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Biomedical subjects

R Davies

Publications and source records attributed to R Davies.

At least 55 records · Page 3Linked to original sources
PubMed2001

Total synthesis of himandravine.

[reaction: see text] The first total synthesis of (+)-himandravine (1) is described, starting from (2S,6S)-cis-2-formyl-6-methyl-N-Boc-piperidine (8) in 11 linear steps and 17% overall yield. The key step involves a highly diastereoselective intramolecular Diels-Alder reaction of the key intermediate 5 that contains the entire latent carbon framework and functional group substitution of himandravine.

Alkaloids↗
PubMed2001

Early Oligocene initiation of North Atlantic Deep Water formation.

Dating the onset of deep-water flow between the Arctic and North Atlantic oceans is critical for modelling climate change in the Northern Hemisphere and for explaining changes in global ocean circulation throughout the Cenozoic era (from about 65 million years ago to the present). In the early Cenozoic era, exchange between these two ocean basins was inhibited by the Greenland-Scotland ridge, but a gateway through the Faeroe-Shetland basin has been hypothesized. Previous estimates of the date marking the onset of deep-water circulation through this basin-on the basis of circumstantial evidence from neighbouring basins-have been contradictory, ranging from about 35 to 15 million years ago. Here we describe the newly discovered Southeast Faeroes drift, which extends for 120 km parallel to the basin axis. The onset of deposition in this drift has been dated to the early Oligocene epoch ( approximately 35 million years ago) from a petroleum exploration borehole. We show that the drift was deposited under a southerly flow regime, and conclude that the initiation of deep-water circulation from the Norwegian Sea into the North Atlantic Ocean took place much earlier than is currently assumed in most numerical models of ancient ocean circulation.

Animals↗
PubMed2001

Gene expression and amplification in breast carcinoma cells with intrinsic and acquired doxorubicin resistance.

The multidrug resistance (MDR) phenotype is a major cause of cancer treatment failure. Here the expressions of 4224 genes were analysed for association with intrinsic or acquired doxorubicin (DOX) resistance. A cluster of overexpressed genes related to DOX resistance was observed. Included in this cluster was ABCB1 the P-glycoprotein transporter protein gene and MMP1 (Matrix Metalloproteinase 1), indicative of the invasive nature of resistant cells, and the oxytocin receptor (OXTR), a potential new therapeutic target. Overexpression of genes associated with xenobiotic transformation, cell transformation, cell signalling and lymphocyte activation was also associated with DOX resistance as was estrogen receptor negativity. In all carcinoma cells, compared with HBL100 a putatively normal breast epithelial cell line, a cluster of overexpressed genes was identified which included several keratins, in particular keratins 8 and 18 which are regulated through the ras signalling pathway. Analysis of genomic amplifications and deletions revealed specific genetic alterations common to both intrinsic and acquired DOX resistance including ABCB1, PGY3 (ABCB4) and BAK. The findings shown here indicate new possibilities for the diagnosis of DOX resistance using gene expression, and potential novel therapeutic targets for pharmacological intervention.

Antineoplastic Agents↗
PubMed2001

A randomized, controlled trial of remacemide for motor fluctuations in Parkinson's disease.

BACKGROUND: Preclinical studies suggest that glutamate antagonists help ameliorate motor fluctuations in patients with PD treated with levodopa. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study, the authors assessed the safety, tolerability, and efficacy of the glutamate receptor blocker remacemide hydrochloride in 279 patients with motor fluctuations treated with levodopa. The primary objective was to assess the short-term tolerability and safety of four dosage levels of remacemide during 7 weeks of treatment. Patients were also monitored with home diaries and the Unified PD Rating Scale (UPDRS) to collect preliminary data on treatment efficacy. RESULTS: Remacemide was well tolerated up to a dosage of 300 mg/d on a twice daily schedule and 600 mg/d on a four times daily schedule. The most common dosage-related adverse events were dizziness and nausea, as observed in previous studies of remacemide. The percent "on" time and motor UPDRS scores showed trends toward improvement in the patients treated with 150 and 300 mg/d remacemide compared with placebo-treated patients, although these improvements were not significant. CONCLUSION: Remacemide is a safe and tolerable adjunct to dopaminergic therapy for patients with PD and motor fluctuations. Although this study had limited power to detect therapeutic effects, the observed improvement is consistent with studies of non-human primates with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian signs and symptoms. Additional studies are warranted to confirm these results over an extended period of observation, and to explore the potential neuroprotective effects of remacemide in slowing the progression of PD.

