Search PubMed⌕ Search

Biomedical subjects

R Young

Publications and source records attributed to R Young.

At least 55 records · Page 3Linked to original sources
PubMed2000

The 5-HT3 agent N-(3-chlorophenyl)guanidine (MD-354) serves as a discriminative stimulus in rats and displays partial agonist character in a shrew emesis assay.

RATIONALE: There is some, albeit conflicting, evidence that 5-HT3 receptors might be involved in the actions of abused stimulants. Most studies have focussed on examinations of 5-HT3 antagonists; this might be due to a lack of high-affinity 5-HT3 agonists that readily penetrate the blood-brain barrier. OBJECTIVES: N-(3-Chlorophenyl) guanidine (MD-354) is a member of a novel class of 5-HT3 ligands developed in our laboratories. We have previously demonstrated that MD-354 can exert agonist effects and now further explore this action. METHODS: Rats (n=9) were trained to discriminate 2 mg/kg MD-354 from saline vehicle in a two-lever drug discrimination task (VI-15 s schedule of reinforcement). The actions of agents with 5-HT3 character were evaluated. The emetic and antiemetic actions of MD-354 were also examined using the shrew as test subject. RESULTS: Various agents with demonstrated 5-HT3 agonist properties substituted for the MD-354 stimulus (MD-354 ED50=0.5 mg/kg): quipazine (ED50=0.2 mg/kg), meta-chlorophenylbiguanide (mCPBG, ED50=1.4 mg/kg), 2-methyl 5-HT (ED50=4.5 mg/kg), 1-(2-naphthyl)biguanide (2-NBG, ED50=1.9 mg/kg), and N-(2-naphthyl)guanidine (2-NG, ED50=0.7 mg/kg). Administration of the training dose of MD-354 in combination with the 5-HT3 antagonists zacopride and tropisetron resulted in stimulus antagonism (AD50=0.02 mg/kg); administered alone, however, zacopride engendered 81% MD-354-appropriate responding (ED50=0.03 mg/kg). MD-354 was shown to produce an emetic effect in the shrew at very high doses (i.e., 40 mg/kg); however, when administered in combination with cisplatin, MD-354 behaved as an antiemetic agent at 10 mg/kg. CONCLUSION: Taken together, the results indicate that MD-354 is a 5-HT3 agonist and that it might be an agent with partial agonist activity.

Animals↗
PubMed2000

Stimulus effects of phenylpropanolamine optical isomers in (+)amphetamine-trained rats.

There are eight phenylpropanolamine optical isomers related in structure to the central stimulants methamphetamine and amphetamine. Some of these are quite well known, such as (-)ephedrine, whereas others are relatively obscure, such as (-)cathine. Although certain of these phenylpropanolamines, such as (-)ephedrine and (+)cathine, retain central stimulant activity and are about 10- to 25-fold less potent than (+)amphetamine, the eight phenylpropanolamines have been compared only once before in drug discrimination studies. This latter study employed (-)ephedrine as the training drug. Because there are striking similarities between (-)ephedrine and (+)amphetamine as training drugs, it was of interest to determine and compare the effect of all eight phenylpropanolamines in (+)amphetamine trained animals. Using rats trained to discriminate 1 mg/kg of (+)amphetamine from saline vehicle under a variable interval 15-s (VI 15-s) schedule of reinforcement, the (+)amphetamine stimulus generalized only to (-)ephedrine (ED(50) = 4. 5 mg/kg) and (+)cathine (ED(50) = 8.0 mg/kg), and both agents were at least 10 times less potent that (+)amphetamine (ED(50) = 0.37 mg/kg). These results stand in contrast to those obtained with the (-)ephedrine-trained animals where the ephedrine stimulus generalized to all of the phenylpropanolamines except for (-)pseudoephedrine and (-)cathine. It is concluded that although there might be some similarity between the (-)ephedrine and (+)amphetamine stimuli, there are clear differences between them as determined in tests of stimulus generalization under the conditions employed.

