Biomedical subjects
Publications and source records attributed to R D Clark.
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.
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.
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.
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.
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.
OBJECTIVES: This study was undertaken to determine whether adding a benefit for preventive services to older Medicare beneficiaries would affect utilization and costs under Medicare. METHODS: The demonstration used an experimental design, enrolling 4195 older, community-dwelling Medicare recipients. Medicare claims data for the 2 years in which the preventive visits occurred were compared for the intervention (n = 2105) and control (n = 2090) groups. Monthly allowable charges for Part A and Part B services and number of hospital discharges and ambulatory visits were compared. RESULTS: There were no significant differences in the charges between the groups owing to the intervention, although total charges were somewhat lower for the intervention group even when the cost of the intervention was included. Charges for both groups rose significantly as would be expected for an aging population. A companion paper describes a modest health benefit. CONCLUSIONS: There appears to be a modest health benefit with no negative cost impact. This finding gives an early quantitative basis for the discussion of whether to extend Medicare benefits to include a general preventive visit from a primary care clinician.
Several series of N-(quinuclidin-3-yl)aryl and heteroaryl-fused pyridones were synthesized and evaluated for 5-HT3 receptor affinity. In the heteroaryl series, 2-(quinuclidin-3-yl)tetrahydropyrido-[4,3-b]indol-1-one (8a) and the 4,5-alkano-bridged analogues (14 and 15) displayed high 5-HT3 receptor affinity with pKi values > 9. The (3S)-quinuclidinyl isomers had > 10 fold higher affinity than the (3R)-isomers. In a series of 2-quinuclidin-3-yl)isoquinolin-1-ones, derivatives substituted with small lipophilic groups (25b-e) and with 4,5-alkano-bridges (34-36) also displayed high affinity. In particular, the hexahydro-1H-benz[de]isoquinolinone (S,S)-37 was the highest affinity 5-HT3 receptor ligand prepared (pKi 10.4). A number of the high affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhibition of the B-J reflex in the anesthetized rat. Again, (S,S)-37 was the most active agent tested (ID50 0.02 microgram/kg i.v.), and this compound was also potent in blocking cisplatin-induced emesis in both the ferret and the dog. Computer modeling studies were performed, and previously reported 5-HT3 receptor antagonist pharmacophore models were refined to include a key lipophilic binding domain.
1. RS-15385-197 ((8aR, 12aS, 13aS)-5,8,8a,9,10,11,12,12a,13,13a-decahydro- 3-methoxy-12-(methylsulphonyl)-6H-isoquino [2,1-g][1,6]-naphthyridine) was evaluated in a series of in vitro and in vivo tests as an antagonist at alpha 2-adrenoceptors. 2. RS-15385-197 had a pKi of 9.45 for alpha 2-adrenoceptors in the rat cortex (pA2 in the guinea-pig ileum of 9.72), whereas the 8aS, 12aR, 13aR enantiomer, RS-15385-198, had a pKi of only 6.32 (pA2 6.47) indicating a high degree of stereoselectivity. The racemate RS-15385-196 had a pKi of 9.18. 3. RS-15385-197 showed unprecedented alpha 2 vs. alpha 1 adrenoceptor selectivity in vitro. In the rat cortex, RS-15385-197 had a pKi of 9.45 in displacing [3H]-yohimbine and 5.29 in displacing [3H]-prazosin (alpha 2/alpha 1 selectivity ratio in binding experiments > 14000). The compound had a pA2 of 9.72 as a competitive antagonist of the inhibitory effects of UK-14,304 in transmurally-stimulated guinea-pig ileum and 10.0 against BHT-920-induced contractions in dog saphenous vein (DSV); this latter value was unaltered by phenoxybenzamine. An apparent pKB of 5.9 was obtained against cirazoline-induced contractions in DSV, whilst a pA2 of 6.05 was obtained against phenylephrine-induced contractions in the rabbit aorta (alpha 2/alpha 1 selectivity ratio in functional experiments > 4000). 4. RS-15385-197 was highly selective for alpha 2-adrenoceptors over other receptors: the compound showed low affinity for 5-HT1A (pKi 6.50) and 5-HT1D (pKi 7.00) receptor subtypes, and even lower affinity (pKi < or = 5) for other 5-HT receptor subtypes, dopamine receptors, muscarinic cholinoceptors, beta-adrenoceptors and dihydropyridine binding sites. RS-15385-197 was devoid of affinity for the non-adrenoceptor imidazoline binding site, labelled by [3H]-idazoxan, which provides further evidence that these sites are not related to alpha 2-adrenoceptors. In the DSV, contractile responses to 5-hydroxytryptamine (5-HT) were unaffected by a concentration of 1 microM RS-15385-197. 