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J D Stone

Publications and source records attributed to J D Stone.

At least 19 recordsLinked to original sources
PubMed2003

Sex dimorphisms in the cognitive-enhancing action of the Alzheimer's drug donepezil in aged Rhesus monkeys.

Brain acetylcholinesterase has been targeted for the development of novel treatments for memory deficits associated with Alzheimer's disease (AD) and other neurodegenerative disorders. The long-acting AChE inhibitor donepezil (Aricept) is used to improve memory and other aspects of cognition in AD patients. Because donepezil and other cholinesterase inhibitors are effective in a restricted population of AD patients, this study was to designed to determine whether aged females monkeys receive the same level of benefit to the mnemonic action of donepezil as do males. In this study, six male and six female rhesus monkeys (>20 years) who were proficient in the performance of a delayed matching-to-sample task each received an ascending series of four doses of donepezil (0.01-0.1 mg/kg) over 5 weeks. As a group, male subjects exhibited improvement in task accuracy across the three highest doses, with the maximum effect occurring after the 0.025 mg/kg dose. However, the females exhibited increased task accuracy only after the highest dose. When data were combined for sessions run 10 min after drug administration and for sessions run 24 h later (in the absence of drug), improvements in task accuracy were greater on average for males. Most of this difference was attributed to the fact that task accuracy by females actually declined during sessions run after the two lowest doses of donepezil. When task performance after donepezil was determined as the individualized Best Dose, as a group, males responded maximally to less than half the dose that was maximal for females. These findings support the concept that aged males and females respond differently to this class of agents, perhaps representing fundamental sex-related differences in memory processing, or in the manner that age affects these processes.

Aging↗
PubMed2003

Repeated exposures to subthreshold doses of chlorpyrifos in rats: hippocampal damage, impaired axonal transport, and deficits in spatial learning.

Organophosphorus (OP) compounds are detectable in the environment for years after use and endanger many populations. Although the effects of acutely toxic doses of many OP compounds are well described, much less is known about repeated low-level exposures. The purpose of these studies was to further evaluate potential toxicological effects of the extensively used OP pesticide chlorpyrifos (CPF) in rats. CPF, across a range of subthreshold doses (i.e., for acute toxicity), reduced rearing and sniffing activity and the magnitude of weight gain over 14 days of repeated exposure. Performance in a spatial learning task was impaired after 14 days of exposure to CPF (18.0 and 25.0 mg/kg) when testing was initiated 24 h after the last injection but not after a 14-day washout. However, inhibition of both fast anterograde and retrograde axonal transport was observed for up to 20 days after exposure to 25.0 mg/kg CPF. Studies using hippocampal cultures indicated that 8 days of continuous exposure to the parent compound, CPF (> or =100 micro M), resulted in cell toxicity and death. Furthermore, a dose (2.5 mg/kg) of CPF that had no effects on weight gain or memory performance when administered 5 days per week over 38 days impaired forelimb grip strength in the later days of testing. Collectively, these results indicate that repeated exposures to subthreshold doses of CPF may lead to growth retardation, behavioral abnormalities, and muscle weakness. Some of these symptoms may be attributed to effects of the OP on axonal transport.

Animals↗
PubMed2001

Receptor proximity, not intermolecular orientation, is critical for triggering T-cell activation.

Engagement of antigen receptors on the surface of T-cells with peptides bound to major histocompatibility complex (MHC) proteins triggers T-cell activation in a mechanism involving receptor oligomerization. Receptor dimerization by soluble MHC oligomers is sufficient to induce several characteristic activation processes in T-cells including internalization of engaged receptors and up-regulation of cell surface proteins. In this work, the influence of intermolecular orientation within the activating receptor dimer was studied. Dimers of class II MHC proteins coupled in a variety of orientations and topologies each were able to activate CD4+ T-cells, indicating that triggering was not dependent on a particular receptor orientation. In contrast to the minimal influence of receptor orientation, T-cell triggering was affected by the inter-molecular distance between MHC molecules, and MHC dimers coupled through shorter cross-linkers were consistently more potent than those coupled through longer cross-linkers. These results are consistent with a mechanism in which intermolecular receptor proximity, but not intermolecular orientation, is the key determinant for antigen-induced CD4+ T-cell activation.