Adrenergic alpha-Agonists↗
PubMed2000

MDMA stimulus generalization to the 5-HT(1A) serotonin agonist 8-hydroxy-2- (di-n-propylamino)tetralin.

The abused substance N-methyl-1-(3, 4-methylenedioxyphenyl)-2-aminopropane, or MDMA, serves as a training drug in animals. Because the 5-HT(1A) receptor antagonist NAN-190 has been shown to partially antagonize the MDMA stimulus, and because NAN-190 binds at several different types of receptors, in the present study we examined other agents (e.g., adrenergic, dopaminergic, sigma) in tests of stimulus generalization and stimulus antagonism to determine their influence on the MDMA stimulus. Each of these agents (i.e., clenbuterol, S(-)propranolol, R(+)SCH-23390, amantadine, NANM) was without effect on MDMA-appropriate responding. The finding that NAN-190 behaves as a 5-HT(1A) partial agonist in some studies prompted examination of the 5-HT(1A) receptor agonist 8-OH DPAT and its optical isomers. MDMA-stimulus generalization occurred to racemic 8-OH DPAT (ED(50) = 0.3 mg/kg), R(+)8-OH DPAT (ED(50) = 0.2 mg/kg), and to the 5-HT(1A) receptor partial agonist S(-)8-OH DPAT (ED(50) = 0.4 mg/kg). The results suggest that the MDMA stimulus might possess a 5-HT(1A) component of action. Furthermore, because 8-OH DPAT is known to enhance the stimulus effects of hallucinogens as discriminative stimuli, and because MDMA reportedly enhances the effects of hallucinogenic agents in humans ("flipping," "candy flipping"), this latter MDMA-induced phenomenon might involve a 5-HT(1A) mechanism.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2000

(+)Amphetamine-stimulus generalization to an herbal ephedrine product.

We have previously demonstrated that a (+)amphetamine stimulus generalizes both to (-)ephedrine and caffeine. Using rats trained to discriminate intraperitoneal (IP) administration of 1.0 mg/kg of (+)amphetamine (ED(50) = 0.4 mg/kg) from saline vehicle in a standard two-lever drug discrimination procedure, the present investigation shows that the (+)amphetamine stimulus generalizes to (+)amphetamine (ED(50) = 1.0 mg/kg) when administered via the intragastric (IG) route, and that (+)amphetamine appears about 2. 5-fold less potent when administered via the IG route compared to the IP route. Likewise, (-)ephedrine (ED(50) = 10.8 mg/kg) and caffeine (ED(50) = 32.9 mg/kg) are also 2.5-fold less potent when administered via the IG route compared to their potency when administered via the IP route. The (+)amphetamine stimulus also generalizes to an IG-administered herbal preparation (i.e., Herbal XTC; the herbal preparation possesses an approximate potency roughly comparable to what might have been expected on the basis of its reported ephedrine and/or caffeine content. These results demonstrate, for the first time, that an ephedrine-containing herbal preparation can produce a (+)amphetamine-like effect in animals.

Animals↗
PubMed2000

Dimerization between the holin and holin inhibitor of phage lambda.

Holins are integral membrane proteins that control the access of phage-encoded muralytic enzymes, or endolysins, to the cell wall by the sudden formation of an uncharacterized homo-oligomeric lesion, or hole, in the membrane, at a precisely defined time. The timing of lambda-infected cell lysis depends solely on the 107 codon S gene, which encodes two proteins, S105 and S107, which are the holin and holin inhibitor, respectively. Here we report the results of biochemical and genetic studies on the interaction between the holin and the holin inhibitor. A unique cysteine at position 51, in the middle of the second transmembrane domain, is shown to cause the formation of disulfide-linked dimers during detergent membrane extraction. Forced oxidation of membranes containing S molecules also results in the formation of covalently linked dimers. This technique is used to demonstrate efficient dimeric interactions between S105 and S107. These results, coupled with the previous finding that the timing of lysis depends on the excess of the amount of S105 over S107, suggest a model in which the inhibitor functions by titrating out the effector in a stoichiometric fashion. This provides a basis for understanding two evolutionary advantages provided by the inhibitor system, in which the production of the inhibitor not only causes a delay in the timing of lysis, allowing the assembly of more virions, but also increases effective hole formation after triggering.

