Biomedical subjects

Kevin Murphy

Publications and source records attributed to Kevin Murphy.

At least 19 recordsLinked to original sources

PubMed2006

The controversial association of ABCB1 polymorphisms in refractory epilepsy: an analysis of multiple SNPs in an Irish population.

Controversy has surrounded the reported association of the single nucleotide polymorphism (SNP) C3435T of the ATP-binding cassette subfamily B member 1 (ABCB1, MDR1) gene, with refractory epilepsy. Here we examine this question by: (1) attempting to replicate the original association, (2) assessing the association of other variants in high linkage disequilibrium (LD) with C3435T, and (3) evaluating and comparing our findings with other published studies. We defined drug-responsiveness as seizure freedom or a 50% or more reduction in seizure frequency in the preceding year. Drug resistance was defined as a less than 50% reduction in seizure frequency in the preceding year. We used a combination of map-based (tagging SNPs) and direct sequence-based methods allowing a comprehensive assessment of variation across the associated interval. Genotypic data on 8 SNPs was collected on 440 patients, of whom 242 were drug-responsive and 198 were drug-resistant. We were unable to observe the original association of drug-resistant epilepsy with C3435T, nor any association with other functional variants at SNP or haplotype level in the ABCB1 gene. Evaluation of other attempted replication studies suggest that if the original C3435T association is indeed real, it would appear highly sensitive to the phenotype used. Alternatively, the discrepant results of this and other association attempts may be indicative of the original report of the CC genotype at C3435T in ABCB1 being a false positive finding. Variability in phenotypic descriptions in genetic association studies may partly explain the inconsistency of attempted replications.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2006

How long to scan? The relationship between fMRI temporal signal to noise ratio and necessary scan duration.

Recent advances in MRI receiver and coil technologies have significantly improved image signal-to-noise ratios (SNR) and thus temporal SNR (TSNR). These gains in SNR and TSNR have allowed the detection of fMRI signal changes at higher spatial resolution and therefore have increased the potential to localize small brain structures such as cortical layers and columns. The majority of current fMRI processing strategies employ multi-subject averaging and therefore require spatial smoothing and normalization, effectively negating these gains in spatial resolution higher than about 10 mm3. Reliable detection of activation in single subjects at high resolution is becoming a more common desire among fMRI researchers who are interested in comparing individuals rather than populations. Since TSNR decreases with voxel volume, detection of activation at higher resolutions requires longer scan durations. The relationship between TSNR, voxel volume and detectability is highly non-linear. In this study, the relationship between TSNR and the necessary fMRI scan duration required to obtain significant results at varying P values is determined both experimentally and theoretically. The results demonstrate that, with a TSNR of 50, detection of activation of above 2% requires at most 350 scan volumes (when steps are taken to remove the influence of physiological noise from the data). Importantly, these results also demonstrate that, for activation magnitude on the order of 1%, the scan duration required is more sensitive to the TSNR level than at 2%. This study showed that with voxel volumes of approximately 10 mm3 at 3 T, and a corresponding TSNR of approximately 50, the required number of time points that guarantees detection of signal changes of 1% is about 860, but if TSNR increases by only 20%, the time for detection decreases by more than 30%. More than just being an exercise in numbers, these results imply that imaging of columnar resolution (effect size=1% and assuming a TR of 1 s) at 3 T will require either 10 min for a TSNR of 60 or 40 min for a TSNR of 30. The implication is that at these resolutions, TSNR is likely to be critical for determining success or failure of an experiment.

Algorithms↗

PubMed2006

Use of an open access spirometry service by general practitioners.

AIMS: To understand better which patients with which diagnoses or suspected diagnoses are referred for spirometry in primary care, and to assess whether all such referrals are appropriate. METHODS: 200 consecutive patient referrals to an open access spirometry service from ten local general practices were evaluated by perusing the request forms, and analysis of the spirometry results and the report sent to the general practitioner (GP). RESULTS: 51% of all referrals had suspected or stated COPD, but airway obstruction was demonstrated in only 53% of cases. A minority had a degree of reversibility which suggested an additional asthma component at least. Airway obstruction was rarely demonstrated in patients referred with stated or suspected asthma. 117 patients were referred with stated or suspected airway disease but had no evidence of airway narrowing on testing. 14.5% of these had an unexpected small lung (restrictive) disorder. Six of these had a BMI of more than 30. CONCLUSION: Most referrals with stated or suspected COPD were highly appropriate since spirometry is required in order to establish the correct diagnosis. Referral of patients with suspected asthma is less likely to be helpful, and a period of home peak flow monitoring may be more useful. Restrictive disorders can be confused with airway disorders, and obesity may be underestimated as a cause of breathlessness.

