Comparison of intensive care outcome prediction models based on admission scores with those based on 24-hour data.

We compared the performance of six outcome prediction models--three based on 24-hour data and three based on admission-only data--in a metropolitan university-affiliated teaching hospital with a 10-bed intensive care unit. The Acute Physiology and Chronic Health Evaluation models, version II (APACHE II) and version III-J, and the Simplified Acute Physiology Score version II (SAPS II) are based on 24-hour data and were compared with the Mortality Prediction Model version II and the SAPS version III using international and Australian coefficients (SAPS IIIA). Data were collected prospectively according to the standard methodologies for each model. Calibration and discrimination for each model were assessed by the standardised mortality ratio, area under the receiver operating characteristic plot and Hosmer-Lemeshow contingency tables and chi-squared statistics (C10 and H10). Predetermined criteria were area under the receiver operating characteristic plot > 0.8, standardised mortality ratio 95% confidence interval includes 1.0, and C10 and H10 P values >0.05. Between October 1, 2005 and December 31, 2007, 1843 consecutive admissions were screened and after the standard exclusions, 1741 were included in the analysis. The SAPS II and SAPS IIIA models fulfilled and the APACHE II model failed all criteria. The other models satisfied the discrimination criterion but significantly over-predicted mortality risk and require recalibration. Outcome prediction models based on admission-only data compared favourably to those based on 24-hour data.

Unplanned admission to the intensive care unit in postoperative patients--an indicator of quality of anaesthetic care?

As a clinical indicator, unplanned admission to the Intensive Care Unit from the operating room has been thought to reflect the quality of anaesthesia care intraoperatively. To explore this concept, we examined all such admissions at three hospitals over a three-month period. Cases were classified according to the Victorian Consultative Council on Anaesthetic Mortality and Morbidity (VCCAMM) classification system and an assessment was made as to whether the admission was inevitable or not. Demographic data were collected as well as co-morbidities, severity of illness, length of stay, discharge functional status and destination. There were 165 admissions identified: 55.8% were male, the median age was 63.5 years (range 15-90). There were 24 in-hospital deaths: 151 patients suffered serious morbidity or mortality. In 32 patients (19.4%), the morbidity or mortality was considered at least partially anaesthetic-related, and in 20 (12.1%), under the control of the anaesthetist. There were 28 admissions (17.0%) with a further 9 anaesthetic-related admissions (5.5%) which were considered potentially avoidable. Avoidable anaesthetic-related admissions were due to drug overdosage (5 cases), drug error (1 case), problems relating to preoperative assessment (1 case), aspiration (1 case) and pulmonary oedema (1 case). These findings suggest that unplanned admission to the Intensive Care Unit from the operating room is not a satisfactory indicator of quality of care by the anaesthesia team. This indicator appears to represent mainly the surgical and medical conditions of the patients, and their complications. Only one in twenty unplanned admissions in this series were potentially avoidable due to complications of the anaesthetic or the postoperative analgesia.

Ventral tegmental area region governs GABA(B) receptor modulation of ethanol-stimulated activity in mice.

Locomotor stimulation in response to ethanol in mice may model human ethanol-induced euphoria. The associated neural substrates, possibly relevant to alcoholism, have not been fully elucidated. Systemic injection of baclofen, a GABA(B) receptor agonist, attenuates ethanol's stimulant effects. GABA(B) receptors on dopamine cell bodies in the ventral tegmental area (VTA) may modulate ethanol-induced dopamine release, a postulated mechanism for ethanol's stimulant effects. However, baclofen's attenuating effects could be associated with peripheral receptor actions. Baclofen was injected i.c.v. or into the VTA of FAST mice, bred for extreme sensitivity to ethanol-induced locomotor stimulation, to test the hypotheses that (1) central GABA(B) receptors influence baclofen's effects on ethanol-stimulated activity, and (2) VTA GABA(B) receptors specifically modulate ethanol's stimulant effects. I.c.v. baclofen dose-dependently attenuated ethanol stimulation, supporting a central locus for baclofen's effects. Anterior VTA baclofen also attenuated ethanol stimulation. However, more posterior VTA infusions unexpectedly potentiated ethanol stimulation. In SLOW mice, bred for resistance to ethanol stimulation, posterior intra-VTA baclofen did not alter EtOH response. However, anterior VTA baclofen alone produced a locomotor depressant effect in SLOW mice, not seen in FAST mice. GABA(B) receptor autoradiography using [(3)H]CGP 54626, a potent GABA(B) receptor antagonist, did not reveal line differences in binding density in the VTA, or in the substantia nigra pars compacta, a nearby brain structure associated with motor control. These results suggest that anterior VTA GABA(B) receptors play a role in baclofen's attenuation of ethanol's stimulant effects, and that posterior VTA GABA(B) receptors serve an opposite role that is normally masked. Selection for differential ethanol stimulant sensitivity has altered VTA GABA(B) systems that influence locomotor behavior. However, differences in GABA(B) receptor densities in the VTA or substantia nigra pars compacta cannot explain the selected line difference.

