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Showing papers by "University of Kentucky published in 1996"


Book ChapterDOI
27 Jun 1996
Abstract: Soil pH is probably the single most informative measurement that can be made to determine soil characteristics. At a single glance, pH tells much more about a soil than merely indicating whether it is acidic or basic. For example, availability of essential nutrients and toxicity of other elements can be estimated because of their known relationship with pH. The term pH was "invented" by the Swedish scientist Sorensen (1909) in order to obtain more convenient numbers and the idea quickly caught on. Gillespie and Hurst (1918) seem to have been among the earliest to determine pH (or PH, as it was then called) electrometrically using a platinum-palladium blackhydrogen gas electrode, a calomel reference electrode and a fairly cumbersome potentiometer and galvanometer system. At that period, it was still much more common to use colorimetric methods with indicator dyes than the electrometric method. This changed rapidly, however. Sharp and Hoagland (1919) used a similar but less involved method than Gillespie and Hurst (1918) and Healy and Karraker (1922) used a commercially available platinum-hydrogen gas electrode, potentiometer and galvanometer which had been designed by Clark (1920). The decade of the 1920s saw the development of the quinhydrone electrode which was less fragile and much less expensive than the hydrogen-platinum electrode. But, it was the development of the glass electrode in the 1930s that brought the determination of pH very rapidly to its present importance and convenience. The Beckman Model G pH meter (circa 1931) was practically indestructible and could be used as a portable as well as a laboratory instrument. Although it was cumbersome by today's standards, it was virtually foolproof (except for the constantly failing batteries) and many are still capable of operating if not actually operating today. As recently as two decades ago, the use of the small, handheld portable pH meters then available to determine pH in the field was a very imprecise and hazardous undertaking because both electrodes and meters were subject to sudden failures but this has changed rather abruptly in the last few years. Microcircuitry and plastic have contributed to rugged pH meters and electrodes that withstand

2,215 citations


Journal ArticleDOI
TL;DR: In this article, a complete set of analytic fits to the nonrelativistic photoionization cross sections for the ground states of atoms and ions of elements from H through Si, and S, Ar, Ca, and Fe were presented.
Abstract: We present a complete set of analytic fits to the nonrelativistic photoionization cross sections for the ground states of atoms and ions of elements from H through Si, and S, Ar, Ca, and Fe. Near the ionization thresholds, the fits are based on the Opacity Project theoretical cross sections interpolated and smoothed over resonances. At higher energies, the fits reproduce calculated Hartree-Dirac-Slater photoionization cross sections. {copyright} {ital 1996 The American Astronomical Society.}

1,826 citations


Book
13 Sep 1996
TL;DR: In this paper, the emergence of practice is discussed and the social constitution of mind/action/body is discussed in the context of practice theory and individual and sociality in practice.
Abstract: Abbreviations Preface and acknowledgements 1. The emergence of practice 2. Mind/action/body 3. The social constitution of mind/action and body 4. Social practices 5. Dimensions of practice theory 6. Practices and sociality Postscript: individual and totality Notes References Index.

1,773 citations


Journal ArticleDOI
TL;DR: X-ray crystal structure analysis, molecular modelling, and protein digest data indicate that the Arg 117 residue is a trypsin-sensitive site, and that loss of this cleavage site would permit autodigestion resulting in pancreatitis.
Abstract: Hereditary pancreatitis (HP) is a rare, early-onset genetic disorder characterized by epigastric pain and often more serious complications. We now report that an Arg–His substitution at residue 117 of the cationic trypsinogen gene is associated with the HP phenotype. This mutation was observed in all HP affected individuals and obligate carriers from five kindreds, but not in individuals who married into the families nor in 140 unrelated individuals. X-ray crystal structure analysis, molecular modelling, and protein digest data indicate that the Arg 117 residue is a trypsin-sensitive site. Cleavage at this site is probably part of a fail-safe mechanism by which trypsin, which is activated within the pancreas, may be inactivated; loss of this cleavage site would permit autodigestion resulting in pancreatitis.