5. RS-15385-197 was non-selective for the alpha 2A- and alpha 2B-adrenoceptor subtypes in that the pKi for the alpha 2A-adrenoceptor in human platelets was 9.90 and the pKi for the alpha 2B-adrenoceptor in rat neonate lung was 9.70. However, RS-15385-197 showed lower affinity for the alpha 2-adrenoceptor subtype in hamster adipocytes (pKi 8.38). 6. In anaesthetized rats, RS-15385-197 was a potent antagonist of the mydriasis response induced by UK-14,304 or clonidine (AD50 5 and 7 microg kg-1, i.v., respectively; 96 microg kg-1, p.o.) and of UK-14,304-induced pressor responses in pithed rats (AD50 7 microg kg-1, i.v.); the compound therefore is both centrally and orally active. Even at a high dose (10 mg kg-1, i.v.), RS-15385-197 did not antagonize pressor responses to cirazoline in pithed rats, indicating that the selectivity for alpha2 vs. alpha1-adrenoceptors was maintained in vivo.8 RS-15385-197 is therefore a very potent, selective, competitive alpha2-adrenoceptor antagonist, both in vitro and in vivo, is orally active and readily penetrates the brain. It will thus be a powerful pharmacological tool for exploring the various physiological roles of alpha2-adrenoceptors.
1. The pharmacological properties of RS 23597-190 (3-(piperdine-1-yl)-propyl-4-amino-5-chloro-2-methoxy benzoate hydrochloride) have been studied in vitro and in vivo. 2. RS 23597-190 competitively antagonized 5-HT4 receptor-mediated relaxations of rat, carbachol precontracted oesophageal muscularis mucosae, (pA2 = 7.8 +/- 0.1; Schild slope = 1.2 +/- 0.2). Affinity estimates (-log KB) at 5-HT4 receptors using either renzapride or SC-53116 as agonists yielded a -log KB value of 8.0 +/- 0.01. In contrast, RS 23597-190 failed to antagonize contractile responses to 5-HT of guinea-pig ileal 5-HT3 receptors, even at concentrations up to 10 microM. 3. Increases in short-circuit current, induced by 5-HT, were studied in guinea-pig ileal mucosal sheets. Concentration-response curves to 5-HT were biphasic, with the high potency phase to 5-HT inhibited by RS 23597-190 and mimicked by 5-methoxytryptamine. The -log KB value for RS 23597-190 at the high potency phase was 7.3 confirming that 5-HT4 receptors mediated the high potency phase. 4. In rat isolated vagus nerve, 5-HT elicited a slow, maintained depolarization at low concentrations and a rapid, transient depolarization at higher concentrations. The high potency, slow depolarizing phase to 5-HT was abolished selectively in the presence of 1 microM RS 23597-190 and the low potency phase was abolished selectively in the presence of 1 microM ondansetron. These data confirm that 5-HT4 and 5-HT3 receptors mediated slow and fast depolarization responses, respectively. 5. At 5-HT3 binding sites in membranes from NG 108-15 cells, labelled by [3H]-quipazine, RS 23597-190 exhibited an apparent affinity (- log Ki) of 5.7 +/- 0.1. At 5-HT3 receptors in membranes from rat cerebral cortex, labelled by [3H]-RS 42358-197, the apparent affinity (- log Ki) of RS 23597-190 was also 5.7 +/- 0.1. In both studies, Hill coefficients were not significantly different from unity. At 5-HT1A, 5-HT2,muscarinic M1, M2, M3, M4 and dopamine D1 and D2 receptors, RS 23597-190 exhibited low apparent affinities, with all - log Ki values less than 5.5.6. Intravenous infusion of RS 23597-190 in the conscious, restrained rat antagonized the von Bezold Jarisch reflex induced by 2-methyl 5-HT, with an ID50 of 300 microg kg-1 min-1, i.v. In the anaesthetized,bilaterally vagotomized micropig, RS 23597-190 (6 mg kg-1, i.v.) antagonized 5-HT-induced tachycardia with a half-life of 77 (63-99) min. Transient arrhythmic effects were noted after administration of the compound.7. In conclusion, RS 23597-190 acts as a high affinity, selective competitive antagonist at 5-HT4 receptors. Thus, the compound appears to be a useful tool for 5-HT4 receptor identification in vitro. In vivo, the compound is rapidly metabolized in pigs such that 5-HT4 blockade is not maintained. However,in the rat, when given by infusion, RS 23597-190 antagonizes 5-HT3 mediated responses, at doses consistent with a low affinity 5-HT3 receptor. These data suggest that, under appropriate experimental conditions, RS 23597-190 may also be used in vivo to characterize further 5-HT4 receptor function.