Thiopental directly depresses lumbar dorsal horn neuronal responses to noxious mechanical stimulation in goats.

BACKGROUND: Thiopental has hypnotic actions in the brain, but it also depresses nociceptive transmission. In this study we examined whether thiopental had direct (spinal) and/or indirect (supraspinal) effects on the responses of single lumbar dorsal horn neurons to noxious mechanical stimulation, using a method to deliver thiopental differentially to either the torso or cranial circulation in goats. METHODS: Goats (n=10) were anesthetized with isoflurane and neck dissections performed to permit cranial bypass. A lumbar laminectomy was made to permit single-unit recording of lumbar dorsal horn neuronal activity (1-2 neurons/animal). Isoflurane was maintained at 0.8+/-0.1% to both head and torso throughout the study. During cranial bypass, thiopental was separately administered to the torso (low dose, 1.5+/-0.5 mg/kg; high dose, 3.7+/-0.5 mg/kg) or cranial (low dose, 0.12+/-0.03 mg/kg; high dose, 0.2 mg/kg) circulation. RESULTS: Thiopental administered to the torso significantly depressed dorsal horn neuronal responses to noxious stimulation at the high dose: 757+/-471 to 392+/-305 impulses/min at 1 min post-injection, P<0.006 (n=14); evoked responses recovered at 5 min post-injection. At the low dose, there was a similar numerical decrease, but this did not reach significance: 876+/-780 to 407+/-499 impulses/min at 1 min post-injection, P>0.05 (n=6). No significant change was observed when thiopental was administered to the cranial circulation: low dose, 1061+/-1167 to 965+/-874 impulses/min at 1 min post-injection, P>0.05 (n=10); high dose, 864+/-331 to 917+/-525 impulses/min at 1 min post-injection, P>0.05 (n=8). CONCLUSION: Thiopental has a direct (spinal) depressant effect on dorsal neuronal responses to noxious stimulus, but no significant supraspinal effect.

A high-resolution radiation hybrid map of the human genome draft sequence.

We have constructed a physical map of the human genome by using a panel of 90 whole-genome radiation hybrids (the TNG panel) in conjunction with 40,322 sequence-tagged sites (STSs) derived from random genomic sequences as well as expressed sequences. Of 36,678 STSs on the TNG radiation hybrid map, only 3604 (9.8%) were absent from the unassembled draft sequence of the human genome. Of 20,030 STSs ordered on the TNG map as well as the assembled human genome draft sequence and the Celera assembled human genome sequence, 36% of the STSs had a discrepant order between the working draft sequence and the Celera sequence. The TNG map order was identical to one of the two sequence orders in 60% of these discrepant cases.

Propofol action in both spinal cord and brain blunts electroencephalographic responses to noxious stimulation in goats.

STUDY OBJECTIVES: Anesthetics, including propofol, depress the electroencephalogram (EEG) and neuronal activity in the midbrain reticular formation (MRF). Because propofol has anesthetic effects in the spinal cord, we hypothesized that it would indirectly depress EEG and MRF neuronal responses to noxious stimulation in part by a spinal cord action. DESIGN: Six goats were anesthetized with isoflurane and the jugular veins and carotid arteries were isolated to permit cranial bypass and differential propofol delivery. A noxious mechanical stimulus was applied to the distal forelimb while recording bifrontal EEG and MRF single-unit activities. Propofol was separately administered to the cranial (0.08 +/- 0.06 mg/kg) and torso circulations (4 mg/kg) and the noxious stimulus applied at 1,5, 10, and 15 min after each injection. SETTING: N/A. PATIENTS OR PARTICIPANTS: N/A. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Noxious stimulation decreased total power (TP) from 96 +/- 33, microV2/Hz to 38 +/- 20microV2/Hz, (mean +/- SD) and increased spectral edge frequency (SEF) from 10 +/- 3 Hz to 19 +/- 5 Hz (p<0.01). Propofol administered to the torso prevented stimulus-evoked changes in TP (121+/- 80 microV2/Hz, 121 +/- 74 microV2/Hz, 114 +/- 74 microV2/Hz at 1,5, and 10 min respectively, p<0.01 compared to control evoked response) and SEF (11 +/- 6Hz, 9 +/- 2Hz, 10 +/- 6Hz, and 12 +/- 5Hz at 1, 5, 10 and 15 min, respectively, p<0.001 compared to control evoked response). Propofol administered to the cranial circulation significantly blunted the EEG and MRF response, while torso-administered propofol had slight effects on MRF responses. CONCLUSIONS: Propofol blunted the EEG response to noxious stimulation in part via a subcortical action.

