Misfolding of galactose 1-phosphate uridylyltransferase can result in type I galactosemia

Type I galactosemia is a genetic disorder that is caused by the impairment of galactose-1-phosphate uridylyltransferase (GALT; EC 2.7.7.12). Although a large number of mutations have been detected through genetic screening of the human GALT (hGALT) locus, for many it is not known how they cause their effects. The majority of these mutations are missense, with predicted substitutions scattered throughout the enzyme structure and thus causing impairment by other means rather than direct alterations to the active site. To clarify the fundamental, molecular basis of hGALT impairment we studied five disease-associated variants p.D28Y, p.L74P, p.F171S, p.F194L and p.R333G using both a yeast model and purified, recombinant proteins. In a yeast expression system there was a correlation between lysate activity and the ability to rescue growth in the presence of galactose, except for p.R333G. Kinetic analysis of the purified proteins quantified each variant's level of enzymatic impairment and demonstrated that this was largely due to altered substrate binding. Increased surface hydrophobicity, altered thermal stability and changes in proteolytic sensitivity were also detected. Our results demonstrate that hGALT requires a level of flexibility to function optimally and that altered folding is the underlying reason of impairment in all the variants tested here. This indicates that misfolding is a common, molecular basis of hGALT deficiency and suggests the potential of pharmacological chaperones and proteostasis regulators as novel therapeutic approaches for type I galactosemia.

Decompressive hemicraniectomy following malignant middle cerebral artery infarctions:a mixed methods exploration of carer experience and level of burden

Purpose: This study explores the experiences and sense of burden of family carers of survivors of malignant middle cerebral artery infarctions who had undergone decompressive hemicraniectomy. To date, there have been no studies examining carer outcomes among this unique population. This study, taken alongside an already published study of survivor outcomes, provides a more holistic picture with regard to sequelae within the sample. Method: Six family carers completed the Sense of Competence Questionnaire and the Hospital Anxiety and Depression Scale. These results were compared with existing normative data. Carers also consented to a semi-structured interview. Interview data were examined using thematic content analysis. Consistent with the mixed methods design, quantitative and qualitative findings were integrated for further analysis. Results: While carers experienced many losses, their overall sense of burden was not outside 'Average' limits, nor did they experience clinically significant symptoms of depression. All carers identified methods of coping with the demands of caregiving. These included intrapersonal, interpersonal and practical strategies. All carers apart from one were able to identify areas of post-traumatic growth. Conclusion: Carers will benefit from information, support and care. In addition, problem solving skills are essential in managing the myriad difficulties that arise in the aftermath of stroke. [Box: see text].

Clinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF:a family based association study

Schizophrenia is clinically heterogeneous and multidimensional, but it is not known whether this is due to etiological heterogeneity. Previous studies have not consistently reported association between any specific polymorphisms and clinical features of schizophrenia, and have primarily used case-control designs. We tested for the presence of association between clinical features and polymorphisms in the genes for the serotonin 2A receptor (HT2A), dopamine receptor types 2 and 4, dopamine transporter (SLC6A3), and brain-derived neurotrophic factor (BDNF). Two hundred seventy pedigrees were ascertained on the basis of having two or more members with schizophrenia or poor outcome schizoaffective disorder. Diagnoses were made using a structured interview based on the SCID. All patients were rated on the major symptoms of schizophrenia scale (MSSS), integrating clinical and course features throughout the course of illness. Factor analysis revealed positive, negative, and affective symptom factors. The program QTDT was used to implement a family-based test of association for quantitative traits, controlling for age and sex. We found suggestive evidence of association between the His452Tyr polymorphism in HT2A and affective symptoms (P = 0.02), the 172-bp allele of BDNF and negative symptoms (P = 0.04), and the 480-bp allele in SLC6A3 (= DAT1) and negative symptoms (P = 0.04). As total of 19 alleles were tested, we cannot rule out false positives. However, given prior evidence of involvement of the proteins encoded by these genes in psychopathology, our results suggest that more attention should be focused on the impact of these alleles on clinical features of schizophrenia.