Bacteriolysis↗
PubMed2000

Genetic and biochemical analysis of dimer and oligomer interactions of the lambda S holin.

Bacteriophage lambda uses a holin-endolysin system for host cell lysis. R, the endolysin, has muralytic activity. S, the holin, is a small membrane protein that permeabilizes the inner membrane at a precisely scheduled time after infection and allows the endolysin access to its substrate, resulting in host cell lysis. lambda S has a single cysteine at position 51 that can be replaced by a serine without loss of the holin function. A collection of 27 single-cysteine products of alleles created from lambda S(C51S) were tested for holin function. Most of the single-cysteine variants retained the ability to support lysis. Mutations with the most defective phenotype clustered in the first two hydrophobic transmembrane domains. Several lines of evidence indicate that S forms an oligomeric structure in the inner membrane. Here we show that oligomerization does not depend on disulfide bridge formation, since the cysteineless S(C51S) (i) is functional as a holin and (ii) shows the same oligomerization pattern as the parental S protein. In contrast, the lysis-defective S(A52V) mutant dimerizes but does not form cross-linkable oligomers. Again, dimerization does not depend on the natural cysteine, since the cysteineless lysis-defective S(A52V/C51S) is found in dimers after treatment of the membrane with a cross-linking agent. Furthermore, under oxidative conditions, dimerization via the natural cysteine is very efficient for S(A52V). Both S(A52V) (dominant negative) and S(A48V) (antidominant) interact with the parental S protein, as judged by oxidative disulfide bridge formation. Thus, productive and unproductive heterodimer formation between the parental protein and the mutants S(A52V) and S(A48V), respectively, may account for the dominant and antidominant lysis phenotypes. Examination of oxidative dimer formation between S variants with single cysteines in the hydrophobic core of the second membrane-spanning domain revealed that positions 48 and 51 are on a dimer interface. These results are discussed in terms of a three-step model leading to S-dependent hole formation in the inner membrane.

Alleles↗
PubMed2000

Occupational exposure to carcinogens in the European Union.

OBJECTIVES: To construct a computer assisted information system for the estimation of the numbers of workers exposed to established and suspected human carcinogens in the member states of the European Union (EU). METHODS: A database called CAREX (carcinogen exposure) was designed to provide selected exposure data and documented estimates of the number of workers exposed to carcinogens by country, carcinogen, and industry. CAREX includes data on agents evaluated by the International Agency for Research on Cancer (IARC) (all agents in groups 1 and 2A as of February 1995, and selected agents in group 2B) and on ionising radiation, displayed across the 55 industrial classes. The 1990-3 occupational exposure was estimated in two phases. Firstly, estimates were generated by the CAREX system on the basis of national labour force data and exposure prevalence estimates from two reference countries (Finland and the United States) which had the most comprehensive data available on exposures to these agents. For selected countries, these estimates were then refined by national experts in view of the perceived exposure patterns in their own countries compared with those of the reference countries. RESULTS: About 32 million workers (23% of those employed) in the EU were exposed to agents covered by CAREX. At least 22 million workers were exposed to IARC group 1 carcinogens. The exposed workers had altogether 42 million exposures (1.3 mean exposures for each exposed worker). The most common exposures were solar radiation (9.1 million workers exposed at least 75% of working time), environmental tobacco smoke (7.5 million workers exposed at least 75% of working time), crystalline silica (3.2 million exposed), diesel exhaust (3.0 million), radon (2.7 million), and wood dust (2.6 million). CONCLUSION: These preliminary estimates indicate that in the early 1990s, a substantial proportion of workers in the EU were exposed to carcinogens.

Carcinogens↗
PubMed2000

Holins: the protein clocks of bacteriophage infections.

