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Biomedical subjects

S Morley

Publications and source records attributed to S Morley.

At least 19 recordsLinked to original sources
PubMed2006

Requirement for Akt-mediated survival in cell transformation by the dbl oncogene.

The dbl oncogene product is the founding member of a large family of oncogenic proteins that function by activating the small GTP-binding proteins Cdc42, Rac and Rho. Through its substrate GTPases, Dbl transduces proliferative signals from cell-surface receptors to diverse cellular effectors and signaling pathways. The mechanisms by which these multiple signals are integrated, as well as their relative contribution to Dbl-induced cell transformation, are presently poorly understood. We investigated the role of the survival regulators PI3-kinase and Akt in Dbl-induced cell transformation. We found that Dbl induced the phosphorylation of Akt on threonine 308, through the GTPases Rac and Cdc42 and in a PI3-kinase dependent manner. Pharmacological or biochemical interference with this pathway lead to a marked, dose-dependent inhibition of the focus formation activity exhibited by Dbl-expressing cells. Dbl expression stimulated the phosphorylation of the anti-apoptotic Akt substrate Bad, and caused a marked decrease in basal levels of apoptosis. Finally, we found that activated Cdc42 existed in cells in complex with phosphoionositide-dependent kinase-1 (PDK1), the downstream mediator of PI3-kinase action. The data indicate that Dbl signaling stimulate the formation of a novel survival complex, through which anti-apoptotic signals are generated and propagated.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2006

Thoracic ventral dural defect: idiopathic spinal cord herniation.

Thoracic ventral dural defect, and resultant idiopathic spinal cord herniation, is a rare but increasingly recognized cause of a chronic progressive thoracic myelopathy, particularly in middle-aged women. A neurosurgically confirmed case is presented, together with a review of the pathogenesis, clinical presentation, imaging features, treatment options and progress of this entity post-treatment.

Adult↗
PubMed2006

Amniocentesis results: investigation of anxiety. The ARIA trial.

OBJECTIVES: The Amniocentesis Results: Investigation of Anxiety (ARIA) trial tested two hypotheses: first, that giving amniocentesis results out on a fixed date alters maternal anxiety during the waiting period, compared with a policy of telling parents that the result will be issued 'when available' (i.e. a variable date), and secondly, that issuing early results from a rapid molecular test alters maternal anxiety during the waiting period, compared with not receiving any results prior to the karyotype. The effects of the two interventions on anxiety 1 month after receiving karyotype results were also examined. DESIGN: A multi-centre, randomised, controlled, open fixed sample, 2 x 2 factorial design trial, with equal randomisation. SETTING: Twelve hospitals in England offering amniocentesis as a diagnostic test for Down's syndrome. PARTICIPANTS: A total of 226 women who had had an amniocentesis were randomised between June 2002 and July 2004. Eight women with abnormal results or test failure were excluded post-randomisation. INTERVENTIONS: Issuing karyotype results on a prespecified fixed date, rather than issuing them as soon as they became available and issuing karyotype results alone, or subsequent to issuing results from a rapid molecular test for the most common chromosomal abnormalities. MAIN OUTCOME MEASURES: Average anxiety during the waiting period, calculated using daily scores from the short version of the Spielberger State-Trait Anxiety Inventory (STAI). Recalled anxiety, measured 1 month after receiving karyotype results, using a rating scale. Anxiety at the 1-month follow-up, measured using the short-form STAI. RESULTS: There was no evidence that giving out karyotype results on a fixed or on a variable date altered maternal anxiety during the waiting period. However, the analysis only had sufficient power to detect a moderate to large effect. Issuing early results from a partial, but rapid, test reduced maternal anxiety during the waiting period, compared with receiving only the full karyotype results. This was a moderate to large effect. In addition, group differences in recalled anxiety reflected fairly closely the differences in anxiety women had experienced while waiting for results. One month after receiving normal karyotype results, anxiety was low in all groups, but women who had been given rapid test results were more anxious than those who had not. This was a small to moderate effect. CONCLUSIONS: Since there are no clear advantages in anxiety terms of issuing karyotype results as soon as they become available, or on a fixed date, women could be given a choice between them. Rapid testing was a beneficial addition to karyotyping, at least in the short term. This does not necessarily imply that early results would be preferred to comprehensive ones if women had to choose between them. There should be further research, including more qualitative studies, into the causes, characteristics and consequences of anxiety associated with prenatal testing. The effects of different testing regimes on short- and long-term anxiety, on the preferences of women and on the relationship between anxiety and preference should be investigated. More research is needed on the ways in which information might be used to minimise anxiety in different testing regimes. Further research is also required into the policy implications of incorporating individual preferences for different testing regimes into prenatal testing programmes.

