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1.  Caffeine and diuresis during rest and exercise: A meta-analysis 
Although ergogenic, acute caffeine ingestion may increase urine volume, prompting concerns about fluid balance during exercise and sport events. This meta-analysis evaluated caffeine induced diuresis in adults during rest and exercise.
A search of three databases was completed on November 1, 2013. Only studies that involved healthy adults and provided sufficient information concerning the effect size (ES) of caffeine ingestion on urine volume were included. Sixteen studies met the inclusion criteria, providing a total of 28 ESs for the meta-analysis. Heterogeneity was assessed using a random-effects model.
The median caffeine dosage was 300 mg. The overall ES of 0.29 (95% confidence interval (CI) = 0.11-0.48, p = 0.001) corresponds to an increase in urine volume of 109 ± 195 mL or 16.0 ± 19.2% for caffeine ingestion vs. non-caffeine conditions. Subgroup meta-analysis confirmed exercise as a strong moderator: active ES = 0.10, 95% CI = −0.07 to 0.27, p = 0.248 vs. resting ES = 0.54, 95% CI = 0.22–0.85, p = 0.001 (Cochran's Q, p = 0.019). Females (ES = 0.75,95% CI = 0.38–1.13, p< 0.001) were more susceptible to diuretic effects than males (ES = 0.13,95% CI = −0.05 to 0.31, p = 0.158) (Cochran's Q, p = 0.003).
Caffeine exerted a minor diuretic effect which was negated by exercise. Concerns regarding unwanted fluid loss associated with caffeine consumption are unwarranted particularly when ingestion precedes exercise.
PMCID: PMC4725310  PMID: 25154702
Methylxanthine; Coffee; Diuretic; Fluid balance; Dehydration
2.  A framework for improving microRNA prediction in non-human genomes 
Nucleic Acids Research  2015;43(20):e138.
The prediction of novel pre-microRNA (miRNA) from genomic sequence has received considerable attention recently. However, the majority of studies have focused on the human genome. Previous studies have demonstrated that sensitivity (correctly detecting true miRNA) is sustained when human-trained methods are applied to other species, however they have failed to report the dramatic drop in specificity (the ability to correctly reject non-miRNA sequences) in non-human genomes. Considering the ratio of true miRNA sequences to pseudo-miRNA sequences is on the order of 1:1000, such low specificity prevents the application of most existing tools to non-human genomes, as the number of false positives overwhelms the true predictions. We here introduce a framework (SMIRP) for creating species-specific miRNA prediction systems, leveraging sequence conservation and phylogenetic distance information. Substantial improvements in specificity and precision are obtained for four non-human test species when our framework is applied to three different prediction systems representing two types of classifiers (support vector machine and Random Forest), based on three different feature sets, with both human-specific and taxon-wide training data. The SMIRP framework is potentially applicable to all miRNA prediction systems and we expect substantial improvement in precision and specificity, while sustaining sensitivity, independent of the machine learning technique chosen.
PMCID: PMC4787757  PMID: 26163062
3.  ProtDCal: A program to compute general-purpose-numerical descriptors for sequences and 3D-structures of proteins 
BMC Bioinformatics  2015;16(1):162.
The exponential growth of protein structural and sequence databases is enabling multifaceted approaches to understanding the long sought sequence-structure-function relationship. Advances in computation now make it possible to apply well-established data mining and pattern recognition techniques to these data to learn models that effectively relate structure and function. However, extracting meaningful numerical descriptors of protein sequence and structure is a key issue that requires an efficient and widely available solution.
We here introduce ProtDCal, a new computational software suite capable of generating tens of thousands of features considering both sequence-based and 3D-structural descriptors. We demonstrate, by means of principle component analysis and Shannon entropy tests, how ProtDCal’s sequence-based descriptors provide new and more relevant information not encoded by currently available servers for sequence-based protein feature generation. The wide diversity of the 3D-structure-based features generated by ProtDCal is shown to provide additional complementary information and effectively completes its general protein encoding capability. As demonstration of the utility of ProtDCal’s features, prediction models of N-linked glycosylation sites are trained and evaluated. Classification performance compares favourably with that of contemporary predictors of N-linked glycosylation sites, in spite of not using domain-specific features as input information.
ProtDCal provides a friendly and cross-platform graphical user interface, developed in the Java programming language and is freely available at: ProtDCal introduces local and group-based encoding which enhances the diversity of the information captured by the computed features. Furthermore, we have shown that adding structure-based descriptors contributes non-redundant additional information to the features-based characterization of polypeptide systems. This software is intended to provide a useful tool for general-purpose encoding of protein sequences and structures for applications is protein classification, similarity analyses and function prediction.
