Characterization of recombinant influenza B viruses with key neuraminidase inhibitor resistance mutations

Objectives and methods: An influenza B virus plasmid-based rescue system was used to introduce site-specific mutations, previously observed in neuraminidase (NA) inhibitor-resistant viruses, into the NA protein of six recombinant viruses. Three mutations observed only among in vitro selected zanamivir-resistant influenza A mutants were introduced into the B/Beijing/1/87 virus NA protein, to change residue E116 to glycine, alanine or aspartic acid. Residue E116 was also mutated to valine, a mutation found in the clinic among oseltamivir-resistant viruses. An arginine to lysine change at position 291 (292 N2 numbering) mimicked that seen frequently in influenza A N2 clinical isolates resistant to oseltamivir. Similarly, an arginine to lysine change at position 149 (152 in N2 numbering) was made to reproduce the change found in the only reported zanamivir-resistant clinical isolate of influenza B virus. In vitro selection and prolonged treatment in the clinic leads to resistance pathways that require compensatory mutations in the haemagglutinin gene, but these appear not to be important for mutants isolated from immunocompetent patients. The reverse genetics system was therefore used to generate mutants containing only the NA mutation. Results and conclusions: With the exception of a virus containing the E116G mutation, mutant viruses were attenuated to different levels in comparison with wild-type virus. This attenuation was a result of altered NA activity or stability depending on the introduced mutation. Mutant viruses displayed increased resistance to zanamivir, oseltamivir and peramivir, with certain viruses displaying cross-resistance to all three drugs.

Targeting the cell cycle machinery for the treatment of cardiovascular disease

Cardiovascular disease represents a major clinical problem affecting a significant proportion of the world's population and remains the main cause of death in the UK. The majority of therapies currently available for the treatment of cardiovascular disease do not cure the problem but merely treat the symptoms. Furthermore, many cardioactive drugs have serious side effects and have narrow therapeutic windows that can limit their usefulness in the clinic. Thus, the development of more selective and highly effective therapeutic strategies that could cure specific cardiovascular diseases would be of enormous benefit both to the patient and to those countries where healthcare systems are responsible for an increasing number of patients. In this review, we discuss the evidence that suggests that targeting the cell cycle machinery in cardiovascular cells provides a novel strategy for the treatment of certain cardiovascular diseases. Those cell cycle molecules that are important for regulating terminal differentiation of cardiac myocytes and whether they can be targeted to reinitiate cell division and myocardial repair will be discussed as will the molecules that control vascular smooth muscle cell (VSMC) and endothelial cell proliferation in disorders such as atherosclerosis and restenosis. The main approaches currently used to target the cell cycle machinery in cardiovascular disease have employed gene therapy techniques. We will overview the different methods and routes of gene delivery to the cardiovascular system and describe possible future drug therapies for these disorders. Although the majority of the published data comes from animal studies, there are several instances where potential therapies have moved into the clinical setting with promising results.

Polymer-drug conjugates: current status and future trends

Polymer conjugates are nano-sized, multicomponent constructs already in the clinic as anticancer compounds, both as single agents or as elements of combinations. They have the potential to improve pharmacological therapy of a variety of solid tumors. Polymer-drug conjugation promotes passive tumor targeting by the enhanced permeability and retention (EPR) effect and allows for lysosomotropic drug delivery following endocytic capture. In the first part of this review, we analyze the promising results arising from clinical trials of polymer-bound chemotherapy. The experience gained on these studies provides the basis for the development of a more sophisticated second-generation of polymer conjugates. However, many challenges still lay ahead providing scope to develop and refine this field. The "technology platform'' of polymer therapeutics allows the development of both new and exciting polymeric materials, the incorporation of novel bioactive agents and combinations thereof to address recent advances in drug therapy. The rational design of polymer drug conjugates is expected to realize the true potential of these "nanomedicines".

Self-exclusion from health care in women at high risk for postpartum depression

Background A significant proportion of women who are vulnerable to postnatal depression refuse to engage in treatment programmes. Little is known about them, other than some general demographic characteristics. In particular, their access to health care and their own and their infants' health outcomes are uncharted. Methods We conducted a nested cohort case-control study, using data from computerized health systems, and general practitioner (GP) and maternity records, to identify the characteristics, health service contacts, and maternal and infant health outcomes for primiparous antenatal clinic attenders at high risk for postnatal depression who either refused (self-exclusion group) or else agreed (take-up group) to receive additional Health Visiting support in pregnancy and the first 2 months postpartum. Results Women excluding themselves from Health Visitor support were younger and less highly educated than women willing to take up the support. They were less likely to attend midwifery, GP and routine Health Visitor appointments, but were more likely to book in late and to attend accident and emergency department (A&E). Their infants had poorer outcome in terms of gestation, birthweight and breastfeeding. Differences between the groups still obtained when age and education were taken into account for midwifery contacts, A&E attendance and gestation;the difference in the initiation of breast feeding was attenuated, but not wholly explained, by age and education. Conclusion A subgroup of psychologically vulnerable childbearing women are at particular risk for poor access to health care and adverse infant outcome. Barriers to take-up of services need to be understood in order better to deliver care.