Adult↗
PubMed2004

Reassurance and the anxious cancer patient.

Many cancer patients are anxious even when disease is in remission. Anxiety about health, 'health anxiety', has distinct features, notably seeking medical reassurance about symptoms. Doctors may then communicate that these symptoms are not due to serious illness, a process known as 'reassurance'. However, reassurance may inadvertently perpetuate some patients' anxiety. We aimed to observe the relation between symptoms, anxiety and reassurance in consultations with cancer patients. A total of 95 outpatients, with breast or testicular cancers in remission, completed questionnaires measuring health anxiety at study entry, then general anxiety - before a consultation, immediately afterwards, 1 week later, and before their next consultation. We examined symptoms reported and reassurance by oncologists from audio recordings of consultations, and the outcome of subjects' anxiety. The results showed that substantial health anxiety was reported by one-third of the patients. Patients with higher levels of health anxiety reported more symptoms during consultations. Reassurance was ubiquitous, but not followed by an enduring improvement in anxiety. Certain forms of reassurance predicted increased anxiety over time, particularly for subjects who were most anxious. In conclusion, health anxiety can be a problem after cancer. Reassurance may not reduce patients' anxiety. Some reassurance was counterproductive for the most anxious patients. Oncologists may need to use reassurance as a procedure, balancing risk, and benefits, and patient selection and to manage cancer patients in remission.

Adolescent↗
PubMed2004

The role of neurotransmission and the Chopper domain in p75 neurotrophin receptor death signaling.

The role of p75 neurotrophin receptor (p75NTR) in mediating cell death is now well characterized, however, it is only recently that details of the death signaling pathway have become clearer. This review focuses on the importance of the juxtamembrane Chopper domain region of p75NTR in this process. Evidence supporting the involvement of K+ efflux, the apoptosome (caspase-9, apoptosis activating factor-1, APAF-1, and Bcl-xL), caspase-3, c-jun kinase, and p53 in the p75NTR cell death pathway is discussed and regulatory roles for the p75NTR ectodomain and death domain are proposed. The role of synaptic activity is also discussed, in particular the importance of neutrotransmitter-activated K+ channels acting as the gatekeepers of cell survival decisions during development and in neurodegenerative conditions.

Animals↗
PubMed2004

Structure-function relationship in the tocopherol transfer protein.

The role of specific amino acid residues in mediating the biochemical functions of tocopherol transfer protein (TTP) was investigated using site-directed mutagenesis and functional assays. These findings further current understanding of TTP mechanism of action and its role in human health.

Carrier Proteins↗
PubMed2003

Psychological therapies for the management of chronic and recurrent pain in children and adolescents.

BACKGROUND: An increasing number of children suffer with pain that lasts for six months or longer. Traditional treatment for such pain has been pharmacological and/or physical. Increasingly, following developments in the field of adult chronic pain management, psychological therapies are being employed to treat children with chronic or recurrent pain. OBJECTIVES: To assess the effectiveness of psychological therapies in treating chronic or recurrent pain in children and adolescents, and to test the null hypothesis that psychological therapies are no more effective than placebo, waiting list control or standard medical care. SEARCH STRATEGY: Electronic searches of the Cochrane Register of Randomised Controlled Trials, MEDLINE (1966-1999), Social Sciences Citation Index (1981-1999) and PsycLit (1974-1999) were made. RCTs were also sought in references of all identified studies, meta-analyses and reviews, and first authors and experts within the field were contacted. Date of the most recent search: December 1999. SELECTION CRITERIA: RCTs with at least five participants in each study arm which compared psychological therapies with placebo, waiting list or standard medical care for children or adolescents with chronic or recurrent pain were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Data were inspected for heterogeneity. For homogeneous dichotomous data the odds ratio with 95% confidence interval were calculated on an intention to treat basis. MAIN RESULTS: Thirty papers were recovered, representing 28 RCTs. Of these, 18 were analysable and included a total of 808 patients, 438 of whom entered treatment conditions. Fifteen were trials of chronic or recurrent headache; two for recurrent abdominal pain; and one for sickle cell pain. Only pain experience data from 13 trials were meta-analysable. Two meta-analyses were conducted. The first analysis of single treatments versus controls gave a pooled odds ratio of 8.83 (95% CI 4.33 to 18.03; z=5.98, P < 0.00001, df = 12 ). The second analysis (combined treatment versus control) produced a similar estimate: pooled odds ratio = 8.64 ( 95% CI = 4.13 to 18.07; z-5.73, P < 0.00001, df = 9 ). Both analyses indicate that psychological treatment is effective when compared with a pooled group of control conditions. From the pooled data set the NNT was 2.32 (95%CI 1.96 to 2.88). REVIEWER'S CONCLUSIONS: There is very good evidence that psychological treatments, principally relaxation and cognitive behavioural therapy, are effective in reducing the severity and frequency of chronic headache in children and adolescents. There is at present no evidence for the effectiveness of psychological therapies in attenuating pain in conditions other than headache, and little evidence for the effectiveness of psychological therapies in improving non-pain outcomes.