Inter-rater reliability of the Frenchay activities index in patients with stroke and their careers.

OBJECTIVE: To measure the inter-rater reliability of the interview-administered version of the Frenchay Activities Index (FAI). DESIGN: Comparison of FAI score on the same person when administered by two raters (mean time between interviews 15.2 days). SUBJECTS: Fifty-nine Oxfordshire residents who either had had a stroke (n = 35) or were the main carer (n = 24). RESULTS: The 95% limits of agreement for the FAI totals were -9.9 to +8.4. The kappa statistic for nine of the 15 items showed a good level of agreement between the two research interviews (0.64-0.80). The other six items showed fair or moderate strength of agreement (0.26-0.52). Three items showed significant differences between the two raters p < 0.05 (Wilcoxon's sign paired rank sum test). The mean difference between the total scores was -0.76 (95% confidence interval from -1.98 to 0.46). Spearman's rho correlation coefficient for FAI totals of rater B against A was r(59) = 0.93 (p < 0.001). CONCLUSION: The FAI is a reliable tool for measuring outcome following stroke. Suggestions are made to strengthen the reliability, and consequently the validity of the measure.

Propofol directly depresses lumbar dorsal horn neuronal responses to noxious stimulation in goats.

PURPOSE: We tested the hypothesis that propofol, acting in the brain, would either enhance, or have no effect, on lumbar dorsal horn neuronal responses to a noxious mechanical stimulus applied to the hindlimb. We recorded the response of lumbar dorsal horn neurons during differential delivery of propofol to the brain and torso of goats. METHODS: Goats were anesthetized with isoflurane and neck dissections performed which permitted cranial bypass. A laminectomy was made to allow microelectrode recording of lumbar dorsal horn neuronal activity. Isoflurane was maintained at 0.8+/-0.1% to both head and torso throughout the study. During cranial bypass propofol was separately administered to the torso (1 mg x kg(-1), n = 7; 3.75 mg x kg(-1), n = 8) or cranial (0.04 mg x kg(-1), n = 7; 0.14 mg kg(-1), n = 8) circulations. RESULTS: Propofol administered to the torso depressed dorsal horn neuronal responses to noxious stimulation: low dose: 500+/-243 to 174+/-240 impulses x min(-1) at one minute post-injection, P<0.001; high dose: 478+/-204 to 91+/-138 impulses x min(-1) at one minute post-injection, P<0.05). Propofol administered to the cranial circulation had no effect: low dose: 315+/-150 to 410+/-272 impulses x min(-1), P>0.05; high dose: 462+/-261 to 371+/-196 impulses x min(-1), P>0.05. CONCLUSIONS: These data indicate that propofol has a direct depressant effect on dorsal horn neuronal responses to noxious stimulation, with little or no indirect supraspinal effect.

Characterization of the effects of the partial dopamine agonist terguride on cocaine self-administration in the rat.

