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J E Nash

Publications and source records attributed to J E Nash.

At least 19 recordsLinked to original sources
PubMed2005

Subcellular redistribution of the synapse-associated proteins PSD-95 and SAP97 in animal models of Parkinson's disease and L-DOPA-induced dyskinesia.

Abnormalities in subcellular localization and interaction between receptors and their signaling molecules occur within the striatum in Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID). Synapse-associated proteins (SAPs), for example, PSD-95 and SAP97 organize the molecular architecture of synapses and regulate interactions between receptors and downstream-signaling molecules. Here, we show that expression and subcellular distribution of PSD-95 and SAP97 are altered in the striatum of unilateral 6-OHDA-lesioned rats following repeated vehicle (a model of PD) or L-DOPA administration (a model of L-DOPA-induced dyskinesia). Furthermore, following dopamine-depletion and development of behavioral deficits in Rotorod performance, indicative of parkinsonism, we observed a dramatic decrease in total striatal levels of PSD-95 and SAP97 (to 25.6 +/- 9.9% and 19.0 +/- 5.0% of control, respectively). The remaining proteins were redistributed from the synapse into vesicular compartments. L-DOPA (6.5mg/kg twice a day, 21 days) induced a rotational response, which became markedly enhanced with repeated treatment (day 1: -15.8+/-7.3 rotations cf day 21: 758.2+/-114.0 rotations). Post L-DOPA treatment, PSD-95 and SAP97 levels increased (367.4 +/- 43.2% and 159.9 +/- 9.5% from control values, respectively), with both being redistributed toward synaptic membranes from vesicular compartments. In situ hybridization showed that changes in total levels of PSD-95, but not SAP97, were accompanied by qualitatively similar changes in mRNA. These data highlight the potential role of abnormalities in the subcellular distribution of SAPs in the pathophysiology of a neurological disease.

Adaptor Proteins, Signal Transducing↗
PubMed2004

The NR2B-selective NMDA receptor antagonist CP-101,606 exacerbates L-DOPA-induced dyskinesia and provides mild potentiation of anti-parkinsonian effects of L-DOPA in the MPTP-lesioned marmoset model of Parkinson's disease.

In Parkinson's disease (PD), degeneration of the dopaminergic nigrostriatal pathway leads to enhanced transmission at NMDA receptors containing NR2B subunits. Previous studies have shown that some, but not all, NR2B-containing NMDA receptor antagonists alleviate parkinsonian symptoms in animal models of PD. Furthermore, enhanced NMDA receptor-mediated transmission underlies the generation of L-DOPA-induced dyskinesia (LID). The subunit content of NMDA receptors responsible for LID is not clear. Here, we assess the actions of the NMDA antagonist CP-101,606 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset model of Parkinson's disease. CP-101,606 is selective for NMDA receptors containing NR2B subunits, with higher affinity for NR1/NR2B complexes compared to ternary NR1/NR2A/NR2B complexes. CP-101,606 had no significant effect on parkinsonian symptoms when administered as monotherapy over a range of doses (0.1-10 mg/kg). CP-101,606 provided a modest potentiation of the anti-parkinsonian actions of L-DOPA (8 mg/kg), although, at doses of 1 and 3 mg/kg, CP-101,606 exacerbated LID. Results of this study provide further evidence of differences in the anti-parkinsonian activity and effects on LID of the NR2B subunit selective NMDA receptor antagonists. These distinctions may reflect disparities in action on NR1/NR2B as opposed to NR1/NR2A/NR2B receptors.

Animals↗
PubMed2000

A common signaling pathway for striatal NMDA and adenosine A2a receptors: implications for the treatment of Parkinson's disease.