1,471 citations


Journal ArticleDOI
TL;DR: In this paper, a perfectly matched layer (PML) absorbing medium composed of a uniaxial anisotropic material is presented for the truncation of finite-difference time domain (FDTD) lattices.
Abstract: A perfectly matched layer (PML) absorbing material composed of a uniaxial anisotropic material is presented for the truncation of finite-difference time-domain (FDTD) lattices It is shown that the uniaxial PML material formulation is mathematically equivalent to the perfectly matched layer method published by Berenger (see J Computat Phys, Oct 1994) However, unlike Berenger's technique, the uniaxial PML absorbing medium presented in this paper is based on a Maxwellian formulation Numerical examples demonstrate that the FDTD implementation of the uniaxial PML medium is stable, equal in effectiveness as compared to Berenger's PML medium, while being more computationally efficient

1,326 citations


Journal ArticleDOI
21 Mar 1996-Nature
TL;DR: Evaluating the effects of GDNF injected intracerebrally into rhesus monkeys that have had the symptomatology and pathophysiological features of Parkinson's disease induced by the neurotoxin 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine indicates that GDNF may be of benefit in the treatment of Parkinson’s disease.
Abstract: PARKINSON 's disease results from the progressive degeneration of dopamine neurons that innervate the striatum1,2. In rodents, glial-cell-line-derived neurotrophic factor (GDNF) stimulates an increase in midbrain dopamine levels, protects dopamine neurons from some neurotoxins, and maintains injured dopamine neurons3–9. Here we extend the rodent studies to an animal closer to the human in brain organization and function, by evaluating the effects of GDNF injected intracerebrally into rhesus monkeys that have had the symptomatology and pathophysiological features of Parkinson's disease induced by the neurotoxin 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP)10–14. The recipients of GDNF displayed significant improvements in three of the cardinal symptoms of parkinsonism: bradykinesia, rigidity and postural instability. GDNF administered every four weeks maintained functional recovery. On the lesioned side of GDNF-treated animals, dopamine levels in the midbrain and globus pallidus were twice s high, and nigral dopamine neurons were, on average, 20% larger, with an increased fibre density. The results indicate that GDNF may be of benefit in the treatment of Parkinson's disease.

973 citations


Journal ArticleDOI
21 Feb 1996-JAMA
TL;DR: Low linguistic ability in early life was a strong predictor of poor cognitive function and Alzheimer's disease in late life.
Abstract: Objective. —To determine if linguistic ability in early life is associated with cognitive function and Alzheimer's disease in late life. Design. —Two measures of linguistic ability in early life, idea density and grammatical complexity, were derived from autobiographies written at a mean age of 22 years. Approximately 58 years later, the women who wrote these autobiographies participated in an assessment of cognitive function, and those who subsequently died were evaluated neuropathologically. Setting. —Convents in the United States participating in the Nun Study; primarily convents in the Milwaukee, Wis, area. Participants. —Cognitive function was investigated in 93 participants who were aged 75 to 95 years at the time of their assessments, and Alzheimer's disease was investigated in the 14 participants who died at 79 to 96 years of age. Main Outcome Measures. —Seven neuropsychological tests and neuropathologically confirmed Alzheimer's disease. Results. —Low idea density and low grammatical complexity in autobiographies written in early life were associated with low cognitive test scores in late life. Low idea density in early life had stronger and more consistent associations with poor cognitive function than did low grammatical complexity. Among the 14 sisters who died, neuropathologically confirmed Alzheimer's disease was present in all of those with low idea density in early life and in none of those with high idea density. Conclusions. —Low linguistic ability in early life was a strong predictor of poor cognitive function and Alzheimer's disease in late life. (JAMA. 1996;275:528-532)

