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J L Wright

Publications and source records attributed to J L Wright.

At least 55 records · Page 3Linked to original sources
PubMed1999

Design, synthesis, and evaluation of chromen-2-ones as potent and selective human dopamine D4 antagonists.

The discovery of a series of chromen-2-ones with selective affinity for the dopamine (DA) D4 receptor is described. Target compounds were tested for binding to cloned human DA D2L, D3, and D4.2 receptor subtypes expressed in Chinese hamster ovary K1 cells. Several compounds demonstrated high affinity (<20 nM, K(i)) and greater than 100-fold selectivity for DA D4.2 versus DA D2L receptors. The results of a SAR study are discussed within. In a DA D4 functional assay measuring [(3)H]thymidine uptake, target compounds showed antagonist activity at the D4.2 receptor. Compound 22, 7-[(2-phenylaminoethylamino)methyl]chromen-2-one, increased DOPA (L-3,4-dihydroxyphenylalanine) accumulation 51% in the hippocampus and 23% in the striatum of rat brains when dosed orally at 20 mg/kg.

Animals↗
PubMed1999

A closer look at General Dental Service orthodontics in England and Wales. I: Factors influencing effectiveness.

OBJECTIVE: To evaluate factors influencing effectiveness in General Dental Service (GDS) orthodontics. DESIGN: Retrospective analysis of systematic 2% sample of GDS (England and Wales) cases. METHOD: Records of cases were collected during 1991. Assessment involved occlusal indices and data from National Health Service forms for 1,411 cases. Multivariate analyses were used with Peer Assessment Rating Index (PAR) score at Finish as the outcome indicator. RESULTS: Dual arch fixed appliances: achieved lower Finish PAR scores than other appliances; only 1.5% of the variance was explained, by treatment time and Dental Health Component of the Index of Orthodontic Treatment Need (DHC). Finish PAR was unaffected by Starting PAR. All other appliances: the model explained 25% of the variance for Finish PAR, which varied with Starting PAR and DHC scores. Social class had effects of little clinical significance, but the data suggested availability of orthodontic treatment was poorer in 'manual class' areas. Orthodontic qualifications, number of arches treated and mixed dentition starts had no significant effects when submitted to multivariate analysis. CONCLUSIONS: The importance of appliance selection is reinforced: dual arch fixed appliances are generally more consistent. Lower social class areas may be poorly provided with orthodontic services.

Age Factors↗
PubMed1999

Subtype-selective N-methyl-D-aspartate receptor antagonists: synthesis and biological evaluation of 1-(arylalkynyl)-4-benzylpiperidines.

A search of our compound library for compounds with structural similarity to ifenprodil (5) and haloperidol (7) followed by in vitro screening revealed that 4-benzyl-1-(4-phenyl-3-butynyl)piperidine (8) was a moderately potent and selective antagonist of the NR1A/2B subtype of NMDA receptors. Substitution on the benzyl group of 8 did not significantly affect NR1A/2B potency, while addition of hydrogen bond donors in the para position of the phenyl group enhanced NR1A/2B potency. Addition of a hydroxyl moiety to the 4-position of the piperidine group slightly reduced NR1A/2B potency while reducing alpha-1 adrenergic and dopamine D2 receptor binding affinities substantially, resulting in improved overall selectivity for NR1A/2B receptors. Finally, the butynyl linker was replaced with propynyl or pentynyl. When the phenyl was para substituted with amine or acetamide groups, the NR1A/2B potency order was butynyl > pentynyl >> propynyl. For the para methanesulfonamide or hydroxyl groups, the order was butynyl approximately propynyl > pentynyl. The hydroxyl propyne (48) and butyne (23) were among the most potent NR1A/2B antagonists from this study. They both potentiated the effects of L-DOPA in the 6-hydroxydopamine-lesioned rat, a model of Parkinson's disease, dosed at 10 mg/kg ip, but 48 was not active at 30 mg/kg po.

Animals↗
PubMed1999

Winter accumulation of paralytic shellfish toxins in digestive glands of mussels from Arcachon and Toulon (France) without detectable toxic plankton species revealed by interference in the mouse bioassay for lipophilic toxins.

Since January 1993, neurological symptoms and rapid deaths (5 to 10 min) were typically observed in the mouse bioassay of acetone extracts of digestive glands from Arcachon and Toulon (France) during the winter season. It was assumed initially that a new lipophilic toxin was present because tests using the AOAC mouse bioassay for paralytic shellfish toxins on acid extracts of whole shellfish meat were negative, no known lipophilic toxins were detected and no toxic phytoplankton species were observed in the area during the poisoning events. In this study, however, preparative isolation of the toxic factor from toxic mussel digestive glands has revealed the presence of paralytic shellfish toxins, the principal ones being gonyautoxins-2 and -3 at Arcachon and gonyautoxins-1, -4, -2 and -3 at Toulon. The toxin concentrations recorded were below levels harmful to consumers and therefore represent a false positive in the mouse bioassay for lipophilic toxins based upon acetone extraction. The origin of the toxins remains to be determined.