Family Practice↗

PubMed2006

Neurocognition and suicidal behaviour in an Irish population with major psychotic disorders.

OBJECTIVES: Although neurocognitive deficits are seen as core to schizophrenia the association between suicidality and neurocognition has received little attention. Our aim was to examine the relationship between neurocognitive variables and suicidal behaviour in patients with schizophrenia and schizoaffective disorder. METHODS: Seventy-eight patients with DSM-IV diagnoses of schizophrenia or schizoaffective disorder were categorised as either having attempted suicide or not having attempted suicide based on clinical interview and chart review. Attempters and non-attempters were compared on an extensive neuropsychological battery examining pre-morbid and current general cognitive functioning, episodic memory, and executive functioning. RESULTS: Suicide attempters tended to out perform non-attempters across all areas of executive functioning, and showed significantly better performances on measures of attention and verbal fluency. After controlling for relevant clinical and demographic variables, the differences between attempters and non-attempters remained significant for measures of attention (F = 4.97, p = 0.03) and verbal fluency (F = 4.28, p = 0.04). CONCLUSION: This study adds to existing data that suicide attempters with schizophrenia or schizoaffective disorder may have higher cognitive functioning than non-attempters. In particular, the preservation of higher executive function may influence the ability to initiate and plan suicidal behaviour.

Adult↗

PubMed2006

Individual differences in the functional neuroanatomy of inhibitory control.

We combined the data of five event-related fMRI studies of response inhibition. The re-analysis (n = 71) revealed response inhibition to be accomplished by a largely right hemisphere network of prefrontal, parietal, subcortical and midline regions, with converging evidence pointing to the particular importance of the right frontal operculum. Functional differences were observed between the sexes with greater activity in females in many of these cortical regions. Despite the relatively narrow age range (18-46), cortical activity, on the whole, tended to increase with age, echoing a pattern of functional recruitment often observed in the elderly. More absent minded subjects showed greater activity in fronto-parietal areas, while speed of Go trial responses produced a varied pattern of activation differences in more posterior and subcortical areas. Although response inhibition produces robust activation in a discrete network of brain regions, these results reveal that individual differences impact on the relative contribution made by the nodes of this network.

Adolescent↗

PubMed2006

Growth velocity in children with perennial allergic rhinitis treated with budesonide aqueous nasal spray.

BACKGROUND: Recent guidelines recommend intranasal corticosteroids as first-line treatment for managing persistent symptoms of moderate to severe allergic rhinitis (AR). However, in children, long-term continual treatment with corticosteroids has raised concerns about potential growth suppression. OBJECTIVE: To evaluate the effects of the recommended once-daily dose of budesonide aqueous nasal spray on growth velocity, as measured with stadiometry, in children with perennial AR. METHODS: In this double-blind, placebo-controlled, multicenter study, 229 prepubertal children (mean age, 5.9 years; age range, 4-8 years) with perennial AR were randomized (2:1) to receive budesonide aqueous nasal spray, 64 microg (32 microg per nostril) once daily, or placebo for 1 year. The change from baseline in growth velocity, height after treatment, and the percentage of patients whose percentile for height decreased from baseline to the end of treatment were evaluated. RESULTS: Growth velocity was not significantly different between the 2 groups. The least-squares mean +/- SE growth velocity during treatment was 5.91 +/- 0.11 cm per year for children receiving budesonide and 6.19 +/- 0.16 cm per year for those receiving placebo. The mean difference in growth velocity between the 2 groups was 0.27 +/- 0.18 cm per year (95% confidence interval, -0.07 to 0.62 cm per year). After treatment, the mean +/- SD height was 128.8 +/- 8.7 cm for children receiving budesonide and 128.2 +/- 8.8 for those receiving placebo. The percentage of children whose percentile for height decreased during treatment was not significantly different between the 2 groups (budesonide, 59%, placebo, 54%; P = .64). The incidence and types of adverse events and the mean 24-hour urinary cortisol-creatinine ratio were similar for the 2 groups. CONCLUSIONS: Treatment with budesonide aqueous nasal spray, 64 microg once daily, for 1 year did not suppress growth velocity compared with placebo and was well tolerated in prepubertal children with perennial AR.

Administration, Intranasal↗

PubMed2006

A validation of event-related FMRI comparisons between users of cocaine, nicotine, or cannabis and control subjects.