972 citations


Journal ArticleDOI
TL;DR: A key role for TNF in injury–induced immune response was demonstrated in TNFR–KO mice, demonstrating that drugs that target TNF signaling pathways may prove beneficial in treating stroke and traumatic brain injury.
Abstract: Brain injury, as occurs in stroke or head trauma, induces a dramatic increase in levels of tumor necrosis factor-alpha (TNF), but its role in brain injury response is unknown. We generated mice genetically deficient in TNF receptors (TNFR-KO) to determine the role of TNF in brain cell injury responses. Damage to neurons caused by focal cerebral ischemia and epileptic seizures was exacerbated in TNFR-KO mice, indicating that TNF serves a neuroprotective function. Oxidative stress was increased and levels of an antioxidant enzyme reduced in brain cells of TNFR-KO mice, indicating that TNF protects neurons by stimulating antioxidant pathways. Injury-induced microglial activation was suppressed in TNFR-KO mice, demonstrating a key role for TNF in injury-induced immune response. Drugs that target TNF signaling pathways may prove beneficial in treating stroke and traumatic brain injury.

951 citations


Journal ArticleDOI
18 Dec 1996-JAMA
TL;DR: Low-dose diuretic-based (chlorthalidone) treatment is effective in preventing major CVD events, cerebral and cardiac, in both non-insulin-treated diabetic and nondiabetic older patients with ISH.
Abstract: Objective. —To assess the effect of low-dose, diuretic-based antihypertensive treatment on major cardiovascular disease (CVD) event rates in older, non-insulintreated diabetic patients with isolated systolic hypertension (ISH), compared with nondiabetic patients. Design. —Double-blind, randomized, placebo-controlled trial: the Systolic Hypertension in the Elderly Program (SHEP). Setting. —Multiple clinical and support centers in the United States. Paticipants. —a total of 4736 men and women aged 60 years and older at baseline with ISH (systolic blood pressure [BP], ≥160 mm Hg; diastolic BP, Intervention. —The active treatment group received a low dose of chlorthalidone (12.5-25.0 mg/d) with a step-up to atenolol (25.0-50.0 mg/d) or reserpine (0.05-0.10 mg/d) if needed. The placebo group received placebo and any active antihypertensive drugs prescribed by patient's private physician for persistently high BP. Main Outcome Measures. —The 5-year rates of major CVD events, nonfatal plus fatal stroke, nonfatal myocardial infarction (MI) and fatal coronary heart disease (CHD), major CHD events, and all-cause mortality. Results. —The SHEP antihypertensive drug regimen lowered BP of both diabetic and nondiabetic patients, with few adverse effects. For both diabetic and nondiabetic patients, all outcome rates were lower for participants randomized to the active treatment group than for those randomized to the placebo group. Thus, 5-year major CVD rate was lower by 34% for active treatment compared with placebo, both for diabetic patients (95% confidence interval [CI], 6%-54%) and nondiabetic patients (95% CI, 21%-45%). Absolute risk reduction with active treatment compared with placebo was twice as great for diabetic vs nondiabetic patients (101/1000 vs 51/1000 randomized participants at the 5-year follow-up), reflecting the higher risk of diabetic patients. Conclusion. —Low-dose diuretic-based (chlorthalidone) treatment is effective in preventing major CVD events, cerebral and cardiac, in both non-insulin-treated diabetic and nondiabetic older patients with ISH.

914 citations


Journal ArticleDOI
26 Sep 1996-Nature
TL;DR: Fluids near their critical point have dissolving power comparable to that of liquids, are much more compressible than dilute gases, and have transport properties intermediate between gas-and liquid-like as discussed by the authors.
Abstract: Fluids near their critical point have dissolving power comparable to that of liquids, are much more compressible than dilute gases, and have transport properties intermediate between gas-and liquid-like. This unusual combination of physical properties can be advantageously exploited in environmentally benign separation and reaction processes, as well as for new kinds of materials processing.