Attribution and the effects of expectancy: how beliefs can influence the experiences of smoking cessation

Research on smoking cessation has found consistencies and similarities during abstinence, but also that the specific signs and symptoms and their intensity vary greatly from individual to individual. One possible source of this variation is the cognitions associated with quitting. We investigated the experiences and associated cognitions in normal cessation by asking quitting smokers to rate their experiences on a questionnaire and to indicate the most likely reason for each experience. Statistical analyses confirmed that attributions to abstinence were significantly higher for increased negative experiences, and there were significantly more reattributions than would be found by chance for items associated with smoking abstinence. Significantly more attributions to abstinence were made by clinic attendees and significantly more attributions of negative experiences to abstinence were made by unaided quitters using self-help materials. These results can be interpreted in the context of attribution theory; quitters may use the cognitions available to them to attribute their negative experiences to quitting. Consequently, counsellors could use cognitive therapy to alter their clients' expectations and explanations of their experiences, and emphasise the positive outcomes of cessation. (C) 2002 Elsevier Science Ltd. All rights reserved.

Threat interpretation in anxious children and their mothers: comparison with nonclinical children and the effects of treatment

Interpretation biases towards threat play a prominent role in cognitive theories of anxiety, and have been identified amongst highly anxious adults and children. Little is known, however, about the development of these cognitive biases although family processes have been implicated. The current study investigated the nature of threat interpretation of anxious children and their mothers through (i) comparison of a clinic and non-clinic population, (ii) analysis of individual differences; and (ill) pre- and post-treatment comparisons. Participants were 27 children with a primary anxiety disorder and 33 children from a non-clinic population and their mothers. Children and mothers completed self-report measures of anxiety and indicated their most likely interpretation of ambiguous scenarios. Clinic and non-clinical groups differed significantly on measures of threat interpretation. Furthermore, mothers' and children's threat interpretation correlated significantly. Following treatment for child anxiety, both children and their mothers reported a reduction in threat interpretation. (c) 2005 Elsevier Ltd. All rights reserved.

Patients' attitudes towards, and information needs in relation to, nurse prescribing in rheumatology

Aims and objectives: To assess the level of confidence that rheumatology patients would have in nurse prescribing, the effects on likely adherence and particular concerns that these patients have. In addition, given that information provision has been cited as a potential benefit of nurse prescribing, the present study assessed the extent to which these patients would want an explanation for the selected medicine, as well as which types of information should be included in such an explanation. Background: Nurse prescribing has been successfully implemented in the UK in several healthcare settings. Existing research has not addressed the effects on patients' confidence and likely adherence, nor have patients' information needs been established. However, we know that inadequate medicines information provision by health professionals is one of the largest causes of patient dissatisfaction. Methods: Fifty-four patients taking disease-modifying drugs for inflammatory joint disease attending a specialist rheumatology clinic self-completed a written questionnaire. Results: Patients indicated a relatively high level of confidence in nurse prescribing and stated that they would be very likely to take the selected medication. The level of concern was relatively low and the majority of concerns raised did not relate to the nurse's status. Strong support was expressed for the nurse providing an explanation for medicine choice. Conclusion: This research provides support for the prescription of medicines by nurses working in the area of rheumatology, the importance of nurses providing a full explanation about the selected medicines they prescribe for these patients and some indication as to which categories of information should be included. Relevance to clinical practice: Rheumatology patients who have not yet experienced nurse prescribing are, in general, positive about nurses adopting this role. It is important that nurses provide appropriate information about the prescribed medicines, in a form that can be understood.