Eighty-one elderly residents of a hostel for the aged (mean age 83.3 years) underwent clinical medical assessments to examine susceptibility to falling. The medical examination was structured and followed a clinical format with particular emphasis upon posture and gait, in addition to routine examination of the cardiovascular, respiratory, neurological, gastrointestinal, haemopoietic, genitourinary, musculoskeletal and visual systems. These subjects were then followed up for 1 year to assess whether these clinical measures were associated with falls. Seventy-six residents were available for follow-up. Thirty-four subjects (44.7%) reported having no falls in the follow-up year, 10 (13.2%) fell once only, 13 (17.1%) fell on two occasions whilst 19 (25.0%) fell three or more times. Seventy-two percent of all falls occurred in the hostel building. Certain clinical factors showed high specificity (i.e. only a few non-fallers screened positive in the tests) but low sensitivity (i.e. there were considerable numbers of residents who screened negatively, but fell in the 12-month follow-up period). Stepwise logistic regression analysis revealed impaired cognition, abnormal reaction to any push or pressure, history of palpitations and abnormal stepping as variables that independently and significantly predicted falling. The equation predicted falls with 70.7% sensitivity and 79.4% specificity, with an overall predictive accuracy of 74.7%. It appears that a modified focussed clinical examination could provide the basis of a short assessment for predicting falls and highlight possible intervention strategies for reducing fall risk.
A case is presented in which apparent non-mosaic trisomy 16 was found in chorionic villi (direct and culture) obtained from a patient undergoing first-trimester prenatal diagnosis. The fetal karyotype subsequently was determined to be 46,XX by follow-up amniocentesis. Serial ultrasonographic examinations revealed placental sonolucencies and intrauterine growth retardation. At 37 weeks, a small-for-gestational-age female was delivered by Caesarean section for fetal distress. Postnatal cytogenetic studies revealed a normal female karyotype in cord blood and mosaic trisomy 16 in placental tissues. These findings suggest that in cases where aneuploidy is confined to placental tissues, it may have biological significance, as evidenced by the apparent placental dysfunction and poor fetal growth in this case.
Recent developments in longitudinal statistical methodology have improved our ability to model dynamic processes such as adaptation to nursing homes. Longitudinal observations provide information on individual patterns of change and factors affecting them. However, longitudinal analyses are often complicated by unequal periods of observation and individual variability in patterns of change. This paper demonstrates the use of a linear mixed-effects model to study adaptation in a longitudinal nursing home study with different numbers of repeated measurements for each individual because of discharges, transfers, and mortality.
Using data from 441 newly admitted nursing home residents, we examined whether the diagnoses of mental illnesses, as well as other resident characteristics, were associated with use of physical restraints in both high restraint and low restraint use homes. Predictors of restraint use during both the first month and the first year of admission were inability to transfer and having a combination of severe ADL and cognitive impairment. Other predictors were wandering, inability to dress, symptoms of depression, and severity of cognitive impairment.
Analogues of the potent alpha 2-adrenoceptor antagonist (8aR,12aS,13aS)-5,8,8a,9,10,11,12,12a,13,13a- decahydro-3-methoxy-12-(methylsulfonyl)- 6H-isoquino[2,1-g][1,6]naphthyridine (1b) were prepared and evaluated for alpha 1- and alpha 2-adrenoceptor affinity. Affinity for alpha 2-adrenoceptors was assessed by displacement of [3H]yohimbine from rat cerebral cortical membranes and although 1b and close structural analogues demonstrated high affinity, none were selective for the alpha 2A or alpha 2B subtypes reputedly present in this tissue. All of the high affinity alpha 2-adrenoceptor ligands were, however, selective with respect to [3H]prazosin (alpha 1) binding. Affinity for [3H]yohimbine-labeled alpha 2-adrenoceptors was found to be highly dependent on the stereochemistry of the tetracyclic system. The 8a beta,12a alpha,13a alpha diastereomer of 1 (56) had moderate affinity for alpha 2-adrenoceptors while the 8a beta,12a beta,13a alpha diastereomer (55) had very low affinity. The affinity and selectivity of these agents for alpha 2-adrenoceptors was found to correspond to that observed for several isomeric yohimbine analogues which have similar relative and absolute stereochemistries. Deviation from the structure of 1 by opening the B ring, changing the position of the sulfonamide nitrogen, or changing the attachment of the D ring led to a dramatic decrease in alpha 2-adrenoceptor affinity. High binding affinity was found to correlate with functional antagonism in the guinea pig ileum. The reversal of clonidine-induced mydriasis in the rat was used to assess bioavailability and indicated that 1b was a potent alpha 2-adrenoceptor antagonist in vivo.