Amino Acid Sequence↗
PubMed2001

Neurofilaments are nonessential to the pathogenesis of toxicant-induced axonal degeneration.

Axonal neurofilament (NF) accumulations occur before development of symptoms and before other pathological changes among idiopathic neurodegenerative diseases and toxic neuropathies, suggesting a cause-effect relationship. The dependence of symptoms and axonal degeneration on neurofilament accumulation has been tested here in a transgenic mouse model (Eyer and Peterson, 1994) lacking axonal NFs and using two prototypic toxicant models. Chronic acrylamide (ACR) or 2,5-hexanedione exposure resulted in progressive and cumulative increases in sensorimotor deficits. Neurobehavioral tests demonstrated similar expression of neurotoxicity in transgenic (T) mice and their nontransgenic (NT) littermates (containing normal numbers of axonal NFs). Axonal lesions were frequently observed after exposure to either toxicant. Quantitation of ACR-induced lesions demonstrated the distal location of pathology and equal susceptibility of T and NT axons. We conclude that axonal NFs have no effect on neurotoxicity and the pattern of pathology in these mammalian toxic neuropathies. These results also suggest that the role of neurofilament accumulation in the pathogenesis of neurodegenerative diseases requires careful evaluation.

Acrylamide↗
PubMed2001

T-cell activation by soluble MHC oligomers can be described by a two-parameter binding model.

T-cell activation is essential for initiation and control of immune system function. T cells are activated by interaction of cell-surface antigen receptors with major histocompatibility complex (MHC) proteins on the surface of other cells. Studies using soluble oligomers of MHC-peptide complexes and other types of receptor cross-linking agents have supported an activation mechanism that involves T cell receptor clustering. Receptor clustering induced by incubation of T cells with MHC-peptide oligomers leads to the induction of T-cell activation processes, including downregulation of engaged receptors and upregulation of the cell-surface proteins CD69 and CD25. Dose-response curves for these T-cell activation markers are bell-shaped, with different maxima and midpoints, depending on the valency of the soluble oligomer used. In this study, we have analyzed the activation behavior using a mathematical model that describes the binding of multivalent ligands to cell-surface receptors. We show that a simple equilibrium binding model accurately describes the activation data for CD4(+) T cells treated with MHC-peptide oligomers of varying valency. The model can be used to predict activation and binding behavior for T cells and MHC oligomers with different properties.

Antigens, CD↗
PubMed2000

Protractive effects of chronic treatment with an acutely sub-toxic regimen of diisopropylflurophosphate on the expression of cholinergic receptor densities in rats.

Individuals chronically exposed to low levels of organophosphate insecticides may present with subtle impairments in cognition. In addition, low level diisopropylflurophosphate (DFP) exposure (0.25 mg/kg per day for 2 weeks) in rats resulted in protracted working memory impairment [29]. The current studies attempt to show a temporal relationship between the DFP-induced impairment in performance of a spatial memory task and the protracted decrease in the expression of cholinergic receptors and acetylcholinesterase in specific brain regions. Cholinergic receptors labeled with the ligands [(3)H]epibatidine and [(3)H]AFDX-384 were affected to a much greater extent and for a longer period of time than were both acetylcholinesterase activities and cholinergic receptors labeled with [(3)H]QNB. Pre-testing administration of nicotine was shown to completely reverse this DFP-induced impairment in memory-related task performance. Additionally, prophylaxis with pyridostigmine bromide (PB) caused DFP-treated animals to exhibit near normal levels of memory-related task performance. These results are consistent with the development of a protracted phase of learning impairment to sub-acute DFP exposure, which may involve the loss of hippocampal nicotinic receptors, and may be prevented or reversed by PB or nicotine, respectively.

Acetylcholinesterase↗
PubMed2000

Neurofilaments are non-essential elements of toxicant-induced reductions in fast axonal transport: pulse labeling in CNS neurons.