Abdominal Pain↗
PubMed2003

Optimizing bowel preparation for multidetector row CT colonography: effect of Citramag and Picolax.

AIM: To compare the adequacy and acceptability of Picolax and Citramag bowel cleansing agents for CT colonography. MATERIALS AND METHODS: Multidetector row CT colonography was performed in 124 subjects; 43 had been prepared with Picolax and 81 with Citramag. Datasets were assessed for retained fluid and solid residue, and overall adequacy of segmental visualization. Preparation acceptability was also assessed. RESULTS: There was significantly less retained fluid with Picolax. The odds of being in the next higher category for retained fluid when using Picolax were 0.33 (CI: 0.22-0.50, p<0.0001) when compared with Citramag, for all segments combined. However there was significantly more retained solid residue with Picolax. The odds of being in the next higher category for retained residue when using Picolax were 2.44 (CI: 1.41-4.24, p=0.002) when compared with Citramag, for all segments combined. There was no significant difference with respect to overall segmental visualization: the odds of a segment being adequately visualized when using Picolax were 1.52 (CI: 0.88-2.65, p=0.14) when compared with Citramag. There was no significant difference with respect to acceptability. CONCLUSION: Picolax results in a significantly drier colon than Citramag and associated with more retained residue. We found Picolax the more suitable preparation for CT colonography.

Adenoma↗
PubMed2003

Use of multidetector-row CT colonography for detection of colorectal neoplasia in patients referred via the Department of Health "2-Week-wait" initiative.

AIM: Patients referred under the Department of Health 2-week wait initiative with symptoms of colorectal cancer frequently undergo whole-colon examination. We investigated the use of computed tomography (CT) colonography as an alternative to colonoscopy in this scenario. MATERIALS AND METHODS: Fifty-four consecutive patients, referred via the 2-week wait initiative and scheduled for colonoscopy, consented to undergo multidetector CT colonography immediately before endoscopy. The site and morphology of any polyp or cancer detected by CT was noted and comparison made with subsequent colonoscopy. RESULTS: Colonoscopy detected polyps or cancer in 29 patients (53.7%). CT colonography prospectively detected 18 of 41 (44%) polyps of 1-5 mm, three of four (75%) polyps of 6-9 mm, four of four (100%) polyps 10 mm or larger, and five of six (83%) cancers. The missed cancer occurred early in the series and was a perceptive error. The overall sensitivity, specificity, positive predictive value and negative predictive value of CT colonography for cancer and polyps 10 mm or greater on a per patient basis were 90, 100, 100 and 98%, respectively. CT detected one renal cancer and one colonic cancer, initially missed due to incomplete colonoscopy. CONCLUSION: CT colonography is a robust technique for investigation of symptomatic patients. The learning curve must be overcome for optimal performance.

Adult↗
PubMed2003

Non-vascularized free toe phalanx transfers in congenital hand deformities--the Great Ormond Street experience.

Many options of varying complexity are available for the management of congenital short digits resulting from aphalangia in symbrachydactyly and constriction ring syndrome. We have used non-vascularized free toe phalanx transfers for these children when a vascularized toe transfer has been contraindicated. We describe our technique and experience with 22 children who underwent a total of 64 transfers of the proximal (35) or middle (29) toe phalanges (average 3 per child). The mean age at initial surgery was 15 months, and the mean follow-up was 5 years. Duration of time until epiphyseal closure could not be determined accurately, but total digital elongation averaged 6mm. Complications of this technique include joint instability, premature epiphyseal closure and, in one patient, infection and graft loss. Donor site deformity was determined according to measured growth deficit and toe function. This technique is a simple option for digital elongation and, if performed in the appropriate age group in short fingered and monodactylous subtypes of symbrachydactyly, has the potential to allow growth and function with minimal donor site deficit.