Electronic supplementary material
The online version of this article (doi:10.1186/s12859-015-0586-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4432771  PMID: 25982853
ProtDCal; Protein feature generation; Protein descriptors; Data mining; Protein function modelling
4.  Immunotherapy for bladder cancer 
It is nearly 40 years since Bacillus Calmette–Guérin (BCG) was first used as an immunotherapy to treat superficial bladder cancer. Despite its limitations, to date it has not been surpassed by any other treatment. As a better understanding of its mechanism of action and the clinical response to it have evolved, some of the questions around optimal dosing and treatment protocols have been answered. However, its potential for toxicity and failure to produce the desired clinical effect in a significant cohort of patients presents an ongoing challenge to clinicians and researchers alike. This review summarizes the evidence behind the established mechanism of action of BCG in bladder cancer, highlighting the extensive array of immune molecules that have been implicated in its action. The clinical aspects of BCG are discussed, including its role in reducing recurrence and progression, the optimal treatment regime, toxicity and, in light of new evidence, whether or not there is a superior BCG strain. The problems of toxicity and non-responders to BCG have led to development of new techniques aimed at addressing these pitfalls. The progress made in the laboratory has led to the identification of novel targets for the development of new immunotherapies. This includes the potential augmentation of BCG with various immune factors through to techniques avoiding the use of BCG altogether; for example, using interferon-activated mononuclear cells, BCG cell wall, or BCG cell wall skeleton. The potential role of gene, virus, or photodynamic therapy as an alternative to BCG is also reviewed. Recent interest in the immune check point system has led to the development of monoclonal antibodies against proteins involved in this pathway. Early findings suggest benefit in metastatic disease, although the role in superficial bladder cancer remains unclear.
PMCID: PMC4427258  PMID: 26000263
immunotherapy; Bacillus Calmette–Guerin; bladder cancer
5.  Timing of High-Dose Rate Brachytherapy With External Beam Radiotherapy in Intermediate and High-Risk Localized Prostate CAncer (THEPCA) Patients and Its Effects on Toxicity and Quality of Life: Protocol of a Randomized Feasibility Trial 
JMIR Research Protocols  2015;4(2):e49.
Prostate cancer is the most common cancer in males in the UK and affects around 105 men for every 100,000. The role of radiotherapy in the management of prostate cancer significantly changed over the last few decades with developments in brachytherapy, external beam radiotherapy (EBRT), intensity-modulated radiotherapy (IMRT), and image-guided radiotherapy (IGRT). One of the challenging factors of radiotherapy treatment of localized prostate cancer is the development of acute and late genitourinary and gastrointestinal toxicities. The recent European guidelines suggest that there is no consensus regarding the timing of high-dose rate (HDR) brachytherapy and EBRT. The schedules vary in different institutions where an HDR boost can be given either before or after EBRT. Few centers deliver HDR in between the fractions of EBRT.
Assessment of acute genitourinary and gastrointestinal toxicities at various time points to better understand if the order in which treatment modality is delivered (ie, HDR brachytherapy or EBRT first) has an effect on the toxicity profile.
Timing of HDR brachytherapy with EBRT in Prostate CAncer (THEPCA) is a single-center, open, randomized controlled feasibility trial in patients with intermediate and high-risk localized prostate cancer. A group of 50 patients aged 18 years old and over with histological diagnosis of prostate cancer (stages T1b-T3BNOMO), will be randomized to one of two treatment arms (ratio 1:1), following explanation of the study and informed consent. Patients in both arms of the study will be treated with HDR brachytherapy and EBRT, however, the order in which they receive the treatments will vary. In Arm A, patients will receive HDR brachytherapy before EBRT. In Arm B (control arm), patients will receive EBRT before HDR brachytherapy. Study outcomes will look at prospective assessment of genitourinary and gastrointestinal toxicities. The primary endpoint will be grade 3 genitourinary toxicity and the secondary endpoints will be all other grades of genitourinary toxicities (grades 1 and 2), gastrointestinal toxicities (grades 1 to 4), prostate-specific antigen (PSA) recurrence-free survival, overall survival, and quality of life.
Results from this feasibility trial will be available in mid-2016.
If the results from this feasibility trial show evidence that the sequence of treatment modality does affect the patients’ toxicity profiles, then funding would be sought to conduct a large, multicenter, randomized controlled trial.
Trial Registration
International Standard Randomized Controlled Trial Number (ISRCTN): 15835424; (Archived by WebCite at
PMCID: PMC4430680  PMID: 25926023
prostate cancer; radiotherapy; brachytherapy; external beam radiotherapy; EBRT; randomized controlled trial; RCT; Southend Hospital
6.  Prevalence, species identification and genotyping Cryptosporidium from livestock and deer in a catchment in the Cairngorms with a history of a contaminated public water supply 
Parasites & Vectors  2015;8:66.
The apicomplexan parasite Cryptosporidium represents a threat to water quality and public health. An important zoonotic species involved in human cryptosporidiosis from contaminated water is Cryptosporidium parvum (C. parvum), the main reservoirs of which are known to be farm livestock particularly neonatal calves, although adult cattle, sheep, lambs and wildlife are also known to contribute to catchment loading of C. parvum. This study aimed to establish Cryptosporidium prevalence, species and genotype in livestock, deer and water in a catchment with a history of Cryptosporidium contamination in the public water supply.
