Feasibility and effectiveness of WhatsApp online group on breastfeeding by peer counsellors: a single-blinded, open-label pilot randomized controlled study.

INTRODUCTION: With mobile technologies becoming more advanced and accessible, mobile health (mHealth) has been incorporated in delivering timely and convenient breastfeeding support. However, its feasibility and potential efficacy remain to be examined. Therefore, the primary objective of this study is to assess the feasibility and acceptability of an online instant messaging peer support group for breastfeeding. The secondary objective is to evaluate the effect of the intervention on breastfeeding outcomes. METHODS: A pilot randomized controlled trial was conducted. A total of 33 primiparous women were recruited in the antenatal clinic at a public hospital in Hong Kong between March and April 2021. They were randomized to receive either standard care (n = 18) or standard care and receive peer-group support in an online instant messaging app (n = 15). Participants received telephone follow-up for up to six months postpartum or until they stopped breastfeeding. After completing the study, six participants in the intervention group were interviewed to understand their perceptions of the intervention. RESULTS: This pilot study shows that online messaging peer support group is feasible and acceptable to women. In total, 54.4% of the eligible women agreed to participate, and 97.0% completed the follow-up. Participants perceived that providing peer support through instant messaging app is appropriate. It serves as a channel for the participants to ask questions and obtain information. Furthermore, meetings of the peer supporters and group members can be held to enhance the effectiveness of the intervention. In addition, no significant differences were found in any and exclusive breastfeeding rates, breastfeeding attitude, and breastfeeding self-efficacy between the two groups. CONCLUSIONS: This study shows that online messaging peer support group is feasible and acceptable. A full-scale study should be conducted to understand the effect of the online instant messaging peer support group on breastfeeding outcomes. TRIAL REGISTRATION: The study protocol is registered on Clinicaltrial.gov (NCT04826796) on 1 April 2021.

Patterns of practice with third-line anti-EGFR antibody for metastatic colorectal cancer.

BACKGROUND: Therapy with anti-epidermal growth factor receptor (egfr) monoclonal antibody improves outcomes for patients with metastatic colorectal cancer (mcrc) in the first-, second-, and third-line trial settings. In British Columbia, the use of egfr inhibitors (egfris) is confined to third-line therapy, which might lower the proportion of patients who receive this therapy. The objective of the present study was to describe egfri treatment patterns when those agents are limited to the third-line setting. The results will inform decisions about optimal use of egfri agents, including earlier in the course of therapy for metastatic disease. METHODS: All patients with newly diagnosed mcrc who were referred to BC Cancer Agency clinics in 2009 were included in the study. Prognostic and treatment information was prospectively collected; KRAS test results were determined by chart review. RESULTS: The study included 443 patients with a median age of 66 years. For the 321 patients who received systemic therapy, median survival was 22.3 months. Of the 117 patients who were treated with 5-fluorouracil, oxaliplatin, and irinotecan, and who were potentially eligible for egfri therapy, 90% (105 patients) were tested for KRAS status. Of the 60 patients with KRAS wild-type tumours, 82% (49 patients) received egfri therapy. CONCLUSIONS: When egfri therapy is limited to the third-line setting, only a small proportion of patients receive such therapy, with death and poor performance status preventing its use in the rest. Availability of egfri in earlier lines of therapy could increase the proportion of patients treated with all active systemic agents.

Raf activation by Ras and promotion of cellular metastasis require phosphorylation of prohibitin in the raft domain of the plasma membrane.

