Antibiotic treatment for animals: effect on bacterial population and dosage regimen optimisation

Concern regarding antimicrobial resistance has led to proposals for the prudent use of antimicrobial agents. Whilst this is appropriate, it is not sufficient. This article proposes that dosage schedules should be developed to provide a basis for the rational use of antimicrobial drugs. This requires knowledge of resistance mechanisms and transfer, the biochemistry and structure of microorganisms and both the pharmacodynamics and pharmacokinetics of antimicrobial drugs. Dosage schedules should maintain concentrations at the site of infection in excess of MIC₉₀ for bacteriostatic drugs and bactericidal drugs acting primarily by time-dependent mechanisms whilst they should provide high AUIC and C_max/minimum inhibitory concentration (MIC) values for agents acting mainly by concentration-dependent mechanisms. It is proposed that pharmacodynamic and population pharmacokinetic data should be integrated through use of the sigmoidal E_max equation, together with mathematical modelling and appropriate statistical analyses, to take account of the natural variation in drug pharmacodynamics and pharmacokinetics.     

甲泼尼龙冲击疗法治疗杰杨-巴勒综合征

杰杨-巴勒综合征患者23例(男14,女9;平均年龄24±19a;病程9±12mo,)用甲泼尼龙冲击疗法治疗。甲泼尼龙1g或20mg/(kg·d)溶于5％葡萄糖溶液500mL中静滴,qd×3d,1mo后根据病情重复第2、3疗程,冲击间歇期口服泼尼松20-40mg/d维持。结果12例(52％)痊愈,9例(39％)显效,2例无效。值得临床试用。     

Subjective and behavioural evaluation of cigarette cravings

Cigarette cravings were evaluated in a sample of moderately heavy smokers, using the Questionnaire on Smoking Urges (QSU: Tiffany and Drobes 1991), which produces scores on two factors, related to the positive (factor I) and negative (factor II)-reinforcing properties of smoking, respectively. Smoking motivation was also assessed behaviourally using a progressive-ratio operant procedure, in which responding on a computer keyboard was reinforced by puffs on a cigarette, under a progressively increasing work requirement. Abstinence (4–14 h) increased scores on both subjective and behavioural measures. In non-deprived subjects, behavioural measures and cigarette liking correlated more strongly with factor I of the QSU than with factor II, while in abstinent subjects, correlations with factor II were stronger than with factor I. The significant relationships between the QSU and cigarette-reinforced progressiveratio operant performance support the validity of both of these procedures as measures of cigarette craving.     

Rapid acquisition of oral phencyclidine self-administration in food-deprived and food-satiated rhesus monkeys: Concurrent phencyclidine and water choice

Eight rhesus monkeys were trained to self-administer orally-delivered phencyclidine, with water concurrently available, under a fixed ratio (FR) schedule during daily 3-hr sessions. Liquid deliveries (0.55 ml) were contingent upon lip-contact responses on solenoid-operated drinking spouts. During the sessions, phencyclidine and water were available under FRs ranging from 1 to 16. Water was always available between sessions (FR 1), and food initially was available 24 hr/day. In Experiment 1 the monkeys initially were given access to water (FR 1) during the 3-hr sessions. Subsequently, phencyclidine (0.25 mg/ml) was substituted for water, and the monkeys were reduced to 85 percent of their free-feeding weights. The FR value was then increased from 1 to 8. Next, the monkeys received concurrent access to water from one spout and phencyclidine from the other (each under the FR 8 schedule), then the FR value was increased to 16 for both drug and water. Orally-delivered phencyclidine was rapidly demonstrated to function as a reinforcer (37.2 sessions) without using food to induce drinking. In Experiment 2 a similar procedure was used for another group of monkeys, except the monkeys remained food satiated throughout the acquisition phase. Phencyclidine was rapidly demonstrated to function as a reinforcer (25.9 sessions), although intakes were lower than in Experiment 1. After concurrent phencyclidine- and water-maintained performance stabilized at FR 16, the monkeys were food deprived, and phencyclidine intake increased to the levels reported in Experiment 1. Food deprivation greatly enhanced the reinforcing effect of phencyclidine and changed the temporal pattern of responding, but neither food deprivation nor food-induced drinking were necessary conditions to demonstrate the drug's reinforcing effects.     

