bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of DOI-induced wet dog shakes in the guinea-pig by 5-HT2 receptor antagonists
Authors: Skingle Malcolm , Cole Nicola , Higgins Guy , Feniuk Wasyl
Published: March 2007

The preferential 5-HT 2/5-HT1C receptor agonist DOI (0.1-4 mg/kg s.c.) caused an increase in locomotor activity, grooming and 'wet-dog' shakes (WDS) in the adult guinea-pig. The DOI-induced WDS behaviour was potently inhibited by several antagonists that have high affinity for the 5-HT2 binding site. The WDS response is likely to be centrally-mediated since the effects of peripherally administered DOI were poorly antagonized by the peripherally-acting 5-HT2 receptor antagonist BW501C67. Although these studies do not exclude an effect of DOI at 5-HT1C receptors, the high potency of ketanserin and spiperone in attenuating the effects of DOI would suggest an effect at the 5-HT2 receptor. The present data suggest that antagonism of the directly-acting agonist DOI may be useful for assessing the selectivity and duration of action of centrally-acting 5-HT2 receptor antagonists in the guinea-pig.
Place avoidance conditioning with D-amphetamine: the effect of screening and the use of preferred and non-preferred sides
Authors: Hinson Riley E. , Wall Anne-Marie , Swayze Ian G.
Published: March 2007

The effect of screening animals to identify unconditioned preferences for stimuli used in subsequent place conditioning, and the effect of pairing drug injections with originally most or least preferred stimuli were investigated in place conditioning with 0.5 and 2.0 mg/kg D-amphetamine. A choice test to identify conditioned approach and avoidance responses was given after every two end compartment drug trials until a total of 10 choice tests had been given. During drug trials, the drug was injected 15 min after the animal was placed in the end compartment and the animal remained in the end compartment for 30 min following drug injection. In confirmation of previous research from our laboratory, during choice tests, animals avoided the end compartment that had been paired with D-amphetamine and this avoidance occurred regardless of whether the animals had been initially screened or not, and regardless of whether the originally most or least preferred stimuli were used as the drug-associated end compartment.
Flumazenil-precipitated withdrawal symptoms in chronic users of therapeutic doses of diazepam
Authors: Bernik Márcio A. , Gorenstein Clarice , Gentil Valentim
Published: March 2007

A prototype benzodiazepine (BDZ) antagonist, flumazenil (1 mg, i.v.) or placebo was administered to eight chronic users (5-15 years) of therapeutic doses of diazepam (10-25 mg/d), in a double-blind, placebo-controlled design in order to evaluate the presence of physiological dependence. The three patients receiving flumazenil developed anxiety reactions, with significant increases in bodily and psychological symptoms, as measured by rating scales. In two these amounted to a panic attack. Subjects on placebo tended to show decreases in measures of anxiety. The severity of precipitated reactions was not related to the total cumulative exposure to diazepam, but to a history of panic attacks. Previous panic may increase the vulnerability to severe reactions to flumazenil.
Lack of effect of a small dose of flumazenil in reversing short-term tolerance to benzodiazepines in normal subjects
Authors: Cittadini Andrea , Lader Malcolm
Published: March 2007

Twelve normal volunteers received two courses of 7 days of either lorazepam (2 mg every morning; six subjects) or oxazepam (30 mg every morning; six subjects). After one of the courses, 0.2 mg of flumazenil was injected, after the other placebo, using a balanced design and double-blind procedures. A test dose of the lorazepam or oxazepam was administered the day after the flumazenil or placebo. A battery of physiological and psychological tests was applied before and after the dose of benzodiazepine on days 1, 4, 8 and 10. The benzodiazepines had the expected effects on the EEG, and event-related potentials (ERP), impaired several psychological tests and induced drowsiness and relaxation. Some tolerance was seen with respect to anxiolytic effects, some EEG and ERP variables and some psychological tests, but not those of memory. Tolerance tended to be more apparent in the subjects given lorazepam than in the oxazepam-treated subjects. No effects of the small dose of flumazenil in reversing tolerance were apparent.
Effects of zinc gluconate and nedocromil sodium on performance deficits produced by the common cold
Authors: Smith A.P. , Tyrrell D.A.J. , Al-Nakib W. , Barrow I. , Higgins P. , Wenham R.
Published: March 2007

Two studies are reported on the effects of drugs on the performance impairments induced by experimentally- produced colds. The first study examined the effects of zinc gluconate on choice reaction time, and showed that the zinc removed the cold-induced performance impairment. The second experiment used nedocromil sodium and, again, the drug was effective in reducing the drop in performance observed in volunteers with colds. While the precise mode of action of these compounds is unclear it is speculated that one mechanism involves changes in trigeminal stimulation, and this could be responsible for both the clinical efficacy and CNS effects of these drugs.
Smoking deprivation and cigarette reinstatement: effects upon visual attention
Authors: Parrott A.C. , Roberts G.
Published: March 2007