804 citations


Patent
06 Aug 1996
TL;DR: In this paper, the isolation, modification and use of wild-type and modified viral FLt promoters of PClSV in the expression of chimeric genes in plant cells is described.
Abstract: The isolation, modification and use of wild-type and modified viral FLt promoters of peanut chlorotic streak caulimovirus (PClSV) in the expression of chimeric genes in plant cells. The FLt promoter from PClSV has been modified to have duplicated enhancer domains.

Journal ArticleDOI
TL;DR: Evidence is summarized to suggest that exposure to novelty activates, at least in part, the same neural substrate that mediates the rewarding effects of drugs of abuse.

Journal ArticleDOI
TL;DR: This article examined whether there are conceptually and empirically distinct dimensions offear of crime by comparing the micro-and macro-level antecedents of such a general, cognitive "fear" - which they call "perceived risk" - with those for a more emotionally based, burglary-specific fear.
Abstract: The conceptualization and measurement of fear of crime have received considerable attention in the research literature. Nevertheless, most sample surveys use indicators that only tap a general, cognitive assessment of safety - assumed to represent fear of violence. This article examines whether there are conceptually and empirically distinct dimensions offear of crime by comparing the micro- and macrolevel antecedents of such a general, cognitive "fear" - which we call "perceived risk" - with thosefor a more emotionally based, burglary-specific fear. Hierarchical logistic regression models for both types offear are presented. Some similarities were found between fear and risk in terms of various predictors, but results generally provide further empirical evidence that the two constructs are quite distinct. At the individual-level, the effect of gender is different across models, and routine-activities variables are somewhat better predictors of burglary-specific fear in comparison to risk perception. At the contextual level, neighborhood integration serves to diminish respondents' perceptions of neighborhood danger, yet this variable is positively related to burglary-specific fear.

Journal ArticleDOI
TL;DR: Copper (Cu), iron (Fe), and zinc (Zn) levels in five different brain regions were determined by instrumental neutron activation analysis (INAA) in samples from Alzheimer's disease patients and age-matched control subjects.

Journal ArticleDOI
TL;DR: The ability to understand the physiological basis for allelopathy in a crop plant may allow the weed scientist or ecologist to work closely with molecular biologists or traditional plant breeders to selectively enhance the traits responsible for weed suppression.
Abstract: Biorational alternatives are gaining increased attention for weed control because of concerns related to pesticide usage and dwindling numbers of labeled products, particularly for minor-use crops. Allelopathy offers potential for biorational weed control through the production and release of allelochemics from leaves, flowers, seeds, stems, and roots of living or decomposing plant materials. Under appropriate conditions, allelochemics may be released in quantities suppressive to developing weed seedlings. Allelochemics often exhibit selectivity, similar to synthetic herbicides. Two main approaches have been investigated for allelopathic weed suppression. One is use of living rotational crops or mulches that interfere with the growth of surrounding weeds [e.g., tall red fescue, Festuca arundinacea Schreb.; creeping red fescue, F. rubra L. subsp. commutata; asparagus, Asparagus officinalis L. var. altilis); sorghum, Sorghum bicolor (L.) Moench; alfalfa, Medicago saliva L.; black mustard, Brassica nigra (L.) Koch; and oat, Avena saliva L.]. Attempts to select germplasm with enhanced suppressive ability have been limited. The second is use of cover crop residues or living mulches to suppress weed growth for variable lengths of time (e.g., winter rye, Secale cereale L.; winter wheat, Triticum aestivum L.; and sorghum). Cover crop residues may selectively provide weed suppression through their physical presence on the soil surface and by release of allelochemics or microbially altered allelochemics. The ability to understand the physiological basis for allelopathy in a crop plant may allow the weed scientist or ecologist to work closely with molecular biologists or traditional plant breeders to selectively enhance the traits responsible for weed suppression.