Disruption and habituation of stable fixed-interval behavior in younger and older monkeys

Reactivity to novel and irrelevant stimuli has been shown to vary as a function of age. Since differential responsivity to irrelevant events may account for purported age differences on other tasks, the present experiment studied the extent to which these age differences may be reduced with repeated exposure, i.e., habituation. Young (2 to 3 years) and old (15+ years) squirrel monkeys were trained and their performance stabilized over months on a fixed-interval operant task. This behavior was then disrupted by periodic presentations of an auditory stimulus of moderate intensity. Disruption of stable behavior and habituation to the tone stimulus were evaluated across several measures including overall response rates between and within the daily sessions; recovery of baseline response rates during the tone stimulus; and the curvature of the fixed interval "scallop." Old monkeys responded for sweet fruit juice more frequently, but less efficiently, than young monkeys. Their responding was more severely disrupted by intermittent novel auditory stimuli, to which they were slower to habituate.     

Profile of drug effects on temporally spaced responding in rats.

A differential reinforcement of low rate schedule was used with rats to test 15 psychotropic drugs. The computer analysis was based on interresponse time (IRT). Mean IRT, IRT standard deviation, median IRT, IRT midrange, modal IRT, frequency of modal IRT, and an efficiency index, in addition to numbers of responses and reinforcements and the IRT histogram were obtained for each rat in each drug test. An increase in number of responses and a peak shift to shorter IRTs in the histograms were observed with amphetamine, methamphetamine, priradrol and nicotine, as reported by many other investigators. Decrease in IRT midrange and less change in number of responses were observed with diazepam and chlordiazepoxide. Long pauses were found with LSD-25, 2,5-dimethoxy-4-methylamphetamine (DOM) and mescaline. In a factor analysis, the following main factors were obtained. High values in factor loading a1 were observed with chlorpromazine, chlordiazepoxide, pentobarbital, imipramine, nialamide, LSD-25, DOM and mescaline. With these drugs, mean IRT and IRT standard deviation were also high. Values for a2, were high with amphetamine, methamphetamine, pipradrol and nicotine. High a3 values were observed in some rats with chlorpromazine, diazepam, chlordiazepoxide, pentobarbital, pipradrol and caffeine. The changes in a3 values were correlated with changes in the IRT midrange. These results may be valuable in classifying new compounds in drug screening programs as being of the amphetamine type, nicotine type, diazepam type of LSD-25 type.     

Therapeutic schedules influence the pattern of intellectual decline after irradiation of posterior fossa tumors

BACKGROUND: To evaluate intellectual decline in children with posterior fossa (PF) tumors treated with different therapeutic protocols. PROCEDURE: Forty children had a complete neuropsychological evaluation prospectively twice, at least 6 months year (y) after the end of their treatment. Patients were classified into four groups according to treatment schedules: Group 1 (n = 7) PF radiotherapy (PFRT) alone at 50 Gy; Group 2 (n = 13) reduced-dose cranio-spinal irradiation (CSI) at 25 Gy with a PF boost; Group 3 (n = 9) standard CSI at 35 Gy and a PF boost; and Group 4 (n = 11) high-dose chemotherapy with stem cell support followed by PFRT at 50 Gy. RESULTS: At the first evaluation (mean interval since diagnosis 3.7 y), the mean Full-Scale Intellectual Quotient (FSIQ) was 80 (SD = 19). Only patients in Group 1 had a normal mean IQ score of 92 (SD = 14). At the second evaluation (mean interval since diagnosis 6.3 y), the mean FSIQ scores were significantly lower with a mean difference of 2.4 points, i.e., a yearly decline of one point. The magnitude of the FSIQ decline was positively correlated with the first IQ score (P = 0.0001) and inversely correlated with age at diagnosis (P = 0.0005). A FSIQ decline was observed in all treatment groups except Group 1 (P = 0.005). The differences in FSIQ observed initially between the four treatment groups persisted at the second evaluation. CONCLUSIONS: This study shows that FSIQ continues to decline more than 4 years after the diagnosis but this yearly decline seems to decrease with time from diagnosis. Therapeutic schedules influence the magnitude of this decline. Long-term follow-up into adulthood is necessary to effectively adapt patient rehabilitation.     