Twenty regular smokers ( > 15 cigarettes/day), were tested on a letter cancellation task, over four successive days. On one of the test days subjects were smoking deprived for > 12 h, while on the other days they were not nicotine deprived (smoking was allowed until 1 h before testing). The first letter cancellation test was given prior to smoking. Then one cigarette was smoked and a second letter cancellation test given. Performance was significantly impaired by nicotine deprivation, when assessed both by response time (p < 0.05) and target detection (p < 0.001). Cigarette smoking led to significant improvements in both speed and accuracy with the deprived smokers. However, this improved performance basically reflected a return to near baseline values. The performance of the non-deprived subjects remained largely unchanged. There was no evidence of performance differences between high, mid and low frequency letter targets. Each showed an accuracy reduction of about 5% during smoking deprivation, and returned to baseline following nicotine reinstatement. Thus, while sustained attention was significantly influenced by nicotine status, there was no evidence of altered attentional selectivity.
Ketanserin and mianserin treatment reverses hyperactivity in neonatally dopamine-lesioned rats
Authors: Luthman J. , Fredriksson A. , Plaznik A. , Archer T.
Published: March 2007

Selective brain dopamine (DA) depletions in rats, induced by neonatal intracisternal administration of 6-hydroxydopamine (6-OHDA; 75 μg), caused spontaneous hyperactivity at the adult stage as measured using determinations of locomotion, rearing and total activity. Treatment with ketanserin (0.5 or 1.0 mg/kg, s.c.) reversed the hyperactivity in 6-OHDA-treated animals during a 90-min period following injection, although only the low dose of ketanserin reduced rearings. In control animals ketanserin treatment did not affect the locomotion or total activity counts, while the high dose of ketanserin increased rearings. Following treatment with mianserin (0.5 or 1.0 mg/kg, s.c.), a similar effect was seen; however, it was longer-lasting and mianserin treatment increased activity in controls. Regional analysis of monoamine levels demonstrated a marked reduction of basal forebrain DA levels, while in striatum an increase in serotonin (5-HT) concentration was seen following the 6-OHDA treatment. The results indicate that drugs with a high affinity to 5-HT2 binding sites can influence the hyperactivity seen in neonatally DA-lesioned rats. This effect might be related to inhibition of 5-HT pathways directly involved in regulation of motor activity or due to alterations in the interaction between the DA and 5-HT systems as a consequence of the early DA lesion.
Assessment of the interaction between a partial agonist and a full agonist of benzodiazepine receptors, based on psychomotor performance and memory, in healthy volunteers
Authors: Patat A. , Perault M.C. , Vandel B. , Danjou Ph. , Brohier S. , Zieleniuk I. , Rosenzweig P.
Published: March 2007

Potential interactions between the imidazopyridine anxiolytic alpidem and the full benzodiazepine agonist lorazepam were assessed in a randomized, double-blind, four-way cross-over, placebo-controlled study in 16 healthy young male volunteers. Each volunteer received alpidem, 50 mg, or a placebo twice daily for 8 days with a 1- week wash-out interval. The interaction between alpidem, at the steady state, and a single oral dose of lorazepam 2 mg or a placebo was assessed after concomitant administration on days 7 or 9 of each treatment period. Psycho motor performance and cognitive function were evaluated before and 2, 4, 6 and 8 h post-dose, using objective tests [critical flicker fusion threshold (CFF), choice reaction time (CRT), digit-symbol substitution (DSST), body sway and short-term memory (Sternberg memory scanning)] and self-ratings [line analogue rating scales: (LARS)]. Long-term memory (delayed free recall and recognition of pictures) was assessed before the dose and 2 and 4 h post-dose. Pharmacodynamic interactions were evaluated by applying repeated measures ANOVA to a 2 x 2 factorial interaction model. Alpidem, 50 mg twice daily at the steady state, was free of any clinically relevant detrimental effects on skilled performance, information processing or memory. In contrast, a single 2 mg dose of lorazepam induced marked impairment of psychomotor performance and cognitive function (significant reductions in CFF and DSST and increases in CRT and body sway), as well as subjective sedation from 2 to 8 h post-dose, depending on the test used. In addition, lorazepam induced anterograde amnesia, characterized by a decrease in delayed free recall and recognition, and a deficit in short-term memory. Finally, alpidem 50 mg did not potentiate the detrimental effects of lorazepam 2 mg. On the contrary, alpidem significantly antagonized the lorazepam-induced CRT increase and anterograde amnesia, and produced similar trends on most of the other cognitive parameters; thus, the results obtained with the combination of alpidem and lorazepam consistently indicated less impairment than those measured after lorazepam alone. These results are consistent with the suggested partial agonsist properties of alpidem at the benzodiazepine receptor and indicate that such properties can be assessed in humans based on antagonism of the effects of a full agonist.
An assessment of resedation following flumazenil-induced antagonism of intravenous midazolam: comparison of psychomotor and amnesic recovery with a non-sedated reference group
Authors: Birch B.R.P. , Miller Ronald A.
Published: March 2007

