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Biomedical subjects

N Fletcher

Publications and source records attributed to N Fletcher.

11 recordsLinked to original sources
PubMed2005

Selamectin is a potent substrate and inhibitor of human and canine P-glycoprotein.

The transport of the antiparasitic agents, ivermectin, selamectin and moxidectin was studied in human intestinal epithelial cell monolayers (Caco-2) and canine peripheral blood lymphocytes (PBL). Both models expressed the mdr1-coded 170 kDa ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp). Fluxes of the P-gp substrate rhodamine-123 (Rh-123) across Caco-2 monolayers showed that ivermectin and selamectin acted as potent P-gp inhibitors with IC50 values of 0.1 microm. In contrast, moxidectin was a weaker P-gp inhibitor with an IC50 of 10 microm. The transport of radiolabelled ivermectin, selamectin and moxidectin through Caco-2 monolayers showed that ivermectin, selamectin and moxidectin were P-gp substrates with secretory/absorptive ratios of 7.5, 4.7 and 2.6 respectively. Secretory transport of [3H]-ivermectin and [3H]-selamectin was blocked by the P-gp inhibitor, verapamil. Ivermectin and selamectin inhibited the efflux of Rh-123 from PBL and the concentration of inhibition was similar to that of verapamil. In contrast, moxidectin did not have a significant effect on Rh-123 efflux from PBL. The data suggest that ivermectin and selamectin are potent P-gp substrates, while moxidectin is a weak one.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Deep brain stimulation of the subthalamic nucleus: effectiveness in advanced Parkinson's disease patients previously reliant on apomorphine.

OBJECTIVES: To assess the efficacy of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with advanced Parkinson's disease previously reliant on apomorphine as their main antiparkinsonian medication. METHODS: Seven patients with motor fluctuations despite optimal medical treatment given as predominantly apomorphine infusion (n=6), or intermittent apomorphine injections (n=1) underwent bilateral STN DBS using frameless stereotactic surgery. Standard assessments of parkinsonism and motor fluctuations, using Unified Parkinson's Disease Rating Scale (UPDRS) were performed before and six months after surgery. Assessments were performed both on and off medication, and postoperative with the stimulators switched on and off. RESULTS: Bilateral STN DBS improved motor scores (UPDRS III) by 61% when off medication (p<0.05). Clinical fluctuations (UPDRS IV items 36-39) were reduced by 46.2% (p<0.05). Total daily apomorphine dose was reduced by 68.9% (p<0.05) and apomorphine infusion via a pump was no longer required in four patients. There were no operative complications. Two patients required treatment for hallucinations postoperatively but there was no significant change in mini-mental state examination. CONCLUSIONS: In patients with advanced Parkinson's disease, previously reliant on apomorphine, bilateral STN DBS is an effective treatment to reduce motor fluctuations and enable a reduction in apomorphine use.

Aged↗
PubMed2003

Variability in position of the subthalamic nucleus targeted by magnetic resonance imaging and microelectrode recordings as compared to atlas co-ordinates.

BACKGROUND: Traditional methods for localisation of target nuclei for deep brain stimulation (DBS) have used brain atlas co-ordinates for initial targeting. It is now possible to visualise the subthalamic nucleus (STN) on magnetic resonance imaging (MRI) and determine the individual variability of its position. METHODS: The present study was performed in patients undergoing STN DBS for Parkinson's disease. The STN was directly targeted from axially obtained MRI and verified with microelectrode recordings. Postoperatively, the most effective contact was identified for each patient, and its position was calculated. RESULTS: Fifty electrodes were inserted in 25 patients. The target position varied considerably in relation to the mid-commissural point. The mean effective contact position lies just dorsal to the location of the STN in a standard brain atlas. CONCLUSION: The STN varies in position, and can be accurately targeted from MRI alone.

Adult↗
PubMed2003

Use of the NeuroMate stereotactic robot in a frameless mode for movement disorder surgery.

BACKGROUND/AIMS: To evaluate the use of the NeuroMate stereotactic robot with a novel ultrasound registration system for movement disorder surgery (MDS). METHODS: Using the robot in a frameless mode, 51 patients underwent MDS. Surgical planning was carried out using MRI data obtained more than 24 h before surgery. RESULTS: 37 out of 50 targets in the subthalamic nucleus were satisfactorily identified with a single microelectrode trajectory and the final electrode positions were at a mean distance of 1.7 mm from the calculated target. There was a significant improvement in motor scores of the Unified Parkinson's Disease Rating Scale III (off medication) at 6 (43%) and 18 months (51.7%) compared to pre-operative scores (p < 0.05). CONCLUSIONS: The frameless robot using only MRI data can be used for MDS. The temporal separation of imaging from the surgical procedure provides additional time for detailed image analysis and planning.

