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Biomedical subjects

R Young

Publications and source records attributed to R Young.

At least 91 records · Page 5Linked to original sources
PubMed1998

Discriminative stimulus effects of S(-)-methcathinone (CAT): a potent stimulant drug of abuse.

Methcathinone ("CAT") is a CNS stimulant that is a very significant drug of abuse in the former Soviet Union. It has also appeared on the clandestine market in the United States and has been recently classified as a Schedule I substance. In the present study, S(-)-methcathinone [S(-)-CAT, 0.50 mg/kg, IP] was employed as the training drug in a two-lever drug discrimination task in rats. Once established, the S(-)-CAT stimulus was shown to have a rapid onset to action (within 5 min) and a duration of effect of approximately 60-90 min. In tests of stimulus generalization (substitution), the S(-)-CAT (ED50 = 0.11 mg/kg) stimulus generalized to S(+)-methamphetamine (ED5 = 0.17 mg/kg), S(-)-cathinone (ED50 = 0.19 mg/kg), S(+)-amphetamine (ED50 = 0.23 mg/kg), aminorex (ED50 = 0.27 mg/kg), (+/-)-CAT (ED50 = 0.25 mg/kg), (+/-)-cathinone (ED50 = 0.41 mg/kg), R(+)-CAT (ED50 = 0.43 mg/kg), cis-4-methylaminorex (ED50 = 0.49 mg/kg), methylphenidate (ED50 = 0.83 mg/kg), and cocaine (ED50= 1.47 mg/kg). S(-)-CAT-stimulus generalization did not occur to fenfluramine, a structurally related nonstimulant anorectic. Lastly, haloperidol (AD50 = 0.18 mg/kg), a dopamine receptor antagonist, potently antagonized the S(-)-CAT stimulus. It is concluded that S(-)-methcathinone is a very potent CNS stimulant, which appears to produce its stimulus effect, at least in part, via a dopaminergic mechanism.

Amphetamine↗
PubMed1998

Methotrexate in patients with Crohn's disease after 6-mercaptopurine.

OBJECTIVE: The objective of this study was to describe the clinical outcome of children with Crohn's disease treated with subcutaneous methotrexate. SUBJECTS/METHODS: Fourteen patients (10 boys) with extensive Crohn's disease diagnosed at a mean age of 10.6 +/- 3.6 years had previously received various medical therapies for 4.3 +/- 4.0 years. Because of the severity of their disease, 6-mercaptopurine had been introduced but discontinued because of the patients' failure to respond (n = 11) or the development of pancreatitis (n = 3). Subsequently, low-dose, weekly, subcutaneous methotrexate was initiated. Pediatric Crohn's Disease Activity Index scores and prednisone requirement were followed as outcome measures. RESULTS: Overall, 9 (64%) of the 14 patients showed improvement, including 6 (55%) of 11 patients who had previously received an adequate trial of 6-mercaptopurine and all three patients who were intolerant of 6-mercaptopurine. Improvement in clinical and laboratory measures occurred by 4 weeks and were similar whether (n = 8) or not (n = 6) the dose of corticosteroids was increased before the start of subcutaneous methotrexate. Three patients were tapered from their initial methotrexate dose after the minimization of corticosteroids and remain well. One patient receiving daily corticosteroids died suddenly after acute onset of illness. Among patients responding, methotrexate was discontinued because of side effects (n = 2) or electively (n = 2). Of the latter two patients, one has resumed methotrexate after disease relapse, whereas the other patient has had a sustained remission. CONCLUSIONS: Low-dose, weekly, subcutaneous methotrexate can induce remission in some pediatric patients with Crohn's disease who fail to adequately respond to other immunomodulator medications.

Adolescent↗
PubMed1998

(-)Ephedrine and caffeine mutually potentiate one another's amphetamine-like stimulus effects.

Using rats trained to discriminate 1 mg/kg of (+)amphetamine (ED50 = 0.4 mg/kg) from saline vehicle in a two-lever drug discrimination procedure, it was shown that (-)ephedrine (ED50 = 4.5 mg/kg), but not (+)ephedrine, substitutes for the (+)AMPH stimulus. It was also shown that caffeine (ED50 = 12.9 mg/kg) can substitute for (+)amphetamine in a dose-related fashion. Doses of (-)ephedrine and caffeine, which produced < or = 1% drug-appropriate responding when administered alone, were able to enhance each other's stimulus effects when administered in combination such that there was a twofold leftward shift in their respective dose-response curves. Furthermore, stimulus generalization occurred when a dose of caffeine that produced saline-appropriate responding when administered alone was administered in combination with (+)ephedrine. It would appear that low doses of (-)ephedrine and caffeine may mutually potentiate one another's stimulus effects in (+)AMPH-trained rats, and that a combination of caffeine and (+)ephedrine result in altered stimulus character when compared to comparable doses of either agent administered alone.