The specific benzodiazepine antagonist flumazenil can enhance patient recovery following local anaesthetic day-case surgery performed under sedation. However, in view of its short elimination half-life, concerns have been expressed about the risk of resedation following its use. An open, randomised, parallel group study was designed to explore this question. Eighty-five patients were studied. Group A (n=43) patients underwent local anaesthetic cystoscopy with intravenous (i.v.) midazolam sedation. Following cystoscopy, and 30 min after the injection of midazolam, a bolus dose of flumazenil (0.5 mg i.v.) was given. Group B (n=42) patients underwent no operation and received no drugs but, in all other respects, were treated in an identical fashion to patients in group A. Tests of psychomotor function and memory were administered at baseline and again at 0.5, 1, 2, 3 and 4 h (or equivalent times for group B patients) following the injection of flumazenil. The test results showed no evidence of resedation, but there was evidence of incomplete reversal, as shown by significant differences in critical flicker fusion and delayed word recall at the 0.5-h test point. Group B patients showed no evidence of practice effects but did demonstrate an impairment in test performance possibly related to motivational factors. In conclusion, this study provides no evidence of resedation when using flumazenil to reverse the acute effects of midazolam. Incomplete reversal of amnesia need not delay patient discharge but has important implications with respect to the timing and nature of information imparted to patients prior to their release from hospital.
The effects of sub-anaesthetic doses of ketamine on memory, cognitive performance and subjective experience in healthy volunteers
Authors: Harborne Giles C. , Watson Frances L. , Healy David T. , Groves Lyndsay
Published: March 2007

The cognitive and subjective effects of sub-anaesthetic doses of ketamine on healthy volunteers were examined. Twelve healthy volunteers received 25 mg ketamine, 10 mg ketamine and saline placebo, i.m. in a double-blind, Latin square design. A cognitive, perceptual and self-report test battery was administered over 45 min. The order of tests was rotated to control for timing effects. Ketamine (25 mg) significantly affected verbal learning and memory, parallel visual search, some measures of psychomotor performance, measures of arousal, subjective mood ratings and visual perception. Measures of attention and frontal lobe functioning were relatively unaffected. Thus, low doses of ketamine had selective, dose-related effects on memory, perceptual and psychomotor functions. The disruption of memory and perceptual processes may help to explain the unique subjective state induced by ketamine.
Discriminative stimulus produced by the imidazoline I2 site ligand, 2 -BFI
Authors: Jordan S. , Jackson H.C. , Nutt D.J. , Handley S.L.
Published: March 2007

2-(2-Benzofuranyl)-2-imidazoline, RX801077 (2-BFI) which has high affinity for imidazoline I2 binding sites and very low aflinity for α2-adrenoceptors, has been investigated for its ability to produce a discriminative stimulus (cue) in drug-discrimination studies in rats since the existence of such a cue could assist in determining the functionality of I2 sites. All rats subjected to training proved able to discriminate the training dose of 2-BFI (33 μmol/kg i.p) from saline vehicle and lower (5-14 μmol/kg) doses exhibited dose-dependent substitution. The mixed α2-adrenoceptor/I 2 site ligand idazoxan fully substituted at 40μmol/kg. However, ethoxy idazoxan (11 μmol/kg) and fluparoxan (13 μmol/kg), selective α 2-adrenoceptor antagonists, also fully substituted for 2- BFI as did the monoamine oxidase (MAO) inhibitors moclobemide (99 μmol/kg) and pargyline (153 μmol/kg). A lower dose of moclobemide (16 μmol/kg) exhibited partial substitution. The α 2-adrenoceptor agonists clonidine (0.1 μmol/kg) and guanabenz (1.4 μmol/kg), and the benzodiazepine diazepam (14 μmol/kg), failed to substitute for 2-BFI indicating cue specificity. However, 2-BFI (14-50 μmol/kg) substituted partially but dose-dependently for clonidine (0.1 μmol/kg) in rats trained to distinguish the latter from saline. Changes in rates of response were independent of the degree of substitution. The observed pattern of drug substitution is consistent with the previously reported ability of 2-BFI to decrease MAO activity and thus increase extracellular monoamines.
The effect of central and systemic injection of the 5-HT1A receptor agonist 8-OHDPAT and the 5-HT1A receptor antagonist WAY100635 on periaqueductal grey-induced defence behaviour
Authors: Beckett S. , Marsden C.A.
Published: March 2007

The effects of the selective 5-HT1A agonist, 8-hydroxy-2-(di- n-propylamino)-tetralin (8-OHDPAT) and the selective 5-HT1A antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperzinyl]ethyl]-N-(pyridinyl) cyclohexanecarboxa mide trichloride (WAY100635) on periaqueductal grey (PAG)-stimulated defence behaviour were tested in the rat. Microinjection of the excitatory amino acid, D, L-homocysteic acid (DLH) into the dorsal region of the PAG produced overt aversive behaviour characteristic of the defence response, consisting of explosive motor behaviours which were quantified in terms of their duration and the number of arena revolutions and jumps made by the animal. Intra-PAG pre-treatment with 8-OHDPAT (3, 10 and 25 nmol in 250 nl) 10 min before DLH stimulation significantly attenuated the defence behaviour. This could be reversed by peripheral application of WAY100635 (0.1 mg/kg). In contrast, peripheral 8-OHDPAT (0.03, 0.1 and 0.3 mg/kg) produced a significant potentiation of the DLH response which could also be blocked by peripheral WAY100635. When WAY100635 (10 nmol in 250 nl) alone was given into the PAG a significant increase in DLH induced behaviours was observed whereas peripherally applied WAY100635 (0.1 mg/kg) was without effect. These data support previous findings which indicate that serotonergic modulation of aversive behaviours such as defence can be mediated by 5-HT 1A receptors. Furthermore there is evidence to indicate a differential involvement of pre- and post synaptic 5-HT1A receptors.
Abuse liability of testosterone
Authors: Fingerhood Michael Ira , Sullivan John Tangney , Testa Margaret , Jasinski Donald R.
Published: March 2007