Prohibitin (PHB) is indispensable for Ras-induced Raf-1 activation, cell migration and growth; however, the exact role of PHB in the molecular pathogenesis of cancer metastasis remains largely unexamined. Here, we found a positive correlation between plasma membrane-associated PHB and the clinical stages of cancer. The level of PHB phosphorylated at threonine 258 (T258) and tyrosine 259 (Y259) in human cancer-cell membranes correlated with the invasiveness of cancer cells. Overexpression of phosphorylated PHB (phospho-PHB) in the lipid-raft domain of the cell membrane enhanced cell migration/invasion through PI3K/Akt and Raf-1/ERK activation. It also enhanced epithelial-mesenchymal transition, matrix metalloproteinase-2 activity and invasiveness of cancer cells in vitro. Immunoprecipitation analysis demonstrated that phospho-PHB associated with Raf-1, Akt and Ras in the membrane and was essential for the activation of Raf-1 signaling by Ras. Mice implanted with cancer cells stably overexpressing PHB in the plasma membrane showed enlarged cervical tumors, enhanced metastasis and shorter survival time compared with mice implanted with cancer cells without PHB overexpression. Dephosphorylation of PHB at T258 by site-directed mutagenesis diminished the in vitro and in vivo effects of PHB. These results suggest that increase in phospho-PHB T258 in the raft domain of the plasma membrane has a role in the Ras-driven activation of PI3K/Akt and Raf-1/ERK-signaling cascades and results in the promotion of cancer metastasis.

Improving the quality of abstract reporting for economic analyses in oncology.

BACKGROUND: The increasing cost of cancer drugs underscores the importance of economic analyses. Although guidelines for abstract reporting of randomized controlled studies and phase i trials are available, similar recommendations for conference abstracts of economic analyses are lacking. Our objectives were to identify items considered to be essential in abstracts of economic analyses;to evaluate the quality of abstracts submitted to the American Society of Clinical Oncology (asco), the American Society of Hematology (ash), and the International Society for Pharmacoeconomics and Outcomes Research (ispor) meetings; andto propose guidelines for future abstract reporting at conferences. METHODS: Health economic experts were surveyed and asked to rate each of 24 possible abstract elements on a 5-point Likert scale. A scoring system for abstract quality was devised based on elements with an average expert rating of 3.5 or greater. Abstracts for economic analyses from asco, ash, and ispor meetings were reviewed and assigned a quality score. RESULTS: Of 99 experts, 50 (51%) responded to the survey (average age: 53 years; 78% men; 54% from the United States, 28% from Europe, 18% from Canada). In total, 216 abstracts were reviewed: asco, 53%; ash, 14%; and ispor, 33%. The median quality score was 75, but notable deficiencies were observed. Cost perspective was reported in only 61% of abstracts, and time horizon was described in only 47%. Abstracts from recent years demonstrated better quality scores. We also observed disparities in quality scores for various cancer sites (p = 0.005). CONCLUSIONS: The quality of conference abstracts for economic analyses in oncology has room for improvement. Abstracts may be enhanced using the guidelines derived from our survey of experts.

Stroop performance in multiple sclerosis: information processing, selective attention, or executive functioning?

Cognitive impairments in information processing speed, attention and executive functioning are widely reported in patients with multiple sclerosis (MS). Several studies have identified impaired performance on the Stroop test in people with MS, yet uncertainty remains over the cause of this phenomenon. In this study, 25 patients with MS were assessed with a neuropsychological test battery including a computerized Stroop test and a computerized test of information processing speed, the Graded Conditional Discrimination Tasks (GCDT). The patient group was compared with an individually age, sex and estimated premorbid IQ-matched healthy control group. The patients' reaction times (RTs) were significantly longer than those of the controls on all Stroop test trials and there was a significantly enhanced absolute (RT(incongruent)-RT(neutral)) and relative (100 x [RT(incongruent)-RT(neutral)]/RT(neutral)) Stroop interference effect for the MS group. The linear function relating RT to stimulus complexity in the GCDT was significantly steeper in the patient group, indicating slowed information processing. The results are discussed with reference to the difference engine model, a theory of diversity in speeded cognition. It is concluded that, in the assessment of people with MS, great caution must be used in the interpretation of performance on neuropsychological tests which rely on RT as the primary measure.

Kondo interactions and magnetic correlations in CePt2 nanocrystals.