Bone Resorption↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗
PubMed2001

Cognitive-processing bias in chronic pain: a review and integration.

Do patients with chronic pain selectively process pain- and illness-related stimuli? The evidence with regard to attention, interpretation, and recall biases is critically reviewed. A model is proposed to account for the findings in which it is suggested that biases in information processing in chronic pain are the result of overlap between 3 schemas: pain, illness, and self. With frequent repeated or continued experience of pain, the pain schema becomes enmeshed with illness and self-schemas. The extent of the enmeshment and the salient content of the schema determine the bias. A fundamental assumption is that all patients with pain selectively process sensory-intensity information. A clinical implication of the results is that processing biases that extend beyond this healthy and adaptive process to enmesh the self-schema with pain and illness schemas could maintain and exacerbate distress and illness behavior in patients with chronic pain.

Anxiety↗
PubMed2001

Expression of individual lamins in basal cell carcinomas of the skin.

In this study we used a unique collection of type specific anti-lamin antibodies to study lamin expression patterns in normal human skin and in skin derived from patients with basal cell carcinomas (BCCs). Lamin expression in serial sections from frozen tissue samples was investigated by single and double indirect immunofluorescence. In normal skin, lamin A was expressed in dermal fibroblasts and in suprabasal epithelial cells but was absent from all basal epithelial cells. Lamin C was expressed in dermal fibroblasts, suprabasal epithelial cells and a majority of basal epithelial cells. However, lamin C was not expressed in quiescent basal epithelial cells. Lamin B1 was expressed in all epithelial cells but was not expressed in dermal fibroblasts. Finally, lamin B2 was expressed in all epithelial cells but was not expressed in dermal fibroblasts. Finally, lamin B2 was expressed in all cell types in normal skin. Lamin expression was also investigated in a collection of 16 BCCs taken from a variety of body sites. Based upon patterns of lamin expression the BCCs were classified into four groups: A-negative (10/16 tumours), C-negative (5/16 tumours), A/C-negative (1/16 tumours) and A/B2-negative (1/16 tumours). Lamin expression was also compared to cell proliferation index by staining serial sections with the proliferation marker Ki67. 9/10 of the lamin A negative tumours were highly proliferative, whereas 4/5 of the lamin C negative tumours were slow growing. Thus as a general rule absence of lamin A was correlated with rapid growth within the tumour, while absence of lamin C was correlated with slow growth within the tumour. Our data supports the hypothesis that lamin A has a negative influence on cell proliferation and its down regulation may be a requisite of tumour progression.

Antibodies↗
PubMed2001

Intravenous safety and pharmacokinetics of a novel dimerizer drug, AP1903, in healthy volunteers.

AP1903 is a novel gene-targeted drug that is being developed for use in drug-regulated cell therapies. An intravenous, single-blind, placebo- and saline-controlled, ascending-dose study was performed to evaluate the safety, tolerability, and pharmacokinetics of AP1903. Twenty-eight normal healthy male volunteers were randomized into five dosage groups of AP1903 (0.01, 0.05, 0.1, 0.5, and 1 mg/kg). Within each group, 4 volunteers received a single dose of AP1903, 1 volunteer received an equal volume of placebo, and 1 received an equal volume of normal saline. The only exception was in the 0.5 mg/kg group, in which 4 volunteers were dosed: 3 received AP1903 and 1 received normal saline. All dosages were administered as intravenous infusions over 2 hours. Clinical safety parameters were monitored, and serial blood and urine samples were collected for analysis of AP1903. No drug-related adverse events were observed at any of the dose levels with the possible exception of facial flushing in 1 volunteer at the 1.0 mg/kg dose level. AP1903 plasma levels were directly proportional to the administered dose, with mean Cmax values ranging from approximately 10 to 1,275 ng/mL over the 0.01 to 1.0 mg/kg dose range. Following the infusion period, blood concentrations revealed a rapid distribution phase, with plasma levels being reduced to approximately 18%, 7%, and 1% of the maximal concentration at 0.5, 2, and 10 hours postdose, respectively. AP1903 was shown to be safe and well tolerated at all dose levels and demonstrated a favorable pharmacokinetic profile at doses well above the anticipated therapeutic dose.