Journal ArticleDOI
TL;DR: It is confirmed that the α1ARs are a heterogeneous group of distinct but related proteins, and this conclusion has been confirmed with the molecular cloning of three distinct α1-receptor subtypes, although until recently discrepancies between the properties of the cloned expressed receptors and those characterized pharmacologically and biochemically have led to confusion.
Abstract: The α1ARs are important mediators of sympathetic nervous system responses, particularly those involved in cardiovascular homeostasis, such as arteriolar smooth muscle constriction and cardiac contraction.1 2 In addition, α1ARs have more recently been implicated in the pathogenesis of cardiac hypertrophy, in ischemia-induced cardiac arrhythmias, and in ischemic preconditioning.1 3 Like other ARs, α1ARs are activated by the catecholamines, norepinephrine and epinephrine. They are intrinsic membrane glycoproteins and are members of the GPCR superfamily. Over the past 10 to 15 years, data initially based on functional, radioligand, and biochemical studies have accumulated, indicating that the α1ARs are a heterogeneous group of distinct but related proteins. This conclusion has been confirmed with the molecular cloning of three distinct α1-receptor subtypes, although until recently discrepancies between the properties of the cloned expressed receptors and those characterized pharmacologically and biochemically have led to confusion in the classification of α1-receptor subtypes and their coupled effector responses. As detailed in the present review, much of this confusion has now been clarified for the three cloned α1ARs. These and other recent insights into the molecular structure, function, and signaling of α1ARs, the control of α1AR-gene expression, and pharmacological evidence for additional α1AR subtypes will be reviewed here. For additional information, the reader is also referred to several previous reviews of α1ARs.4 5 6 7 Functional studies of AR responses, particularly from the laboratories of McGrath8 and Ruffolo,9 provided the initial evidence that there may be subtypes of α1ARs. These studies indicated that postjunctional responses mediated by α1ARs could not be explained adequately on the basis of a single population of receptors. This concept was further advanced …

Journal ArticleDOI
09 Aug 1996-Science
TL;DR: The hypotensive response to α2AR agonists was lost in the mutant mice, demonstrating that the α2aAR subtype plays a principal role in this response.
Abstract: α 2 -Adrenergic receptors (α 2 ARs) present in the brainstem decrease blood pressure and are targets for clinically effective antihypertensive drugs. The existence of three α 2 AR subtypes, the lack of subtype-specific ligands, and the cross-reactivity of α 2 AR agonists with imidazoline receptors has precluded an understanding of the role of individual α 2 AR subtypes in the hypotensive response. Gene targeting was used to introduce a point mutation into the α 2a AR subtype in the mouse genome. The hypotensive response to α 2 AR agonists was lost in the mutant mice, demonstrating that the α 2a AR subtype plays a principal role in this response.

Journal ArticleDOI
17 May 1996-Science
TL;DR: This work found that total L-type Ca2+ channel activity in patches was found to increase with aging, primarily because of an increase in the density of functional channels.
Abstract: Voltage-activated calcium (Ca 2+ ) influx is increased in mammalian CA1 hippocampal neurons during aging. However, the molecular basis for this elevation is not known. The partially dissociated hippocampal (“zipper99) slice preparation was used to analyze single Ca 2+ channel activity in CA1 neurons of adult and aged rats. Total L-type Ca 2+ channel activity in patches was found to increase with aging, primarily because of an increase in the density of functional channels. Learning in aged animals was inversely correlated with channel density. This increase in functional Ca 2+ channels with aging could underlie the vulnerability of neurons to age-associated neurodegenerative conditions.

Journal ArticleDOI
TL;DR: A set of minimum clinical guidelines for use by primary care physicians in the evaluation and management of patients with thyroid nodules or thyroid cancer was developed by consensus by an 11-member Standards of Care Committee of the American Thyroid Association.
Abstract: A set of minimum clinical guidelines for use by primary care physicians in the evaluation and management of patients with thyroid nodules or thyroid cancer was developed by consensus by an 11-member Standards of Care Committee (the authors of the article) of the American Thyroid Association, New York, NY. The participants were selected by the committee chairman and by the president of the American Thyroid Association based on their clinical experience. The committee members represented different geographic areas within the United States, to reflect different practice patterns. The guidelines were developed based on the expert opinion of the committee participants, as well as on previously published information. Each committee participant was initially assigned to write a section of the document and to submit it to the committee chairman, who revised and assembled the sections into a complete draft document, which was then circulated among all committee members for further revision. Several of the committee members further revised and refined the document, which was then submitted to the entire membership of the American Thyroid Association for written comments and suggestions, many of which were incorporated into a final draft document, which was reviewed and approved by the Executive Council of the American Thyroid Association.