The striatum is the major input region of the basal ganglia, playing a pivotal role in the selection, initiation, and coordination of movement both physiologically and in pathophysiological situations such as Parkinson's disease. In the present study, we characterize interactions between NMDA receptors, adenosine receptors, and cAMP signaling within the striatum. Both NMDA (100 micrometer) and the adenosine A(2a) receptor agonist CPCA (3 micrometer) increased cAMP levels (218.9 +/- 19.9% and 395.7 +/- 67.2%, respectively; cf. basal). The NMDA-induced increase in cAMP was completely blocked when slices were preincubated with either the NMDA receptor antagonist 7-chlorokynurenate or the adenosine A(2) receptor antagonist DMPX (100 micrometer), suggesting that striatal NMDA receptors increase cAMP indirectly via stimulation of adenosine A(2a) receptors. Thus, NMDA receptors and adenosine A(2a) receptors might share a common signaling pathway within the striatum. In striatal slices prepared from the 6-hydroxydopamine-lesioned rat model of Parkinson's disease, NMDA receptor-mediated increases in cAMP were greater on the lesioned side compared with the unlesioned side (349.6 +/- 40.2% compared with 200.9 +/- 21.9% of basal levels, respectively). This finding substantiates previous evidence implicating overactivity of striatal NMDA receptors in parkinsonism and suggests that a common NMDA receptor-adenosine A(2a) receptor-cAMP signaling cascade might be an important mechanism responsible for mediating parkinsonian symptoms.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2000

Antiparkinsonian actions of ifenprodil in the MPTP-lesioned marmoset model of Parkinson's disease.

Dopamine-replacement strategies form the basis of most symptomatic treatments for Parkinson's disease. However, since long-term dopamine-replacement therapies are characterized by many side effects, most notably dyskinesia, the concept of a nondopaminergic therapy for Parkinson's disease has attracted great interest. To date, it has proved difficult to devise a nondopaminergic therapy with efficacy comparable to that of dopamine replacement. In animal models of Parkinson's disease, loss of striatal dopamine leads to enhanced excitation of striatal NR2B-containing NMDA receptors. This is responsible, in part at least, for generating parkinsonian symptoms. Here we demonstrate that, in the MPTP-lesioned marmoset, monotherapy with the NR2B-selective NMDA receptor antagonist, ifenprodil, administered de novo, has antiparkinsonian effects equivalent to those of l-DOPA (administered as its methyl ester form). In MPTP-lesioned marmosets, median mobility scores, following vehicle-treatment were 12.5/h (range 6-21), compared to 61/h (range 26-121) in normal, non-MPTP-lesioned animals. Following ifenprodil (10 mg/kg) treatment in MPTP-lesioned marmosets, the median mobility score was 66/h (range 34-93), and following l-DOPA (10 mg/kg i.p.) treatment 89/h (range 82-92). The data support the proposal that NR2B-selective NMDA receptor antagonists have potential as a nondopaminergic monotherapy for the treatment of parkinsonian symptoms when given de novo.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1999

Antiparkinsonian actions of blockade of NR2B-containing NMDA receptors in the reserpine-treated rat.

Current symptomatic treatment for Parkinson's disease is based largely on dopamine-replacing agents. The fact that long-term treatment with these drugs is characterized by many side effects has lead to widespread interest in nondopaminergic therapies. To date, however, it has proved difficult to devise a nondopaminergic therapy with significant antiparkinsonian efficacy when administered as monotherapy. Overactivity of the striatolateral pallidal pathway, the "indirect" striatal output pathway, is thought be responsible for the generation of parkinsonian symptoms. Indeed, it has been suggested that selective reduction in the activity of the "indirect" pathway may be achieved by blockade of NR2B-containing NMDA receptors. In the present study, we demonstrate that selective blockade of NR2B-containing NMDA receptors with the polyamine antagonists ifenprodil and eliprodil causes a significant increase in locomotor activity in the reserpine-treated rat model of Parkinson's disease (30 mg/kg ifenprodil, 221.2 +/- 54 mobile counts compared to vehicle, 19.6 +/- 6.87, P < 0.001). Additionally, we show that, subsequent to dopamine depletion, the ability of ifenprodil to bind to the polyamine site and inhibit binding of the NMDA channel blocker [3H] MK-801 is increased fourfold (IC50 3.7 +/- 0.4 microM compared to vehicle, IC50 14.3 +/- 2.34 microM, P < 0.01). We suggest that ifenprodil selectively targets the polyamine site on overactive NR2B-containing NMDA receptors. Thus, we propose that NR2B-selective NMDA receptor antagonists may prove useful in the treatment of Parkinson's disease.

Animals↗
PubMed1999

The Angio-Seal hemostatic puncture closure device. Concept and experimental results.

The Angio-Seal hemostatic puncture closure device is the culmination of development efforts dating from 1986. Development was driven to solve problems of delivering a multi-piece bioabsorbable puncture closure assembly through an introducer, the precise placement of the device in the vessel, the mastery of molding tiny absorbable polymer components, the manufacture of collagen hemostatic sponges having strong tear strength, and the testing of very large samples to establish safety and efficacy. Improvements included in the new 6F device to improve deployment reliability are also discussed.