Amphetamine↗
PubMed1998

Discriminative stimulus properties of (-)ephedrine.

Ephedrine, a structural analog of methamphetamine, is one of the major constituents of legally available herbal dietary supplements. Although racemic ephedrine and ephedra extract have been previously used as training drugs in drug discrimination studies, there is evidence that the two optical isomers of ephedrine do not produce identical amphetamine-like stimulus effects in rats. Consequently, we trained a group of six male Sprague-Dawley rats to discriminate 4 mg/kg of the more potent optical isomer of ephedrine, (-)ephedrine, from saline vehicle. The (-)ephedrine stimulus (ED50 = 0.8 mg/kg) generalized to other central stimulants such as S(+)amphetamine (ED50 = 0.4 mg/kg), cocaine (ED50 = 2.7 mg/kg), methylphenidate (ED50 = 1.2 mg/kg), S(-)methcathinone (ED50 = 0.3 mg/kg), and caffeine (ED50 = 36.7 mg/kg), but stimulus generalization failed to occur to either S(+)methamphetamine or N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA). In addition, although we have previously shown that a (+)amphetamine stimulus generalizes to (-)ephedrine but not to (+)ephedrine, in the present investigation the (-)ephedrine stimulus generalized to (+)ephedrine (ED50 = 2.6 mg/kg). From the findings (a) that (-)ephedrine is approximately 10 times less potent than (+)amphetamine in (+)amphetamine-trained rats, whereas it is only half as potent as (+)amphetamine in (-)ephedrine-trained animals; (b) that the (-)ephedrine stimulus failed to generalize to (+)methamphetamine; and (c) that the (-)ephedrine stimulus generalized to (+)ephedrine, it is concluded that the stimulus effects of (+)amphetamine and (-)ephedrine as training drugs, while similar, are not identical. It is also concluded that the stimulus effects of (-)ephedrine and those of the designer drug MDMA, while perhaps sharing some amphetaminergic commonality, are nonidentical.

Animals↗
PubMed1998

Frequent ED users: patterns of use over time.

The objective of this study was to examine the pattern of emergency department (ED) use by frequent ED users over time. This study was a retrospective study of adults with more than 10 visits to a university hospital ED from 8/90 through 7/91. ED visits of this cohort to all hospitals in the metropolitan area were followed for 3 years. Records were reviewed for the etiology of each patient's ED visits. This cohort was comprised of 76 patients making 1,119 (1.9%) of the total 59,051 ED visits. Thirty-five of the 76 (46%) were frequent ED users in only the initial year. Thirteen of the 76 (17%) made more than 10 visits in all 4 years. The remainder had sporadic episodes of ED use. Thirty-five (46%) were evaluated at three or more EDs in years in which they were frequent users. Forty-two (55%) had a medical problem for the cause of the majority of their ED visits. Fifty-eight percent of patients making more than 10 visits in more than 1 year had psychiatric or substance abuse problems. The pattern of ED use in this cohort changed over time and was influenced by substance abuse and psychiatric problems. These data suggest that most patients do not remain frequent ED users over time.

Adult↗
PubMed1998

The prevalence of common skin conditions in Australian school students: 1. Common, plane and plantar viral warts.

Although viral warts are common, their exact frequency in the community is often underestimated and not well recorded. A random sample of 2491 students from schools throughout the State of Victoria, Australia were examined by dermatologists and dermatology registrars to record the prevalence of common, plantar and plane warts. The overall prevalence of warts adjusted for the age and sex of Victorian school children was 22% (95% confidence interval (CI) 20.1-20.7) varying from 12% (95% CI 9.4-15.7) in 4-6 year olds to 24% (95% CI 18.3-30.4) in 16-18 year olds. Common warts were the most frequent (16%) compared with plantar warts (6%) and plane warts (2%). There was no difference in the overall frequency of warts between males and females and there was no difference in frequency between those who had eczema and those who did not. Almost 40% of those found to have warts on examination had indicated on the survey questionnaire that they did not have any of these lesions. Of those who knew that they had warts, only 38% had used any treatment for them. These data, the first community-based prevalence data on warts ever published from Australia, confirm that warts are indeed common. They suggest the need for education programmes in schools on the nature of these lesions and the treatment available.