Journal ArticleDOI
TL;DR: It is hypothesized that amyloid formation could be inhibited by peptides homologous to A beta with a similar degree of hydrophobicity, but with a very low propensity to adopt a beta-sheets conformation by incorporating proline residues (anti-beta-sheet peptides or beta-sheet inhibitors).

Journal ArticleDOI
TL;DR: Results support a major role for free radical generation in ADR toxicity as well as suggesting mitochondria as the critical site of cardiac injury.
Abstract: Adriamycin (ADR) is a potent anticancer drug known to cause severe cardiac toxicity. Although ADR generates free radicals, the role of free radicals in the development of cardiac toxicity and the intracellular target for ADR-induced cardiac toxicity are still not well understood. We produced three transgenic mice lines expressing increased levels of human manganese superoxide dismutase (MnSOD), a mitochondrial enzyme, as an animal model to investigate the role of ADR-mediated free radical generation in mitochondria. The human MnSOD was expressed, functionally active, and properly transported into mitochondria in the heart of transgenic mice. The levels of copper-zinc SOD, catalase, and glutathione peroxidase did not change in the transgenic mice. Electron microscopy revealed dose-dependent ultrastructural alterations with marked mitochondrial damage in nontransgenic mice treated with ADR, but not in the transgenic littermates. Biochemical analysis indicated that the levels of serum creatine kinase and lactate dehydrogenase in ADR-treated mice were significantly greater in nontransgenic than their transgenic littermates expressing a high level of human MnSOD after ADR treatment. These results support a major role for free radical generation in ADR toxicity as well as suggesting mitochondria as the critical site of cardiac injury.

Journal ArticleDOI
TL;DR: In this article, LiCoO(sub 2)-O(1.15) was found to be Li{sub 1.15}CoO{sub 2.16} or, within experimental uncertainty, LiCo(sub + 0.08)O(0.05 to 0.5 {micro}m thick.
Abstract: Thin-film rechargeable lithium batteries with amorphous and crystalline LiCoO{sub 2} cathodes were investigated. The lithium cobalt oxide films were deposited by radio-frequency (RF) magnetron sputtering of an LiCoO{sub 2} target in a 3:1 Ar/O{sub 2} mixture gas. From proton-induced {gamma}-ray emission analysis (PIGE) and Rutherford backscattering spectrometry (RBS), the average composition of these films was determined to be Li{sub 1.15}CoO{sub 2.16} or, within experimental uncertainty, LiCoO{sub 2} + 0.08 Li{sub 2}O. The X-ray powder diffraction patterns of films annealed in air at 500 to 700 C were consistent with the regular hexagonal structure observed for crystalline LiCoO{sub 2}. The discharge curves of the cells with amorphous LiCoO{sub 2} cathodes showed no obvious structural transition between 4.2 and 2.0 V, while the discharge curves of the cells with polycrystalline cathodes were consistent with a two-phase potential plateau at {approximately}3.9 V with a relatively large capacity. Two lower capacity plateaus were observed at {approximately} 4.2 and 4.1 V with the 600 and 700 C annealed cathodes; the {minus}dq/dV peaks were broader and weaker for the 600 C annealed cathodes and were not present at all with the 500 C annealed films. The chemical diffusion coefficients of Li{sup +} in the cathodes obtainedmore » from ac impedance measurements at cell potentials of {approximately} 4 V ranged from {approximately} 10{sup {minus}12} cm{sup 2}/s for the as-deposited amorphous cathodes to {approximately} 10{sup {minus}9} cm{sup 2}/s for the films annealed at 700 C. The capacity loss on extended cycling of the thin-film cells varied with the crystallinity and thickness of the cathodes and with temperature. With the highly crystalline, 700 C annealed material, losses on cycling between 4.2 and 3.8 V at 25 C ranged from 0.0001%/cycle (> 10{sup 4} cycles) to 0.002%/cycle for cells with cathodes form 0.05 to 0.5 {micro}m thick.« less