A novel method of processing adult ruminant faecal sample was used to concentrate oocysts, followed by a nested species specific multiplex (nssm) PCR, targeting the 18S rRNA gene, to speciate Cryptosporidium. A multilocus fragment typing (MLFT) tool was used, in addition to GP60 sequencing, to genotype C. parvum positive samples.
A very high prevalence of Cryptosporidium was detected, with speciation identifying a predominance of C. parvum in livestock, deer and water samples. Four GP60 subtypes were detected within C. parvum with the majority IIaA15G2R1 which was detected in all host species and on all farms. Multilocus fragment typing further differentiated these into 6 highly related multilocus genotypes.
The high prevalence of Cryptosporidium detected was possibly due to a combination of the newly developed sample processing technique used and a reflection of the high rates of the parasite present in this catchment. The predominance of C. parvum in livestock and deer sampled in this study suggested that they represented a significant risk to water quality and public health. Genotyping results suggested that the parasite is being transmitted locally within the study area, possibly via free-roaming sheep and deer. Further studies are needed to verify particular host associations with subtypes/MLGs. Land and livestock management solutions to reduce Cryptosporidium on farm and in the catchment are planned with the aim to improve animal health and production as well as water quality and public health.
PMCID: PMC4324427  PMID: 25650114
Cryptosporidium; Livestock; Deer; Water; Catchment; C. parvum; Genotyping; Prevalence; Transmission
7.  Management of pregnant and postnatal women with pre-existing diabetes or cardiac disease using multi-disciplinary team models of care: a systematic review 
More women with an increased risk of poor pregnancy outcome due to pre-existing medical conditions are becoming pregnant. Although clinical care provided through multi-disciplinary team (MDT) working is recommended, little is known about the structure or working practices of different MDT models, their impact on maternal and infant outcomes or healthcare resources. The objectives of this review were to consider relevant international evidence to determine the most appropriate MDT models of care to manage complex medical conditions during and after pregnancy, with a specific focus on pre-existing diabetes or cardiac disease in high income country settings.
Quantitative and qualitative evidence of MDT models of care for the management of pregnant/postnatal women with pre-existing diabetes and cardiac disease was considered. A search of the literature published between January 2002 - January 2014 was undertaken. Methodological quality was assessed using checklists developed by the Joanna Briggs Institute. Given limited primary and secondary research evidence, guidelines and opinion papers were included. Two independent reviewers conducted critical appraisal of included papers.
Nineteen papers were included from UK, Canada, USA, the Netherlands and Singapore. No studies were found which had compared MDT models for pregnant/postnatal women with pre-existing diabetes or cardiac disease. Two small retrospective studies reported better outcomes for women with cardiac disease if an MDT approach was used, although evidence to support this was limited. Due to study heterogeneity it was not possible to meta-analyse data. No evidence was identified of MDT management in the postnatal period or impacts of MDT working on healthcare resources.
Despite widespread promotion of MDT models of care for pregnant and postnatal women with pre-existing diabetes or cardiac disease, there is a dearth of primary evidence to inform structure or working practices or beneficial impact on maternal and infant outcomes or healthcare resources. Primary research into if or how MDT models of care improve outcomes for women with complex pregnancies is urgently needed.
Electronic supplementary material
The online version of this article (doi:10.1186/s12884-014-0428-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4296678  PMID: 25528045
Multidisciplinary team; Pregnancy; Diabetes; Cardiac disease; Maternity; Antenatal; Postnatal; Complex pregnancies
8.  Efficient prediction of human protein-protein interactions at a global scale 
BMC Bioinformatics  2014;15(1):383.
Our knowledge of global protein-protein interaction (PPI) networks in complex organisms such as humans is hindered by technical limitations of current methods.
On the basis of short co-occurring polypeptide regions, we developed a tool called MP-PIPE capable of predicting a global human PPI network within 3 months. With a recall of 23% at a precision of 82.1%, we predicted 172,132 putative PPIs. We demonstrate the usefulness of these predictions through a range of experiments.
The speed and accuracy associated with MP-PIPE can make this a potential tool to study individual human PPI networks (from genomic sequences alone) for personalized medicine.
Electronic supplementary material
The online version of this article (doi:10.1186/s12859-014-0383-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4272565  PMID: 25492630
Protein-protein interactions; Computational prediction; Human proteome; Massively parallel computing; Personalized medicine; Interactome; Network analysis
9.  Highly Polygenic Variation in Environmental Perception Determines Dauer Larvae Formation in Growing Populations of Caenorhabditis elegans 
PLoS ONE  2014;9(11):e112830.
Determining how complex traits are genetically controlled is a requirement if we are to predict how they evolve and how they might respond to selection. This requires understanding how distinct, and often more simple, life history traits interact and change in response to environmental conditions. In order to begin addressing such issues, we have been analyzing the formation of the developmentally arrested dauer larvae of Caenorhabditis elegans under different conditions.