The evolution of the Kondo effect and antiferromagnetic (AF) correlations with size reduction in CePt2 nanoparticles (3.1-26 nm) is studied by analysis of the temperature-dependent specific heat and magnetic susceptibility. The AF correlations diminish with size reduction. The Kondo effect predominates at small particle size with trivalent, small Kondo temperature (TK) magnetic regions coexisting with strongly mixed-valent, large TK nonmagnetic regions. We discuss the role of structural disorder, background density of states and the electronic quantum size effect on the results.

Use of the CRABEL Score for improving surgical case-note quality.

INTRODUCTION: Quality assurance of medical record keeping in general surgery is facilitated by use of the CRABEL Score. Critical appraisal and constant feedback to staff plays an important part in improving case-note quality. MATERIALS AND METHODS: For each case-note audit, a house officer reviewed two sets of case notes for each of six consultant surgeons. Scores were awarded according to initial clerking, subsequent entries, consent, and discharge summary. Overall scores were derived by subtracting deductions for omissions in each category from a starting score of 100. A larger number of points deducted due to absent data leads to a lower overall score and indicates poorer quality case notes. After four audits, a clerking proforma specifically designed to address some of the common areas of weakness identified in our record keeping was introduced and a further audit was performed in March 2004 to assess its impact. RESULTS: The mean score was lowest in the September 2001 audit and improved over the next two audits. However, there was a small reduction in September 2003 compared to September 2002. When the individual sections of the score were looked at separately, the greatest contribution to a poor score comes from the 'subsequent entries' section since there are five entries scored individually leading to a cumulative effect on the overall score. Within both the 'initial clerking' and 'subsequent entries' sections, early audits showed poor performance across a range of areas but consistent poor implementation of the guidelines was seen in a small number of specific areas as record keeping improved. The quality of medical notes improved over the first three cycles but the improvement was not maintained subsequently. DISCUSSION: The CRABEL score has been shown to be a useful, reproducible and easy-to-perform objective assessment of the quality of medical record keeping. Repeated audit cycles have ensured that case-note quality remains a high priority and have also led to the development of standardised admission documentation. Introduction of the latter has led to a measurable improvement in medical record keeping.

Effects of fenfluramine on free-operant timing behaviour: evidence for involvement of 5-HT2A receptors.

RATIONALE: Temporal differentiation in the free-operant psychophysical procedure is sensitive to the 5-hydroxytryptamine (5-HT)1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and the 5-HT2 receptor agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI); both drugs shift the psychophysical curve leftwards, reducing the indifference point, T50. We have examined the effect of the 5-HT releasing agent fenfluramine on temporal differentiation. OBJECTIVE: We examined whether fenfluramine's effect on temporal differentiation can be antagonised by the 5-HT1A receptor antagonist N-[2-(4-[2-methoxy-phenyl]-1-piperazinyl)ethyl]-N-2-pyridinylcyclohexane-carboxamide (WAY-100635) and the 5-HT2A receptor antagonist ketanserin, and compared the effects of fenfluramine, DOI and 8-OH-DPAT in intact rats and rats whose 5-HTergic pathways had been destroyed by 5,7-dihydroxytryptamine. METHODS: Rats were trained under the free-operant psychophysical procedure to press levers A and B in 50-s trials in which reinforcers were provided intermittently for responding on A in the first half, and B in the second half of the trial. Percent responding on B (%B) was recorded in successive 5-s epochs of the trials; logistic psychophysical curves were fitted to the data for derivation of timing indices (T50, time corresponding to %B=50%, and Weber fraction). Experiment 1 examined the effects of acute treatment with fenfluramine, and the interaction between fenfluramine and the 5-HT1A and 5-HT2A receptor antagonists WAY-100635 and ketanserin; experiment 2 compared the effects of fenfluramine, 8-OH-DPAT and DOI in intact rats and rats whose 5-HTergic pathways had been destroyed by intra-raphe injection of 5,7-dihydroxytryptamine. Concentrations of 5-HT and catecholamines in the brain were measured by high-performance liquid chromatography. RESULTS: Experiment 1: fenfluramine (2 mg/kg) reduced T50; this effect was attenuated by ketanserin (1.0 mg/kg) but not by WAY-100635 (100 microg/kg). Experiment 2: 8-OH-DPAT (100 microg/kg) and DOI (250 microg/kg) reduced T50 in both groups; fenfluramine reduced T50 only in the sham-lesioned group. Levels of 5-HT were reduced by 80% in the lesioned group; catecholamine levels were not affected. CONCLUSIONS: The results suggest that fenfluramine affects temporal differentiation via the release of endogenous 5-HT which acts mainly on postsynaptic 5-HT2A receptors.