Journal ArticleDOI
29 Nov 1996-Cell
TL;DR: The results indicate that CstF-64 plays a key role in regulating IgM heavy chain expression during B cell differentiation, and that the microm site is stronger in a reconstituted in vitro processing reaction.

Journal ArticleDOI
TL;DR: In this paper, the authors presented new calculations and analytic fits to the rates of radiative recombination toward H-like, He-like and Li-like ions of all elements from H through Zn.
Abstract: We present new calculations and analytic fits to the rates of radiative recombination toward H-like, He-like, Li-like, and Na-like ions of all elements from H through Zn ({ital Z}=30). The fits are valid over a wide range of temperature, from 3 K to 10{sup 9} K. {copyright} {ital 1996 The American Astronomical Society.}

Journal ArticleDOI
TL;DR: Dementia results from a combination of structural and neurochemical pathologies and the most reliable index of cognition in both postmortem and biopsy brain is synapse loss.

Journal ArticleDOI
TL;DR: The HPA stress response appears to be a product of both the physiologic importance of the stimulus and the specific pathways a given stimulus excites, and may require interaction with homeostatic information prior to promoting an HPA response.
Abstract: The hypothalamo-pituitary-adrenocortical (HPA) axis is the primary modulator of the adrenal glucocorticoid stress response. Activation of this axis occurs by way of a discrete set of neurons in the hypothalamic paraventricular nucleus (PVN). The PVN neuron appears to be affected by multiple sources, including (1) brainstem aminergic/peptidergic afferents; (2) blood-borne information; (3) indirect input from limbic system-associated regions, including the prefrontal cortex, hippocampus, and amygdala; and (4) local-circuit interactions with the preoptic-hypothalamic continuum. Analysis of the literature suggests that different classes of stressor employ different stress circuits. Severe physiologic ("systemic") stress appears to trigger brainstem/circumventricular organ systems that project directly to the paraventricular nucleus. In contrast, stressors requiring interpretation with respect to previous experience ("processive" stressors) reach the PVN by way of multisynaptic limbic pathways. Limbic regions mediating processive stress responses appear to have bisynaptic connections with the PVN, forming intervening connections with preoptic/hypothalamic GABAergic neurons. Stressors of the latter category may thus require interaction with homeostatic information prior to promoting an HPA response. The HPA stress response thus appears to be a product of both the physiologic importance of the stimulus and the specific pathways a given stimulus excites.

Journal ArticleDOI
04 Jan 1996-Nature
TL;DR: Calcium imaging studies indicate that activation of K+ channels mediates the ability of sAPPs to decrease [Ca2+]i, suggesting that modulation of neuronal excitability may be a major mechanism by which β-APP regulates developmental and synaptic plasticity in the nervous system.
Abstract: THE Alzheimer's β-amyloid precursor protein (β-APP) is widely expressed in neural cells, and in neurons secreted forms of β-APP (sAPPs) are released from membrane-spanning holo-βAPP in an activity-dependent manner1,2. Secreted APPs can modulate neur-ite outgrowth, synaptogenesis, synaptic plasticity and cell survival3–9; a signal transduction mechanism of sAPPs may involve modulation of intracellular calcium levels ([Ca2+]i)4,10. Here we use whole-cell perforated patch and single-channel patch-clamp analysis of hippocampal neurons to demonstrate that sAPPs suppress action potentials and hyperpolarize neurons by activating high-conductance, charybdotoxin-sensitive K+ channels. Activation of K+ channels by sAPPs was mimicked by a cyclic GMP analogue and sodium nitroprusside and blocked by an antagonist of cGMP-dependent kinase and a phosphatase inhibitor, suggesting that the effect is mediated by cGMP and protein dephosphorylation. Calcium imaging studies indicate that activation of K+ channels mediates the ability of sAPPs to decrease [Ca2+]i. Modulation of neuronal excitability may be a major mechanism by which β-APP regulates developmental and synaptic plasticity in the nervous system.