We find that 18 of 22 previously identified quantitative trait loci (QTLs) affecting dauer larvae formation in growing populations, assayed by determining the number of dauer larvae present at food patch exhaustion, can be recovered under various environmental conditions. We also show that food patch size affects both the ability to detect QTLs and estimates of effect size, and demonstrate that an allele of nath-10 affects dauer larvae formation in growing populations. To investigate the component traits that affect dauer larvae formation in growing populations we map, using the same introgression lines, QTLs that affect dauer larvae formation in response to defined amounts of pheromone. This identifies 36 QTLs, again demonstrating the highly polygenic nature of the genetic variation underlying dauer larvae formation.
These data indicate that QTLs affecting the number of dauer larvae at food exhaustion in growing populations of C. elegans are highly reproducible, and that nearly all can be explained by variation affecting dauer larvae formation in response to defined amounts of pheromone. This suggests that most variation in dauer larvae formation in growing populations is a consequence of variation in the perception of the food and pheromone environment (i.e. chemosensory variation) and in the integration of these cues.
PMCID: PMC4231163  PMID: 25393108
10.  “No decision about me without me” in the context of cancer multidisciplinary team meetings: a qualitative interview study 
Cancer care is commonly managed by multidisciplinary teams (MDTs) who meet to discuss and agree treatment for individual patients. Patients do not attend MDT meetings but recommendations for treatments made in the meetings directly influence the decision-making process between patients and their responsible clinician. No research to-date has considered patient perspectives (or understanding) regarding MDTs or MDT meetings, though research has shown that failure to consider patient-based information can lead to recommendations that are inappropriate or unacceptable, and can consequently delay treatment.
Semi-structured interviews were conducted with current cancer patients from one cancer centre who had either upper gastrointestinal or gynaecological cancer (n = 9) and with MDT members (n = 12) from the teams managing their care. Interview transcripts were analysed thematically using Framework approach. Key themes were identified and commonalities and discrepancies within and between individual transcripts and within and between patient and team member samples were identified and examined using the constant comparative method.
Patients had limited opportunities to input to or influence the decision-making process in MDT meetings. Key explanatory factors included that patients were given limited and inconsistent information about MDTs and MDT meetings, and that MDT members had variable definitions of patient-centredness in the context of MDTs and MDT meetings. Patients that had knowledge of medicine (through current/previous employment themselves or that of a close family member) appeared to have greater understanding and access to the MDT. Reassurance emerged as a ‘benefit’ of informing patients about MDTs and MDT meetings.
There is a need to ensure MDT processes are both efficient and patient-centred. The operationalization of “No decision about me without me” in the context of MDT models of care – where patients are not present when recommendations for treatment are discussed - requires further consideration. Methods for ensuring that patients are actively integrated into the MDT processes are required to ensure patients have an informed choice regarding engagement, and to ensure recommendations are based on the best available patient-based and clinical evidence.
Electronic supplementary material
The online version of this article (doi:10.1186/s12913-014-0488-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4210563  PMID: 25339192
Cancer; Multi-disciplinary team; Clinical decision-making; Patient-centredness; Qualitative; Interviews
11.  Strategies to improve the efficiency and utility of multidisciplinary team meetings in urology cancer care: a survey study 
The prevalence of multidisciplinary teams (MDT) for the delivery of cancer care is increasing globally. Evidence exists of benefits to patients and healthcare professionals. However, MDT working is time and resource intensive. This study aims to explore members’ views on existing practices of urology MDT working, and to identify potential interventions for improving the efficiency and productivity of the MDT meeting.
Members of urology MDTs across the UK were purposively recruited to participate in an online survey. Survey items included questions about the utility and efficiency of MDT meetings, and strategies for improving the efficiency of MDT meetings: treating cases by protocol, prioritising cases, and splitting the MDT into subspeciality meetings.
173 MDT members participated (Oncologists n = 77, Cancer Nurses n = 54, Urologists n = 30, other specialities n = 12). 68% of respondents reported that attending the MDT meeting improves efficiency in care through improved clinical decisions, planning investigations, helping when discussing plans with patients, speciality referrals, documentation/patient records. Participants agreed that some cases including low risk, non-muscle invasive bladder cancer and localised, low-grade prostate cancer could be managed by pre-agreed pathways, without full MDT review. There was a consensus that cases at the MDT meeting could be prioritised by complexity, tumour type, or the availability of MDT members. Splitting the MDT meeting was unpopular: potential disadvantages included loss of efficiency, loss of team approach, unavailability of members and increased administrative work.
Key urology MDT members find the MDT meeting useful. Improvements in efficiency and effectiveness may be possible by prioritising cases or managing some low-risk cases according to previously agreed protocols. Further research is needed to test the effectiveness of such strategies on MDT meetings, cancer care pathways and patient outcomes in clinical practice.