A comparison of Diamond Forrester and coronary calcium scores as gatekeepers for investigations of stable chest pain

To determine if calcium scores (CS) could act as a more effective gatekeeper than Diamond Forrester (DF) in the assessment of patients with suspected coronary artery disease (CAD). A sub-study of the Cardiac CT for the Assessment of Chest Pain and Plaque (CAPP) study, a randomised control trial evaluating the cost-effectiveness of cardiac CT in symptomatic patients with stable chest pain. Stable pain was defined as troponin negative pain without symptoms of unstable angina. 250 patients undergoing cardiac CT had both DF scores and CS calculated, with the accuracy of both evaluated against CT coronary angiogram. Criteria given in UK national guidelines were compared. Of the 250 patients, 4 withdrew. 140 (57 %) patients were male. The mean DF was 47.8 and mean CS 172.5. Of the 144 patients with non-anginal pain 19.4 % had significant disease (>50 % stenosis). In general the DF over estimated the presence of CAD whereas the CS reclassified patients to lower risk groups, with 91 in the high risk DF category compared to 26 in the CS. Both receiver operating curve and McNemar Bowker test analysis suggested the DF was less accurate in the prediction of CAD compared to CS [Formula: see text] Projected downstream investigations were also calculated, with the cost per number of significant stenoses identified cheaper with the CS criteria. Patients with suspected stable CAD are more accurately risk stratified by CS compared to the traditional DF. CS was more successful in the prediction of significant stenosis and appears to be more effective at targeting clinical resources to those patients that are in need of them.

Association of physical activity with future mental health in older, mid-life and younger women

Background: Mental ill-health, particularly depression and anxiety, is a leading and increasing cause of disability worldwide, especially for women.

Methods: We examined the prospective association between physical activity and symptoms of mental ill-health in younger, mid-life and older working women. Participants were 26 913 women from the ongoing cohort Finnish Public Sector Study with complete data at two phases, excluding those who screened positive for mental ill-health at baseline. Mental health was assessed using the 12-item General Health Questionnaire. Self-reported physical activity was expressed in metabolic equivalent task (MET) hours per week. Logistic regression models were used to analyse associations between physical activity levels and subsequent mental health.

Results: There was an inverse dose–response relationship between physical activity and future symptoms of mental ill-health. This association is consistent with a protective effect of physical activity and remained after adjustments for socio-demographic, work-related and lifestyle factors, health and body mass index. Furthermore, those mid-life and older women who reported increased physical activity by more than 2 MET hours per week demonstrated a reduced risk of later mental ill-health in comparison with those who did not increase physical activity. This protective effect of increased physical activity did not hold for younger women.

Conclusions: This study adds to the evidence for the protective effect of physical activity for later mental health in women. It also suggests that increasing physical activity levels may be beneficial in terms of mental health among mid-life and older women. The alleviation of menopausal symptoms may partly explain age effects but further research is required.

A pilot study of a family focused, psychosocial intervention with war-exposed youth at risk of attack and abduction in north-eastern Democratic Republic of Congo