Effects of orbital prefrontal cortex dopamine depletion on inter-temporal choice: a quantitative analysis.

RATIONALE: Lesions of the orbital prefrontal cortex (OPFC) can cause pathologically impulsive behaviour in humans. Inter-temporal choice behaviour (choice between reinforcers differing in size and delay) has been proposed as a model of "impulsive choice" in animals. We recently found that destruction of the OPFC disrupted inter-temporal choice in rats. It is not known whether the dopaminergic projection to the OPFC contributes to the regulation of inter-temporal choice. OBJECTIVE: A quantitative method was used to compare inter-temporal choice in rats whose OPFC had been depleted of dopamine with that of sham-lesioned control rats. METHODS: Under halothane anaesthesia, rats received injections of 6-hydroxydopamine into the OPFC (2 microg microl(-1), 0.5 microl, two injections in each hemisphere), or sham lesions (injections of the vehicle). They were trained to press two levers (A and B) for sucrose reinforcement (0.6 M) in discrete-trials schedules. In free-choice trials, a press on A resulted in delivery of 50 microl of the sucrose solution after a delay dA; a press on B resulted in delivery of 100 microl of the same solution after a delay dB. dB was increased progressively across successive blocks of six trials in each session, while dA was manipulated systematically across phases of the experiment. The indifference delay, dB(50) (value of dB corresponding to 50% choice of B) was estimated for each rat in each phase. Linear functions of dB(50) versus dA were derived, and the parameters of the function compared between the groups. Concentrations of monoamines in the OPFC were determined by high-performance liquid chromatography at the end of the experiment. RESULTS: In both groups, dB(50) increased linearly with dA (r2>0.9 in each case). The slope of the function was significantly steeper in the lesioned group than the sham-lesioned group, whereas the intercept did not differ significantly between the groups. When delays of 4 or 8 s were imposed on the smaller reinforcer, the lesioned rats showed greater tolerance of delay to the larger reinforcer (i.e. they exhibited longer values of dB(50)) than the sham-lesioned rats. Dopamine, noradrenaline and 5-hydroxytryptamine levels in the OPFC of the lesioned group were 20, 75 and 98% of those of the sham-lesioned group. CONCLUSIONS: The results indicate that dopaminergic afferents to the OPFC contribute to the regulation of inter-temporal choice behaviour due to their role in determining organisms' sensitivity both to reinforcer size and to delay of reinforcement.

Rapid development of an advanced squamous-cell carcinoma of the esophagus.

This report describes the case of a 42-year-old alcoholic man who developed advanced squamous-cell carcinoma of the esophagus following an endoscopic examination showing grossly normal mucosa only 8 months previously. We believe this is the first case report providing endoscopic images illustrating a progression from grossly normal mucosa to advanced carcinoma of the esophagus in only 8 months.

High-speed detection of occult tumor cells in peripheral blood.