Sitting and standing tolerance in patients with chronic back pain: comparison between physician prediction and covert observation

OBJECTIVES: To measure covertly observed continuous sitting and standing tolerance in patients with chronic back pain and to compare observations to physician predictions. DESIGN: Blinded, prospective, cohort study. SETTING: Ambulatory referral centers, both public and private, at 5 major medical centers in the eastern United States. PARTICIPANTS: All volunteers (N=154; 64.0% women, mean age, 48.7y; 16.8% had active lawsuits) with diagnosis codes of the International Classification of Diseases, 9th Revision consistent with thoracic and/or lumbosacral back pain were selected from a cohort of 651 outpatients with chronic pain enrolled in the Multiperspective Multidimensional Pain Assessment Protocol (MMPAP). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Continuous sitting and standing tolerance was measured by (1). covert observation of subjects during the MMPAP trial and (2). blinded expert physician prediction based on complete history and physical examination. RESULTS: Most (124/154, 80.5%) subjects stood for 30 minutes or more and most (124/154, 80.5%) sat for 60 minutes or more. Overall, physicians underpredicted the ability to sit 60 minutes or more and to stand 30 minutes or more. Physician prediction showed poor correlation to covert observation for sitting tolerance (kappa=-.061, P=.221) and standing tolerance (kappa=-.021, P=.727). CONCLUSIONS: The majority of this sample demonstrated the ability to sit continuously 60 minutes or more and to stand continuously 30 minutes or more while being covertly observed. Expert physician prediction showed poor correlation to covertly observed sitting and standing tolerances, raising doubt about the validity of using physician evaluation to establish work restrictions in patients with chronic back pain. These findings are preliminary, follow only a brief period of covert observation, and indicate the need for further research in this area.     

Effects of the dopamine reuptake inhibitor PTT on reinstatement and on food- and cocaine-maintained responding in rhesus monkeys

Rationale High-affinity, slow-onset, long-acting dopamine transporter (DAT) inhibitors are being considered as potential agonist replacement therapies for cocaine addiction, and therefore the ability of these drugs to reinstate cocaine seeking and to selectively decrease cocaine-maintained responding should be assessed.Objectives The purpose of these experiments was to evaluate the effects of the active enantiomer of a high-affinity, slow-onset, long-acting DAT inhibitor, (–)2-propanoyl-3-(4-tolyl)-tropane (PTT), and cocaine on food- and cocaine-maintained responding and on extinguished responding previously maintained by cocaine in non-human primates using a within-subjects design.Methods Rhesus monkeys (n=3) responded under a multiple fixed-ratio schedule of food (1 g) and drug reinforcement, and cocaine dose-response curves (saline, 0.003–0.3 mg/kg per injection) were determined. The effects of pretreatment with (–)PTT (0.001–0.056 mg/kg, IV) and cocaine (0.03–0.3 mg/kg, IV) were determined when the dose of cocaine that maintained peak response rates (0.03 mg/kg per injection) or saline was available.Results (–)PTT and cocaine reduced cocaine intake; (–)PTT affected cocaine self-administration only at doses that also decreased food-maintained responding. (–)PTT and cocaine reinstated responding that was previously reinforced by cocaine at lower doses than were necessary to decrease cocaine-maintained responding. For all studies, PTT was at least 1.0 log-unit more potent than cocaine. Compared to cocaine, PTT had a longer duration of action in all behavioral measures.Conclusions These results suggest that PTT would decrease cocaine use, but only at doses that disrupted other behaviors. It appears that the potency of this class of drugs to reinstate cocaine-seeking is substantially greater than their potency at decreasing cocaine self-administration.     

Introduction of night shift call system for surgical trainees: a prospective self-controlled trial

OBJECTIVE: The number of hours worked by specialty trainees has come under scrutiny recently. One approach aimed at decreasing the number of consecutive hours worked is the night shift call system (NSCS). This study aimed to determine the advantages and disadvantages of an NSCS compared with those of the conventional overnight call system (ONCS). SUBJECTS AND METHODS: Sixteen basic surgical trainees (BSTs) from our unit participated in this prospective, self-controlled trial. During April 2000, the conventional 1-in-4 ONCS with a post-call half-day off was instituted. From May to June 2000, each BST rotated to work 1 week of night duty (20.00-08.00) and 7 weeks of daytime duty. A battery of neuropsychological tests were administered to the group after call during the study period. RESULTS: On average the numbers of consecutive hours worked during the NSCS and ONCS periods were 12 and 28 hours, respectively. There was no difference in numbers of errors committed and no difference in discrepancy between diagnoses made on admission and discharge. Two of the simple neuropsychological tests (memory scanning and addition tests) showed a significant fall-off in performance during the ONCS period (P < 0.05). Most specialists preferred the ONCS, while the majority of the BSTs preferred the NSCS (P < 0.05). This was because without extra manpower, the overall workloads of senior staff were increased. CONCLUSIONS: The NSCS is 1 way of reducing work hours, and was associated with significantly less impaired cognition on the part of our BSTs. It is only feasible if extra relieving staff are available to cover daytime duties.