Rural communities in the Haut-Uele Province of northern Democratic Republic of Congo live in constant danger of attack and/or abduction by units of the Lord's Resistance Army operating in the region. This pilot study sought to develop and evaluate a community-participative psychosocial intervention involving life skills and relaxation training and Mobile Cinema screenings with this war-affected population living under current threat. 159 war-affected children and young people (aged 7-18) from the villages of Kiliwa and Li-May in north-eastern DR Congo took part in this study. In total, 22% of participants had been abduction previously while 73% had a family member abducted. Symptoms of post-traumatic stress reactions, internalising problems, conduct problems and pro-social behaviour were assessed by blinded interviewers at pre- and post-intervention and at 3-month follow-up. Participants were randomised (with an accompanying caregiver) to 8 sessions of a group-based, community-participative, psychosocial intervention (n=79) carried out by supervised local, lay facilitators or a wait-list control group (n=80). Average seminar attendance rates were high: 88% for participants and 84% for caregivers. Drop-out was low: 97% of participants were assessed at post-intervention and 88% at 3 month follow-up. At post-test, participants reported significantly fewer symptoms of post-traumatic stress reactions compared to controls (Cohen's d=0.40). At 3 month follow up, large improvements in internalising symptoms and moderate improvements in pro-social scores were reported, with caregivers noting a moderate to large decline in conduct problems among the young people. Trial Registration clinicalTrials.gov, Identifier: NCT01542398.

Pharmacological evaluation of selective α2c-adrenergic agonists in experimental animal models of nasal congestion

Nasal congestion is one of the most troublesome symptoms of many upper airways diseases. We characterized the effect of selective α2c-adrenergic agonists in animal models of nasal congestion. In porcine mucosa tissue, compound A and compound B contracted nasal veins with only modest effects on arteries. In in vivo experiments, we examined the nasal decongestant dose-response characteristics, pharmacokinetic/pharmacodynamic relationship, duration of action, potential development of tolerance, and topical efficacy of α2c-adrenergic agonists. Acoustic rhinometry was used to determine nasal cavity dimensions following intranasal compound 48/80 (1%, 75 µl). In feline experiments, compound 48/80 decreased nasal cavity volume and minimum cross-sectional areas by 77% and 40%, respectively. Oral administration of compound A (0.1-3.0 mg/kg), compound B (0.3-5.0 mg/kg), and d-pseudoephedrine (0.3 and 1.0 mg/kg) produced dose-dependent decongestion. Unlike d-pseudoephedrine, compounds A and B did not alter systolic blood pressure. The plasma exposure of compound A to produce a robust decongestion (EC(80)) was 500 nM, which related well to the duration of action of approximately 4.0 hours. No tolerance to the decongestant effect of compound A (1.0 mg/kg p.o.) was observed. To study the topical efficacies of compounds A and B, the drugs were given topically 30 minutes after compound 48/80 (a therapeutic paradigm) where both agents reversed nasal congestion. Finally, nasal-decongestive activity was confirmed in the dog. We demonstrate that α2c-adrenergic agonists behave as nasal decongestants without cardiovascular actions in animal models of upper airway congestion.

Adolescent ecstasy use and depression: cause and effect, or two outcomes of home environment?

Background: This study assessed the association between adolescent ecstasy use and depressive symptoms in adolescence. Methods: The Belfast Youth Development Study surveyed a cohort annually from age 11 to 16 years. Gender, Strengths and Difficulties Questionnaire emotional subscale, living arrangements, parental affluence, parent and peer attachment, tobacco, alcohol, cannabis and ecstasy use were investigated as predictors of Short Mood and Feelings Questionnaire (SMFQ) outcome. Results: Of 5371 respondents, 301 (5.6%) had an SMFQ > 15, and 1620 (30.2) had missing data for SMFQ. Around 8% of the cohort had used ecstasy by the end of follow-up. Of the non-drug users, ∼2% showed symptoms of depression, compared with 6% of those who had used alcohol, 6% of cannabis users, 6% of ecstasy users and 7% of frequent ecstasy users. Without adjustment, ecstasy users showed around a 4-fold increased odds of depressive symptoms compared with non-drug users [odds ratio (OR) = 0.26; 95% confidence interval (CI) = 0.10, 0.68]. Further adjustment for living arrangements, peer and parental attachment attenuated the association to under a 3-fold increase (OR = 0.37; 95% CI = 0.15, 0.94). There were no differences by frequency of use. Conclusions: Ecstasy use during adolescence may be associated with poorer mental health; however, this association can be explained by the confounding social influence of family dynamics. These findings could be used to aid effective evidence-based drug policies, which concentrate criminal justice and public health resources on reducing harm.