Anabolic-androgenic steroids (AAS) are used by athletes to enhance performance and physique. Case reports and observations propose that AAS have mood elevating properties and that chronic use leads to addiction. The aim of this study was to evaluate the subjective and physiological effects of single doses of testosterone. In a double-blind fashion, according to a balanced Latin square, 10 paid adult male volunteers received doses of i.m. testosterone (50, 100 and 200 mg), morphine (10 mg) or placebo for five consecutive days. Subjective and physiological responses were measured during each drug condition. Testosterone produced no significant changes in self-reported or observed measures, unlike morphine, which produced statistically significant changes in several measures, including 'feel the drug', 'like the drug' and 'feel high'. There were no adverse effects of administering high doses of testosterone. In conclusion, single doses of testosterone are devoid of the usual pharmacologic effects that are associated with abuse.
Risperidone in the treatment of schizophrenia: a meta-analysis of randomized controlled trials
Authors: Fujian Song
Published: March 2007

This study evaluates the relative effectiveness and side-effects of risperidone as compared with conventional neuroleptics in the treatment of schizophrenia, by meta-analysis of 11 double-blind, randomized controlled trials. The proportion of patients showing clinical improvement; use of medications for extrapyramidal side- effects (EPS); the treatment drop-out rates; and the changes in negative PANSS scores were measured. Compared with conventional neuroleptics, slightly more patients in the risperidone group showed clinical improvement [57 vs 52%; odds ratio 1.27, 95% confidence interval (CI): 1.04, 1.56]. The use of concomitant medications for EPS was significantly less in the risperidone group than in the conventional neuroleptic group (22.8 vs 38.4%; odds ratio 0.51, 95% CI: 0.41, 0.63). The overall drop-out rate was lower in the risperidone group than in other neuroleptic group (29.1 vs 33.9%; odds ratio 0.75, 95% CI: 0.61, 0.94). The difference in changes in negative PANSS score between the risperidone and the haloperidol group was —0.74 (95% CI: -1.50, 0.02). Weight gain and tachycardia are more common in patients treated with risperidone. Sensitivity analysis of different analytic approaches did not materially change the main estimates. It was concluded that the short- term efficacy of risperidone is comparable to other neuroleptics in the treatment of schizophrenia. It is associated with significantly fewer EPS than conventional neuroleptics (mainly haloperidol).
Is carbamazepine a potential drug of abuse?
Authors: Sullivan Gary , Davis Stephen
Published: March 2007

A case is reported of a 20-year-old female student who had been abusing carbamazepine with alcohol and described a resulting sense of euphoria. The literature is reviewed for evidence to support this claim, and possible mechanisms to account for the euphorigenic effect of alcohol and carbamazepine are discussed.
Psychopharmacological profile of the selective serotonin reuptake inhibitor, paroxetine: implication of noradrenergic and serotonergic mechanisms
Authors: Redrobe John P. , Bourin Michel , Colombel Marie Claude , Baker Glen B.
Published: March 2007

The present study was designed to evaluate the psychopharmacological profile of the selective serotonin reuptake inhibitor paroxetine, and thus assess potential noradrenergic and/or serotonergic activity. Paroxetine dose-dependently increased mobility time in the mouse forced swimming test (8, 16, 32 and 64 mg/ kg, i.p.) and reduced spontaneous locomotor activity when administered at a high dose (64 mg/kg, i.p.). Prior administration of 8-hydroxy-2-(di- n-propylamino)tetralin (1 mg/kg, i.p.), (±) pindolol (32 mg/kg, i.p.) or 5- methoxy-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (RU 24969) (1 mg/kg, i.p.) potentiated the antidepressant- like effects of subactive doses of paroxetine (1, 2 and 4 mg/kg, i.p.) in the mouse forced swimming test. These effects were antagonized by prior administration of 1-(2-methoxyphenyl)-4-[-(2-phthalimido)butyl]piperazine) (0.5 mg/kg, i.p.). Complementary studies suggested that RU24969-induced anti-immobility effects were a result of an increase in locomotor activity; other interactions were without increase/decrease in locomotor activity. Acute administration of paroxetine (8,16, and 32 mg/kg, i.p.) antagonized the hypothermia induced by the D2/D1receptor agonist, apomorphine (16 mg/kg, s.c.), while repeated treatment with paroxetine (32 mg/kg) attenuated clonidine-induced (0.5 mg/kg, i.p.) hypothermia. Pre-treatment with the serotonergic neurotoxin, para chlorophenylalanine attenuated the anti-immobility effects of low doses of paroxetine (8 and 16 mg/kg, i.p.) in the forced swimming test, whereas a higher dose of paroxetine remained active (32 mg/kg, i.p.). The results of the present study indicated that paroxetine displayed both noradrenergic-like and serotonergic-like activity in the pre-clinical psychopharmacological tests employed.
Sertraline, a selective serotonin reuptake inhibitor modulates extracellular noradrenaline in the rat frontal cortex
Authors: Thomas D. Nigel , Nutt David J. , Holman R. Bruce
Published: March 2007