Perceptions of the risks and benefits of medicines in patients with rheumatoid arthritis and other painful musculoskeletal conditions

Objectives. To examine beliefs about medication risks and benefits in patients attending a specialist rheumatology clinic for pain-related conditions. Methods. Eighty-one patients (37 first attendees and 44 existing clinic patients) completed a written questionnaire which asked about current treatments, perceived effectiveness, main risks and benefits, and compliance. Results. Existing clinic patients perceived medications to be more effective and more risky than did the new patients, although both groups rated risks to be moderately low. The main perceived risks were adverse side-effects, although patients reported only moderately low levels of experiencing such effects. Conclusions. In contrast to some other studies, many of our patients were aware of medication risks and were prepared to accept them provided benefits were seen to be high. Existing clinic patients were more aware of risks and benefits, and reported higher compliance levels than new patients, possibly as a result of the hospital education programme. Future studies should evaluate the effects of the programme more systematically.

A randomised controlled trial of cognitive behavioural treatment for obsessive compulsive disorder in children and adolescents

Cognitive behaviour therapy (CBT) for young people with obsessive compulsive disorder (OCD) has become the treatment of first choice. However, the literature is largely based on studies emphasising exposure and response prevention. In this study, we report on a randomised controlled trial of CBT for young people carried out in typical outpatient clinic conditions which focused on cognitions. A randomised controlled trial compares 10 sessions of manualised cognitive behavioural treatment with a 12-week waiting list for adolescents and children with OCD. Assessors were blind to treatment allocation. 21 consecutive patients with OCD aged between 9 and 18 years were recruited. The group who received treatment improved more than a comparison group who waited for 3 months. The second group was treated subsequently using the same protocol and made similar gains. In conclusion, CBT can be delivered effectively to young people with OCD in typical outpatient settings.

Mirror lightpipes: daylighting performance in real buildings

Mirror lightpipes are useful for providing healthy and energy-efficient daylight into buildings where windows and skylights are unsuitable, insufficient or generate too much heat gain. The lightpipes have been installed in dozens of buildings in the UK. Field monitoring has been carried out to assess their performance in four different buildings: the headquaters of a major insurance company, a health clinic, a residential building and a college dining hall In those cases where lighipipes with moderate aspect ratios were installed, good illuminance of up to 450 lux has been obtained with internal/external illuminance ratios around 1%. When long and narrow lightpipes with many bends are used, however, the ratio reduced to around 0.1%. These results showed that lightpipes can be effective daylighting devices provided that excessive aspect ratios and numbers of bends are avoided. Lightpipes with larger diameters should be used whenever possible. The lightpipes often improved signiScantly the visual quality af the interior environment, and high user satisfaction was found even in buildings where a relatively low level of daylight was admitted through the lightpipes

Low cost brain-computer interface: first results

Brain-Computer Interfacing (BCI) has been previously demonstrated to restore patient communication, meeting with varying degrees of success. Due to the nature of the equipment traditionally used in BCI experimentation (the electroencephalograph) it is mostly conned to clinical and research environments. The required medical safety standards, subsequent cost of equipment and its application/training times are all issues that need to be resolved if BCIs are to be taken out of the lab/clinic and delivered to the home market. The results in this paper demonstrate a system developed with a low cost medical grade EEG amplier unit in conjunction with the open source BCI2000 software suite thus constructing the cheapest per electrode system available, meeting rigorous clinical safety standards. Discussion of the future of this technology and future work concerning this platform are also introduced.

Public Art Commission Rung by Rung, Tina O'Connell

Research based on a significant public art commissions awarded through competition (peer reviewed) – Pearse Street Clinic Public Art Commission (€20K). Research was examining issues of the relationship between sculpture, exchange and communication, health and well-being. The research used an approach to question the aspirations and dreams of those who were visiting the health centre as part of a routine of daily life. Based on the aspirational concerns of individual visitors, and secondary research of positive effects of light, the final output draws on ideas based around the language of physical signage to occupy a space concerned with visitor health and wellbeing – a Health Clinic. The output has had an impact both at the site and more broadly in the context of examining sculpture and fine art as a social catalyst - based on work of socially-engaged historical practices. The installation at Pearse Street work in Dublin in Nov 09 has received critical and local acclaim. Further commissions within the public arena have been forthcoming despite difficult local economic landscape.