Acetamides↗
PubMed2001

Use of hematopoietic progenitors in whole blood to support dose-dense chemotherapy: a randomized phase II trial in small-cell lung cancer patients.

PURPOSE: Small-cell lung cancer (SCLC) is exquisitely chemosensitive, but few patients are cured by conventional chemoradiotherapy. Recent studies suggest that increased cytotoxic dose-intensity might improve survival. In this randomized phase II study, we tested the feasibility of dose intensification using sequential reinfusion of hematopoietic progenitors in whole blood. PATIENTS AND METHODS: SCLC patients with a favorable prognosis were treated with six cycles of ifosfamide, carboplatin, and etoposide (ICE), at 4-week (standard treatment) or 2-week (intensified treatment) intervals. Intensified treatment was supported by daily subcutaneous filgrastim injections and reinfusion of 750 mL of autologous blood collected immediately before each cycle. RESULTS: Fifty consecutive patients were randomized to standard (n = 25) or intensified (n = 25) ICE. A total of 94% completed at least three treatment cycles, and 70% completed six cycles; 96% of treatments were given at full dose. The planned dose-intensity was 1.0 for standard and 2.0 for intensified ICE. The median received dose-intensity for cycles 1 through 3 was 0.99 (range, 0.33 to 1.02) for the standard treatment arm and 1.80 (range, 0.99 to 1.97) for the intensified treatment arm (P <.001). Over all six cycles, the median received dose-intensity was 0.95 (range, 0.17 to 1.03) for the standard treatment arm and 1.60 (range, 0.60 to 2.01) for the intensified treatment arm (P <.001). Febrile neutropenia was more common on the standard treatment arm (84% v 56%), resulting in more days of intravenous antibiotics (median, 10 v 3 days; P =.035). Transfusion requirements were similar in the two groups. CONCLUSION: Sequential reinfusion of hematopoietic progenitors in whole blood can safely support substantial increases in dose-intensity of ICE chemotherapy for SCLC.

Adult↗
PubMed2001

Tamoxifen mutagenesis and carcinogenesis in livers of lambda/lacI transgenic rats: selective influence of phenobarbital promotion.

Administration of tamoxifen (TAM) (20 mg/kg per day p.o.) for 6 weeks to female lambda/lacI transgenic rats caused a 4-fold increase in mutation frequency (MF) at the lacI gene locus in the livers of dosed animals compared with controls. After cessation of dosing, the MF showed a further increase with time at 2, 12 and 24 weeks, respectively. Phenobarbital promotion of similarly treated animals resulted in no increase in mutation frequency compared with TAM alone. Treatment with phenobarbital or TAM+phenobarbital resulted in time-dependent increases in liver weight compared with the corresponding controls. There was an increase in cell proliferation in the phenobarbital and TAM+phenobarbital groups, and at 24 weeks in the TAM dosed animals compared with controls. There was also a progressive increase in the number of GST-P expressing foci in the livers of TAM and TAM + phenobarbital rats compared with controls. The induction of cell proliferation and GSTP foci in the rat liver by phenobarbital is consistent with its ability to promote tamoxifen-initiated liver tumours in the rat. If the lacI gene is regarded as being representative of the rat genome in general (albeit that the gene is bacterial) the above observations suggest that promotion by tamoxifen confers selective advantage on mutated genes at loci that contribute to the tumour phenotype and that promotion of rat liver tumours by tamoxifen is not dependent simply upon the enhancement of cellular proliferation.

Animals↗
PubMed2001

Maintaining contact with people with severe mental illness: 5-year follow-up of assertive outreach.