Acrylamide (ACR) and g-diketones (g-DK) produce distal sensory-motor neuropathy in a variety of species, including humans. The specific molecular site and mechanism of toxicant action leading to specific morphological and behavioral abnormalities requires definition. The relative roles of fast anterograde axonal transport and neurofilaments (NF) are investigated using optic nerves of mice, with and without axonal neurofilaments. Segmental analysis, following pulse labeling with 3H-leucine into the vitreous body, was used to detect changes in fast anterograde transport in the optic nerve and tract. Single injections of ACR significantly reduced the quantity of radiolabeled proteins transported in both transgenic (lacking NF) and non-transgenic (containing NF) mice by 68.4% and 46.2%, respectively. Similarly, single injections of 2,5-hexanedione (2,5-HD) reduced the quantity of radiolabeled transport in transgenic and non-transgenic mice by 55.2% and 47.1%, respectively. Equimolar doses of propionamide and 3,4-hexanedione (non-neurotoxic analogues of ACR and 2,5-HD, respectively) produced no changes in the quantity or apparent rate of optic nerve transport. Additionally, no differences in quantity or apparent rate of transport between transgenic and non-transgenic animals were observed under control or experimental conditions. Therefore, ACR and 2,5-HD reduce the quantity of fast anterograde axonal transport in mouse CNS axons in a comparable amount to previously reported reductions in rat PNS axons. The absence of axonal neurofilaments had no effect on normal fast transport. Furthermore, the presence or absence of neurofilaments did not alter the effect of these toxicants on fast axonal transport. We conclude that toxicant-induced reductions in fast axonal transport are unrelated to ACR and g-diketone effects on NF or their accumulation.

Acrylamide↗
PubMed1999

Axonal neurofilaments are nonessential elements of toxicant-induced reductions in fast axonal transport: video-enhanced differential interference microscopy in peripheral nervous system axons.

Neurofilament modification and accumulation, occurring in toxicant-induced neuropathies, has been proposed to compromise fast axonal transport and contribute to neurological symptoms or pathology. The current study compares the effects of the neurotoxicants acrylamide (ACR) and 2,5-hexanedione (2,5-HD) on the quantity of fast, bidirectional vesicular traffic within isolated mouse sciatic nerve axons from transgenic mice lacking axonal neurofilaments (Eyer and Peterson, Neuron 12, 1-20, 1994) and nontransgenic littermates possessing neurofilaments. Fast anterograde and retrograde membrane bound organelle (MBO) traffic was quantitated within axons, before and after toxicant exposure, using video-enhanced differential interference contrast (AVEC-DIC) microscopy. Addition of 0.7 mM ACR to the buffer bathing the nerve produced a time-dependent reduction in bidirectional transport with a similar time to onset and magnitude in both transgenic and nontransgenic mice. 2,5-HD (4 mM) exposure reduced bidirectional vesicle traffic by a similar amount in both transgenic and nontransgenic animals. The time to onset of the transport reduction was less and the magnitude of the reduction was greater with 2,5-HD compared to ACR. A single 10-min exposure to ACR or 2,5-HD produced a similar reduction in transport to that produced by prolonged (1 h) exposure. Nonneurotoxic propionamide or 3,4-hexanedione (3,4-HD) produced no changes in bidirectional transport in either transgenic or nontransgenic animals. We conclude that ACR or 2,5-HD produces a rapid, saturable, nonreversible, neurotoxicant-specific reduction in fast bidirectional transport within isolated peripheral nerve axons. These actions are mediated through direct modification of axonal component(s), which are independent of toxicant-induced modifications of, or accumulations of, neurofilaments.

Acrylamide↗
PubMed1997

Aberrant TCR-mediated signaling in CD45-null thymocytes involves dysfunctional regulation of Lck, Fyn, TCR-zeta, and ZAP-70.