Animals↗
PubMed1999

Pulmonary epithelial expression of human alpha1-antitrypsin in transgenic mice results in delivery of alpha1-antitrypsin protein to the interstitium.

Alpha1-antitrypsin (alpha1AT) therapy is used as a treatment for alpha1AT deficiency. It has also been proposed as a therapy for cigarette smoke-induced emphysema, although the efficacy of such therapy is as yet unproven. Moreover, the optimal route of delivery of alpha1AT to the lung interstitium, the crucial locus of action, is unknown. We created transgenic mice with expression of the human alpha1AT gene directed by a human surfactant protein C (SpC) promoter fragment or a rat Clara cell 10-kDa protein (CC10) promoter fragment in order to examine the ability of pulmonary epithelial cell expression of alpha1AT to deliver protein to the interstitium, and to produce a model that would allow studies on the efficacy of alpha1AT in preventing lung damage after cigarette smoke exposure. Four transgenic lines were studied. In situ hybridization and light microscopic immunohistochemistry showed that two CC10 driven lines expressed human alpha1AT in type 11 alveolar cells and airway epithelial cells; alpha1AT expression was seen in the alveolar parenchyma in two SpC driven lines, and in small airway epithelium in one of the SpC lines. Electron microscopic immunochemistry showed the presence of the human alpha1AT protein in the interstitium in all lines. Mean levels of human protein varied from 0.37 to 2.9 microg/g lung protein and serum levels from 0.72 to 1.3 microg/ml, compared to normal human serum alpha1AT levels of 2-5 mg/ml. We conclude that transgene-mediated expression of alpha1AT in pulmonary epithelial cells results in diffuse expression of the transgene in the alveolar parenchyma and reproducibly leads to transfer of protein to the interstitium. The present model is, however, limited by low levels of protein production; limited protein production may be a problem in other forms of gene therapy in which relatively large amounts of extracellular protein are needed in the lung for a therapeutic effect.

Animals↗
PubMed1999

Injury surveillance in a pediatric emergency department.

In this study we have tried to determine physician success in the collection of injury data during the emergency department visit. Prospective data were collected from all children between the ages of 0 to 18 treated for an injury. Data were collected at the time of the visit and by chart review the next day. At an urban, university-affiliated, children's hospital, data were collected on 2,156 injured children. Fifty-one percent of the data forms were completed by the treating physician. Physician completion rate was lower on the weekends (46%) than on weekdays (52%, P = .02). The most common mechanisms of injury were falls (34%), motor-vehicle crashes or pedestrians struck (13%), and nonintentional struck by blunt object (12%). The most common mechanism of injury in all age groups was falls. Our results demonstrate that emergency physicians are not successful data collectors. However, when physician data collection is combined with next-day review of patient records, virtually 100% of patients are captured. Active emergency department data collection is important because in contrast to studies which use hospital discharge and mortality data, we found that overall falls account for more injuries presenting to the ED than transportation-related causes. An active surveillance system in emergency departments that does not require extra work on the part of the treating physician would be ideal and may give a more comprehensive description of the scope of the injury problem.

Adolescent↗
PubMed1999

Dissociation of chronic vascular cell proliferation and vascular contractility after chronic cigarette smoke exposure.

In guinea pigs, chronic cigarette smoke exposure produces physiological and structural alterations in the pulmonary vasculature via unknown mechanisms. This study aimed to determine whether chronic cigarette smoke exposure can induce altered pulmonary vascular reactivity, and whether chronic smoke exposure would be associated with a continued increase in vascular cell deoxyribonucleic acid (DNA) synthesis, indicative of cell proliferation. Guinea-pigs were therefore exposed to two regimens of smoke. In the first experiment, animals were exposed once to the smoke of seven cigarettes, and sacrificed 24 h post-smoke, while in the second experiment, the guinea-pigs were exposed for 5 days each week for 4 months. Control animals were exposed to air. Lung explant preparations and computer linked image photography were utilized to determine vascular reactivity, and DNA synthesis was assessed using the 5-bromo-2'-deoxyuridine technique. Neither acute nor chronic smoke exposure affected vascular reactivity, although the older animals had lesser reactivity. In the chronically smoked animals, evidence was found of ongoing vascular DNA synthesis, and evidence of structural alterations with increased muscularization of the arterioles (34.7+/-7.6% of arterioles in control versus 62.7+/-5.5% after smoke exposure). Despite evidence of continued deoxyribonucleic acid synthesis in the peribronchiolar vessels, the alterations of vascular physiology previously found in this model cannot be ascribed to increased reactivity at this site. Instead, the chronic deoxyribonucleic acid synthesis in the arterioles adjacent to the alveolar ducts, culminating in an increased number of fully muscularized vessels, would suggest this compartment as the most probable source.