Animals↗
PubMed1998

Privacy and confidentiality in the publication of pedigrees: a survey of investigators and biomedical journals.

CONTEXT: Pedigree diagrams efficiently communicate family information to genetics investigators; however, the publication of pedigrees poses a risk to the privacy and confidentiality of individuals depicted in the diagrams. Two sets of authoritative guidelines have been published to protect the privacy and confidentiality of subjects, but the influence of these guidelines on publication practices for pedigrees is unknown. OBJECTIVE: To determine the attitudes, practices, and experiences of investigators and journals with respect to privacy and confidentiality concerns in the publication of pedigrees. DESIGN: Investigators who have published pedigrees and editors of 26 biomedical journals were surveyed. Journals were reviewed for content in their "information for authors" sections and for documentation of informed consent in articles containing pedigrees. OUTCOME MEASURES: Practices regarding confidentiality and privacy reported by investigators and editors. RESULTS: Of 226 surveys sent to investigators, 177 were returned (78% response rate). Sixty-one investigators (36%) stated that family members were not informed that their pedigree would be published; 131 (78%) do not obtain informed consent specifically for pedigree publication and only 12 (28%) of the 43 who obtained consent obtained consent from all family members depicted. Thirty-two individuals (19%) reported having altered published pedigrees and 14 (45%) of 31 who had altered pedigrees stated that alterations were not disclosed to journals. Of the 14 journals that responded (54% response rate), only 3 reported written policies for managing potentially identifying information. Two journals reported having asked authors to alter pedigrees and 3 stated they had permitted alterations. A review of 5 genetics journals over a 2-year period revealed no documentation of consent for pedigree publication. CONCLUSIONS: Current practices in the publication of pedigrees do not conform with established recommendations and risk the privacy and confidentiality of subjects, often without informed consent. Attempts to address this problem through the alteration of data are being used, although this practice impairs the integrity of scientific communication.

Confidentiality↗
PubMed1996

Activation of the cannabinoid receptor by delta 9-tetrahydrocannabinol reduces gamma-aminobutyric acid uptake in the globus pallidus.

The interaction between GABA (gamma-aminobutyric acid) and cannabinoids in the globus pallidus was investigated by evaluating the effects of delta 9-tetrahydrocannabinol on [3H]GABA uptake into slices of rat globus pallidus. delta 9-Tetrahydrocannabinol caused a concentration-dependent decrease in GABA uptake (51% decrease at 100 microM delta 9-tetrahydrocannabinol, IC50 = 18.95 microM). This effect was reversed in a concentration-dependent manner (IC50 = 11.9 microM) by the cannabinoid receptor antagonist SR 141716A (N-(piperidin-1-yl-)5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1 H-pyrazole-3-arboxiamidehydrochloride. SR 141716A alone did not affect GABA uptake. These results show that cannabinoid receptor activation reduces GABA uptake in the globus pallidus.

Animals↗
PubMed1996

Further evidence for the presence of cannabinoid CB1 receptors in guinea-pig small intestine.