Adolescent↗
PubMed1998

A study of filgrastim (rG-CSF) priming of etoposide/cisplatin in advanced non-small cell lung cancer.

A previous phase II study (CALGB 9132) of etoposide/cisplatin + rG-CSF in patients with advanced non-small cell lung cancer (NSCLC) showed a marked difference in the absolute neutrophil count (ANC) nadirs between courses 1 and 2. Median ANC nadirs for courses 1 and 2 were 200 and 2500, respectively, suggesting a priming effect for rG-CSF. The present study was designed to determine whether rG-CSF given prior to the first cycle of chemotherapy would decrease the severity and duration of neutropenia. Twelve patients with stage IIIB or IV NSCLC and performance status 0-1 received rG-CSF 5 microg/kg for 5 consecutive days starting 7 days before treatment with etoposide 200 mg/m2 on days 1-3 and cisplatin 35 mg/m2 on days 1-3, repeated every 3 weeks. Patients also received rG-CSF 5 microg/kg s.c. day 4 to postnadir ANC > 10,000. The median WBC nadir, ANC nadir, and platelet nadir after the first cycle of chemotherapy in the historical group (CALGB 9132) were 1300 cells/microl, 200 cells/microl, and 80,000 cells/microl, respectively. In the present study, the median WBC nadir, ANC nadir, and platelet nadir were 1300 cells/microl, 144 cells/microl, and 56,000 cells/microl, respectively. The median time for ANC to reach 10,000 cells/microl was 15 days in both the historical and the present study. For course 2, the WBC, ANC, platelet nadirs, and duration of grade 4 neutropenia were 2600, 1450, 70,000, and 0 days, respectively. This study failed to show a priming effect for rG-CSF when given in this dose and schedule.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Hirsutes. I: Diagnosis.

Hirsutes, the coarse, androgen-dependent growth of hair in women, is a common problem faced by doctors. Whether a woman presents to a clinician or not depends on cultural and racial factors. The clinician must differentiate normal biological variation from cases of hirsutes. In the vast majority of cases, androgen excess is only found locally at the level of the hair follicle; that is, the hirsutism is idiopathic. Important causes of androgen excess, such as an ovarian tumour, need to be excluded. Part one describes the causes of hirsutism and how to differentiate them using history, examination and investigation.

Adrenocortical Hyperfunction↗
PubMed1998

Hirsutes. II: Treatment.

The treatment of hirsutes includes cosmetic measures, such as bleaching, plucking, electrical epilation and, more recently, laser epilation. Pharmacological therapy consists of anti-androgens and includes the androgen receptor blockers spironolactone and cyproterone acetate. Other drugs reducing androgen expression include oral contraceptives and corticosteroids. A new follicular 5 alpha reductase inhibitor, finasteride, is currently under evaluation, as is the anti-androgen flutamide. Gonadotrophin-releasing hormone agonists reduce androgen expression and show early promise in the treatment of hirsutes.

5-alpha Reductase Inhibitors↗
PubMed1998

Oligohistidine tag mutagenesis of the lambda holin gene.

Holins are a diverse group of small integral membrane proteins elaborated by bacteriophages to lyse bacterial hosts and effect release of progeny phages in a precisely timed manner. Recently, the holin S gene of phage lambda was overexpressed and the holin protein was purified to homogeneity by means of an oligohistidine tag procedure and immobilized metal affinity chromatography (D. L. Smith, D. K. Struck, J. M. Scholtz, and R. Young, J. Bacteriol. 180:2531-2540, 1998). Numerous locations within the S gene were tested as sites for an oligohistidine-tag-encoding insertion which preserves holin function. The lysis phenotypes of these alleles, expressed from moderate-copy-number transactivation plasmids, were characterized. A striking class of mutants, previously referred to as early-dominant, have been found to have severe lysis defects but are fully functional in the presence of wild-type protein. Results presented here reveal that the early-dominance phenotype is independent of S107 inhibitor function. The results provide insight into the mechanism of hole formation and indicate that, while oligomerization is required in the pathway to hole formation, a nucleation event may also be required.

Alleles↗
PubMed1998

Purification and biochemical characterization of the lambda holin.