Two proteins, an endolysin and a holin, are essential for host lysis by bacteriophage. Endolysin is the term for muralytic enzymes that degrade the cell wall; endolysins accumulate in the cytosol fully folded during the vegetative cycle. Holins are small membrane proteins that accumulate in the membrane until, at a specific time that is "programmed" into the holin gene, the membrane suddenly becomes permeabilized to the fully folded endolysin. Destruction of the murein and bursting of the cell are immediate sequelae. Holins control the length of the infective cycle for lytic phages and so are subject to intense evolutionary pressure to achieve lysis at an optimal time. Holins are regulated by protein inhibitors of several different kinds. Holins constitute one of the most diverse functional groups, with >100 known or putative holin sequences, which form >30 ortholog groups.

Amino Acid Sequence↗
PubMed2000

Frames of reference for the display of battlefield information: judgment-display dependencies.

In 2 experiments, U.S. Army soldiers viewed computer-generated displays that presented battlefield information from 3 different frames of reference: a 2D plan view display (with contour lines), a 3D exocentric perspective display, and an interactive 3D immersed display. In Experiment 1, soldiers made geographical judgments. The results suggested that both 3D displays suffered from ambiguity of distance estimates but that the 3D immersed display was most accurate for judging whether a location is directly visible from another. In Experiment 2, the 3D exocentric display was compared with a 3D immersed view, coupled with a small 2D inset map, in a more continuous battlefield scenario in which judgments of enemy activity were made. The findings of 3D ambiguity were replicated from Experiment 1. The accuracy of judgments of enemy activity suffered with the immersed display when information necessary to answer correctly did not appear in the initial forward view and required panning to acquire, reflecting the cognitive demands of integration across different views. This display also hindered soldiers' ability to report changes in enemy activity from one scene to the next. The results of this research will help to provide guidelines for the appropriate choice of computer display technology to assist in designing battlefield visualization aids. Caution should be exercised in choosing immersive viewpoints.

Computer Systems↗
PubMed2000

Managed care companies and the practice of medicine.

One of the major issues pertaining to the pending legislation for Patient's Bill of Rights is the potential of liability health care plans, particularly when they decline coverage they consider not medically necessary. We call these contracts "managed health care" plans. But, realistically, when is it managing? When is it medicine? When, if at all, does management undermine medicine? And if it does, should managed care organizations--and their representatives--be held legally liable for medical decisions that go wrong? A panel of seven experts examines these questions from medical, payment, patient, legal, insurance, and governing viewpoints.

Clinical Trials as Topic↗
PubMed2000

National Cancer Policy Board Report.

While collecting information for a consumer pamphlet to assist cancer patients in navigating through the medical system, the National Cancer Policy Board discovered the data that were available were critically insufficient. In response, the turned their attention to analyzing our ability to assess quality of cancer care. Their findings along with ten recommendations were published in April 1999. In particular, their conclusions concerning data collection and volume outcomes surprised many in the oncology community. These comments along with five of their recommendations--high-volume settings, standard guidelines, the elements of quality care, measuring and monitoring quality care, and end-of-life care--are presented in this panel discussion.

Health Policy↗
PubMed1999

An examination of isomeric phenylpropanolamines in (-)ephedrine-trained rats.

A total of eight isomeric phenylpropanolamines are possible when the terminal amine is either an N-monomethylamine or a primary amine: (-)ephedrine, (+)ephedrine, (+)pseudoephedrine, (-)pseudoephedrine, (-)norephedrine, (+)norephedrine, (+)cathine, and (-)cathine. Few previous studies have examined the individual optical isomers of these phenylpropanolamines and, with the exception of one report on locomotor effects, no comparative behavioral data have been published on this series of agents. Using rats trained to discriminate 4 mg/kg of (-)ephedrine (i.p.) from saline vehicle using standard operant conditioning with a VI 15-s schedule of reinforcement, all eight agents were examined in tests of stimulus generalization. The (-)ephedrine stimulus (ED50 = 0.90 mg/kg) generalized to (+)ephedrine (ED50 = 2.64 mg/kg), (+)pseudoephedrine (ED50 = 6.58 mg/kg), (-)norephedrine (ED50 = 1.86 mg/kg), (+)norephedrine (ED50 = 5.75 mg/kg), and (+)cathine (ED50 = 4.87 mg/kg). The (-)ephedrine stimulus failed to generalize to either (-)pseudoephedrine or (-)cathine; the latter agents produced a maximum of 29 and 31% (-)ephedrine-appropriate responding, respectively. Thus, (a) six of the eight phenylpropanolamines produced ephedrine-like stimulus effects, (b) (-)ephedrine was the most potent of the examined agents, and (c) where stimulus generalization occurred, ED50 values spanned less than a tenfold range.