The selective action of selective serotonergic reuptake inhibitors (SSRIs) on 5-hydroxytryptamine (5-HT) neurotransmission underlies the therapeutic effectiveness of this class of drugs. Yet there is increasing evidence that changes in extracellular 5-HT content may result in changes in the regulation of other neurotransmitter systems. The present study examines the effects of acute and chronic administration of the SSRI sertraline on release of endogenous noradrenaline (NA) in the frontal cortex and hippocampus of the rat using in vivo microdialysis. Acute administration of sertraline did not significantly alter NA release in either the cortex or the hippocampus. However, 24 h after chronic (14 days) administration of the drug (10 mg/kg i.p. once daily), NA release in the cortex but not hippocampus was significantly enhanced. The lack of an effect on NA release following a challenge with the α2-antagonist idazoxan suggests that chronic drug treatment has reduced the sensitivity of cortical pre-synaptic α2-adrenoceptors, activation of which would normally inhibit further NA release. The possible mechanisms underlying the regional specificity of the effect of chronic and not acute sertraline administration and the implications of these results for our understanding of depression are discussed.
The novel buspirone analogue, 8-[4-[2-(1,2,3,4-tetrahydroisoquinolinyl) [butyl]-8 -azaspiro[4.5] decane-7,9 dione, with anxiolytic-like and antidepressant-like effects in rats
Authors: Dereń-Wesolek Anna , Tatarczyńska Ewa , Chojnacka-Wójcik Ewa
Published: March 2007

In the conflict drinking test, used as a model to examine anxiolytic-like activity, the novel buspirone analogue 8- [4-[2-(1,2,3,4-tetrahydroisoquinolinyl)]butyl)-8-azaspiro[4.5]decane-7,9-dione (MM199) (0.62-2.5 mg/kg) and buspirone (0.62-5 mg/kg), significantly increased the punished drinking in water-deprived rats, without affecting water consumption or perception of the stimulus. The anticonflict activity of MM199 (1.25 mg/kg) was blocked by (S)-WAY 100135 (20 mg/kg), a 5-hydroxytrypatmine1A (5-HT1A) receptor antagonist. In the forced swimming test, used as a model to examine the antidepressant-like activity, MM199 (5-20 mg/kg) reduced the immobility time, while buspirone (5-20 mg/kg) had no such effect. The reduced immobility induced by MM199 (20 mg/kg) was antagonized by (S)-WAY100135 (10 mg/kg). The above findings suggest that MM199 possesses potent anxiolytic- and antidepressant-like properties which are mediated by activation of 5- HT1A receptors.
A Clinical Decision Analysis Program for the Apple Computer
Authors: Silverstein Marc D.
Published: March 2007

A computer program written in BASIC and implemented on a 48K RAM Apple II computer was developed to assist physicians in using decision analysis to solve clinical problems. Clinicians familiar with decision analysis can easily enter, modify, store, and retrieve decision trees. Probabilities and utilities can be calculated and a sensitivity analysis can be performed and printed. An entire decision tree can be listed, and a graphic display of any node with its branches, branch probabilities, and node utilities can be viewed and printed. The program is easy to use and can be learned in a few hours. Its flexibility and power will facilitate the application of decision analysis to a wide variety of clinical problems. (Med Decis Making 3:29-37, 1983)
Radionuclide Detection of Biliary Atresia
Authors: Politser Peter E.
Published: March 2007

This paper illustrates the conceptual framework for test evaluation developed in the preceding paper. Reanalysis of published data, guided by this framework, contradicts preliminary conclusions about the limited statistical discrimination of a radionuclide scan to discriminate neonatal hepatitis from biliary atresia. It also clarifies the need in future evaluations to consider a number of factors not mentioned in many previous studies. (Med Decis Making 5:437-446, 1985)
Eliciting Preferences for Alternative Cancer Drug Treatments
Authors: Cormier O'Connor Annette M. , Boyd Norman F. , Tritchler David L. , Kriukov Yuri , Sutherland Heather , Till James E.
Published: March 2007

In oncology there is increasing interest in the development of techniques to help patients choose between alternative therapies in ways that are consistent with their preferences. The purpose of this study was to examine some methodological problems associated with the elicitation of preferences. Preferences for alternative drug therapies were sought from 208 visitors to an open house at the Ontario Cancer Institute and from 216 university nursing students. Preferences were not significantly dependent on the sex, age or professional status of the respondents, nor on the medium used for elicitation of preferences (computer terminal versus pencil-and-paper questionnaire). In contrast, the importance of the way decision problems are framed was confirmed. Comparison of a positive frame (outcomes expressed as the probability of surviving) with a negative frame (outcomes expressed as the probability of dying) and a mixed frame (probabilities of surviving and dying were both given) pointed to the presence or absence of the word "survive" in the outcome description as the main source of framing bias. The framing effect was in the opposite direction to that hypothesized. (Med Decis Making 5 :453-463, 1985)
Probabilistic Analysis of Decision Trees Using Monte Carlo Simulation
Authors: Critchfield Gregory C. , Willard Keith E.
Published: March 2007

The authors describe methods for modeling uncertainty in the specification of decision tree probabilities and utilities using Monte Carlo simulation techniques. Exact confidence levels based upon the underlying probabilistic structure are provided. Probabilistic measures of sensitivity are derived in terms of classical information theory. These measures identify which variables are probabilistically important components of the decision. These techniques are illustrated in terms of the clinical problem of anticoagulation versus observation in the setting of deep vein thrombosis during the first trimester of pregnancy. These methods provide the decision analyst with powerful yet simple tools which give quantitative insight into the structure and inherent limitations of decision models arising from specification uncertainty. The tech niques may be applied to complex decision models. Key words: decision analysis; sensitivity analysis; statistical analysis; statistical confidence; information theory. (Med Decis Making 6:85-92, 1986)
Probabilistic Analysis of Decision Trees Using Symbolic Algebra
Authors: Willard Keith E. , Critchfield Gregory C.
Published: March 2007