PMCID: PMC4162937  PMID: 25196248
Urology; Multidisciplinary; Team; Decision-making; Efficacy; Efficiency
12.  Using peer observers to assess the quality of cancer multidisciplinary team meetings: a qualitative proof of concept study 
Multidisciplinary team (MDT) working is well established as the foundation for providing cancer services in the UK and elsewhere. A core activity is the weekly meeting (or case conference/tumor boards) where the treatment recommendations for individual patients are agreed. Evidence suggests that the quality of team working varies across cancer teams, and this may impact negatively on the decision-making process, and ultimately patient care. Feedback on performance by expert observers may improve performance, but can be resource-intensive to implement. This proof of concept study sought to: develop a structured observational assessment tool for use by peers (managers or clinicians from the local workforce) and explore its usability; assess the feasibility of the principle of observational assessment by peers; and explore the views of MDT members and observers about the utility of feedback from observational assessment.
For tool development, the content was informed by national clinical consensus recommendations for best practice in cancer MDTs and developed in collaboration with an expert steering group. It consisted of ten subdomains of team working observable in MDT meetings that were rated on a 10-point scale (very poor to very good). For observational assessment, a total of 19 peer observers used the tool (assessing performance in 20 cancer teams from four hospitals). For evaluation, telephone interviews with 64 team members and all peer observers were analyzed thematically.
The tool was easy to use and areas for refinement were identified. Peer observers were identified and most indicated that undertaking observation was feasible. MDT members generally reported that observational assessment and feedback was useful, with the potential to facilitate improvements in team working.
This study suggests that observation and feedback by peers may provide a feasible and acceptable approach to enhance MDT performance. Further tool refinement and validation is required.
PMCID: PMC4134023  PMID: 25143743
cancer; multidisciplinary team; team working; observational assessment
13.  Novel Analogue of Colchicine Induces Selective Pro-Death Autophagy and Necrosis in Human Cancer Cells 
PLoS ONE  2014;9(1):e87064.
Colchicine, a natural product of Colchicum autumnae currently used for gout treatment, is a tubulin targeting compound which inhibits microtubule formation by targeting fast dividing cells. This tubulin-targeting property has lead researchers to investigate the potential of colchicine and analogs as possible cancer therapies. One major study conducted on an analogue of allocolchicine, ZD 6126, was halted in phase 2 clinical trials due to severe cardio-toxicity associated with treatment. This study involves the development and testing of novel allocolchicine analogues that hold non-toxic anti-cancer properties. Currently we have synthesized and evaluated the anti-cancer activities of two analogues; N-acetyl-O-methylcolchinol (NSC 51046 or NCME), which is structurally similar to ZD 6126, and (S)-3,8,9,10-tetramethoxyallocolchicine (Green 1), which is a novel derivative of allocolchicine that is isomeric in the A ring. NSC 51046 was found to be non-selective as it induced apoptosis in both BxPC-3 and PANC-1 pancreatic cancer cells and in normal human fibroblasts. Interestingly, we found that Green 1 was able to modestly induce pro-death autophagy in these pancreatic cancer cells and E6-1 leukemia cells but not in normal human fibroblasts. Unlike colchicine and NSC 51046, Green 1 does not appear to affect tubulin polymerization indicating that it has a different molecular target. Green 1 also caused increased reactive oxygen species (ROS) production in mitochondria isolated from pancreatic cancer cells. Furthermore, in vivo studies revealed that Green 1 was well tolerated in mice. Our findings suggest that a small change in the structure of colchicine has apparently changed the mechanism of action and lead to improved selectivity. This may lead to better selective treatments in cancer therapy.
PMCID: PMC3900699  PMID: 24466327
14.  Whirlin, a cytoskeletal scaffolding protein, stabilizes the paranodal region and axonal cytoskeleton in myelinated axons 
BMC Neuroscience  2013;14:96.
Myelinated axons are organized into distinct subcellular and molecular regions. Without proper organization, electrical nerve conduction is delayed, resulting in detrimental physiological outcomes. One such region is the paranode where axo-glial septate junctions act as a molecular fence to separate the sodium (Na+) channel-enriched node from the potassium (K+) channel-enriched juxtaparanode. A significant lack of knowledge remains as to cytoskeletal proteins which stabilize paranodal domains and underlying cytoskeleton. Whirlin (Whrn) is a PDZ domain-containing cytoskeletal scaffold whose absence in humans results in Usher Syndromes or variable deafness-blindness syndromes. Mutant Whirlin (Whrn) mouse model studies have linked such behavioral deficits to improper localization of critical transmembrane protein complexes in the ear and eye. Until now, no reports exist about the function of Whrn in myelinated axons.