Psychosocial aspects in cardiac rehabilitation: From theory to practice. A position paper from the Cardiac Rehabilitation Section of the European Association of Cardiovascular Prevention and Rehabilitation of the European Society of Cardiology

A large body of empirical research shows that psychosocial risk factors (PSRFs) such as low socio-economic status, social isolation, stress, type-D personality, depression and anxiety increase the risk of incident coronary heart disease (CHD) and also contribute to poorer health-related quality of life (HRQoL) and prognosis in patients with established CHD. PSRFs may also act as barriers to lifestyle changes and treatment adherence and may moderate the effects of cardiac rehabilitation (CR). Furthermore, there appears to be a bidirectional interaction between PSRFs and the cardiovascular system. Stress, anxiety and depression affect the cardiovascular system through immune, neuroendocrine and behavioural pathways. In turn, CHD and its associated treatments may lead to distress in patients, including anxiety and depression. In clinical practice, PSRFs can be assessed with single-item screening questions, standardised questionnaires, or structured clinical interviews. Psychotherapy and medication can be considered to alleviate any PSRF-related symptoms and to enhance HRQoL, but the evidence for a definite beneficial effect on cardiac endpoints is inconclusive. A multimodal behavioural intervention, integrating counselling for PSRFs and coping with illness should be included within comprehensive CR. Patients with clinically significant symptoms of distress should be referred for psychological counselling or psychologically focused interventions and/or psychopharmacological treatment. To conclude, the success of CR may critically depend on the interdependence of the body and mind and this interaction needs to be reflected through the assessment and management of PSRFs in line with robust scientific evidence, by trained staff, integrated within the core CR team.

Designing for dementia : an assessment of the impact of the physical environment on wayfinding success for residents in long term care settings

It is acknowledged that one of the consequences of the ageing process is cognitive decline, which leads to an increase in the incidence of illnesses such as dementia. This has become ever more relevant due to the projected increase in the ageing demographic. Dementia affects visuo-spatial perception, causing difficulty with wayfinding, even during the early stages of the disease. The literature widely recognises the physical environment’s role in alleviating symptoms of dementia and improving quality of life for residents. It also identifies the lack of available housing options for older people with dementia and consequently the current stock is ill-equipped to provide adequate support.
Recent statistics indicate that 80% of those residing in nursing or residential care homes have some form of dementia or severe memory problems. The shift towards institutional care settings, the need for specialist support and care, places a greater impetus on the need for a person-centred approach to tackle issues related to wayfinding and dementia.
This thesis therefore aims to improve design for dementia in nursing and residential care settings in the context of Northern Ireland. This will be undertaken in order to provide a better understanding of how people with dementia experience the physical environment and to highlight features of the design that assist with wayfinding. Currently there are limited guidelines on design for dementia, meaning that many of these are theoretical, anecdotal and not definitive. Hence a greater verification to address the less recognised design issues is required. This is intended to ultimately improve quality of life, wellbeing, independence and uphold the dignity of people with dementia living in nursing or residential care homes.
The research design uses a mixed methods approach. A thorough preparation and consideration of ethical issues informed the methodology. The various facets were also trialled and piloted to identify any ethical, technological, methodological, data collection and analysis issues. The protocol was then amended to improve or resolve any of the aforementioned issues. Initially a questionnaire based on leading design recommendations was conducted with home managers. Semi-structured interviews were developed from this and conducted with staff and resident’s next of kin. An evidence-based approach was used to design a study which used ethnographic methods, including a wayfinding task. This followed a repeated measures design which would be used to actively engage residents with dementia in the research. Complementary to the wayfinding task, conversational and semi-structured interviews were used to promote dialogue and direct responses with the person with dementia. In addition to this, Space Syntax methodologies were used to examine the physical properties of the architectural layout. This was then cross-examined with interview responses and data from the wayfinding tasks.
A number of plan typologies were identified and were determined as synonymous with decision point types which needed to be made during the walks. The empirical work enabled the synthesis of environmental features which support wayfinding.
Results indicate that particular environmental features are associated with improved performance on the wayfinding tasks. By enhancing design for dementia, through identifying the attributes, challenges with wayfinding may be overcome and the benefits of the physical environment can be seen to promote wellbeing.
The implications of this work mean that the environmental features which have been highlighted from the project can be used to inform guidelines, thus adding to existing knowledge. Future work would involve the dissemination of this information and the potential for it to be made into design standards or regulations which champion design for dementia. These would increase awareness for designers and stakeholders undertaking new projects, extensions or refurbishments.
A person-centred, evidence-based design was emphasised throughout the project which guaranteed an in-depth study. There were limitations due to the available resources, time and funding. Future research would involve testing the identified environmental features within a specific environment to enable measured observation of improvements.