Animals↗
PubMed1999

A new paradigm of injury intentionality.

OBJECTIVE: To improve understanding of processes leading to injury and assess more specifically the degree of intentionality. METHODS: A new paradigm was developed that characterizes the act of inflicting injury (self, other, not inflicted) and the motive. Motives are determined for the act of injury and for the outcome. To test this, 986 cases of adolescent injuries in seven hospitals were reviewed. Three investigators independently classified all cases using the new paradigm and three used standard definitions of intent. Inter-rater reliability was measured. RESULTS: Of injuries inflicted by others, 61% were intentional using the standard classification. In the new paradigm 67% were intended acts and 59% involved intentional motive for outcome. Altogether 87% of sports injuries were coded as unintentional acts compared with 96% using standard methods. Using standard classification there was 93% agreement between paired raters, with an average kappa of 0.86. In the new paradigm questions on intentionality of act, outcome, and infliction of act, the agreement was 89%, 91%, 88%, with a kappa of 0.79, 0.80, 0.76, respectively. CONCLUSIONS: This paradigm defines a spectrum of injury intent, enhances understanding of the causal sequence of injury, and has important implications for research and prevention.

Adolescent↗
PubMed1999

Cigarette smoke exposure causes constriction of rat lung.

Cigarette smoke is known to cause acute increases in airway resistance, but the mechanisms behind this effect are unknown. Lung explants were utilized to examine the constrictive effects of acute cigarette smoke exposure on bronchioles from rats in vitro that had or had not been previously exposed to cigarette smoke in vivo. It was found that smoke induced a small but consistent degree of contraction of the airways in vitro, which could be reduced by an endothelin receptor antagonist in the animals which had had no previous smoke exposure in vivo, and reduced by the oxidant scavengers superoxide dismutase or catalase in the animals with previous smoke exposure. In conclusion, cigarette smoke induces acute small airways constriction through both endothelin release and direct oxidant effects; which mechanisms are operative depends on the prior smoking status.

Animals↗
PubMed1999

Effects of cigarette smoke on nitric oxide synthase expression in the rat lung.

To examine the effects of cigarette smoke on nitric oxide synthase (NOS) gene expression and protein production, groups of rats were exposed to smoke once only or daily and were sacrificed after 1, 2, 7, or 28 days of exposure. NOS-1, NOS-2, and NOS-3 mRNAs in whole lung were quantified using reverse transcription polymerase chain reaction (RT-PCR), and NOS protein levels were determined by Western blots. Neither NOS-1 gene expression nor protein levels changed with smoke exposure. Levels of NOS-2 expression were more than doubled in smokers at Day 1 and decreased to control values during 1 month with daily smoke exposure, while protein levels did not change. NOS-3 expression was increased approximately 35% after 2 days of smoke exposure and remained increased to 28 days, whereas protein levels were increased by approximately 60% at Day 7 and remained elevated. In situ hybridization showed that NOS-2 was diffusely expressed in the lung parenchyma, airways, and vessels, and that NOS-3 was strongly expressed in vascular endothelium. Protein distribution, as determined by immunohistochemical staining, was identical to mRNA tissue distribution, and these distributions were not changed by smoke. We conclude that smoke exposure induces a rapid but transient increase in transcription of NOS-2, and a sustained increase in transcription and translation of NOS-3; up-regulation of NOS occurs within the anatomic compartment where these genes are normally expressed. These findings indicate that cigarette smoke can directly and rapidly affect NOS expression, and thus potentially affect the function of the pulmonary vasculature.

Animals↗
PubMed1998

Analysis of domoic acid in shellfish by thin-layer chromatography.

A thin-layer chromatography (TLC) method has been developed for the semi-quantitative analysis of domoic acid (DA) in shellfish tissues. Tissues were extracted in a single-step homogenization of tissue with 50 % aqueous methanol and then taken through a selective strong anion exchange cleanup. Cleaned extracts were applied directly to silica gel TLC plates and developed with a butanol-acetic acid-water mixture (3:1:1, Rf = 0.45 for DA). As little as 10 microg DA per gram of tissue could be detected after chromatography using a hand-held short-wave UV lamp to detect fluorescence quenching. Confirmation was provided by spraying the plate with ninhydrin, which reacts with the secondary amine of DA to give a distinctive yellow colored product. The extraction, cleanup and TLC procedures are fast and simple, and do not require the use of expensive equipment. This method should prove useful for the routine screening of shellfish tissues in those laboratories not equipped with an LC system. It should also be useful as a chemical confirmation method for DA in samples tested positive by assay methods such as immunoassay.

Animals↗
PubMed1998

Long term cigarette smoke exposure does not increase airway responsiveness in rats.