RT-PCR and immunoblot analyses revealed expression of Whrn mRNA and Whrn full-length protein, respectively, in several stages of central and peripheral nervous system development. Comparing wild-type mice to Whrn knockout (Whrn−/−) mice, we observed no significant differences in the expression of standard axonal domain markers by immunoblot analysis but observed and quantified a novel paranodal compaction phenotype in 4 to 8 week-old Whrn−/− nerves. The paranodal compaction phenotype and associated cytoskeletal disruption was observed in Whrn−/− mutant sciatic nerves and spinal cord fibers from early (2 week-old) to late (1 year-old) stages of development. Light and electron microscopic analyses of Whrn knockout mice reveal bead-like swellings in cerebellar Purkinje axons containing mitochondria and vesicles by both. These data suggest that Whrn plays a role in proper cytoskeletal organization in myelinated axons.
Domain organization in myelinated axons remains a complex developmental process. Here we demonstrate that loss of Whrn disrupts proper axonal domain organization. Whrn likely contributes to the stabilization of paranodal myelin loops and axonal cytoskeleton through yet unconfirmed cytoskeletal proteins. Paranodal abnormalities are consistently observed throughout development (2 wk-1 yr) and similar between central and peripheral nervous systems. In conclusion, our observations suggest that Whrn is not required for the organization of axonal domains, but once organized, Whrn acts as a cytoskeletal linker to ensure proper paranodal compaction and stabilization of the axonal cytoskeleton in myelinated axons.
PMCID: PMC3844453  PMID: 24011083
Myelinated axons; Axonal domains; Paranodal domain; Axonal cytoskeleton; Whirlin
15.  Benefits of multidisciplinary teamwork in the management of breast cancer 
The widespread introduction of multidisciplinary team (MDT)-work for breast cancer management has in part evolved due to the increasing complexity of diagnostic and treatment decision-making. An MDT approach aims to bring together the range of specialists required to discuss and agree treatment recommendations and ongoing management for individual patients. MDTs are resource-intensive yet we lack strong (randomized controlled trial) evidence of their effectiveness. Clinical consensus is generally favorable on the benefits of effective specialist MDT-work. Many studies have shown the benefits of receiving treatment from a specialist center, and evidence continues to accrue from comparative studies of clinical benefits of an MDT approach, including improved survival. Patients’ views of the MDT model of decision-making (and in particular its impact on involvement in decisions about their care) have been under-researched. Barriers to effective teamwork and poor decision-making include excessive caseload, low attendance at meetings, lack of leadership, poor communication, role ambiguity, and failure to consider patients’ holistic needs. Breast cancer nurses have a key role in relation to assessing holistic needs, and their specialist contribution has also been associated with improved patient experience and quality of life. This paper examines the evidence for the benefits of MDT-work, in particular for breast cancer. Evidence is considered within a context of growing cancer incidence at a time of increased financial restraint, and it may now be important to reevaluate the structure and models of MDT-work to ensure that MDTs are an efficient use of resources.
PMCID: PMC3929250  PMID: 24648761
interdisciplinary teams; interprofessional interactions; multidisciplinary collaboration; teams; teamwork
16.  Identification of thyroid hormone receptor binding sites in developing mouse cerebellum 
BMC Genomics  2013;14:341.
Thyroid hormones play an essential role in early vertebrate development as well as other key processes. One of its modes of action is to bind to the thyroid hormone receptor (TR) which, in turn, binds to thyroid response elements (TREs) in promoter regions of target genes. The sequence motif for TREs remains largely undefined as does the precise chromosomal location of the TR binding sites. A chromatin immunoprecipitation on microarray (ChIP-chip) experiment was conducted using mouse cerebellum post natal day (PND) 4 and PND15 for the thyroid hormone receptor (TR) beta 1 to map its binding sites on over 5000 gene promoter regions. We have performed a detailed computational analysis of these data.
By analysing a recent spike-in study, the optimal normalization and peak identification approaches were determined for our dataset. Application of these techniques led to the identification of 211 ChIP-chip peaks enriched for TR binding in cerebellum samples. ChIP-PCR validation of 25 peaks led to the identification of 16 true positive TREs. Following a detailed literature review to identify all known mouse TREs, a position weight matrix (PWM) was created representing the classic TRE sequence motif. Various classes of promoter regions were investigated for the presence of this PWM, including permuted sequences, randomly selected promoter sequences, and genes known to be regulated by TH. We found that while the occurrence of the TRE motif is strongly correlated with gene regulation by TH for some genes, other TH-regulated genes do not exhibit an increased density of TRE half-site motifs. Furthermore, we demonstrate that an increase in the rate of occurrence of the half-site motifs does not always indicate the specific location of the TRE within the promoter region. To account for the fact that TR often operates as a dimer, we introduce a novel dual-threshold PWM scanning approach for identifying TREs with a true positive rate of 0.73 and a false positive rate of 0.2. Application of this approach to ChIP-chip peak regions revealed the presence of 85 putative TREs suitable for further in vitro validation.
This study further elucidates TRβ gene regulation in mouse cerebellum, with 211 promoter regions identified to bind to TR. While we have identified 85 putative TREs within these regions, future work will study other mechanisms of action that may mediate the remaining observed TR-binding activity.