Circulating insulin-like factor 3 (INSL3) in healthy and infertile women

STUDY QUESTION: How does insulin-like factor 3 (INSL3) concentration in blood vary across the menstrual cycle in women? SUMMARY ANSWER: INSL3 is secreted by the theca interna cells of growing antral follicles and is phasic in its expression. WHAT IS KNOWN ALREADY: The relaxin-like hormone INSL3 is known to be expressed in follicles of several mammal species, and was recently shown in cows to be specifically secreted into the bloodstream by growing antral follicles, corresponding to follicular waves. In males INSL3 is known to be acutely independent of the hormones of the hypothalamic-pituitary-gonadal axis, suggesting that in women INSL3 might be a novel biomarker for antral follicle recruitment and development. STUDY DESIGN, SIZE, DURATION: Two cohorts of women were studied. First, 18 healthy women of reproductive age were followed longitudinally for one and a half cycles, with blood sampling and hormone measurement every 2-3 days. A second cohort comprised a cross-sectional study of 909 women attending an infertility clinic, with a single blood sample taken at entry, together with other clinical and hormonal parameters. PARTICIPANTS/MATERIALS, SETTING, METHODS: Blood samples from both retrospective cohorts were analyzed for INSL3 using a highly sensitive time-resolved fluorescent immunoassay, and data were analyzed in comparison with other clinical and hormonal parameters. MAIN RESULT AND THE ROLE OF CHANCE: For young healthy women of reproductive age, we showed a phasic expression of INSL3 corresponding to antral follicle growth in both the follicular and luteal phases of the cycle, which was significantly (P < 0.05) elevated compared with that during menses. For women attending an infertility clinic, those with diagnosed polycystic ovarian syndrome indicated significantly (P < 0.0005) greater circulating INSL3 levels and those with low ovarian reserve showed significantly (P < 0.002) decreased INSL3 values. LIMITATIONS, REASONS FOR CAUTION: These were retrospective studies and the results were obtained from natural cycles only, with their inherent variability. WIDER IMPLICATIONS OF THE FINDINGS: We show for the first time that INSL3 in women does vary across the menstrual cycle, and appears to reflect the number of growing antral follicles recruited within both follicular and luteal phases. STUDY FUNDING/COMPETING INTEREST(S): The present retrospective study was largely supported by departmental funds. There were no competing interests.

Complex extreme learning machine applications in terahertz pulsed signals feature sets

This paper presents a novel approach to the automatic classification of very large data sets composed of terahertz pulse transient signals, highlighting their potential use in biochemical, biomedical, pharmaceutical and security applications. Two different types of THz spectra are considered in the classification process. Firstly a binary classification study of poly-A and poly-C ribonucleic acid samples is performed. This is then contrasted with a difficult multi-class classification problem of spectra from six different powder samples that although have fairly indistinguishable features in the optical spectrum, they also possess a few discernable spectral features in the terahertz part of the spectrum. Classification is performed using a complex-valued extreme learning machine algorithm that takes into account features in both the amplitude as well as the phase of the recorded spectra. Classification speed and accuracy are contrasted with that achieved using a support vector machine classifier. The study systematically compares the classifier performance achieved after adopting different Gaussian kernels when separating amplitude and phase signatures. The two signatures are presented as feature vectors for both training and testing purposes. The study confirms the utility of complex-valued extreme learning machine algorithms for classification of the very large data sets generated with current terahertz imaging spectrometers. The classifier can take into consideration heterogeneous layers within an object as would be required within a tomographic setting and is sufficiently robust to detect patterns hidden inside noisy terahertz data sets. The proposed study opens up the opportunity for the establishment of complex-valued extreme learning machine algorithms as new chemometric tools that will assist the wider proliferation of terahertz sensing technology for chemical sensing, quality control, security screening and clinic diagnosis. Furthermore, the proposed algorithm should also be very useful in other applications requiring the classification of very large datasets.

Decomposition of surface electromyographic signal using Hidden Markov Model

The detection of physiological signals from the motor system (electromyographic signals) is being utilized in the practice clinic to guide the therapist in a more precise and accurate diagnosis of motor disorders. In this context, the process of decomposition of EMG (electromyographic) signals that includes the identification and classification of MUAP (Motor Unit Action Potential) of a EMG signal, is very important to help the therapist in the evaluation of motor disorders. The EMG decomposition is a complex task due to EMG features depend on the electrode type (needle or surface), its placement related to the muscle, the contraction level and the health of the Neuromuscular System. To date, the majority of researches on EMG decomposition utilize EMG signals acquired by needle electrodes, due to their advantages in processing this type of signal. However, relatively few researches have been conducted using surface EMG signals. Thus, this article aims to contribute to the clinical practice by presenting a technique that permit the decomposition of surface EMG signal via the use of Hidden Markov Models. This process is supported by the use of differential evolution and spectral clustering techniques. The developed system presented coherent results in: (1) identification of the number of Motor Units actives in the EMG signal; (2) presentation of the morphological patterns of MUAPs in the EMG signal; (3) identification of the firing sequence of the Motor Units. The model proposed in this work is an advance in the research area of decomposition of surface EMG signals.