1. CP 50,556, CP 55,940, nabilone, CP 56,667, delta 9 -tetrahydrocannabinol (THC) and cannabinol each inhibited electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation of guinea-pig small intestine in a concentration-related manner. The IC50 values of these cannabinoids, respectively 3.45, 3.46, 30.61, 162.94, 214.63, and 3913.5 nM, correlate well with previously obtained potency values for displacement of [3H]-CP 55,940 from cannabinoid binding sites. 2. Electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation were also inhibited by AM 630 (6-iodo-pravadoline) and by WIN 55,212-2 (IC50 = 1923.0 and 5.54 nM, respectively). The present finding that AM 630 is an agonist, contrasts with a previous observation that it behaves as a cannabinoid receptor antagonist in the mouse isolated vas deferens. 3. SR141716A produced dose-related parallel rightward shifts in the log concentration-response curves of CP 55,940, WIN 55,212-2, THC and AM 630 for inhibition of electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation. SR141716A (1 microM) did not reverse the inhibitory effects of normorphine and clonidine on electrically-evoked contractions or potentiate the contractile response to acetylcholine. 4. Doses of naloxone and yohimbine that reversed the inhibitory effects of normorphine or clonidine on electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation did not affect the inhibitory response to WIN 55,212-2. 5. Electrically-evoked release of acetylcholine from strips of myenteric plexus-longitudinal muscle was decreased by 200 nM CP 55,940 and this inhibitory effect was almost completely reversed by 1 microM SR141716A. Acetylcholine-induced contractions were not affected by 200 nM CP 55,940. 6. These results support the hypothesis that guinea-pig small intestine contains prejunctional cannabinoid CB1 receptors through which cannabinoids act to inhibit electrically-evoked contractions by reducing release of the contractile transmitter, acetylcholine. 7. THC was found to be more susceptible to antagonism by SR141716A than CP 55,940 or AM 630, raising the possibility that guinea-pig small intestine contains more than one type of cannabinoid receptor. 8. At concentrations of 10 nM and above, SR141716A produced small but significant increases in the amplitude of electrically-evoked contractions of the myenteric plexus-longitudinal muscle preparation suggesting that this tissue may release an endogenous cannabinoid receptor agonist or that some cannabinoid receptors in this tissue are precoupled and that SR141716A can reduce the number of receptors in this state.

Acetylcholine↗
PubMed1994

The effect of acute and chronic administration of the beta-agonist, cimaterol, on protein synthesis in ovine skin and muscle.

The action of intravenous infusion of the beta-agonist cimaterol (2.5 mg/d) on whole-body N retention and protein synthesis in peripheral tissues was examined in growing sheep. Wool growth was determined from skin patch clippings and adjusted to total fibre production. Protein synthesis was measured, using sequential large dose injections of [1-13C]valine, leucine and phenylalanine and then [ring-d5]phenylalanine, on biopsy samples from skin and m. longissimus dorsi taken before beta-agonist administration, at day 3 and day 15 of cimaterol infusion, and 15 d after withdrawal of the drug. Cimaterol increased total N retention by 1.9-2.3 g N/d (P < 0.01) over three successive 5 d periods. In contrast, wool growth was significantly reduced by 0.7 g N/d (P < 0.001) and the proportion of total N retained in wool declined from 0.71 to 0.25 (P < 0.01). The reduction in wool growth was accompanied by a decrease in protein fractional synthesis rate (FSR) in skin (11.6 v. 6.3%/d, P < 0.01). Muscle protein FSR, on the other hand, was markedly stimulated during cimaterol infusion (1.45 v. 3.01%/d, P < 0.001) as was RNA concentration (P < 0.001), RNA:protein (P < 0.001) and protein:DNA (P < 0.05). The estimated increase in total protein synthesis in muscle (+24 to 30 g/d) due to cimaterol administration was counterbalanced by reductions for skin (-25 to 27 g/d); this may account for the lack of changes in whole-body protein synthesis following beta-agonist administration reported in other studies. Although N retention rapidly returned to control values following withdrawal of the drug, both wool growth and skin protein synthesis remained depressed, while muscle protein FSR declined, but not to pre-treatment values. These results suggest a persistent action of cimaterol, but whether this is a function of residue concentrations or long-term metabolic responses is not known.

Adrenergic beta-Agonists↗
PubMed1993

Protein synthesis in ovine muscle and skin: sequential measurements with three different amino acids based on the large-dose procedure.

1. Protein synthesis has been determined in biopsies from ovine skin and muscle by sequential use of three [13C] amino acids, valine leucine and phenylalanine, as large-dose injections. 2. Leucine and phenylalanine increased plasma insulin concentrations within 40 min of injection. 3. All three amino acids decreased the plasma concentrations of other amino acids. 4. Intracellular free amino acids in muscle decreased while those in skin increased. 5. The fractional rates of protein synthesis were similar, regardless of which amino acid was used, although the rates for muscle were significantly less than for skin (2.1 vs 11.0%/day, P < 0.001).

Animals↗
PubMed1991

Percutaneous rotational contact biliary lithotripsy: initial clinical results with the Kensey Nash lithotrite.