PMCID: PMC3716714  PMID: 23701648
17.  Diagnostic Stability in Very Young Children with Autism Spectrum Disorders 
Autism Spectrum Disorders (ASD) diagnosis in very young children may be delayed due to doubts about validity. In this study, 77 children received a diagnostic and developmental evaluation between 16 and 35 months and also between 42 and 82 months. Diagnoses based on clinical judgment, Childhood Autism Rating Scale, and the Autism Diagnostic Observation Schedule were stable over time. Diagnoses made using the Autism Diagnostic Interview were slightly less stable. According to clinical judgment, 15 children (19%) moved off the autism spectrum by the second evaluation; none moved onto the spectrum. Results indicate diagnostic stability at acceptable levels for diagnoses made at age 2. Movement off the spectrum may reflect true improvement based on maturation, intervention, or over-diagnosis at age 2.
PMCID: PMC3625643  PMID: 17924183
Autism; PDD-NOS; Diagnostic stability; Early detection
18.  Localization of PDZD7 to the stereocilia ankle-link associates this scaffolding protein with the Usher syndrome protein network 
Usher syndrome is the leading cause of genetic deaf-blindness. Monoallelic mutations in PDZD7 increase the severity of Usher type II syndrome caused by mutations in USH2A and GPR98, which respectively encode usherin and GPR98. PDZ domain-containing 7 protein (PDZD7) is a paralog of the scaffolding proteins harmonin and whirlin, which are implicated in Usher type 1 and type 2 syndromes. While usherin and GPR98 have been reported to form hair cell stereocilia ankle-links, harmonin localizes to the stereocilia upper tip-link density and whirlin localizes to both tip and ankle-link regions. Here, we used mass spectrometry to show that PDZD7 is expressed in chick stereocilia at a comparable molecular abundance to GPR98. We also show by immunofluorescence and by overexpression of tagged proteins in rat and mouse hair cells that PDZD7 localizes to the ankle-link region, overlapping with usherin, whirlin, and GPR98. Finally, we show in LLC-PK1 cells that cytosolic domains of usherin and GPR98 can bind to both whirlin and PDZD7. These observations are consistent with PDZD7 being a modifier and candidate gene for USH2, and suggest that PDZD7 is a second scaffolding component of the ankle-link complex.
PMCID: PMC3518401  PMID: 23055499
19.  The Modified Checklist for Autism in Toddlers: A Follow-up Study Investigating the Early Detection of Autism Spectrum Disorders 
Autism spectrum disorders (ASD) often go undetected in toddlers. The Modified Checklist for Autism in Toddlers (M-CHAT) was used to screen 3,793 children aged 16–30 months from low- and high-risk sources; screen positive cases were diagnostically evaluated. Re-screening was performed on 1,416 children aged 42–54 months. Time 1 Positive Predictive Value (PPV) was .36 for the initial screening and .74 for the screening plus follow-up telephone interview; values were similar for Time 2 PPV. When separating referral sources, PPV was low for the low-risk sample but acceptable with the follow-up telephone interview. Children with ASD from the low-risk and high-risk samples were highly similar. Results indicate that the M-CHAT continues to be a promising instrument for the early detection of ASD.
PMCID: PMC3612529  PMID: 17882539
Autism; Early identification; Pediatric screening
20.  Using the Childhood Autism Rating Scale to Diagnose Autism Spectrum Disorders 
This study investigated the childhood autism rating scale (CARS) as a tool for ASD diagnoses for 2-year-old (n = 376) and 4-year-old (n = 230) children referred for possible autism. The cut-off score to distinguish autistic disorder from PDD-NOS was 32 in the 2-year-old sample (consistent with Lord in J Child Psychol Psychiatry Allied Discipl, 36, 1365–1382, 1995), and 30 in the 4-year-old sample, with good sensitivity and specificity at both ages. The cut-off score to distinguish ASD from non-ASD at both ages was 25.5, with good sensitivity and specificity. Results confirm the utility of the CARS in distinguishing autistic disorder from PDD-NOS, and distinguishing ASD from other developmental disorders and typical development and suggest that an ASD cutoff around 25, which is in common clinical use, is valid.
PMCID: PMC3612531  PMID: 20054630
Autism spectrum disorders; Childhood autism rating scale; Diagnosis; PDD-NOS
21.  The cancer multi-disciplinary team from the co-ordinators’ perspective: results from a national survey in the UK 
The MDT-Coordinators’ role is relatively new, and as such it is evolving. What is apparent is that the coordinator’s work is pivotal to the effectiveness and efficiency of an MDT. This study aimed to assess the views and needs of MDT-coordinators.
Views of MDT-coordinators were evaluated through an online survey that covered their current practice and role, MDT chairing, opinions on how to improve MDT meetings, and coordinators’ educational/training needs.
265 coordinators responded to the survey. More than one third of the respondents felt that the job plan does not reflect their actual duties. It was reported that medical members of the MDT always contribute to case discussions. 66.9% of the respondents reported that the MDTs are chaired by Surgeons. The majority reported having training on data management and IT skills but more than 50% reported that they felt further training is needed in areas of Oncology, Anatomy and physiology, audit and research, peer-review, and leadership skills.