Although detection of tumor cells in peripheral blood using imitiunocytochemistry and optical scanning is a promising method for screening and monitoring cancer, it poses a major technical challenge due to the extremely low tumor cell concentration in blood. The preferred detection method - digital microscopy - is far too slow for analysis of the large numbers of cells required for statistical validity. We describe here a novel prescan instrument that rapidly identifies a small number of candidates for subsequent examination by digital microscopy to determine if they are genuine tumor cells. The prescan is 500 times faster than digital microscopy and yet has a similar sensitivity. The high prescan speed is accomplished by trading resolution for field of view. The resolution of the prescan is determined by the laser spot size of about 10 microns. While this resolution is much coarser than the submicron resolution of microscopes, it is still sufficient for detecting fluorescent cells because it matches the size of a typical cell. The wide field of view and high scan rate are enabled by a novel application of fiber optics.

Effects of a 5-HT2 receptor agonist, DOI (2,5-dimethoxy-4-iodoamphetamine), and antagonist, ketanserin, on the performance of rats on a free-operant timing schedule.

This experiment examined the effect of a 5-HT2 receptor agonist DOI (2,5-dimethoxy-4-iodoamphetamine), and antagonist, ketanserin, on temporal differentiation performance. Twelve rats were trained under the free-operant psychophysical procedure to press two levers (A and B) in 50-s trials in which sucrose reinforcement (0.6 mol/l, 50 microl) was provided intermittently for responding on A during the first half, and on B during the second half of the trial. Psychometric curves were derived from percent responding on B (%B), recorded in successive 5-s epochs of the trials; logistic functions were fitted to these data for the derivation of timing indices (T50 [time corresponding to %B=50%], epsilon [slope of the logistic curve], Weber fraction). Cumulative probability of switching in successive 5-s epochs was used to estimate the mean switching time, S50. DOI (0.0625, 0.125 and 0.25 mg/kg, s.c.) dose-dependently reduced T50 and S50. These effects of DOI (0.25 mg/kg) were antagonized by ketanserin (1.0 mg/kg). The results show that DOI alters temporal differentiation in the free-operant psychophysical procedure. The antagonistic effect of ketanserin indicates that the effect of DOI was probably mediated by 5-HT2A rather than 5-HT2C receptors, since ketanserin is relatively selective for 5-HT2A receptors. Comparison of these results with our previous findings with a 5-HT1A receptor agonist indicates that 5-HT1A and 5-HT2A receptors mediate qualitatively similar effects on temporal differentiation.

Role of the orbital prefrontal cortex in choice between delayed and uncertain reinforcers: a quantitative analysis.

'Inter-temporal choice' refers to choice between two or more outcomes that differ with respect to their sizes, delays, and/or probabilities of occurrence. According to the multiplicative hyperbolic model of inter-temporal choice, the value of a reinforcer increases as a hyperbolic function of its size, and decreases as a hyperbolic function of its delay and the odds against its occurrence. These functions, each of which contains a single discounting parameter, are assumed to combine multiplicatively to determine the overall value of the reinforcer. The model gives rise to a quantitative methodology for analysing inter-temporal choice, based on a family of linear null equations which describe performance under conditions of indifference, when the values of the reinforcers are assumed to be equal. This approach was used to examine the effect of lesions of the orbital prefrontal cortex (OPFC) on inter-temporal choice in rats. Under halothane anaesthesia, rats received injections of the excitotoxin quinolinate into the OPFC or sham lesions. They were trained to press two levers (A and B) for food-pellet reinforcers in discrete-trials schedules. In free-choice trials, a press on A resulted in delivery of a pellet after a delay d(A) with a probability P=0.5; a press on B resulted in delivery of a pellet with a probability P=1 after a delay d(B). d(B) was increased progressively across successive blocks of six trials in each session, while d(A) was manipulated systematically across phases of the experiment. The indifference delays, d(B(50)) (value of d(B) corresponding to 50% choice of B) was estimated for each rat in each phase. Linear functions of d(B(50)) versus d(A) were derived, and the parameters of the function compared between the groups. In both groups, d(B(50)) increased linearly with d(A). The slope of the linear function was significantly steeper in the lesioned group than in the sham-lesioned group, whereas the intercept did not differ significantly between the groups. Analysis based on the relevant null equation indicated that the lesion of the OPFC increased the rate of both delay and odds discounting. Possible implications of the results for interpreting the effects of OPFC lesions on inter-temporal choice behaviour in man are discussed.