The percutaneous rotary lithotrite introduces a new concept to fragmentation and percutaneous removal of gallstones. A fluid vortex is generated, pulling calculi into a high-speed blade that fragments stones to predominantly under 500 microns. The results of treating the first 10 patients with this instrument reveal that large stone burdens as well as small stones (2-3 mm) of any composition can be removed if the gallbladder is of sufficient size to accommodate the six-pronged basket. Rotation times of 7-39 minutes were required. Nine of 10 procedures were completed; access was lost in one case. One major complication occurred. At repeat oral cholecystography, the gallbladder was visualized after 3-6 weeks in eight of the nine patients. Ursodeoxycholic acid was administered from 3 to 12 months to five patients with either residual stones or aggregates. The hospital stay ranged from 48 to 72 hours. All patients (except the patient who underwent surgery) resumed light activity in 3-4 days and strenuous activity and full diet within 3 weeks.

Cholelithiasis↗
PubMed1991

Percutaneous gallstone lithotripsy. Results in acute and chronic swine models.

The authors describe here a rotary catheter for the percutaneous fragmentation of gallstones. Gallstones are drawn into the rotating impeller by a powerful vortex and mechanically fragmented. Fragments are aspirated from the gallbladder following use of the device. The safety and efficacy of the device was tested after placement of human gallstones in the pig's gallbladder in 19 acute, 15 chronic, and two control experiments. In 27 completed experiments, 206 human gallstones (6-20 mm) were implanted. Most residual fragments were less than 2 mm; 24 fragments were 2 to 4 mm and seven were 5 to 8 mm. Acute histologic changes included focal loss of mucosa, mucosal and submucosal hemorrhage, and deposition of biliary material in the mucosa and submucosa. At 30 and 90 days, gallbladder histology revealed regeneration of the mucosa with isolated granuloma formation.

Acute Disease↗
PubMed1990

Mechanical disruption of pulmonary emboli in dogs with a flexible rotating-tip catheter (Kensey catheter).

Pulmonary embolism was induced in 11 dogs by the injection of three- to four-day-old allogeneic blood clots. The clots were made radiopaque by soaking them in contrast material. The resulting clots were firm, 3 to 4 cm long, and 1 cm in diameter. Injection of the clots into the external jugular vein consistently produced occlusion of at least one of the lobar pulmonary arteries. In every instance in which the tip of the catheter could be positioned at the clot embolus (six dogs), the clots were readily fragmented with a number 8 French (2.67 mm OD) flexible rotating tip catheter (Kensey catheter) activated at 80,000 rpm. Overall perfusion was shown by posttreatment angiograms to be markedly improved. These studies show that catheter-tip fragmentation of pulmonary emboli with a Kensey catheter has excellent potential for therapeutic application in patients with pulmonary embolism.

Animals↗
PubMed1989

Experimental percutaneous gallstone lithotripsy: results in swine.

The Kensey-Nash device is used to fragment gallstones percutaneously. It is inserted into the gallbladder through an 8-F introducer sheath, a cage is expanded to protect the gallbladder, and the impeller is activated. A strong vortex automatically pulls the stones into the basket. The device was tested in 24 pigs in which human gallstones (5-19 mm, bilirubin and cholesterol types) had been implanted and in two control pigs with no gallstones. All pigs except two were killed immediately after the procedure (acute studies); the two were followed up for 36 days and then killed. Fragments (1-3 mm) were similar in size to those seen in current extracorporeal shock wave lithotripsy studies. A complication occurred in one animal, and technical failures occurred in two, causing these three studies to be aborted.

Animals↗
PubMed1989

Influence of nicotine and caffeine on skeletal development in the rat.

The effects of nicotine and caffeine at dose levels approximating human consumption on skeletal development was investigated in Sprague-Dawley rats. One group of animals received nicotine administered subcutaneously by an Alzet miniosmotic pump from gestational d 6 through 12 (25 mg over 7 d; rate 149 micrograms/h). Control animals received physiological saline in a similar manner. A2. group received a single intravenous injection of caffeine (25 mg/kg) on gestational d 6. Control animals were treated with physiological saline. A further group received both nicotine and caffeine on gestational d 6 as described for the 2 previous groups. Evaluation of the fetal skeletal system on gestational d 20 revealed a significant decrease in the number of complete sternal ossification centers, as well as delays in the ossification of the skull and face, following combined nicotine and caffeine treatment. Other skeletal anomalies and variations were frequently observed, but their incidences were not significantly increased in any of the treatment groups, compared to the corresponding controls. A coteratogenic effect is evident between nicotine and caffeine on account of the increased incidence of delayed and abnormal skeletal development.

Animals↗