Animals↗
PubMed1999

Endoscopic management of hydrocephalus secondary to tumors of the posterior third ventricle.

Management of the obstructive hydrocephalus that accompanies tumors located in the third ventricle has traditionally involved either urgent tumor resection, with resultant ventricular decompression, or cerebrospinal fluid diversion that requires either ventriculostomy or shunt placement prior to tumor removal. Although this approach has worked well for the better part of a century, it has both short- and long-term sequelae that can possibly be avoided. Beacause a number of lesions in this area are benign or are amenable to radiotherapy, a less invasive approach to their treatment is desirable. The advances in both instrumentation and techniques of endoscopic surgery have established alternatives to the traditional treatment of third ventricular tumors and resultant hydrocephalus. The authors review the treatment of 19 patients with posterior third ventricular tumors who presented to Arkansas Children's Hospital over a 5-year period (September 1993-July 1999). In 11 patients signs and/or symptoms of hydrocephalus were demonstrated and were treated with endoscopic third ventriculostomy, additionally, a biopsy procedure, resection, or fenestration of the tumor was performed in a number of patients. Endoscopy was believed to have been of benefit in all patients, despite the eventual failure of the ventriculostomy in one patient. There were no complications in this series. The algorithm thus developed by the authors provides both a diagnostic and therapeutic pathway that may ultimately reduce the morbidity associated with the treatment of patients with posterior third ventricular lesions.

Journal Article↗
PubMed1999

Update on Parkinson's disease.

Parkinson's disease is a progressive degenerative disorder of the central nervous system. The hallmark physical signs are tremor, rigidity and bradykinesia. Idiopathic Parkinson's disease is caused by the progressive loss of dopaminergic neurons in the substantia nigra and nigrostriatal pathway of the midbrain. Secondary parkinsonism may be caused by certain drugs (e.g., metoclopramide and haloperidol) or by cerebrovascular disease (e.g., multiple lacunar strokes). The disease can usually be diagnosed based on the history and physical findings. Dopamine replacement is still considered the most efficacious treatment for Parkinson's disease, but dopamine agonists, formerly prescribed only as adjunctive therapy, are emerging as useful initial therapy. Other pharmacologic treatments include drugs that inhibit dopamine-metabolizing enzymes (monoamine oxidase-B and catechol O-methyltransferase). Injections of botulinum toxin can be helpful in patients with associated dystonia or blepharospasm. Surgery may be indicated for certain patients or when symptoms do not respond to medical therapy. Additional adjunctive therapies include physical therapy, nutritional counseling and techniques to help patients manage emotional and cognitive changes related to the disease.

Antiparkinson Agents↗
PubMed1999

Crystal structures of two Sm protein complexes and their implications for the assembly of the spliceosomal snRNPs.

The U1, U2, U4/U6, and U5 small nuclear ribonucleoprotein particles (snRNPs) involved in pre-mRNA splicing contain seven Sm proteins (B/B', D1, D2, D3, E, F, and G) in common, which assemble around the Sm site present in four of the major spliceosomal small nuclear RNAs (snRNAs). These proteins share a common sequence motif in two segments, Sm1 and Sm2, separated by a short variable linker. Crystal structures of two Sm protein complexes, D3B and D1D2, show that these proteins have a common fold containing an N-terminal helix followed by a strongly bent five-stranded antiparallel beta sheet, and the D1D2 and D3B dimers superpose closely in their core regions, including the dimer interfaces. The crystal structures suggest that the seven Sm proteins could form a closed ring and the snRNAs may be bound in the positively charged central hole.

Amino Acid Sequence↗