Uncertainty in medical decision making techniques occurs in the specification of both decision tree probabilities and utilities. Using a computer-based algebraic approach, methods for modeling this uncertainty have been formulated. This analytic procedure allows an exact calculation of the statistical variance at the final decision node using automated symbolic manipulation. Confidence and conditional confidence levels for the preferred decision are derived from gaussian theory, and the mutual information index that identifies probabilistically important tree variables is provided. The computer-based algebraic method is illustrated for a problem previously analyzed by Monte Carlo simulation. This methodology provides the decision analyst with a procedure to evaluate the outcome of specification uncertainty, in many decision problems, without resorting to Monte Carlo analysis. Key words: decision analysis; sensitivity analysis; statistical analysis; symbolic algebra; statistical confidence; information theory. (Med Decis Making 6:93-100, 1986)
An Exponential Model Used for optimal Threshold selection on ROC Curues
Authors: England William L.
Published: March 2007

A two-parameter exponential equation for modeling a receiver operating characteristic (ROC) curve is presented, where the area under the curve is a simple function of one of the parameters. The model makes no distributional assumptions about the underlying normal and abnormal patient populations or about the shape of the resulting ROC curves. In a computer simulation of 75 ROC curves, the model provides a fit equivalent to the maximum likelihood estimate method commonly used for ROC curve fitting. Similar results are obtained using the model to fit ROC curve data from the literature. The model's equation calculates the true-positive ratio as a function of the false-positive ratio, and has a first derivative that is useful for finding the optimal decision threshold for a diagnostic testing procedure. In particular, the model is useful in a computer program for finding jointly optimal thresholds for multiple sequential tests. Key words: receiver operating characteristic (ROC) curve; decision theory; optimization; computer simulation. (Med Decis Making 8:120-131, 1988)
The Robustness of the "Binormal" Assumptions Used in Fitting ROC Curves
Authors: Hanley James A.
Published: March 2007

The binormal form is the most common model used to formally fit ROC curves to the data from signal detection studies that employ the "rating" method. The author lists a number of justifications that have been offered for this choice, ranging from theoretical considerations of probability laws and signal detection theory, to mathematical tractability and convenience, to empirical results showing that "it fits!" To these justifications is added another, namely that even if an alternative formulation based on another underlying form (e.g., power law) or model (e.g., binomial, Poisson, or gamma type distributions) were in fact correct, the binormal fit differs so little from the true form as to be of no practical consequence. Moreover, the small lack of fit is unlikely to be demonstrated in practice: it is obscured by the much larger variation that can be attributed to sampling of cases. In addition, even if a very large sample of cases could be studied, the small number of rating categories used does not permit seemingly very different models to be distinguished from one another. Key words: binormal assumptions; ROC curves; signal detection theory; rating method. (Med Decis Making 8:197-203, 1988)
Making Moral Decisions on a Double-blinded Drug Trial in Progress without Breaking the Code
Authors: Allen Allen D.
Published: March 2007

The double blinding of drug trials to prevent bias deprives physicians of information they need in order to comply with their duty to treat patients and do them no harm. This ethical dilemma can be ameliorated with a standard statistical method known as posterior analysis. The clinical researcher can use posterior analysis to calculate the probability that a patient in a double-blinded drug trial is in the placebo group, based on the patient's clinical status. The clinician can also calculate the probability that the drug is safe and efficacious, as compared with the placebo, without breaking the code.
Sequential Decision Making with Continuous Disease States and Measurements
Authors: Schechter Clyde B.
Published: March 2007

The model and strategy for sequential decision making using normally distributed measure ments proposed in a companion paper are applied to the problem of diagnosing diastolic hypertension. The assumptions of the model are discussed and justified clinically. Methods for assigning values to the model's parameters are explained and illustrated in the context of a hypothetical "generic" patient. Although current national recommendations and the sequential strategy both lead to an average of 1.89 measurements per patient prior to diagnosis, the sequential strategy applies a sequence of four or more measurements to 12% of patients. Fewer than 1% of patients would require ten or more measurements under this strategy. The sequential strategy leads to fewer patients' receiving unnecessary treatment and substantially higher expected utility for the patient. The role of multiple blood pressure determinations per visit is explored in the absence of appropriate estimates. Even under "best-case" assumptions, however, it is shown that obtaining more than one observation per visit is called for only in about 15% of visits. While the exact role of multiple determinations cannot be specified from existing data, it is likely to be much more limited than current recommendations suggest.
Information Gathering and Integration as Sources of Error in Diagnostic Decision Making
Authors: Gruppen Larry D. , Wolf Fredric M. , Billi John E.
Published: March 2007

