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Biomedical subjects

R D Clark

Publications and source records attributed to R D Clark.

At least 19 recordsLinked to original sources
PubMed2000

Computer-aided video exposure monitoring.

A computer-aided video exposure monitoring system was used to record exposure information. The system comprised a handheld camcorder, portable video cassette recorder, radio-telemetry transmitter/receiver, and handheld or notebook computers for remote data logging, photoionization gas/vapor detectors (PIDs), and a personal aerosol monitor. The following workplaces were surveyed using the system: dry cleaning establishments--monitoring tetrachoroethylene in the air and in breath; printing works--monitoring white spirit type solvent; tire manufacturing factory--monitoring rubber fume; and a slate quarry--monitoring respirable dust and quartz. The system based on the handheld computer, in particular, simplified the data acquisition process compared with earlier systems in use by our laboratory. The equipment is more compact and easier to operate, and allows more accurate calibration of the instrument reading on the video image. Although a variety of data display formats are possible, the best format for videos intended for educational and training purposes was the review-preview chart superimposed on the video image of the work process. Recommendations for reducing exposure by engineering or by modifying work practice were possible through use of the video exposure system in the dry cleaning and tire manufacturing applications. The slate quarry work illustrated how the technique can be used to test ventilation configurations quickly to see their effect on the worker's personal exposure.

Aerosols↗
PubMed1999

Behavioral style of young boys with fragile X syndrome.

To study the behavioral style or temperament of 45 boys, aged 47 to 88 months, with full-mutation fragile X syndrome (FXS), 102 parent ratings on the Behavioral Style Questionnaire (McDevitt and Carey 1978) were recorded. These ratings were analysed with a variety of statistical techniques. Considerable variability was evident in temperament profiles; consequently, a characteristic profile was not identified for FXS. Boys with FXS differed significantly from the reference sample on five of nine temperament dimensions. They were more active and less intense, approachable, adaptable, and persistent. No significant differences were found in distractibility, rhythmicity, mood, or sensory threshold. Only 16 of the 45 boys in the sample could be classified as easy, difficult, or slow to warm up. There was no link between severity of developmental disability and temperament ratings. This supports the theory that intelligence and temperament are separate constructs. Scores on temperament dimensions were stable over time. Our results suggest that many of the behaviors observed in boys with FXS may be related to temperament. Consequently, parent counseling and environmental modifications should be considered as first line treatment. The question of whether the behavior problems observed in boys with FXS are innate or whether they result from poorness of fit between child and environment is an important issue that needs further study.

Child↗
PubMed1999

Divalproex in posttraumatic stress disorder: an open-label clinical trial.

Posttraumatic stress disorder (PTSD) is characterized by intrusive, avoidance, and hyperarousal symptoms. This study was conducted to investigate the effectiveness of divalproex in reducing PTSD symptoms, depression, and anxiety in patients with PTSD. Sixteen patients with a DSM-IV diagnosis of PTSD at the Albuquerque VAMC outpatient PTSD treatment program received an open-label trial of divalproex. The patients were evaluated at baseline and at 8 weeks by a trained rater using the Clinician Administered PTSD Scale (CAPS), the Hamilton Rating Scale for Depression (HAM-D) and the Hamilton Rating Scale for Anxiety (HAM-A). Plasma valproate levels were measured at the 8-week post-treatment assessment. Three patients stopped the medications due to side effects. Intrusion and hyperarousal symptoms decreased significantly, while no significant change was seen in avoidance/numbing symptoms. Depressive symptoms, as measured by the HAM-D, unexpectedly decreased at post-treatment assessment. HAM-A scores also decreased significantly. Controlled trials are needed to further study the efficacy of divalproex in the treatment of PTSD.

Adult↗
PubMed1999

Monilethrix: a novel mutation (Glu402Lys) in the helix termination motif and the first causative mutation (Asn114Asp) in the helix initiation motif of the type II hair keratin hHb6.