CD45 is a transmembrane phosphotyrosine phosphatase expressed on all nucleated hemopoietic cells. Targeting of CD45 exon 9 has generated a mouse line completely lacking CD45 expression (CD45-null) in which there are severe abnormalities in T cell development. Defects in TCR-mediated signals underlying these abnormalities have now been investigated using CD45-null T cells. No T cell proliferation was detected in response to a CD3 mAb. In thymocytes the p56(lck) and p59(fyn) tyrosine kinases were hyperphosphorylated, and p56(lck) was in its inactive conformation. Both basal and TCR-stimulated tyrosine phosphorylation of TCR-zeta and CD3-epsilon were much reduced, and TCR stimulation induced an abnormal p18 phosphoisomer of TCR-zeta previously noted in T cells stimulated by altered peptide ligands. These defects were associated with the failure of ZAP-70 kinase recruitment to the TCR-zeta chain. TCR coupling to the tyrosine phosphorylation of several proteins, including HS1 and p120(cbl), was also much reduced. However, TCR-induced signaling was not ablated, and significant inositol phosphate and calcium signals were observed in CD45-null thymocytes. Our molecular analysis suggests that the threshold for TCR signal transduction is greatly increased in CD45-null T cells, thus explaining the profound defects in thymic development.

Animals↗
PubMed1997

The effect of anterior cruciate ligament graft fixation site at the tibia on knee stability: evaluation using a robotic testing system.

Despite its current popularity and relative success, endoscopic reconstruction of the anterior cruciate ligament (ACL) using a bone-patellar tendon-bone (BPTB) graft has not yet been perfected. Using a recently developed robotic/UFS testing system, we assessed the overall stability of porcine knees following ACL reconstruction with different sites of tibial graft fixation--proximal, central, and distal. Testing of the intact knee was performed first to determine the normal anterior-posterior (A-P) displacements and in situ forces of the ACL under 110 N of anterior tibial loading of 30 degrees, 60 degrees, and 90 degrees of knee flexion. The knee was then reconstructed with a BPTB autograft, and the distal end of the graft was fixed sequentially at three different locations in each specimen--proximal, central, distal. A-P testing was repeated for each fixation site, and the resulting knee kinematics and the in situ forces of the grafts were compared to the intact case. The site of tibial fixation was demonstrated to have a significant effect on the resulting anterior displacement and internal rotation of the tibia as well as the in situ forces of the graft. Proximal fixation produced the most stable knee (A-P displacements reduced to 120% of intact at 30 degrees and 170% at 90 degrees), becoming significantly less stable with more distal fixation. These results suggest that proximal graft fixation may provide the most acute stability of the reconstructed knee.

Animals↗
PubMed1997

Nitroprusside treatment of erythromelalgia in an adolescent female.

OBJECTIVE: To report a case of erythromelalgia in an adolescent patient successfully treated with nitroprusside. CASE SUMMARY: A 15-year-old girl with erythromelalgia resistant to aspirin therapy received an infusion of nitroprusside. The response of the erythromelalgia to nitroprusside was dramatic, with complete pain resolution within 17 hours after the start of therapy. No relapse of erythromelalgia was seen when nitroprusside was discontinued and the patient remained well after 6 months. DISCUSSION: This case adds to existing literature substantiating the benefit of nitroprusside for the treatment of erythromelalgia in pediatric patients. Erythromelalgia in children may represent a different disease entity than that seen in adults, which is commonly responsive to aspirin therapy. The pathogenesis of erythromelalgia is unclear and precludes formulating a proposed mechanism by which nitroprusside has benefit in children. CONCLUSIONS: Nitroprusside is valuable for erythromelalgia resistant to aspirin therapy in pediatric patients. Because of unanswered questions regarding the disease, aspirin remains the agent of first choice in all patients with this rare disease.

Adolescent↗
PubMed1996

Seasonal effects of supplemental fat or undegradable protein on the growth and metabolism of Holstein calves.