Dopamine neurotransmission is an important neuropharmacological component of cocaine self-administration in rodents. Terguride is a prototype drug belonging to a recently characterized class of compounds, dopamine partial agonists, which appear to possess a unique pharmacological profile in altering dopamine neurotransmission, where these drugs act as antagonists in conditions of high dopaminergic tone. The aim of the present study was therefore to test the effects of systemic administration of terguride in rats self-administering cocaine intravenously. The different aspects of cocaine self-administration examined after treatment with terguride were (a) the acute reinforcing properties of cocaine in rats exposed to limited-access self-administration of cocaine, (b) a full cocaine dose-effect function, (c) the reinforcing properties of cocaine as measured by a progressive ratio schedule and (d) the ability of terguride to maintain self-administration by itself. Terguride (0.025-0.4 mg/kg i.p.) significantly and dose-dependently reduced the acute reinforcing properties of cocaine as measured by an increase in responding for a single training dose of cocaine and a reduction of the inter-reinforcement interval. In addition, terguride (0.2-0.4 mg/kg) shifted the entire cocaine dose-effect function to the right, thus showing an antagonism of the reinforcing properties of cocaine independent of response rate. Moreover, in rats trained to self-administer cocaine on a progressive ratio schedule, terguride reduced the maximum fixed ratio ("breaking point") for cocaine reinforcement, also suggesting a decrease in the reinforcing properties of cocaine. Finally, in rats trained to self-administer cocaine terguride did not substitute for cocaine, thus indicating that terguride does not maintain intravenous self-administration by itself.

An STS-based radiation hybrid map of the human genome.

We have constructed a physical map of the human genome by using a panel of 83 whole genome radiation hybrids (the Stanford G3 panel) in conjunction with 10,478 sequence-tagged sites (STSs) derived from random genomic DNA sequences, previously mapped genetic markers, and expressed sequences. Of these STSs, 5049 are framework markers that fall into 1766 high-confidence bins. An additional 945 STSs are indistinguishable in their map location from one or more of the framework markers. These 5994 mapped STSs have an average spacing of 500 kb. An additional 4484 STSs are positioned with respect to the framework markers. Comparison of the orders of markers on this map with orders derived from independent meiotic and YAC STS-content maps indicates that the error rate in defining high-confidence bins is < 5%. Analysis of 322 random cDNAs indicates that the map covers the vast majority of the human genome. This STS-based radiation hybrid map of the human genome brings us one step closer to the goal of a physical map containing 30,000 unique ordered landmarks with an average marker spacing of 100 kb.

Placebo response in anxiety disorders.

OBJECTIVE: To review literature on placebo response in anxiety, to discuss sources and levels of placebo response in various anxiety disorders, and to suggest methods to prevent high placebo response rates in clinical research trials. DATA SOURCE: Data from scientific literature were identified using a MEDLINE search, and were extracted and summarized for this review. STUDY SELECTION: Representative findings were selected from clinical and epidemiologic studies, review articles, letters to the editor, book chapters, and proceedings. DATA EXTRACTION: Data from English-language reports of studies on humans were included. Only the most representative conclusions drawn from review articles were used. DATA SYNTHESIS: Anxiety disorders in general are thought to be extremely susceptible to a variety of influences, including patient characteristics and environmental variables. Reported placebo response levels in clinical studies of anxiolytics for generalized anxiety disorder and panic disorder vary widely, with a tendency to be rather high, although studies in social phobia and obsessive compulsive disorder appear to have consistently low placebo response rates. Comparisons of anxiety studies with studies of other indications, such as depression, show similar overall placebo response rates. To determine efficacy, drug response rates and placebo response rates must be clearly differentiated. CONCLUSIONS: Examination of the literature suggests that placebo response rates in studies of anxiolytics are influences by a number of factors, including both endogenous and exogenous variables. High placebo response rates may mask true drug response rates and may result from poor study design or lack of procedural standardization. The use of certain design methods may help to prevent high placebo response rates in anxiolytic clinical trials.

The effect of partial sleep deprivation on weight-lifting performance.

This study examined the effects of partial sleep deprivation on submaximal and maximal weight-lifting tasks and on subjective states pre- and post-activity. Eight male subjects (aged 18-24 years) were restricted to a nightly ration of 3 h sleep for 3 successive nights after baseline measures on the first day. A 4 day period where normal sleep was permitted fulfilled a control condition, the normal and sleep-deprived conditions being counterbalanced and separated by 10 days. The weight-lifting tasks consisted of biceps curl, bench press, leg press, and dead lift. For each exercise a submaximal load, corresponding to a fixed value on a category ratio scale of exertion, was determined for 20 repetitions; the maximal lift for that exercise was then obtained. A profile of mood states and subjective sleepiness were determined at each test occasion, tests being conducted in the evening of each day. There was no significant effect of sleep loss on performance of maximal biceps curl (p < 0.05) but a significant effect was noted on maximal bench press, leg press, and dead lift (p < 0.001). Trend analysis indicated decreased performance in submaximal lifts for all the 4 tasks: the deterioration was significant after the second night of sleep loss (p < 0.01). Performing the lifts had little influence on sleepiness ratings which increased linearly with successive days of sleep loss. Mood states of confusion, vigour, and fatigue were affected significantly by the sleep deprivation regimen (p < 0.001), but there was no significant effect of sleep loss or anger, tension, and depression (p > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Newly synthesized prolactin is preferentially secreted by the adenohypophysis in a primary cell culture system.