BACKGROUND: Assertive outreach is a central strand of Government mental health policy in England. Are different long-term models of mental health care which include assertive outreach associated with different service user outcomes and cost? METHOD: We conducted a multi-site 5-year follow-up study of people with severe mental illness. From 0 to 18 months all three sites had Intensive Case Management (ICM) teams practising assertive outreach. From 18 to 60 months one team sustained ICM, one team merged and another was disbanded. All 131 original ICM team clients were the study participants. Outcome was measured in terms of sustained engagement with statutory mental health services, psychiatric symptoms, social functioning, resource use and cost. RESULTS: All 120 live participants were traced. Only four people had no service contact; when contacted by a researcher they appeared to be coping well. No incidents of serious violence were discovered. No differences existed between teams in the mean total symptom or total social functioning change scores at follow-up, after controlling for baseline differences. No differences existed in mean cost between teams during the first 18 months. Mean (standard deviation) annualised costs varied considerably in the 18-60 month period: sustained team Pound Sterling13,734 (10,820); integrated team Pound Sterling11,037 (13,603); disbanded team Pound Sterling5,742 (7,007) (F=4.4, 105 df, p=0.015). CONCLUSION: Continued specialist assertive outreach service models have higher costs than non-specialist services for no apparent benefit. In the long term new assertive outreach services should have procedures in place to transfer people to lower intensity and lower cost care.

Case Management↗
PubMed2001

Comparative investigations of the desensitising efficacy of a new dentifrice.

OBJECTIVES: In two clinical trials of 8 weeks duration, the ability of a new dentifrice, containing potassium nitrate, stannous fluoride and sodium fluoride to reduce dentine hypersensitivity was compared with either a non-desensitising fluoride dentifrice or a commercially available desensitising dentifrice (Sensodyne F) to reduce dentine hypersensitivity. METHOD: In both studies, the participants had to have at least two sensitive root surfaces. Subjects were stratified by baseline tactile and air blast sensitivity scores and the number of sensitive teeth and randomly allocated to 2 balanced groups. In the first study (N=81) the new dentifrice was compared with a fluoride dentifrice and in the second study (N=105) with Sensodyne F. Participants were requested to brush with their assigned dentifrice twice a day for one minute. At 4 and 8 weeks the sensitive teeth were again examined and their tactile and air blast sensitivity scores recorded. RESULTS: In study 1, the group using the new dentifrice tolerated greater pressure after 4 (34.9 g) and 8 weeks (38.4 g) than the group using the fluoride dentifrice (22.9 g and 19.0 g, respectively). These differences were statistically significant (p<0.001). At 4 and 8 weeks, the mean air blast scores for the group using the new dentifrice (1.39 and 0.83) were lower than for the group using fluoride dentifrice (1.78 and 1.76) and were significantly different at 8 weeks (p<0.001). In study 2 the group using the new dentifrice tolerated greater pressure after 4 (40.5 g) and 8 weeks (43.7 g) than the group using Sensodyne F (27.8 g and 33.2 g, respectively). These differences were statistically significant (p<0.001). At 4 and 8 weeks, the mean air blast scores for the group using the new dentifrice (1.10 and 0.67) were significantly lower than the group using Sensodyne F (1.90 and 1.57) (p<0.001). CONCLUSIONS: These studies demonstrate that the new dentifrice, containing potassium nitrate, stannous fluoride and sodium fluoride is significantly better at reducing dentine hypersensitivity than both the dentifrice containing sodium fluoride and the one containing potassium chloride, triclosan and sodium fluoride (Sensodyne F).

Adolescent↗
PubMed2001

A review of evaluative studies of computer-based learning in nursing education.

Although there have been numerous attempts to evaluate the learning benefits of computer-based learning (CBL) packages in nursing education, the results obtained have been equivocal. A literature search conducted for this review found 25 reports of the evaluation of nursing CBL packages since 1966. Detailed analysis of the evaluation methods used in these reports revealed that most had significant design flaws, including the use of too small a sample group, the lack of a control group, etc. Because of this, the conclusions reached were not always valid. More effort is required in the design of future evaluation studies of nursing CBL packages.

Computer-Assisted Instruction↗
PubMed2001

Short-term dosing of alpha-hydroxytamoxifen results in DNA damage but does not lead to liver tumours in female Wistar/Han rats.