OBJECTIVE: Noninvasive brain imaging techniques are a powerful tool for researching the effects of drug abuse on brain activation measures. However, because many drugs have direct vascular effects, the validity of techniques that depend on blood flow measures as a reflection of neuronal activity may be called into question. This may be of particular concern in event-related functional magnetic resonance imaging (fMRI), where current analytic techniques search for a specific shape in the hemodynamic response to neuronal activity. METHOD: To investigate possible alterations in task-related activation as a result of drug abuse, fMRI scans were conducted on subjects in four groups as they performed a simple event-related finger-tapping task: users of cocaine, nicotine, or cannabis and control subjects. RESULTS: Activation measures, as determined by two different analytic methods, did not differ between the groups. A comparison between an intravenous saline and an intravenous cocaine condition in cocaine users found a similar null result. Further in-depth analyses of the shape of the hemodynamic responses in each group also showed no differences. CONCLUSIONS: This study demonstrates that drug groups may be compared with control subjects using event-related fMRI without the need for any post hoc procedures to correct for possible drug-induced cardiovascular alterations. Thus, fMRI activation differences reported between these drug groups can be more confidently interpreted as reflecting neuronal differences.

Adult↗

PubMed2005

Deriving the optimal number of events for an event-related fMRI study based on the spatial extent of activation.

Event-related fMRI is a powerful tool for localising psychological functions to specific brain areas. However, the number of events required to produce stable activation maps is a poorly investigated and understood problem. Huettel and McCarthy [Huettel, S.A., McCarthy, G., 2001. The effects of single-trial averaging upon the spatial extent of fMRI activation. NeuroReport 12, 2411-2416] have shown that the spatial extent of activation increases monotonically with the number of events in an analysis. In the present paper, this result is replicated and shown to be a consequence of the cross-correlation technique used to determine active voxels and does not hold, for example, for a GLM analysis. Another analysis technique, that does not depend on goodness-of-fit to the data, is also proposed. This technique calculates an impulse response function (IRF) for each voxel, finds the best fitting haemodynamic shape to the IRF and returns an area-under-the-curve (%AUC) activation measure. Using spatial extent as a measure, asymptotic behaviour is evident after as few as 25 events for the %AUC analysis technique in a finger-tapping task with non-overlapping haemodynamic responses and for both the GLM and %AUC techniques in a similar task that allows responses to overlap. The experimental validity of the %AUC technique to identify active brain regions while minimising false positive levels is demonstrated in a group study with 25 participants.

Adult↗

PubMed2005

Psychosocial treatments for ADHD in teens and adults: a practice-friendly review.

Although stimulant medication is a cornerstone of treatment for attention deficit hyperactivity disorder (ADHD), numerous nonpharmacological treatments can be employed in combination with medication to assist in the lifelong management of the disorder. A multimodal treatment combining psychoeducation, medication, psychotherapy, compensatory behavioral/self-management skills, technological tools and devices, coaching, advocacy, and reasonable school or workplace accommodations is probably the most comprehensive and effective. This article describes a variety of psychosocial treatments that are commonly used for adolescents and adults suffering from ADHD.

Activities of Daily Living↗

PubMed2005

Post burn muscle wasting and the effects of treatments.

Severe burns are typically followed by a hypermetabolic response that lasts for at least 9-12 months post-injury. The endocrine status is also markedly altered with an initial and then sustained increase in proinflammatory 'stress' hormones such as cortisol and other glucocorticoids, and catecholamines including epinephrine and norepinephrine by the adrenal medulla and cortex. These hormones exert catabolic effects leading to muscle wasting, the intensity of which depends upon the percentage of total body surface area (TBSA) involved, as well as the time elapsed since initial injury. Pharmacological and non-pharmacological strategies may be used to reverse the catabolic effect of thermal injury. Non-pharmacological strategies include early excision and wound closure of burn wound, aggressive treatment of sepsis, elevation of the environmental temperature to thermal neutrality (31.5+/-0.7 degrees C), high carbohydrate, high protein continuous enteral feeding and early institution of resistive exercise programs. Pharmacological modulators of the post-burn hypermetabolic response may be achieved through the administration of recombinant human growth hormone, low dose insulin infusion, use of the synthetic testosterone analogue, oxandrolone and beta blockade with propranolol. This paper aims to review the current understanding of post-burn muscle proteolysis and the effects of clinical and pharmacological strategies currently being studied to reverse it curb these debilitating sequelae of severe burns.