Effects of 8-OH-DPAT and WAY-100635 on performance on a time-constrained progressive-ratio schedule.

RATIONALE: Performance on progressive-ratio schedules has been proposed as a means of assessing the effects of drugs on motivation. We have adopted a mathematical model proposed by Killeen to analyse the effects of drugs acting at 5-HT(1A) receptors on progressive-ratio performance. According to this model, the relationship between response rate and ratio size is described by a bitonic (inverted-U) function. One parameter of the function, a, expresses the motivational or "activating" effect of the reinforcer (duration of activation of responding produced by the reinforcer), whereas another parameter, delta, expresses the minimum time needed to execute a response and is regarded as an index of "motor capacity". OBJECTIVE: To examine the effect of the selective 5-HT(1A) receptor agonist 8-OH-DPAT [8-hydroxy-2-(di- n-propylamino)tetralin] and the antagonist WAY-100635 [ N-[2-(4-[2-methoxyphenyl]-1-piperazinyl)ethyl]- N-2-pyridinylcyclo-hexanecarboxamide] on progressive-ratio schedule performance. METHODS: Sixteen rats responded for a food-pellet reinforcer on a time-constrained progressive-ratio schedule (55-min sessions). In phase 1, they received single doses (s.c.) of 8-OH-DPAT (25, 50, 100, 200 microg kg(-1), four treatments at each dose) or the vehicle (0.9% saline solution). In phase 2, they received WAY-100635 (30, 100, 300 microg kg(-1)) according to the same regimen. In phase 3, they received 8-OH-DPAT (100 microg kg(-1)) alone or in combination with WAY-100635 (30 microg kg(-1)). 8-OH-DPAT dose dependently increased the value of a, significant increases being seen with the 50, 100 and 200 microg kg(-1) doses. The highest dose also increased delta. WAY-100635 did not significantly alter either a or delta. WAY-100635 significantly attenuated the effect of 8-OH-DPAT on both a and delta. CONCLUSIONS: The results suggest that 8-OH-DPAT enhanced the activating effect of the reinforcer (the highest dose may also have induced motor debilitation). The finding that the effect of 8-OH-DPAT on a was attenuated by WAY-100635 implicates 5-HT(1A) receptors in this effect. The results are consistent with previous reports that 8-OH-DPAT facilitates feeding and food-reinforced operant responding in rats and suggest that these effects may be brought about by an increase in food motivation.

Effects of quinolinic acid-induced lesions of the orbital prefrontal cortex on inter-temporal choice: a quantitative analysis.

RATIONALE: Lesions of the orbital prefrontal cortex (OPFC) can cause pathologically impulsive behaviour in humans. Inter-temporal choice behaviour (choice between reinforcers differing in size and delay) has been proposed as a model of "impulsive choice" in animals. OBJECTIVE: A quantitative method was used to analyse inter-temporal choice in rats with lesions of the OPFC and sham-lesioned control rats. METHODS: Under halothane anaesthesia, rats received injections of the excitotoxin quinolinate into the OPFC (0.1 M, 0.5 micro l; two injections in each hemisphere), or sham lesions (injections of the vehicle). They were trained to press two levers (A and B) for sucrose reinforcement (0.6 M) in discrete-trials schedules. In free-choice trials, a press on A resulted in delivery of 50 micro l of the sucrose solution after a delay d (A); a press on B resulted in delivery of 100 micro l of the same solution after a delay d (B). d (B) was increased progressively across successive blocks of six trials in each session, while d (A) was manipulated systematically across phases of the experiment. The indifference delay, d (B(50)) (value of d (B) corresponding to 50% choice of B) was estimated for each rat in each phase. Linear functions of d (B(50)) versus d (A) were derived, and the parameters of the function compared between the groups. The locations of the lesions were verified histologically at the end of the experiment. RESULTS: In both groups, d (B(50)) increased linearly with d (A) ( r(2)>0.98 in each case). The slope of the function was significantly steeper in the lesioned group than the sham-lesioned group, whereas the intercept did not differ significantly between the groups. The brains of the lesioned rats showed extensive atrophy/gliosis of the OPFC, with sparing of the dorsolateral prefrontal cortex. CONCLUSIONS: The results indicate that lesions of the OPFC can alter inter-temporal choice, either promoting or suppressing "impulsive choice", depending upon the relative sizes and delays of the two choice alternatives. Theoretical analysis based on a quantitative model of inter-temporal choice indicates that the pattern of effect of the OPFC lesion is likely to reflect two actions: (i) an increase in the rate of time discounting; (ii) an increase in sensitivity to the ratio of the sizes of two reinforcers.