A relationship between prolactinin synthesis and release was studied using a dispersed adenohypophysial cell primary-culture system. Newly synthesized prolactin was identified by the amount of prolactin-associated tritium activity. No new prolactin was synthesized during a 1-h incubation with 3H-Leu. After 4 h a significant amount of newly synthesized prolact was released into the medium but no labelled prolactin was detected in the cells. Radioimmunoassayable prolactin, however, was equally divided between the cells and the medium indicating that the newly synthesized prolactin was preferentially secreted. In contrast, approx. 2 times more newly labelled GH was found in the cell extract than in the medium while by GH-radioimmunoassay, the cells contained twice as much GH as the medium in the control group. During the 1-h incubation, estradiol (1.0 ng/ml) increased prolactin content in the medium, although no newly synthesized prolactin appeared in the medium or the cells. During the 4-h incubation period significantly more labelled prolactin was released into the medium in the presence of estradiol (1.0 ng/ml) than in the control. These results indicate that (1) estradiol has a stimulatory effect on prolactin secretion, (2) estradiol activates a prolactin-synthesis mechanism, (3) newly synthesized prolactin is preferentially released, and (4) the rate of release of newly synthesized prolactin and GH having different mechanisms of hypothalamic control, an inhibiting factor for the prolactin and a releasing factor for GH.

Comparative studies of prolactin secretion in estradiol-primed and normal male rats induced by ether stress, pimozide and TRH.

The differences in plasma prolactin concentration between normal and estradiol-implanted male rats were compared after treatment with 3 different stimulating agents of prolactin secretion [ether anesthesia, pimozide (a "specific' dopaminergic receptor blocking agent) and TRH] using conscious, free-moving rats implanted with permanent intra-atrial cannulae. It has recently been shown that ether stress raises the circulating prolactin concentration by stimulating PRF secretion. The ether stress elevated prolactin concentration from 100 to 400 ng/ml in the estradiol-implanted rat and from 10 to 40 ng/ml in the normal male. Thus, the ether stress elevated the prolactin concentration 4 times over the basal level in both normal male and estradiol-implanted male rats, implying that the physiological role of the PRF is not changed by the estradiol implantation. A bolus injection of pimozide (1 mg/kg) elevated the plasma prolactin concentration in both the normal and estradiol-implanted male with an initial surge followed by descent to a maintained plateau level. This plateau level in the estradiol-primed rat was 600 ng/ml and in the nonprimed male rat, 50 ng/ml. The ratio of the plateau concentration over the basal level was 4 times for both groups, suggesting that the physiological role of the PIF in the estradiol-implanted rat is not different from that in the normal male rat. It is known that TRH not only stimulates TSH secretion but will stimulate prolactin secretion as well. A very large dose (0.6 mg/kg) of TRH elevated prolactin concentration 6-fold in the estradiol-implanted rat but stimulate little prolactin secretion in the normal male rat. Since ether exposure appears to stimulate prolactin secretion in both estradiol-primed and non-primed male rats through PRF secretion, while TRH was not able to stimulate a significant amount of prolactin secretion in the normal male rat, we concluded that TRH acts to stimulate prolactin secretion in estradiol-primed rats but through a different mechanism than that operating for PRF.

Normal and abnormal forgetting in organic amnesia: effect of locus of lesion.

Speed of forgetting by the patient H.M. was examined in two experiments using picture recognition tests. In both experiments stimulus duration was manipulated to equalize initial performance by H.M. and others, and speed of forgetting was investigated over a period of one week. In the first experiment, where initial performance was high, H,M. appeared to forget faster than normal controls. In the second experiment, where initial performance was somewhat lower, H.M. was shown to forget faster than both controls and Korsakoff patients (who forget at a normal rate). These results suggest a functional difference between the amnesia with hippocampal lesions and the amnesia of Korsakoff's disease.