Anabolic Agents↗

PubMed2005

Effects of growth hormone on anthropometric measurements and cardiac function in children with thermal injury.

UNLABELLED: Severe burn injuries are associated with growth delays a persistent hypermetabolic response and severe muscle catabolism and wasting. Growth hormone (GH), a potent anabolic agent and salutary modulator of post-traumatic metabolic responses has been shown to decrease muscle wasting, improve net protein synthesis and attenuate growth delays in burned children. In non-burned populations, GH has recently been shown to be of benefit in enhancing cardiac performance and improving cardiac contractility and efficiency. Yet, whether administration of GH will induce similar improvements in cardiac function in severely burned children is presently unknown. We therefore, investigated whether the administration of GH initiated upon hospital discharge (95% healed) and continued for 1-year post-burn would improve resting cardiac function in burned children. Severely burned children were randomized to receive either saline placebo (n = 37) or 0.05 mg/kg per day of GH (n = 39) from discharge until 12-month post-burn. Outcome variables included height, weight, lean body mass, resting energy expenditure, cardiac index, stroke-volume index, heart rate and left ventricular ejection fraction. RESULTS: height, weight, lean body mass and ejection fraction showed a significant increase with GH. Our results indicate that severely burned children treated with long-term GH show a significant improvement in left ventricular ejection fraction.

Adolescent↗

PubMed2004

me-PCR: a refined ultrafast algorithm for identifying sequence-defined genomic elements.

We have adapted the originally described electronic PCR (e-PCR) algorithm to perform string searches more accurately and much more rapidly than previously possible. Our implementation [multithreaded e-PCR (me-PCR)] runs sufficiently fast to allow even desktop machines to query quickly large genomes with very large genomic element sets. In addition, me-PCR is multithreaded, interprets all IUPAC nucleotide symbols, allows searches with elements specified by long sequences (such as SNPs), accepts ranges in the expected PCR size input field, requires substantially less memory for analysis of large sequences and corrects a number of minor flaws causing misreporting of hits in exceptional cases. Thus, me-PCR provides increased annotation capabilities for complex genomes to non-expert laboratories.

Algorithms↗

PubMed2004

Outcome measures in burn care. Is mortality dead?

Health care systems constantly struggle with ways to provide higher quality care in a cost-effective manner. Outcome measures serve to evaluate what works and what does not. Whether they are used for research or for the improvement of clinical practice, they are as such, efficiency markers and the first step in determining the consequences of health care. The accomplishments of the past decade have placed us in the midst of an exciting paradigm shift from what used to be primary concern (i.e. mortality), to areas that are more likely to enhance the quality of life of burn survivors. Optimal management of severely burned persons is enormously expensive, and even after survival is ensured, may require a protracted period of surgical, medical and psychological rehabilitative measures for many years. This article aims to review the outcome measures in the acute phase of burn management (mortality and morbidity from the post-burn hypermetabolic response). We further discuss long-term outcome measures (such as, quality of life measures, exercise tolerance and evaluation of return to pre-burn activities) that are now becoming of equal importance as the numbers of burn survivors increase.

Burns↗

PubMed2004

Is central nervous system processing altered in patients with heart failure?

AIMS: Breathlessness is a cardinal symptom of heart failure and the altered regulation of breathing is common. The contribution of abnormal central nervous system activity has not previously been investigated directly, although abnormal autonomic responses have been described. Our aim was to assess whether heart failure patients exhibit different patterns of regional brain activation after exercise stress. METHODS: We used positron emission tomography with H2(15)O, to measure changes in regional cerebral blood flow (rCBF) and absolute global cerebral blood flow (gCBF) in 6 male class II/III heart failure patients and 6 normal controls. Breathlessness (0-5 visual analogue scale) and respiratory parameters were measured at rest, after horizontal bicycle exercise and during isocapnic hyperventilation. CBF was measured in each condition in all subjects. RESULTS: Both groups were similarly breathless after exercise and the respiratory parameters were comparable. rCBF differences for the main comparison (exercise vs hyperventilation) were: activation of the right frontal medial gyrus (P < 0.001, Z = 4.90) and left precentral gyrus (P < 0.03, Z = 4.66) in controls but not in patients. Both groups had rCBF increases in the left anterior cingulate (P < 0.05, Z = 4.67) and right dorsal cingulate cortex (P < 0.05, Z = 4.66). The gCBF did not differ between exercise, isocapnic hyperventilation and rest in patients but, in controls, gCBF was greater after exercise compared to either isocapnic hyperventilation or rest. CONCLUSION: Heart failure patients had a distinct pattern of regional cortical activity with exercise-induced breathlessness but unvarying CBF values between conditions. These central neural differences in activity may contribute to some features of heart failure, such as variability in symptoms and autonomic dysregulation.