Adult↗
PubMed2000

Hair removal using the long-pulsed ruby laser in children.

OBJECTIVE: The purpose of this study was to assess the efficacy of laser assisted hair removal in children aged 16 and under using the long pulsed ruby laser. BACKGROUND DATA: Unwanted hair in the pediatric population can be due to congenital hairy nevi and hypertrichosis. Methods of effecting hair removal include shaving, electrolysis, and laser depilation. The long-pulsed ruby laser is an established treatment modality in adults, but its use specifically in children has not been investigated. METHODS: Patients aged 16 or under undergoing treatment with the ruby laser for unwanted hair were assessed. Hair counts were determined before and after treatment and an assessment of overall satisfaction was made using a parental questionnaire. RESULTS: Treatment was regarded as successful in 25 out of 28 cases where there was a clear reduction in hair growth at the site treated with an average fall in hair count of 63% at 6 months follow up. There was no scarring or hyperpigmentation in this group and no serious complications. Total suppression of hair growth was not permanent but usually lasted between 3 and 6 months. Few problems were encountered from using the technique specifically in children, and pain was well controlled in most cases. CONCLUSIONS: We would recommend the long-pulsed ruby laser as a useful form of hair removal in children that is quick, simple and well tolerated. At present, the technique leads to hair loss that is temporary but most patients and their parents feel the treatment gives worthwhile benefits.

Adolescent↗
PubMed2000

Availability bias in clinical formulation: the first idea that comes to mind.

This study tested whether initial client formulations are based simply on the ideas that come most readily to mind, irrespective of the validity of these ideas. This phenomenon is known in decision theory literature as availability bias. The study tested the influence of two possible sources of availability bias in formulation: (a) theoretical orientation; and (b) a suggestion in a referral letter. Forty-four qualified and 20 trainee clinical psychologists participated in a procedure designed to reflect clinical practice. Clinical materials consisted of a fictional referral letter describing a client with adult attachment difficulties and post-traumatic stress disorder. Participants recalled information from the referral letter, described their areas of further interest and initial hypotheses. Results showed no evidence of an availability bias in clinical formulation as a result of theoretical orientation. Theoretical orientation towards attachment did appear to influence the availability of attachment ideas and predicted clinicians taking a stronger attachment focus when discussing the client. In particular, a self-report measure of theoretical orientation demonstrated high predictive validity. However, orientation towards attachment did not predict bias in the sense of selective recall of attachment information or neglect of alternative psychological frameworks. The study provided an inadequate test of availability bias as a result of a suggestion in the referral letter, possibly due to a ceiling effect, and no conclusions can be drawn as to clinical materials as a potential source of availability bias. The discussion addresses implications for further research and for a scientist-practitioner approach to individual case formulation.

Adult↗
PubMed2000

'I always seem to be there'--a qualitative study of frequent attenders.

BACKGROUND: Much is still unknown about the consultation behaviour of frequent attenders, including why they consult as often as they do and why they consult in the patterns that they do. AIM: To determine why frequent attenders to general practice consult in the patterns that they do. METHOD: A qualitative study based on semi-structured interviews. Twenty-eight frequent attenders were purposively sampled from three practices; 13 exhibited a 'burst and gap' pattern of attendance and 15 exhibited a 'regular' pattern of attendance. RESULTS: A two-part model is proposed. The first part encompasses each individual decision to consult and is based around eight questions that may be asked as part of the decision-making process (these concern the perception of the general practitioner's [GP's] role, past experience of symptoms and consulting, comparison with others' consulting, relationship with the GP, balancing fears, lay consulting, individual reasons, and whether it was a symptom that they would not normally consult for). The second part determines the pattern of consulting and has four major themes: predominantly medical reasons for attending, experience of what happens during the consultation, accessibility of the GP, and periods of not consulting. Two further themes are proposed: 'multiplicity', whereby the reasons for consulting lead to further consulting for related and unrelated problems, and 'passivity', whereby consulting seems to be out of control. CONCLUSIONS: The reasons underpinning each individual decision to consult were complex. The control that GPs were perceived to have over the pattern of consulting, for example concerning prescribing, review visits, and in addressing further help-seeking behaviour, may provide more possibilities for developing intervention strategies than targeting frequent attenders themselves. An understanding of the processes behind the consulting behaviour of frequent attenders may lead to more functional consultations and better clinical care as a result.

Adult↗