One summer (heat stress) and one winter (neutral conditions) trial were conducted to assess the effects of varied amounts of RUP and fat on the growth and metabolic responses of calves. In each trial, 190-kg Holstein calves (n = 45) were fed a basal diet of corn and cottonseed hulls supplemented with soybean meal (control) or supplemented with raw or roasted whole soybeans or the basal ration plus prilled hydrogenated tallow either with or without a mixture of feather meal and blood meal. Prilled tallow was more detrimental to fiber digestion and growth performance than were whole soybeans, especially during summer. During winter, calves fed a high (49%) percentage of the dietary CP as RUP had similar BW gain and efficiency of feed usage as did calves fed a moderate percentage (39%), but, during summer, calves fed the high percentage of RUP had greater BW gain and efficiency than did calves fed moderate percentages of RUP. Ruminal concentrations of VFA were parallel to digestibilities of fiber in the total tract. Ruminal concentrations of ammonia or blood concentrations of urea were not consistent with the concentrations of RDP fed. Concentrations of glucose, NEFA, insulin, and thyroid hormones in the blood were primarily affected by season. Data suggested that a higher percentage and AA quality of RUP improved the growth of calves during summer but not during winter.

Ammonia↗
PubMed1995

Differences in viral distribution and cell adhesion molecule expression in the intestinal tract of rhesus macaques infected with pathogenic and nonpathogenic SIV.

We investigated SIV infection and expression of adhesion molecules in the small intestine of rhesus macaques infected with pathogenic SIV (SIVmac) or nonpathogenic clone (SIV1A11). There was a wider dissemination and marked difference in tissue localization of SIVmac relative to SIV1A11. Our results also indicate that viral pathogenicity is associated with increased migration of inflammatory cells expressing VLA-alpha 4, LFA-1 alpha, Mac-1 alpha, ICAM-1, and beta 2 integrin into the intestinal mucosa.

Animals↗
PubMed1995

Alteration of carbamazepine pharmacokinetics in patients with traumatic brain injury.

All patients admitted to a rehabilitation unit with closed-head injury over a 3-year period were reviewed for carbamazepine use exceeding 30 days in the hospital. Nine patients met the study inclusion criteria for age and duration of carbamazepine therapy. On review of the dose:serum concentration relationship, significant changes were noted in four patients. An initial increase in the dose:serum concentration ratio during the first few months of therapy was thought to reflect the well-known auto-induction of carbamazepine metabolism. However, unexplainable decreases in the dose:serum concentration occurred in the following months, and suggested alteration of carbamazepine pharmacokinetics in patients with traumatic brain injury. The finding may be important in determining the optimal approach to therapeutic drug monitoring of carbamazepine in brain-injured patients.

Adult↗
PubMed1994

Development of malabsorption and nutritional complications in simian immunodeficiency virus-infected rhesus macaques.

OBJECTIVE: To assess the development and cause of malabsorption in rhesus macaques following experimental simian immunodeficiency virus (SIV) infection and to evaluate its impact on nutritional status. DESIGN: Clinical malabsorption tests and serial jejunal aspirates and biopsies were obtained from nine SIV-infected and three uninfected animals prior to infection and at 1, 2, 4, 8, 12, 24, 40 and 52 weeks postinoculation. METHODS: Malabsorption was measured by sucrose breath hydrogen (H2) analysis and blood assay of D-xylose. Digestive enzyme activity was determined in jejunal mucosal homogenates. Bacterial and protozoal flora were determined in jejunal aspirates. Nutritional assessment was evaluated using specific blood micronutrient values. Cellular targets of SIV in the jejunum were determined by combined in situ hybridization and immunohistochemistry. RESULTS: Eight out of nine SIV-infected monkeys, including asymptomatic animals, exhibited malabsorption by either increased breath H2 and/or decreased blood D-xylose. All animals that died of AIDS had diarrhea, D-xylose malabsorption and decreased sucrase activity. Significant changes in nutritional status were associated with malabsorption. Bacterial overgrowth was not considered to be a cause of malabsorption. Histopathological biopsy findings included dilated villus lacteals, excessive cellular debris, lymphoplasmocytic infiltrates and cytoplasmic vacuoles in crypt epithelial cells. SIV-infected T cells and macrophages were detected as early as 1 week postinoculation. CONCLUSIONS: SIV-associated malabsorption can occur prior to clinical complications of disease. Severe intestinal complications are associated with malabsorption and malnutrition in the terminal stages of AIDS. The high proportion of macaques experiencing malabsorption without detectable pathogens, suggests an enteropathogenic role for SIV.

Animals↗