Monilethrix, a rare human hair disorder with autosomal dominant transmission, can be caused by mutations in hair keratins. Up to now, causative mutations have only been found in two type II cortex keratins, hHb6 and hHb1. In these hair keratins, the helix termination motif, HTM, was the only site in which mutations were located. The most frequent mutation, which has been found in 22 cases, was a Glu413Lys substitution in hHb6, whereas other mutations, i.e., hHb6 Glu413Asp, hHb1 Glu413Lys, and hHb1 Glu402Lys, have been reported in a distinctly lower number of cases. In this study, we describe the equivalent of the hHb1 Glu402Lys mutation in the HTM of cortex keratin hHb6. The mutation occurred in an American family in which it could only be detected in one clinically affected individual. Thus the underlying G-->A transition represents a spontaneous germ-line mutation in the hHb6 gene. This new mutation indicates that both the hHb6/hHb1 Glu413Lys substitution and the hHb6/hHb1 Glu402Lys substitution, represent mutational hotspots in the HTM of type II cortex keratins. However, we also describe a monilethrix-causing mutation in the helix initiation motif, HIM, of the cortex keratin hHb6. The critical Asn114Asp substitution was only found in affected members of a large Swedish three-generation family. Considering that since childhood, half of the affected individuals suffer from complete baldness and follicular keratosis, the new HIM mutation seems to be associated with a rather severe disease phenotype. In conclusion, our data strongly suggest that monilethrix is a disease of the hair cortex, whose etiology is interesting in that causative mutations seem to be restricted to type II hair keratins.

Amino Acid Sequence↗
PubMed1998

Autistic behavior in young boys with fragile X syndrome.

A sample of 57 boys with fragile X syndrome (fraX) between the ages of 24 and 133 months was rated using the Childhood Autism Rating Scale (CARS) to assess the extent to which autism and autistic features were evident in a young population. Fourteen subjects (approximately 25% of the sample) scored above the cutoff for autism, suggesting a relatively high incidence of autistic behavior. All but 2 of these 14 were in the mildly or moderately autistic range, however, and only a few items received severe ratings, suggesting that severe autism is relatively rare in fraX, at least during the early years. The CARS resulted in a continuum of autistic ratings in the fraX population, but no particular items on the CARS contributed disproportionately to autism ratings. A visual comparison of ratings on an autistic, non-fraX sample revealed similar profiles of ratings, suggesting that differentiating fraX and autism on the basis of CARS ratings is not likely. Within the fraX group, chronological age and socioeconomic status did not correlate with CARS ratings, but severity of delay was strongly related, such that more severely delayed children scored higher (more autistic) on the CARS.

Autistic Disorder↗
PubMed1998

Bupropion treatment in veterans with posttraumatic stress disorder: an open study.

This study was designed to investigate the efficacy of the antidepressant drug bupropion in the treatment of posttraumatic stress disorder (PTSD). Seventeen male combat veterans with chronic PTSD were treated with bupropion in an open-label fashion for 6 weeks. Patients were evaluated with the Clinical Global Impressions Scale for Improvement (CGI-I) at follow-up and rated blindly at baseline and posttreatment with the Clinician Administered PTSD Scale (CAPS), the Hamilton Rating Scale for Depression (HAM-D), and the Hamilton Rating Scale for Anxiety. Three patients discontinued bupropion prematurely because of side effects. Of the remaining 14 patients, 10 were classified as treatment responders by the CGI-I. HAM-D scores decreased significantly from baseline to follow-up. The improvement seen in hyperarousal symptoms was significant but was less significant than the change in depressive symptoms. There was no significant change in Intrusion, Avoidance, or total CAPS scores. It was concluded that bupropion was well tolerated. Patients who had experienced sexual dysfunction with selective serotonin reuptake inhibitors reported no complaints during bupropion treatment. Bupropion decreased depressive symptoms and most patients reported global improvement, although PTSD symptoms remained mostly unchanged. Controlled trials should further clarify the role of bupropion in the treatment of PTSD.