Humans↗
PubMed2001

Hepatic vitamin a depletion is a sensitive marker of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure in four rodent species.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-treated animals show altered retinoid homeostasis and exhibit signs of toxicity similar to those of vitamin A-deficient animals. In this study we established dose-response curves for sublethal oral doses of TCDD and hepatic vitamin A gain in four rodent species. This was done to evaluate any potential correlation between decreased hepatic vitamin A gain and other TCDD-induced effects, particularly depressed body weight gain and hepatic CYP1A induction. Young Hartley guinea pigs, Sprague-Dawley rats, C57BL/6 mice, and Golden Syrian hamsters were given single oral doses of TCDD at up to 2.5, 100, 1000, and 1000 microg/kg bw, respectively, and killed 28 days after treatment. Hepatic vitamin A gain was decreased 25% compared to controls at estimated doses of 0.1, 0.9, 1.1 and 3.6 microg/kg bw in guinea pigs, hamsters, rats, and mice, respectively. CYP1A induction and hepatic vitamin A gain were affected at similar dose levels and showed similar, but inverse dose-response curves in each of the four species, consistent with the hypothesis that altered vitamin A homeostasis is Ah-receptor mediated. In addition, there was an apparent correlation between the dose-response curves for decreased hepatic vitamin A gain and decreased body weight gain in all species. Taken together with the known importance of vitamin A in body weight regulation, this result was consistent with a contributing role for altered retinoid homeostasis in the wasting syndrome induced by TCDD.

Administration, Oral↗
PubMed2000

Neuromuscular dysfunction in critical illness: what are we dealing with?

Neuromuscular weakness is a very common and debilitating problem for survivors of critical illness. Neurophysiological abnormalities are almost ubiquitous in these patients, and often favour a diagnosis of axonal polyneuropathy, whereas muscle histology, where available, reveals a high incidence of atrophy and necrosis. The precise nature and aetiology of this complex disorder is not yet well understood.

Journal Article↗
PubMed1996

Effect of the 5-HT1A agonist, 8-OH-DPAT on instrumental performance in rats.

These experiments assessed whether reported increases in food consumption and food-reinforced instrumental performance in undeprived rats by the 5-HT1A agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) are due to an increment in the incentive value of foods. Against this hypothesis, we found that when undeprived rats were trained to lever press for the food pellets and then allowed to consume the pellets under 8-OH-DPAT, this reexposure decreased subsequent instrumental extinction performance regardless of test drug condition relative to reexposure under vehicle. Although both food consumption and reinforced lever press performance were incremented, 8-OH-DPAT was found generally to reduce instrumental extinction performance and lever pressing during a period when the reinforcer was delivered non-contingently. Rats injected with 8-OH-DPAT were, however, more sensitive to delay of reinforcement, and increased their lever press performance at a 3-s delay but decreased performance at 6-s and 12-s delays relative to animals injected with vehicle. These results are consistent with the hypothesis that 8-OH-DPAT modifies arousal processes in a manner similar to mild stress, thereby acting both to elevate rewarded instrumental performance and to increase sensitivity to the effects of non-reward.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1988

Work at sea: a study of sleep, and of circadian rhythms in physiological and psychological functions, in watchkeepers on merchant vessels. IV. Rhythms in performance and alertness.

Performance scores on both a simple detection task and a complex visual judgment task, together with subjective alertness ratings, were collected 4-hourly from 19 watchkeepers working a "4-on/8-off" routine, and from 20 dayworkers, over consecutive days of voyages on merchant ships. Adaptation of the circadian rhythms in the measures to the shifted hours of work of the three sections of the watchkeeping crews was at best only partial. These rhythms resulted in a depression of the levels of most measures during the night hours, which was exacerbated by the effects of recent awakening from sleep. It is suggested that these unwanted variations in operational effectiveness could be largely removed by replacing the 4-on/8-off watchkeeping system, with its associated "split" sleep pattern, by one which allows a single full length sleep each day. Such a system would encourage better adaptation of the rhythms; effects of recent awakening could be avoided by the provision of an adequate "waking up" period before duty begins.

Arousal↗
PubMed1988

Work at sea: a study of sleep, and of circadian rhythms in physiological and psychological functions, in watchkeepers on merchant vessels. VI. A sea trial of an alternative watchkeeping system for the merchant marine.

A trial of an alternative to the traditional 4-on/8-off watchkeeping system was made on a container ship during a round trip from Europe to the Far East. The three navigating officers on the ship operated the new system, which involved "compressed" working hours with a long unbroken period of rest, during two sections of the voyage, one of which included six stops at ports. Despite unforeseen problems arising mainly from these stops, questionnaire responses concerning the new system were not altogether unfavourable to it, and daily records kept by the officers gave some support to the hypothesis that sleep would be better than under the traditional system. However, a number of difficulties were encountered; these are discussed in relation to the design of future studies of alternative watchkeeping systems.

Circadian Rhythm↗
PubMed1988

Work at sea: a study of sleep, and of circadian rhythms in physiological and psychological functions, in watchkeepers on merchant vessels. II. Sleep duration, and subjective ratings of sleep quality.

Sleep length and sleep quality scores were collected on board ships over periods of up to two weeks from 38 watchkeepers working a '4-on/8-off routine' and 29 dayworkers. All watchkeepers exhibited fragmented sleeping patterns, which indicated a lack of adaptation of the sleep/wakefulness cycle to the hours of work. There were only slight differences in total sleep length between watchkeepers and dayworkers, however, both groups did not obtain an adequate amount of sleep. Within the watchkeeping crews the 3rd Officers had by far the shortest sleep length. Concerning sleep quality, daytime sleep was generally given the lowest ratings, whereas sleep starting before midnight was on average evaluated as the best, both by watchkeepers and dayworkers. Watchkeeping personnel do not normally have any "days off" during a voyage so that missed sleep might even amount to a sleep deficit. A solution for this problem could perhaps be a new, stabilized system that allows a single uninterrupted sleep, which is required for full recuperation, to be taken each day.

Circadian Rhythm↗