Holins are small phage-encoded cytoplasmic membrane proteins, remarkable for their ability to make membranes permeable in a temporally regulated manner. The purification of S105, the lambda holin, and one of the two products of gene S is described. Because the wild-type S105 holin could be only partially purified from membrane extracts by ion-exchange chromatography, an oligohistidine tag was added internally to the S105 sequence for use in immobilized metal affinity chromatography. An acceptable site for the tag was found between residues 94 and 95 in the highly charged C-terminal domain of S. This allele, designated S105H94, had normal lysis timing under physiological expression conditions. The S105H94 protein was overproduced, purified, and characterized by circular dichroism spectroscopy, which revealed approximately 40% alpha-helix conformation, consistent with the presence of two transmembrane helices. The purified protein was then used to achieve release of fluorescent dye loaded in liposomes in vitro, whereas protein from an isogenic construct carrying an S mutation known to abolish hole formation was inactive in this assay. These results suggest that S is a bitopic membrane protein capable of forming aqueous holes in bilayers.

Amino Acid Sequence↗
PubMed1998

Stereotactic radiosurgery toxicity in the treatment of intracanalicular acoustic neuromas: the Seattle Northwest gamma knife experience.

Patients with acoustic neuromas have several treatment options. The appropriate individual treatment decision and expected control rates and risks for the individual techniques have been outlined in several texts [1-4, 6-8]. This article describes radiosurgery toxicity in those patients with acoustic neuromas who have intracanalicular disease. 52 patients with 54 acoustic neuromas were treated between September 1993 and April 1997. 14 tumors were intracanalicular lesions, with a mean diameter <1 cm and volume <1 cm3. Dose to the periphery of the intracanalicular lesion extension ranged from 12-18 Gy (mean 16 Gy). The margin isodose was 40-60% (mean 47%). 32 isocenters were used to treat the 14 intracanalicular tumors (mean 2.3 isocenters per patient). At a mean follow-up of 18 months (range 1-39 months), 12/12 or 100% of the intracanalicular lesions demonstrated regression or no change in size on subsequent imaging. The following acute side effects were observed posttreatment in intracanalicular tumors: diminished hearing 14%, facial neuropathy 43%, trigeminal neuropathy 21%, balance disorder 14%, dizziness 7%, and headache 7%. Facial and trigeminal neuropathy, balance disorder, dizziness, vertigo and headaches were more common in patients with intracanalicular tumors than those with an extracanalicular extension. Although it has been suggested that small acoustic neuromas (i.e. <1 cm3) tolerate doses of 18 Gy with acceptable toxicity, when the lesion is located in the auditory canal a lesser dose may be warranted to minimize potential side effects. For now, our center has established a protocol that limits radiosurgical stereotactic intracanalicular peripheral doses to 12 Gy until further toxicity studies have been collected and reviewed.

Cranial Nerve Diseases↗
PubMed1998

The lambda holin accumulates beyond the lethal triggering concentration under hyperexpression conditions.

Most bacteriophages terminate infection by creating lesions in the cytoplasmic membrane, which not only cause immediate cell death but also allow escape of a phage-encoded endolysin. Destruction of the peptidoglycan and cell lysis follows very rapidly, allowing efficient release of the progeny virions. These membrane lesions are formed by a small integral membrane protein called a holin. Holins have highly charged carboxyl-termini that are thought to have two transmembrane alpha-helical domains. Holins are believed to oligomerize and form large holes in the inner membrane. The prototype holin is the S protein from bacteriophage lambda. Scheduling of the lytic event is determined in part by the "structure directed initiation" or sdi translational control region. Inductions of S, cloned under a variety of native and nonnative promoters but with native translational control, resulted in cell lysis at about 1000 molecules of holin per cell, and thus do not produce biochemically useful amounts of S protein. By utilizing a plasmid-based system with the T7 RNA polymerase promoter in tandem with a consensus ribosome binding site, Coomassie blue-detectable quantities of S protein were obtained upon induction, corresponding to an approximately 100-fold increase over the normal lethal level of holin. Characterization of this expression system is presented and discussed with respect to the current model of holin function.

Amino Acid Sequence↗
PubMed1997

Gravity Waves in Jupiter's Thermosphere

The Atmosphere Structure Instrument on the Galileo probe detected wavelike temperature fluctuations superimposed on a 700-kelvin temperature increase in Jupiter's thermosphere. These fluctuations are consistent with gravity waves that are viscously damped in the thermosphere. Moreover, heating by these waves can explain the temperature increase measured by the probe. This heating mechanism should be applicable to the thermospheres of the other giant planets and may help solve the long-standing question of the source of their high thermospheric temperatures.

Journal Article↗
PubMed1997

Clobenzorex: evidence for amphetamine-like behavioral actions.

