaPP). Both SAP and another extracellular matrix binding protein, basic fibroblastic growth factor bind to the heparinase sensitive sites of A beta deposits in this model. However, no endogenous SAP immunoreactivity was found in the transgenic mouse brain. These results suggest that SAP is not required for A beta deposition, and that this mouse model does not develop the same BBB abnormalities as those seen in AD.

Alzheimer Disease↗
PubMed1999

Increased neuronal glucose-6-phosphate dehydrogenase and sulfhydryl levels indicate reductive compensation to oxidative stress in Alzheimer disease.

We analyzed glucose-6-phosphate dehydrogenase, the rate-controlling enzyme of the pentose phosphate pathway and free sulfhydryls, to study redox balance in Alzheimer disease. Glucose-6-phosphate dehydrogenase plays a pivotal role in homeostatic redox control by providing reducing equivalents to glutathione, the major nonenzymatic cellular antioxidant. There is a multitude of evidence that marks oxidative stress proximally in the natural history of Alzheimer disease. Consistent with a role for glutathione in defense against increased reactive oxygen, we found an upregulation of glucose-6-phosphate dehydrogenase together with increased sulfhydryls in Alzheimer disease. These data indicate that reductive compensation may play an important role in combating oxidative stress in Alzheimer disease.

Adolescent↗
PubMed1999

Evidence of an agrin receptor in cortical neurons.

Agrin plays a key role in directing the differentiation of the vertebrate neuromuscular junction. Understanding agrin function at the neuromuscular junction has come via molecular genetic analyses of agrin as well as identification of its receptor and associated signal transduction pathways. Agrin is also expressed by many populations of neurons in brain, but its role remains unknown. Here we show, in cultured cortical neurons, that agrin induces expression of the immediate early gene c-fos in a concentration-dependent and saturable manner, as expected for a signal transduction pathway activated by a cell surface receptor. Agrin is active in cortical neurons at picomolar concentrations, is Ca(2+) dependent, and is inhibited by heparin and staurosporine. Despite marked differences in acetylcholine receptor (AChR)-clustering activity, all alternatively spliced forms of agrin are equally potent inducers of c-fos in cortical neurons. A similar, isoform-independent response to agrin was also observed in cultures prepared from the hippocampus and cerebellum. Only agrin with high AChR-clustering activity was effective in cultured muscle, whereas non-neuronal cells were agrin insensitive. Although consistent with a receptor tyrosine kinase model similar to the muscle-specific kinase-myotube-associated specificity component complex in muscle, our data suggest that CNS neurons express a unique agrin receptor. Evidence that neuronal signal transduction is mediated via an increase in intracellular Ca(2+) means that agrin is well situated to influence important Ca(2+)-dependent functions in brain, including neuronal growth, differentiation, and adaptive changes in gene expression associated with synaptic remodeling.

Agrin↗
PubMed1999

Cancer surveillance series [corrected]: brain and other central nervous system cancers: recent trends in incidence and mortality.

BACKGROUND: During the 1980s, the incidence of primary malignant brain and other central nervous system tumors (hereafter called brain cancer) was reported to be increasing among all age groups in the United States, while mortality was declining for persons younger than 65 years. We analyzed these data to provide updates on incidence and mortality trends for brain cancer in the United States and to examine these patterns in search of their causes. METHODS: Data on incidence, overall and according to histology and anatomic site, and on relative survival were obtained from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute for 1975 through 1995. Mortality data were obtained from the National Center for Health Statistics. Medicare procedure claims from the National Cancer Institute's SEER-Medicare database were used for imaging trends. Statistically significant changes in incidence trends were identified, and annual percent changes were computed for log linear models. RESULTS/CONCLUSIONS: Rates stabilized for all age groups during the most recent period for which SEER data were available, except for the group containing individuals 85 years of age or older. Mortality trends continued to decline for the younger age groups, and the steep increases in mortality seen in the past for the elderly slowed substantially. Patterns differed by age group according to the site and grade of tumors between younger and older patients. During the last decade, use of computed tomography scans was relatively stable for those 65-74 years old but increased among those 85 years old or older. IMPLICATIONS: Improvements in diagnosis and changes in the diagnosis and treatment of elderly patients provide likely explanations for the observed patterns in brain cancer trends.

Adolescent↗
PubMed1999

Loss of the ataxia-telangiectasia gene product causes oxidative damage in target organs.

Ataxia-telangiectasia (A-T) is characterized by a markedly increased sensitivity to ionizing radiation, increased incidence of cancer, and neurodegeneration, especially of the cerebellar Purkinje cells. Ionizing radiation oxidizes macromolecules and causes tissue damage through the generation of reactive oxygen species (ROS). We therefore hypothesized that A-T is due to oxidative damage resulting from loss of function of the A-T gene product. To assess this hypothesis, we employed an animal model of A-T, the mouse with a disrupted Atm gene. We show that organs which develop pathologic changes in the Atm-deficient mice are targets of oxidative damage, and that cerebellar Purkinje cells are particularly affected. These observations provide a mechanistic basis for the A-T phenotype and lay a rational foundation for therapeutic intervention.

Animals↗
PubMed1999

Activation of neuronal extracellular receptor kinase (ERK) in Alzheimer disease links oxidative stress to abnormal phosphorylation.

Responses to increased oxidative stress may be the common mechanism responsible for the varied cytopathology of Alzheimer disease (AD). A possible link in support of this hypothesis is that one of the most striking features of AD, the abnormal accumulation of highly phosphorylated tau and neurofilament proteins, may be brought about by extracellular receptor kinase (ERK) whose activation is a common response to oxidative stress. In this study, we demonstrate that activated ERK is specifically increased in the same vulnerable neurons in AD that are the site of oxidative damage and abnormal phosphorylation. These findings suggest that ERK dysregulation, likley resulting from oxidative stress, could play an important role in the increased phosphorylation of cytoskeletal proteins observed in AD.

Adult↗