This research examined the relative importance of information gathering versus information utilization in accounting for errors in diagnostic decision making. Two experiments compared physicians' performances under two conditions: one in which they gathered a limited amount of diagnostic information and then integrated it before making a decision, and the other in which they were given all the diagnostic information and needed only to integrate it. The physicians. 1) frequently failed to select normatively optimal information in both experimental conditions; 2) were more confident about the correctness of their information selection when their task was limited to information integration than when it also included information gath ering; and 3) made diagnoses in substantial agreement with those indicated by applying normative procedures to the same data Physicians appear to have difficulties recognizing the diagnosticity of information, which often results in decisions that are pseudodiagnostic or based on diagnostically worthless information. Key words. diagnostic reasoning; infor mation gathering; information integration; Bayes' theorem; medical decision making (Med Decis Making 1991;11:233-239)
Eualuation of Nonlinear Optimization for Scheduling of follow-up cystoscopies to Detect Recurrent Bladder Cancer
Authors: Kent Daniel L. , Nease Robert A. , Sox Harold C. , Shortliffe Linda D. , Shachter Ross
Published: March 2007

Standard recommendations for patients who have had superficial bladder cancer are in spection by cystoscopy quarterly for a year or two after tumor removal, then half-yearly and yearly. The authors assessed the potential for improvement in scheduling cystoscopies according to probabilistic optimization techniques. Eight hypothetical practices were created, based on retrospective analysis of 918 bladder-cancer-patient charts. Standard and alter native recommendations for the interval to next cystoscopy were compared. The alternatives were derived from patient-specific predictions of future tumor risks (based on the patient's prior recurrence rate and tumor stage and grade) and a nonlinear optimization approach to allocation of the same number of cystoscopies as were available for standard follow-up. The optimization proposed longer intervals between visits for low-risk patients and shorter inter vals for high-risk patients. Overall, optimization reduced expected tumor detection delays by 30%, from 12.6 to 8.7 weeks. When optimization intervals were shorter than standard, cancer was found more often at subsequent cystoscopies (34% vs 27%, p < 0.05), suggesting that the optimization was a better predictor of cancer recurrence. If reduction in tumor-detection delay is the goal of follow-up for recurrent cancers, then urologists can improve monitoring by using probabilistic optimization methods for scheduling cystoscopies. Further understand ing of the accuracy of predictive models for bladder-cancer recurrence rates is desirable. Subsequently, the optimization method developed here may be tested prospectively. Key words: bladder cancer; nonlinear optimization; operations research; follow-up studies; mon itoring; cystoscopy; health services; decision analysis. (Med Decis Making 1991;11:240- 248)
A Model for Planning Optimal Follow-up for Outpatients on Warfarin Anticoagulation
Authors: Kent Daniel L. , Vermes Domokos , McDonell Mary , Henikoff Jorja , Fihn Stephan D.
Published: March 2007

Patients taking warfarin for long-term anticoagulation require frequent clinic visits to monitor the prothrombin time ratio (PTR), a measure of blood clotting. A dynamic stochastic model using nonlinear optimization was developed to select follow-up visit intervals that minimize the overall costs of patient care. Assuming that fluctuations in a patient's PTR behave as a random diffusion process, future PTR fluctuations are unknown, except as revealed by past PTRs. To determine the incidence and costs of complications in relation to PTR, the authors reviewed the charts of 216 patients who had 719 patient-years of follow-up with 695 trivial, significant, life-threatening, or fatal complications. They modeled the relationship between costs of complications and deviation of the PTR from the therapeutic target as a fourth-order convex polynomial. The model is used to compute the interval to the next follow-up visit to minimize accumulated potential costs. Variables in the optimization are the cost of a mon itoring visit and the expected costs of complications. The latter are derived from the current PTR, the variability of the patient's past PTR values, the number of past PTRs available, and the target PTR for the patient. No attempt is made to predict the level of the next PTR or suggest adjustments in the warfarin dose. Shorter follow-up is recommended for patients who have histories of large fluctuations in past PTRs and for patients with few prior PTR determinabons. As visits accumulate, the patient's degree of variability can be estimated more accurately and visit intervals adjusted accordingly The scheduling method balances costs to the health care system of monitoring each patient against the expected costs of complications. This approach has the potential to reduce the number of monitoring visits necessary for safe management of anticoagulated patients with stable PTRs and to improve control among unstable patients. Key words: warfarin; anticoagulation, ambulatory care; follow-up studies; stochastic processes. (Med Decis Making 1992;12:132-141)
Hormonal Replacement Therapy
Authors: Elstein Arthur S. , Holzman Gerald B. , Belzer Laurie J. , Ellis Ruth D.
Published: March 2007

The authors investigated strategies employed by resident physicians to decide whether to prescribe hormonal replacement therapy (HRT) for menopausal women, a matter of contin uing clinical controversy. Verbal protocols were obtained from 21 residents in three specialties as they responded to 12 brief case descriptions. The cases incorporated three levels of cancer risk and two levels of osteoporosis risk in a 3 x 2 factorial design with two replications in each cell. Substantial variation in willingness to prescribe HRT was observed. By clustering subjects with relatively similar approaches to the problem, three treatment strategies were formulated that accounted for the decisions of 20 subjects. Each strategy is a simplified representation of the conflicting considerations in this clinical dilemma that facilitates rapid decision making. The differences between these representations and formal decision-analytic models help to explain why observed clinical decisions were inconsistent with expected utility maximization. Key words: hormonal replacement therapy; decision making; subjective prob ability estimates; regret; intuitive clinical reasoning. (Med Decis Making 1992;12:265-273)
Integrating Stratum-specific Likelihood Ratios with the Analysis of ROC Curves
Authors: Peirce John C. , Cornell Richard G.
Published: March 2007