To ascertain whether chronic cigarette smoke exposure induces increased airway responsiveness, we performed methacholine response tests in Sprague-Dawley rats by calculating pulmonary resistance after nebulization of saline followed by an increasing concentration of methacholine. We also calculated the concentration of methacholine which doubled the baseline resistance (R200). Tests were performed at baseline and after 2, 4, 8, and 12 months of exposure to the smoke of seven cigarettes per day, 5 days each week; control animals were exposed to room air. At the completion of the study, there were 13 rats in the smoke-exposed group and 7 rats remaining in the control group. Airway morphology was assessed using a point counting technique. We found that (1) chronic exposure to cigarette smoke did not alter either the baseline resistance or the R200; (2) the saline baseline resistance decreased over time in the control animals; and (3) at the 12-month time point, smokers with increased baseline airway resistance had greater amounts of airway smooth muscle compared with the smoke-exposed animals without increased resistance. We conclude that in this animal model, long term exposure to cigarette smoke did not alter the response to methacholine but did increase airway smooth muscle and baseline resistance in some but not all animals.

Airway Resistance↗
PubMed1998

Successful approaches to community violence intervention and prevention.

The field of injury prevention and control is diverse, cross-cutting, and has attracted the efforts of individuals from multiple disciplines. Many types of interventions have been applied in the area on intentional injury, specifically interpersonal violence. The results have been variable with few projects demonstrating scientific efficacy. Among the acknowledged stumbling blocks have been issues of project design, and deficiencies in the incorporation of communities into project development and implementation. This article discusses those elements that are critical to the creation of any community-based violence prevention intervention and offers guidelines for establishing a project's community context.

Adolescent↗
PubMed1998

Cross-reactivity of an anti-okadaic acid antibody to dinophysistoxin-4 (DTX-4), dinophysistoxin-5 (DTX-5), and an okadaic acid diol ester.

The cross-reactivity of the 6/50 monoclonal anti-okadaic acid antibody (mAb) to the recently discovered diarrhetic shellfish poisoning (DSP) metabolites dinophysistoxin-4 (DTX-4), dinophysistoxin-5 (DTX-5), and an okadaic acid (OA) diol ester was determined using a competitive indirect enzyme-linked immunosorbent assay (ELISA). The reactivity of the antibody to these molecules was compared to that with OA; the 6/50 mAb recognized all of these DSP compounds with equal sensitivity within the working range of the antibody (10-100 nM for OA). This confirms the ability of the antibody to detect all DSP compounds when used in analyses including ELISA and immunocytochemistry.

Animals↗
PubMed1998

Pharmacological characterization of PD 152255, a novel dimeric benzimidazole dopamine D3 antagonist.

152255 (E-1,1'-(2-butene-1,4-diyl)bis[2-[4-[3-(1-piperidinyl)propoxy]-phe nyl]-1H-benzimidazole]) exhibited high affinity (Ki = 12.7 nM) for human dopamine (DA) D3 receptors expressed in CHO K1 cells but not for DA D2L receptors (Ki = 565 nM), DA D42 or DA D1 receptors (Ki > 3 microM) and a number of other neurotransmitter receptors. Affinity for human muscarinic receptors was seen in vitro but no functional muscarinic agonist and/or antagonist action was observed in vivo. Antagonist activity at DA D3 receptors was demonstrated by blockade of quinpirole-stimulated [3H]-thymidine uptake in D3 transfected cells, an effect that was 28-fold more potent than in D2-transfected cells. Unlike classical DA D2 antagonists, PD 152255 did not increase rat brain DA synthesis and it increased locomotion in habituated rats. However, like antipsychotics, PD 152255 reduced locomotor activity in mice and reduced spontaneous and amphetamine-stimulated locomotion in nonhabituated rats. These results demonstrate that PD 152255 is a DA D3 antagonist that may have antipsychotic activity.

Animals↗
PubMed1998

Data elements for emergency department systems, release 1.0 (DEEDS): a summary report. DEEDS Writing Committee.

Variations in the way that data are entered in ED record systems impede the use of ED records for direct patient care and deter their reuse for many other legitimate purposes. To foster more uniform ED data, the Centers for Disease Control and Prevention's (CDC) National Center for Injury Prevention and Control is coordinating a public-private partnership that has developed recommended specifications for many observations, actions, instructions, conclusions, and identifiers that are entered in ED records. The partnership's initial product. Data Elements for Emergency Department Systems, Release 1.0 (DEEDS), is intended for use by individuals and organizations responsible for ED record systems. If the recommended specifications are widely adopted, then problems--such as data incompatibility and high costs of collecting, linking, and using data--can be substantially reduced. The collaborative effort that led to DEEDS, Release 1.0 sets a precedent for future review and revision of the initial recommendations.

Emergency Service, Hospital↗