Clobenzorex, an optically active N-substituted derivative of (+)amphetamine, has been identified on the illicit market. Because so little is known regarding the pharmacology or abuse potential of this agent, it was examined in tests of stimulus generalization in rats trained to discriminate 1 mg/kg of (+)amphetamine from vehicle to determine if it would produce amphetamine-appropriate responding. Clobenzorex (ED50 = 6.6 mg/kg) substituted for (+)amphetamine (ED50 = 0.3 mg/kg) but was approximately twenty times less potent than the training drug. Clobenzorex was also compared with (+)amphetamine and cocaine for its ability to induce locomotor stimulation and rearing frequency in mice. Clobenzorex was active in both assays but was less potent than either (+)amphetamine or cocaine. It is concluded that, although weaker than (+)amphetamine, clobenzorex constitutes an agent with amphetamine-like central stimulant behavioral properties.

Amphetamine↗
PubMed1997

Cathinone: an investigation of several N-alkyl and methylenedioxy-substituted analogs.

Structurally, methcathinone is to cathinone what methamphetamine is to amphetamine. Due to increased interest in the abuse of such agents we wished to determine if certain derivatives of cathinone would behave in a manner consistent with what is known about their amphetamine counterparts; that is, can amphetamine structure-activity relationships be extrapolated to cathinone analogs? As expected on the basis of known structure-activity relationships for amphetaminergic agents, both N-monoethylcathinone and N-mono-n-propylcathinone (N-Et CAT and N-Pr CAT; ED50 = 0.77 and 2.03 mg/kg, respectively) produced amphetamine-like stimulus effects in rats trained to discriminate 1 mg/kg of (+)amphetamine from vehicle and were somewhat less potent than racemic methcathinone. In contrast, (-)N,N-dimethylcathinone or (-)Di Me CAT (ED50 = 0.44 mg/kg) was more potent than expected; although (+)N,N-dimethylamphetamine is sevenfold less potent than (+)methamphetamine, (-)Di Me CAT is only about 1.6-fold less potent than (-)methcathinone, and is essentially equipotent with (-)cathinone. In addition, although it has been previously demonstrated that 1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDA) results in stimulus generalization in rats trained to discriminate (+)amphetamine or DOM from vehicle, the cathinone counterpart of MDA (i.e., MDC) resulted in partial (maximum: 58%) generalization in (+)amphetamine-trained animals, and failed to produce >7% DOM-appropriate responding in rats trained to discriminate DOM from vehicle. On the other hand, the N-methyl analog of MDC (i.e., MDMC) behaved in a manner similar to that of the N-methyl analog of MDA (i.e., MDMA); that is, a (+)amphetamine stimulus (MDMC: ED50 = 2.36 mg/kg) but not a DOM stimulus generalized to MDMC. In MDMA-trained rats, stimulus generalization occured both to MDC and MDMC (ED50 = 1.64 and 1.60 mg/kg, respectively). Although this and previous studies have demonstrated that significant parallelisms exist between the structure-activity relationships of amphetamine analogs and cathinone analogs, we now report several unexpected qualitative and/or quantitative differences. It is suggested that caution be used in attempting to draw conclusions or make predictions about the activity and potency of novel cathinone analogs by analogy to the structure-activity relationships derived from amphetamine-related agents; it would appear that each new cathinone analog will require individual investigation.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1997

Mutational analysis of slyD, an Escherichia coli gene encoding a protein of the FKBP immunophilin family.

slyD encodes a 196 amino acid polypeptide that is a member of the FKBP family of cis-trans peptidyl-prolyl isomerases (PPlases). slyD mutations affect plaque formation by the phage phiX174 by blocking the action of the phage lysis protein E. Here we describe the selection of a set of spontaneous slyD mutations conferring resistance to the expression of gene E from a plasmid. These mutations occur disproportionately in residues of SlyD that, based on the structure of the prototype mammalian FKBP12, make ligand contacts with immunosuppressing drug molecules or are conserved in other FKBP proteins. A wide variation in the plating efficiency of phiX174 on these E(R) strains is observed, relative to the parental, indicating that these alleles differ widely in residual SlyD activity. Moreover, it is found that slyD mutations cause significant growth rate defects in Escherichia coli B and C backgrounds. Finally, overexpression of slyD causes filamentation of the host. Thus, among the FKBP genes found in organisms across the evolutionary spectrum, slyD is unique in having three distinct drug-independent phenotypes.

Alleles↗