It is now generally accepted that activation of tamoxifen occurs as a result of metabolism to alpha-hydroxytamoxifen. In this study, alpha-hydroxytamoxifen was given to female Wistar/Han rats (0.103 or 0.0103 mmol/kg, intraperitoneally, daily for 5 days). This resulted in liver DNA damage, determined by (32)P-post-labelling, of 3333 +/- 795 or 343 +/- 68 adducts/10(8) nucleotides, respectively (mean +/- SD, n = 4). Following HPLC separation, the retention times of the major alpha-hydroxytamoxifen DNA adducts were similar to those seen following the administration of tamoxifen. However, after rats were treated with alpha-hydroxytamoxifen (0.103 mmol/kg) for 5 days and the animals kept for up to 13 months, no liver tumours developed (0/7 rats), even with phenobarbital promotion (0/5 rats). GST-P foci were detected in the liver, but only after 13 months was their number or area significantly increased over the corresponding controls. When alpha-hydroxytamoxifen was given to female lambda/lacI transgenic rats (0.103 mmol/kg orally for 10 days) and the animals killed 46 days later, there was an approximate 1.8-fold increase in mutation frequency but no significant increase in G:C to T:A transversions as described after tamoxifen treatment. It is concluded that DNA damage alone, resulting from the short-term administration of alpha-hydroxytamoxifen, is not sufficient to initiate liver tumours even with phenobarbital promotion. As with tamoxifen, long-term exposure may be required to allow promotion and progression of transformed cells.

Animals↗
PubMed2001

Interference between postural control and mental task performance in patients with vestibular disorder and healthy controls.

OBJECTIVES: To determine whether interference between postural control and mental task performance in patients with balance system impairment and healthy subjects is due to general capacity limitations, motor control interference, competition for spatial processing resources, or a combination of these. METHOD: Postural stability was assessed in 48 patients with vestibular disorder and 24 healthy controls while they were standing with eyes closed on (a) a stable and (b) a moving platform. Mental task performance was measured by accuracy and reaction time on mental tasks, comprising high and low load, spatial and non-spatial tasks. Interference between balancing and performing mental tasks was assessed by comparing baseline (single task) levels of sway and mental task performance with levels while concurrently balancing and carrying out mental tasks. RESULTS: As the balancing task increased in difficulty, reaction times on both low load mental tasks grew progressively longer and accuracy on both high load tasks declined in patients and controls. Postural sway was essentially unaffected by mental activity in patients and controls. CONCLUSIONS: It is unlikely that dual task interference between balancing and mental activity is due to competition for spatial processing resources, as levels of interference were similar in patients with vestibular disorder and healthy controls, and were also similar for spatial and non-spatial tasks. Moreover, the finding that accuracy declined on the high load tasks when balancing cannot be attributed to motor control interference, as no motor control processing is involved in maintaining accuracy of responses. Therefore, interference between mental activity and postural control can be attributed principally to general capacity limitations, and is hence proportional to the attentional demands of both tasks.

Adult↗
PubMed2001

The relationship between atopic status and IL-10 nasal lavage levels in the acute and persistent inflammatory response to upper respiratory tract infection.

We examined the influence of atopy on virus-induced airway inflammation by comparing the nasal response to naturally acquired upper respiratory tract infection in atopic and nonatopic subjects by measurement of cytokine, chemokine, and mediator levels in nasal lavage from 44 adults (23 atopic) taken during the acute and the convalescent phases of the common cold. Nasal aspirates were examined for the presence of upper respiratory viruses by RT-PCR. In atopic and nonatopic subjects there were increased levels of IL-1beta, IL-6, IL-8, TNF-alpha, RANTES, sICAM-1, MPO, ECP, IL-10, and IFN-gamma in nasal lavage during the acute compared with the convalescent phase (p < 0.001). During the acute phase histamine levels were significantly higher in the atopic than in the nonatopic subjects (p < 0.05), whereas IL-10 levels were significantly greater in the nonatopic than in the atopic subjects (p < 0.05). At convalescence levels of IL-1beta, IL-6, sICAM-1, ECP, RANTES and albumin were significantly higher in the atopic group (p < 0.05). An upper respiratory tract virus was found in 27 volunteers (61%) during the acute stage and in two volunteers (4%) at convalescence. We conclude that virus-induced inflammatory changes within the nose are more prolonged in atopic than in nonatopic subjects and that this is associated with reduced IL-10 levels in atopic compared with nonatopic subjects during the acute phase of upper respiratory tract infection.

Acute-Phase Proteins↗