Journal ArticleDOI
TL;DR: It is reported that expression of PS-1 mutation L286V in cultured PC12 cells exaggerates Ca2+ responses to agonists (carbachol and bradykinin), and an antagonist of voltage-dependent calcium channels (nifedipine), and a blocker of Ca2- release from ER (dantrolene), counteract the adverse consequences of the PS- 1 mutation.
Abstract: Mutations in the presenilin-1 (PS-1) gene on chromosome 14 are linked to autosomal dominant early-onset Alzheimer's disease. The amino acid sequence of PS-1 predicts an integral membrane protein and immunocytochemical studies indicate that PS-1 is localized to endoplasmic reticulum (ER). We report that expression of PS-1 mutation L286V in cultured PC12 cells exaggerates Ca2+ responses to agonists (carbachol and bradykinin) that induce Ca2+ release from ER. Cells expressing L286V exhibit enhanced elevations of [Ca2+]i following exposure to amyloid beta-peptide (A beta) and increased vulnerability to A beta toxicity. An antagonist of voltage-dependent calcium channels (nifedipine), and a blocker of Ca2+ release from ER (dantrolene), counteract the adverse consequences of the PS-1 mutation. By perturbing Ca2+ homeostasis, PS-1 mutations may sensitize neurons to A beta-induced apoptosis.

Journal ArticleDOI
19 Jul 1996-Science
TL;DR: Yersinia pestis hms mutants established long-term infection of the flea's midgut but failed to colonize the proventriculus, the site in the foregut where blockage normally develops, leading to a change in blood-feeding behavior and to efficient transmission of plague.
Abstract: Yersinia pestis, the cause of bubonic plague, is transmitted by the bites of infected fleas. Biological transmission of plague depends on blockage of the foregut of the flea by a mass of plague bacilli. Blockage was found to be dependent on the hemin storage (hms) locus. Yersinia pestis hms mutants established long-term infection of the flea's midgut but failed to colonize the proventriculus, the site in the foregut where blockage normally develops. Thus, the hms locus markedly alters the course of Y. pestis infection in its insect vector, leading to a change in blood-feeding behavior and to efficient transmission of plague.

Journal ArticleDOI
TL;DR: This paper showed that SAA is the most sensitive non-invasive biochemical marker for allograft rejection, and compared the measurement of SAA to CRP could reveal other indications for its specific use.
Abstract: Serum amyloid A (SAA) proteins comprise a family of apolipoproteins synthesized in response to cytokines released by activated monocytes/macrophages. Acute-phase protein concentrations have been advocated as objective biochemical indices of disease activity in a number of different inflammatory processes. Clinical studies in large groups of patients with a variety of disorders confirmed the rapid production and exceptionally wide dynamic range of the SAA response. It is as sensitive a marker for the acute-phase as C-reactive protein (CRP). Recent studies indicate that SAA is the most sensitive non-invasive biochemical marker for allograft rejection. Further studies comparing the measurement of SAA to CRP could reveal other indications for its specific use. These studies are now more feasible given newer assays to measure this acute-phase reactant. Observations that the acute-phase response is tightly coupled to lipoprotein abnormalities and the fact that acute-SAA proteins are mainly associated with plasma lipoproteins of the high density range suggested a possible role of this apolipoprotein (apo SAA) in the development of atherosclerosis. The expression of SAA mRNA in human atherosclerotic lesions and the induction of acute-phase SAA by oxidized low-density lipoproteins strengthen the hypothesis that SAA might play a role in vascular injury and atherogenesis.