Aged↗
PubMed1997

A Hypertext tutorial for teaching cephalometrics.

Hypertext is a non-linear method of text presentation. It necessitates the use of a computer to store data as a series of nodes that can be called up in any desired sequence and, as such, is a new form of discovery-based learning. This paper describes a Hypertext tutorial in cephalometrics and its subsequent testing on first-year clinical dental students. Students were divided into two groups: the first received a conventional lecture; the second used the Hypertext tutorial. Testing was by means of conventional multiple choice questions. The results showed that there was no statistically significant difference between the two groups, although the computer tutor was shown more consistently to improve the knowledge of the students than did the conventional lecture. Most students who used the computer program found it enjoyable, but time consuming; less than half found it easy to follow.

Attitude↗
PubMed1997

Family communication and delinquency.

The importance of positive communication for optimal family functioning has important implications for delinquent behavior. Using self-reported delinquency in conjunction with self-reported perceptions of open and closed communication with one's parents, the relationship between communication and delinquency is explored. Results indicate that communication is related to the commission of delinquent behavior. Differences in age, sex, and family marital status are noted.

Adolescent↗
PubMed1996

Evaluation in rat of RS-79948-197 as a potential PET ligand for central alpha 2-adrenoceptors.

Tritium-labelled RS-79948-197 {(8aR,12aS,13aS)-5, 8,8a,9,10,11,12,12a,13,13a-decahydro-3-methoxy-12-(ethylsulphon yl)-6H-iso- quino[2,1-g][1,6]naphthyridine} was evaluated in rat brain as an in vivo ligand for central alpha 2-adrenoceptors, as a preliminary step in the development of a radioligand for positron-emission tomography (PET) studies. The maximal receptor-specific signal was achieved within 90-120 min after i.v. injection of [ethyl-3H]RS-79948-197 and was selective for the alpha 2- compared with the alpha 1-adrenoceptor, with no detectable binding to the imidazoline-I2 site. Estimates for binding potential (approximating to Bmax/Kd) ranged between 3.4 in entorhinal cortex and 0.5 in medulla oblongata. The results, which indicate a similarly localised but 2-fold increase in specific binding compared with that previously demonstrated using [3H]RX 821002 (2-methoxy-idazoxan), are sufficiently encouraging as to support further investment in the development of 11C-labelled RS-79948-197, or a close structural analogue, as a ligand for clinical PET.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1996

Neighborhood behavior: a useful concept for validation of "molecular diversity" descriptors.

When searching for new leads, testing molecules that are too "similar" is wasteful, but when investigating a lead, testing molecules that are "similar" to the lead is efficient. Two questions then arise. Which are the molecular descriptors that should be "similar"? How much "similarity" is enough? These questions are answered by demonstrating that, if a molecular descriptor is to be a valid and useful measure of "similarity" in drug discovery, a plot of differences in its values vs differences in biological activities for a set of related molecules will exhibit a characteristic trapezoidal distribution enhancement, revealing a "neighborhood behavior" for the descriptor. Applying this finding to 20 datasets allows 11 molecular diversity descriptors to be ranked by their validity for compound library design. In order of increasing frequency of usefulness, these are random numbers = log P = MR = strain energy < connectivity indices < 2D fingerprints (whole molecule) = atom pairs = autocorrelation indices < steric CoMFA fields = 2D fingerprints (side chain only) = H-bonding CoMFA fields.

Algorithms↗
PubMed1996

Bioisosterism as a molecular diversity descriptor: steric fields of single "topomeric" conformers.

The comparative molecular field analysis steric field of a single "topomeric" conformer is introduced as a molecular diversity descriptor particularly useful for combinatorial chemistry involving variations around a fixed "core". Using this new descriptor, 736 commercially available thiols are divided into 231 bioisosteric clusters, whose compositions agree at least as well with medicinal chemical experience and intuition as do clusters derived from Tanimoto differences between 2D fragment occurrences. However, in practice topomeric steric fields complement 2D fingerprints, being the two most frequently useful descriptors yet found for neighborhood-based design of combinatorial libraries.