Data used to construct receiver operating characteristic (ROC) curves and to calculate the area under the curve (ROC AUC) can be used to derive stratum-specific likelihood ratios (SSLRs) with their 95% confidence intervals (95% Cls). The purpose of this study was to determine whether useful information can be obtained by adding SSLRs to the analysis of ROC curves. The authors analyzed four previously reported sets of data: 1) serum creatine kinase (SCK) for diagnosing acute myocardial infarction (AMI) in the coronary care unit (CCU); 2) SCK in the evaluation of chest pain in the emergency center (EC); 3) four predictor variables in the diagnosis of strep throat; and 4) the ordinal assessment of computed tom ographic (CT) images. Use of SCK in the CCU produced four strata that had posttest probabilities that were highly discriminating, whereas SCK in the EC resulted in only two strata with limited discriminating ability. In either study the cutpoint at which the SSLR changed from less than to greater than 1.0 was higher than the reported upper normal for the test, thereby quantitating spectrum bias. The maximum number of strata of predictor signs and symptoms for strep throat was three rather than the five used in previous studies. With a larger sample size or pooling, four strata could probably be developed. With CT images, "definitely normal," "probably normal," and "questionable" were collapsed to one negative stratum. "Probably abnormal" became the true "questionable" stratum and "defi nitely abnormal" was the only positive stratum. The authors conclude that additional useful information is obtained by deriving stratum-specific likelihood ratios as part of the analysis of an ROC curve. Key words: diagnosis; decision making; ROC curves; likelihood ratios. (Med Decis Making 1993;13:141-151)
Healthy-years Equivalents versus Quality-adjusted Life Years
Authors: Mehrez Abraham , Gafni Amiram
Published: March 2007

The authors respond to the contention that healthy-years equivalents (HYEs) do not fulfil claims they previously made. They refute the argument for the equivalence of the two-stage lottery and the time tradeoff and show that it fails to recognize the difference between choice problems under uncertainty versus certainty. They also dismiss the claim that HYEs assume risk neutrality with respect to healthy years of life, and show that HYEs are superior to the "general" (risk-averse) form of QALYs because HYEs employ fewer assumptions; in partic ular, they do not assume a specific form of the individual's utility function. The examples they used earlier are demonstrated to be conclusive, and the authors respond to arguments about the practical aspects of using HYEs vs QALYs. Finally, they take issue with the assumption that the roots of the QALY model are all attributable to utility theory. Key words: quality-adjusted life years; healthy-years equivalents; medical decision making; individual preferences; time tradeoff; standard gamble; utility theory. (Med Decis Making 1993;13:287- 292)
Collaborative Medical Decision Making
Authors: Christensen Caryn , Larson James R.
Published: March 2007

Collaborative decision making occurs whenever two or more individuals contribute their diverse knowledge and expertise to the decision-making process. In medicine, this happens during morning rounds, case conferences, consultations, and elsewhere. This paper presents an analysis of collaborative medical decision making, focusing on two factors that can powerfully influence the kind of information that gets discussed, and hence the nature of the decisions that are made. These are 1) the pre-discussion distribution of problem-relevant information/knowledge, and 2) each participant's awareness of other individuals' knowledge and talents. The authors review previous psychological research on group decision making that concerns these factors, and call attention to several lines of inquiry that might fruitfully be pursued in clinical settings. Key words: decision making; group decisions; group process; collaborative diagnoses. (Med Decis Making 1993;13:339-346)
Determining Transition Probabilities
Authors: Miller Douglas K. , Homan Sharon M.
Published: March 2007

Confusion regarding proper use of the terms rate and risk persists in the literature. This has implications for the proper modeling of prognosis and transition between health states in decision analysis and related techniques. The issue is complicated by the plethora of terms related to rate and risk. Although the suggestion to use the terms force and probability as substitutes for rate and risk has some appeal, the change in terminology by itself is unlikely to solve all the confusion or misuse of terms. This paper clarifies the proper definitions and estimations of rates and risks and suggests critical factors for the decision analyst to re member when using, modeling, or interpreting transition rates and risks. Key words: decision models; rate; risk; force; probability; transitions. (Med Decis Making 1994;14:52-58)
ROC Curves for Classification Trees
Authors: Raubertas Richard F. , Rodewald Lance E. , Humiston Sharon G. , Szilagyi Peter G.
Published: March 2007

A common problem in medical diagnosis is to combine information from several tests or patient characteristics into a decision rule to distinguish diseased from healthy patients. Among the statistical procedures proposed to solve this problem, recursive partitioning is appealing for the easily-used and intuitive nature of the rules it produces. The rules have the form of classification trees, in which each node of the tree represents a simple question about one of the predictor variables, and the branch taken depends on the answer. The authors consider the role of misclassification costs in developing classification trees. By varying the ratio of costs assigned to false negatives and false positives, a series of clas sification trees are generated, each optimal for some range of cost ratios, and each with a different sensitivity and specificity. The set of sensitivity-specificity combinations define a curve that can be used like an ROC curve. Key words: recursive partitioning; receiver operating characteristic; decision tree; misclassification; CART. (Med Decis Making 1994;14:169-174)