Aged↗

PubMed2004

An empirical investigation into the number of subjects required for an event-related fMRI study.

Optimising the number of subjects required for an event-related functional imaging study is critical for ensuring sufficient statistical power. We report an empirical investigation of this issue by employing a resampling approach to the data of 58 subjects drawn from four previous GO/NOGO studies. Using voxelwise measures and setting the activation map from the complete sample to be a "gold standard", analyses revealed the statistical power to be surprisingly low at typical sample sizes (n = 20). However, voxels that were significantly active from smaller samples tended to be true positives, that is, they were typically active in the gold standard map and correlated well with the gold standard activation measure. The numerous false negatives that resulted from the lower SNR of the smaller samples drove the poor statistical power of those samples. Splitting the sample into two groups provided a test of the reproducibility of activation maps that was assessed using an alternative measure that quantified the distances between centres-of-mass of activated areas. These analyses revealed that although the voxelwise overlap may be poor, the locations of activated areas provide some optimism for studies with typical sample sizes. With n = 20 in each of two groups, it was found that the centres-of-mass for 80% of activated areas fell within 25 mm of each other. The reported analyses, by quantifying the spatial reproducibility for various sample sizes performing a typical event-related cognitive task, thus provide an empirical measure of the disparity to be expected in comparing activation maps.

Adult↗

PubMed2004

Beyond common resources: the cortical basis for resolving task interference.

Recent studies have suggested that declining inhibitory control observed during simultaneous increases in working memory (WM) demands may be due to sharing common neural resources, although it is relatively unclear how these processes are successfully combined at a neural level. Event-related functional MRI was used to examine task performance that required inhibition of varying numbers of items held in WM. Common activation regions for WM and inhibition were observed and this functional overlap may constitute the cortical basis for task interference. However, maintaining successful inhibitory control under increasing WM demands tended not to increase activation in these overlapping regions as might be expected if these common areas reflect common resources essential for task performance. Instead, increased activation was observed predominantly in unique, inhibition-specific regions including dorsolateral prefrontal cortex. The finding that successfully maintaining weaker stimulus--response relationships in the face of competition from stronger, prepotent responses requires greater activity in these regions reveals the means by which the brain resolves task interference and supports theories of how top-down attentional control is implemented.

Adult↗

PubMed2004

Prefrontal-subcortical dissociations underlying inhibitory control revealed by event-related fMRI.

Using event-related fMRI, this study investigated the neural dynamics of response inhibition under fluctuating task demands. Fourteen participants performed a GO/NOGO task requiring inhibition of a prepotent motor response to NOGO events that occurred as part of either a Fast or Slow presentation stream of GO stimuli. We compared functional activations associated with correct withholds (Stops) required during the Fast presentation stream of stimuli to Stops required during the Slow presentation stream. A predominantly right hemispheric network was activated across conditions, consistent with previous studies. Furthermore, a functional dissociation of activations between conditions was observed. Slow Stops elicited additional activation in anterior dorsal and polar prefrontal cortex and left inferior parietal cortex. Fast Stops showed additional activation in a network that included right dorsolateral prefrontal cortex, insula and dorsal striatum. These results are discussed in terms of our understanding of the impact of preparation on the distributed network underlying response inhibition and the contribution of subcortical areas, such as the basal ganglia, to executive control processes.

Adult↗

PubMed2004

Predicting success: patterns of cortical activation and deactivation prior to response inhibition.

The present study investigated the relationships between attention and other preparatory processes prior to a response inhibition task and the processes involved in the inhibition itself. To achieve this, a mixed fMRI design was employed to identify the functional areas activated during both inhibition decision events and the block of trials following a visual cue introduced 2 to 7 sec prior (cue period). Preparing for successful performance produced increases in activation for both the cue period and the inhibition itself in the frontoparietal cortical network. Furthermore, preparation produced activation decreases in midline areas (insula and medial prefrontal) argued to be responsible for monitoring internal emotional states, and these cue period deactivations alone predicted subsequent success or failure. The results suggest that when cues are provided to signify the imminent requirement for behavioral control, successful performance results from a coordinated pattern of preparatory activation in task-relevant areas and deactivation of task-irrelevant ones.

Adult↗