Drug Evaluation, Preclinical↗
PubMed1996

Comparison of 5-HT4 receptors in guinea-pig colon and rat oesophagus: effects of novel agonists and antagonists.

5-HT4 receptors in isolated distal colon myenteric plexus of guinea-pig, mediating contraction of longitudinal smooth muscle, have been further characterized by selective agonists and antagonists. The indole agonists, 5-HT and 5-methoxytryptamine (5-MeOT), were full agonists (relative to 5-HT) with potency values (pEC50) of 8.0 +/- 0.1 (n = 50) and 7.8 +/- 0.1 (n = 12), respectively. 5-HT4 receptor agonists of other structural classes, including benzimidazolones (BIMU 1 and BIMU 8), and benzamides ((S)-zacopride, (R)-zacopride, renzapride, SC 49518) were partial agonists with intrinsic activities less than that of 5-HT. In general, the potencies for these compounds at 5-HT4 receptors in guinea-pig colon were similar to the potencies seen in the rat isolated oesophagus, where 5-HT4 receptors mediate relaxation. GR 113808 ¿[1-[2-[(methylsulfonyl)amino]ethyl]-4-piperidinyl] methyl1-methyl-1H-indole-3-carboxylate¿, RS 39604 ¿1-[4-amino-5-chloro-2-(3, 5-dimethoxybenzyloxy)phenyl]-3[1-[2-[(methylsulfonyl)amino] ethyl]-4-piperidinyl]-1-propanone hydrochloride and SB 204070 ¿(1-n-butyl-4-piperidinyl)methyl 8-amino-7-chloro-1, 4-benzodioxane-5-carboxylate¿ antagonized 5-HT responses with pA2 values of 9.1 +/- 0.1, 9.0 +/- 0.2 and 11.0 +/- 0.1, respectively. These affinity values were similar to those obtained at 5-HT4 receptors in isolated rat oesophagus (9.0+/- 0.4, 9.3 +/- 0.1 and 10.6 +/- 0.1 respectively). Despite these operational similarities between 5-HT4 receptors in guinea-pig colon and rat oesophagus, several novel compounds have revealed important differences between 5-HT4 receptors in the two tissues. For example, the substituted benzoate, RS 23597 ¿3-(piperidine-1-yl) propyl-4-amino-5-chloro-2-methoxybenzoate hydrochloride, acted as a partial agonist (intrinsic activity 0.5) in guinea-pig colon with a potency of 7.6 +/-0.1 (n = 16). In isolated rat oesophagus, however, this compound was a surmountable antagonist (pA2 = 7.8 +/- 0.1) with no intrinsic activity. In contrast, the substituted naphthalimide (S)RS 56532 ¿(S)-6-amino-5-chloro-2-(1-azabicyclo[2, 2, 2]octan-3-yl) 2,3-dihydro-1H-benz[de] isoquinoline-1,3-dione hydrochloride¿, was a potent (pEC50 = 7.9 +/- 0.1), efficacious partial agonist (intrinsic activity = 0.8) in the rat oesophagus. However, in guinea-pig colon, it was a surmountable antagonist with an affinity (pKB) of 9.4 +/- 0.1. Furthermore, several novel, selective, 5-HT4 compounds also showed opposing patterns of intrinsic activities similar to those described for RS 23597 and (S)RS 56532. It is concluded that these differences are inconsistent with differences in 5-HT4 receptor reserves, and may suggest that 5-HT4 receptors in the guinea-pig colon and the rat oesophagus can be operationally distinguished.

Animals↗
PubMed1996

Contemporary marketing.

Practice success in the near future will only come to those of us who become formidable marketers. Veterinarians are running out of leverage. Profitable vaccines, ovariohysterectomies, castrations, and declaws have been reduced to a commodity. We must learn how to differentiate our services from these average or standard services.