Visual acuity and contrast sensitivity were measured in 95 residents of a hostel for the aged (mean age = 83 years) using a dual-contrast letter chart and the Melbourne Edge Test (MET). Vision (as measured by visual acuity, the MET, low-contrast visual acuity, and difference between high- and low-contrast acuity) decreased significantly with age and all four measures were significantly correlated. Subjects with a clinical eye disorder had poorer vision than those without a disorder although the differences were not significant. Visual acuity and contrast sensitivity were not associated with body sway when subjects were standing on a firm base. However, when the subjects were placed in a situation which provided reduced support (standing on a compliant surface), body sway was associated with poor visual acuity and contrast sensitivity. There was also a difference in contrast sensitivity between those who fell one or more times in a year of follow-up and those who did not fall. It appears that reduced vision may be a predisposing factor to postural imbalance and falls in elderly persons.
A battery of 13 visual, vestibular, sensorimotor, and balance tests was administered to 95 elderly persons (mean age 82.7 years) to examine the relationships between specific sensorimotor functions and measures of postural stability. When subjects stood on a firm surface, increased body sway was associated with poor tactile sensitivity and poor joint position sense. When subjects stood on a compliant surface (which reduced peripheral sensation) with their eyes open, increased body sway was associated with poor visual acuity and contrast sensitivity, reduced vibration sense, and decreased ankle dorsiflexion strength as well as reduced joint position sense. Increased body sway with eyes closed on the compliant surface was associated with poor tactile sensation, reduced quadriceps and ankle dorsiflexion strength, and increased reaction time. Poor performance in two clinical measures of postural stability was associated with reduced sensation in the lower limbs as measured by joint position sense, tactile sensitivity and vibration sense, reduced quadriceps and ankle dorsiflexion strength, and slow reaction times. The prevalence of vestibular impairments was high in this group, but vestibular function was not significantly associated with sway under any of the test conditions. The results suggest that reduced sensation, muscle weakness in the legs, and increased reaction time are all important factors associated with postural instability. An analysis of the percentage increases in sway under conditions where visual and peripheral sensation systems are removed or diminished, compared with sway under optimal conditions, indicated that peripheral sensation is the most important sensory system in the maintenance of static postural stability.
OBJECTIVE: To determine whether a battery of 13 sensorimotor, vestibular, and visual tests discriminates between elderly fallers and elderly non-fallers. DESIGN: One-year prospective study. SETTING: Conducted at a 124-bed Hostel for Aged Persons, in Sydney, Australia. PARTICIPANTS: Ninety-five persons aged between 59 and 97 years (mean age 82.7 years) took part in the study. Of the 29 non-participants, four were ill, five were absent (on holidays, etc), and 20 declined. Residents were generally independent in activities of daily living although personal care assistance was available. RESULTS: Eighty-four participants were available for follow-up. In the follow-up year, 40 subjects experienced no falls, 11 subjects fell one time only, 33 residents fell on two or more occasions. There was a total of 145 falls. Discriminant function analysis identified proprioception in the lower limbs visual contrast sensitivity, ankle dorsiflexion strength, reaction time, and sway with the eyes closed as the variables that significantly discriminated between subjects who experienced multiple falls and subjects who experienced no falls or one fall only. This procedure correctly classified 79% of subjects into multiple faller or non-multiple faller groups. Quadriceps strength was poorer in the multiple fallers compared with the non-fallers and once-only fallers, although the difference was not statistically significant. There was little difference in the mean scores for the tests of vestibular function in the non-fallers, once-only fallers, and multiple fallers. CONCLUSION: It appears that this approach highlights some key physiological factors that predispose elderly individuals to falls.
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