MDT-Coordinators’ role is central to the care of cancer patients. The study reveals areas of training requirements that remain unmet. Improving the resources and training available to MDT-coordinators can give them an opportunity to develop the required additional skills and contribute to improved MDT performance and ultimately cancer care. Finally, this study looks forward to the impact of the recent launch of a new e-learning training programme for MDT coordinators and discusses implications for future research.
PMCID: PMC3539898  PMID: 23237502
Multidisciplinary team; Cancer; Coordinator; Training; Decision
22.  Screaming, Yelling, Whining and Crying: Categorical and intensity differences in Vocal Expressions of Anger and Sadness in Children's Tantrums 
Emotion (Washington, D.C.)  2011;11(5):1124-1133.
Young children's temper tantrums offer a unique window into the expression and regulation of strong emotions. Previous work, largely based on parental report, suggests that two emotions, anger and sadness, have different behavioral manifestations and different time courses within tantrums. Individual motor and vocal behaviors, reported by parents, have been interpreted as representing different levels of intensity within each emotion category. The present study used high fidelity audio recordings to capture the acoustic features of children's vocalizations during tantrums. Results indicated that perceptually categorized screaming, yelling, crying, whining, and fussing each have distinct acoustic features. Screaming and yelling form a group with similar acoustic features while crying, whining, and fussing form a second acoustically related group. Within these groups, screaming may reflect a higher intensity of anger than yelling while fussing, whining and crying may reflect an increasing intensity of sadness.
PMCID: PMC3192404  PMID: 21707157
Temper tantrums; Vocalizations; Acoustic Features; Anger; Sadness
23.  Label-Free Enrichment of Functional Cardiomyocytes Using Microfluidic Deterministic Lateral Flow Displacement 
PLoS ONE  2012;7(5):e37619.
Progress in cardiac cell replacement therapies and tissue engineering critically depends on our ability to isolate functional cardiomyocytes (CMs) from heterogeneous cell mixtures. Label-free enrichment of cardiomyocytes is desirable for future clinical application of cell based products. Taking advantage of the physical properties of CMs, a microfluidic system was designed to separate CMs from neonatal rat heart tissue digest based on size using the principles of deterministic lateral displacement (DLD). For the first time, we demonstrate enrichment of functional CMs up to 91±2.4% directly from the digested heart tissue without any pre-treatment or labeling. Enriched cardiomyocytes remained viable after sorting and formed contractile cardiac patches in 3-dimensional culture. The broad significance of this work lies in demonstrating functional cell enrichment from the primary tissue digest leading directly to the creation of the engineered tissue.
PMCID: PMC3362623  PMID: 22666372
24.  Short Co-occurring Polypeptide Regions Can Predict Global Protein Interaction Maps 
Scientific Reports  2012;2:239.
A goal of the post-genomics era has been to elucidate a detailed global map of protein-protein interactions (PPIs) within a cell. Here, we show that the presence of co-occurring short polypeptide sequences between interacting protein partners appears to be conserved across different organisms. We present an algorithm to automatically generate PPI prediction method parameters for various organisms and illustrate that global PPIs can be predicted from previously reported PPIs within the same or a different organism using protein primary sequences. The PPI prediction code is further accelerated through the use of parallel multi-core programming, which improves its usability for large scale or proteome-wide PPI prediction. We predict and analyze hundreds of novel human PPIs, experimentally confirm protein functions and importantly predict the first genome-wide PPI maps for S. pombe (∼9,000 PPIs) and C. elegans (∼37,500 PPIs).
PMCID: PMC3269044  PMID: 22355752
25.  Prevalence of Internet use amongst an elective spinal surgery outpatient population 
European Spine Journal  2010;19(10):1776-1779.
Nationally 62% of individuals in Ireland have internet access. Previous published work has suggested that internet use is higher among those with low back pain. We aimed to determine the levels of internet access and use amongst an elective spinal outpatient population and determine what characteristics influence these. We distributed a self-designed questionnaire to patients attending elective spinal outpatient clinics. Data including demographics, history of surgery, number of visits, level of satisfaction with previous consultations, access to the internet, possession of health insurance, and details regarding use of the internet to research one’s spinal complaint were collected. 213 patients completed the questionnaire. 159 (75%) had access to the internet. Of this group 48 (23%) used the internet to research their spinal condition. Increasing age, higher education level, and possession of health insurance were all significantly associated with access to the internet (p < 0.05). A higher education level predicted greater internet use while possession of insurance weakly predicted non-use (p < 0.05). In our practice, internet access is consistent with national statistics and use is comparable to previous reports. Approximately, one quarter of outpatients will use the internet to research their spinal condition. Should we use this medium to disseminate information we need to be aware some groups may not have access.
PMCID: PMC2989229  PMID: 20361342
Internet; Outpatient clinic

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