Antagonism by WAY-100635 of the effects of 8-OH-DPAT on performance on a free-operant timing schedule in intact and 5-HT-depleted rats.

In this experiment we examined the effect of a serotonin receptor (5-HT1A) agonist and antagonist WAY-100635 (N-[2-(4-[2-methoxy-phenyl]-1-piperazinyl)ethyl]-N-2-pyridinylcyclohexane-carboxamide) on temporal differentiation, in intact rats and rats whose serotonergic (5-HTergic) pathways had been destroyed by 5,7-dihydroxytryptamine (5,7-DHT). Thirteen rats received 5,7-DHT-induced lesions of the median and dorsal raphe nuclei; 14 rats received sham lesions. They were trained to press two levers (A and B) in 50-s trials, in which reinforcement was contingent upon responding on A in the first half, and B in the second half, of the trial. Logistic psychophysical curves were fitted to the relative response rate data (percent responding on B, %B), for derivation of timing indices [T50 (time corresponding to %B=50%), slope, Weber fraction] following WAY-100635, 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin], combinations of WAY-100635+8-OH-DPAT, and vehicle alone. WAY-100635 (30, 100 and 300 microg/kg, s.c.) did not affect the timing indices. 8-OH-DPAT (100, 200 microg/kg, s.c.) reduced T50 without affecting the Weber fraction. WAY-100635 (300 microg/kg) abolished the effect of 8-OH-DPAT on T50 in both the lesioned and sham-lesioned groups. 5-HT levels in the neocortex, hippocampus, amygdala, nucleus accumbens and hypothalamus of the lesioned group were <20% of those in the sham-lesioned group; catecholamine levels were unaffected. The results confirm that 8-OH-DPAT disrupts temporal differentiation in a free-operant psychophysical schedule, reducing T50, and indicate that this effect of 8-OH-DPAT is mediated by postsynaptic 5-HT1A receptors.

Development and inter-rater reliability of a standardized verbal instruction manual for the Chinese Geriatric Depression Scale-short form.

The Geriatric Depression Scale (GDS) is a common screening tool for elderly depression in Hong Kong. This study aimed at (1) developing a standardized manual for the verbal administration and scoring of the GDS-SF, and (2) comparing the inter-rater reliability between the standardized and non-standardized verbal administration of GDS-SF. Two studies were reported. In Study 1, the process of developing the manual was described. In Study 2, we compared the inter-rater reliabilities of GDS-SF scores using the standardized verbal instructions and the traditional non-standardized administration. Results of Study 2 indicated that the standardized procedure in verbal administration and scoring improved the inter-rater reliabilities of GDS-SF.

SB-242235, a selective inhibitor of p38 mitogen-activated protein kinase. II: in vitro and in vivo metabolism studies and pharmacokinetic extrapolation to man.