Marketing of Health Services↗
PubMed1996

Simple physiological and clinical tests for the accurate prediction of falling in older people.

A 1-year prospective study was conducted in an intermediate care institution to determine whether a combined assessment of physiological and clinical measures discriminates between elderly fallers and elderly nonfallers. Seventy persons aged between 72 and 96 years (mean 85.6), who were generally independent in activities of daily living, took part in the study, and 66 were available to follow-up. In the follow-up year, 24 subjects experienced no falls, 20 subjects fell one time only and 22 residents fell on two or more occasions. Discriminant analysis identified reaction time, body sway, quadriceps strength, tactile sensitivity, gait impairment, cognitive impairment, psychoactive drug use and age as the variables that significantly discriminated between subjects who experienced falls and those who did not. This procedure correctly classified 86% of subjects into faller and nonfaller groups. These findings suggest that an assessment that combines physiological and clinical factors provides excellent discrimination between elderly fallers and nonfallers.

Accidental Falls↗
PubMed1995

Neuroleptic use and behavioral disturbance in nursing homes: a 1-year study.

This article discusses a longitudinal study of change in disruptive behaviors among nursing home residents treated with neuroleptics compared with those not treated with neuroleptics. Observations were made of 201 participants on admission to and after 1 year in eight skilled nursing facilities. Nine disruptive behaviors were measured using the Psychogeriatric Dependency Rating Scale with nursing assistants. Neuroleptic use was documented from medication records. Odds ratios are reported for the association of behavior at baseline and use of neuroleptics on nine problem behaviors. For those who received neuroleptics during the year, there was greater change in both developing and resolving disruptive behaviors than for those not receiving neuroleptics. For both groups, restless or pacing behavior and belligerent behavior manifested by refusing instructions changed the most, both in developing and in apparently resolving. Our results show that change in disruptive behaviors occurs among nursing home residents regardless of neuroleptic use, but it occurs more frequently among those who receive neuroleptic medication. Knowledge of which disruptive behaviors are most likely to resolve or develop is important in training nursing home staff to cope with the behaviors as well as in planning interventions that may modify such behaviors.

Adult↗
PubMed1995

RS 39604: a potent, selective and orally active 5-HT4 receptor antagonist.

1. Selective antagonism of 5-HT4 receptors may provide therapeutic benefit in certain disorders of the myocardium, alimentary and lower urinary tract. We now report on RS 39604, a novel and selective 5-HT4 receptor antagonist and compare its pharmacological properties with those of SB 204070. 2. In guinea-pig striatal membranes, both RS 39604 and SB 204070 inhibited specific binding of [3H]-GR 113808 in a concentration-dependent manner yielding pKi estimates of 9.1 and 10.9, respectively. RS 39604 displayed a low affinity (pKi < 6.5) for 5-HT1A, 5-HT2C, 5-HT3, alpha 1c, D1, D2, M1, M2, AT1, B1 and opioid mu receptors and moderate affinity for sigma 1, (pKi = 6.8) and sigma 2 (pKi = 7.8) sites. 3. In the rat isolated oesophagus, precontracted with carbachol, RS 39604 (30-300 nM) behaved as a competitive antagonist towards 5-HT-induced relaxation (pA2 = 9.3; Schild slope = 1.0). We and others have shown previously that SB 204070 behaves as an unsurmountable antagonist in this preparation (pA2 approximately 10.5). In the guinea-pig isolated ileal mucosa, RS 39604 (30 nM) antagonized 5-MeOT-induced increase in short-circuit current (pA2 = 9.1). 4. In anaesthetized vagotomized micropigs, RS 39604, administered by the i.v. or intraduodenal (i.duod.) route, produced dose-dependent inhibition of 5-HT-induced tachycardia (ID50 = 4.7 micrograms kg-1, i.v. and 254.5 micrograms kg-1, i.duod). At maximal doses of 30 micrograms kg-1, i.v. and 6 mg kg-1, i.duod., the inhibitory effects of RS 39604 lasted for more than 6 h. In this preparation, SB 204070 was as potent as RS 39604by the i.v. route but was inactive by the intraduodenal route at doses up to 3 mg kg-1.5. In conscious mice, RS 39604, administered by the i.p. or p.o. route, produced dose-depend entinhibition of 5-hydroxytryptophan (5-HTP)-induced diarrhoea (ID50= 81.3 microg kg-1, i.p. and 1.1 mg kg-1,p.o.). In this assay, SB 204070 was inactive by the oral route at doses up to 30 mg kg-1.6. In anaesthetized guinea-pigs, RS 39604 antagonized the contractile effect of 5-HT in the proximal colon by producing parallel, dextral displacement of the dose-response curve to 5-HT. The mean dose ratios to 5-HT at 0.1 mg kg-1, i.v., 1 mg kg-1, i.v. and 10 mg kg-1, i.duod. were 4.6, 30.7 and 10.8,respectively. SB 204070 behaved as an unsurmountable antagonist in this assay.7. In a model of visceral pain in conscious rats, RS 39604 (0.01-1 mg kg-1, i.v.) did not affect colorectal distension-induced increases in arterial pressure whereas morphine (1 mg kg-1, i.v.) produced significant inhibition of the response, implying that 5-HT4 receptors are not involved in nociception in this model.8. The data suggest that RS 39604 is a high affinity and selective 5-HT4 receptor antagonist that is orally active and long-lasting in vivo. It is concluded that RS 39604 may be the preferable probe to use for investigating the physiological and pathophysiological role of 5-HT4 receptors in vivo.