1. Inhibition of p38 MAP kinase has been investigated extensively as a potential therapy for cytokine-mediated diseases such as autoimmune and inflammatory diseases. SB-242235 (1-(4-piperidinyl)-4-(4-fluorophenyl)-5-(2-methoxy-4-pyrimidinyl) imidazole) is a potent and selective p38 MAP kinase inhibitor; the preclinical pharmacokinetics of SB-242235 have been described previously. The present studies were conducted to describe the in vitro metabolic rates and routes of SB-242235 metabolism, to characterize its in vivo preclinical metabolism, and to use these data to aid in the prediction of the pharmacokinetic behaviour of SB-242235 in man. 2. SB-242235 was metabolically stable in rat, dog, monkey and human hepatic microsomes, isolated hepatocytes and liver slices in vitro. The in vivo preclinical metabolism studies were consistent with the in vitro findings; SB-242235 was minimally metabolized, and was primarily excreted unchanged in the urine (45 and 67% of the administered dose in the rat and monkey, respectively). 3. Allometric scaling using various correction factors predicted that SB-242235 would have low clearance in man with a predicted half-life ranging from 11.5 to 18.7h. This prediction was consistent with the observed mean half-life of 16.4h in the first-in-man study for SB-242235. An allometric scaling method with a correction for interspecies differences in glomerular filtration rate provided the most accurate prediction of the pharmacokinetic behaviour of SB-242235 in humans, although the clinical data also highlight potential difficulties in conducting prospective allometry.

5-Hydroxytryptamine and interval timing behaviour.

Interval timing behaviour is revealed by prospective, immediate and retrospective timing schedules. Prospective timing tasks are used to study intertemporal choice (choice between outcomes occurring after different delays), immediate timing tasks to study temporal differentiation (temporal regulation of the animal's behaviour) and retrospective timing tasks to study temporal discrimination (discrimination between the durations of external events). Central 5-hydroxytryptamine (5-HT) depletion promotes preference for small early reinforcers over large delayed reinforcers, possibly by facilitating the time-dependent degradation of reinforcer value. Central 5-HT depletion retards the learning of temporal differentiation, and increases the variability of timing in some immediate timing tasks; however, it does not impede (in some cases it facilitates) the acquisition of temporal discrimination. Attempts to ascribe all the effects of 5-HT depletion on timing to a single behavioural process have been unsuccessful, although disinhibition of switching between operant responses may account for some of the findings. Acute treatment with drugs affecting 5-HTergic mechanisms alters timing behaviour in qualitatively different ways in different timing schedules, casting doubt on the idea that the effects of these drugs are mediated by interaction with a unitary timing process. The receptors that mediate 5-HT's putative involvement in interval timing behaviour remain to be identified.

Effect of 8-OH-DPAT on temporal discrimination following central 5-hydroxytryptamine depletion.

The 5-hydroxytryptamine (5-HT)(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) alters performance in discrete-trials timing schedules. 5-HT(1A) receptors occur both presynaptically and postsynaptically, but it is not known which receptor population mediates the effects of 8-OH-DPAT on timing. Rats received intra-raphe injections of 5,7-dihydroxytryptamine (n=16) or sham lesions (n=14). They were trained in a discrete-trials psychophysical procedure in which levers were presented at a predetermined time after the onset of each trial (2.5, 7.5,., 47.5 s). A response on lever A was reinforced if lever presentation occurred < 25 s after trial onset; a response on lever B was reinforced if lever presentation occurred >25 s after trial onset. After 70 preliminary sessions, the rats received 8-OH-DPAT (25, 50, 100, 200 microg kg(-1) sc) and saline vehicle. The percentage of responses on lever B (%B) increased as a function of time from trial onset. Under the baseline (vehicle-treatment) condition, performance did not differ between the two groups. 8-OH-DPAT did not alter the indifference point (time corresponding to %B=50%), but dose-dependently increased the Weber fraction in both groups. Forebrain concentrations of 5-HT and 5-HIAA in the lesioned group were approximately 10% of control levels. The results suggest that the effect of 8-OH-DPAT on performance on discrete-trials timing schedules is mediated by postsynaptic 5-HT(1A) receptors.