Administration, Oral↗
PubMed1995

Pharmacological characterization of two novel and potent 5-HT4 receptor agonists, RS 67333 and RS 67506, in vitro and in vivo.

1. The pharmacology of two novel 5-HT4 receptor agonists, RS 67333 (1-(4-amino-5-chloro-2-methoxy-phenyl)-3-[1(n-butyl)-4-piperidinyl]-1- propanone HCl) and RS 67506 (1-(4-amino-5-chloro-2-methoxy-phenyl)-3-[1-(2-methyl sulphonylamino)ethyl-4-piperidinyl]-1-propanone HCl) have been assessed in vitro and in vivo. 2. RS 67333 and RS 67506 exhibited affinities (pKi = 8.7 and 8.8, respectively) for the 5-HT4 binding sites, labelled with [3H]-GR 113808, in guinea-pig striatum. The Hill coefficients from these displacement curves were not significantly different from unity. The compounds exhibited lower affinities (< 6.0) at several other receptors including 5-HT1A, 5-HT1D, 5-HT2A, 5-HT2C, dopamine D1, D2 and muscarinic M1-M3 receptors. However, RS 67333 and RS 67506 did exhibit affinities for the sigma 1 (pKi = 8.9 and 7.9, respectively) and sigma 2 (pKi = 8.0 and 7.3, respectively) binding sites. 3. At the 5-HT4 receptor mediating relaxation of the carbachol-precontracted oesophagus, RS 67333 and RS 67506 acted as potent (pEC50 8.4 and 8.6, respectively), partial agonists (intrinsic activities, with respect to 5-HT were 0.5 and 0.6, respectively) with respect to 5-HT. Relaxant responses to RS 67333 or RS 67506 were surmountably antagonized by GR 11308 (10 nM), with apparent affinities (pKB) of 9.1 and 9.0, respectively. RS 67333 and RS 67506 induced dose-dependent increases in heart rate of the anaesthetized micropig (ED50 4.9 and 5.4 micrograms kg-1, i.v.), with maximal increases of 35 and 47 beats min-1, respectively. 4. RS 67333 and RS 67506, therefore, acted as potent, partial 5-HT4 receptor agonists in vitro and in vivo. These compounds, by virtue of their high potency and selectivity, may have some utility in elucidating the physiological role of 5-HT4 receptors.

Animals↗