“They should stay at their desk until the work’s done”: a qualitative study examining perceptions of sedentary behaviour in a desk-based occupational setting

Background: Workplace sedentary behaviour is a priority target for health promotion. However, little is known about how to effect change. We aimed to explore desk-based office workers’ perceptions of factors that influenced sedentary behaviour at work and to explore the feasibility of using a novel mobile phone application to track their behaviours.

Methods: We invited office employees (n = 12) and managers (n = 2) in a software engineering company to participate in semi-structured interviews to explore perceived barriers and facilitators affecting workplace sedentary behaviour. We assessed participants’ sedentary behaviours using an accelerometer before and after they used a mobile phone application to record their activities at self-selected time intervals daily for 2 weeks. Interviews were analysed using a thematic framework.

Results: Software engineers (5 employees; 2 managers) were interviewed; 13 tested the mobile phone application; 8 returned feedback. Major barriers to reducing workplace sedentary behaviour included the pressure of ‘getting the job done’, the nature of their work requiring sitting at a computer, personal preferences for the use of time at and after work, and a lack of facilities, such as a canteen, to encourage moving from their desks. Facilitators for reduced sedentariness included having a definite reason to leave their desks, social interaction and relief of physical and mental symptoms of prolonged sitting. The findings were similar for participants with different levels of overall physical activity. Valid accelerometer data were tracked for four participants: all reduced their sedentary behaviour. Participants stated that recording data using the phone application added to their day’s work but the extent to which individuals perceived this as a burden varied and was counter-balanced by its perceived value in increasing awareness of sedentary behaviour. Individuals expressed a wish for flexibility in its configuration.

Conclusions: These findings indicate that employers’ and employees’ perceptions of the cultural context and physical environment of their work, as well as personal factors, must be considered in attempting to effect changes that reduce workplace sedentary behaviour. Further research should investigate appropriate individually tailored approaches to this challenge, using a framework of behaviour change theory which takes account of specific work practices, preferences and settings.

Microplasma Processed Ultrathin Boron Nitride Nanosheets for Polymer Nanocomposites with Enhanced Thermal Transport Performance

This paper reports on the enhancement of the thermal transport properties of nanocomposite materials containing hexagonal boron nitride in poly (vinyl alcohol)through room-temperature atmospheric pressure direct-current microplasma processing. Results show that the microplasma treatment leads to exfoliation of the hexagonal boron nitride in isopropyl alcohol, reducing the number of stacks from >30to a few or single layers. The thermal diffusivity of the resulting nanocomposites reaches 8.5 mm2 s-1, 50 times greater than blank poly (vinyl alcohol) and twice that ofnanocomposites containing non-plasma treated boron nitride nanosheets. From TEM analysis, we observe much less aggregation of the nanosheets after plasma processing along with indications of an amorphous carbon interfacial layer which may contribute to stable dispersion of boron nitride nanosheets in the resulting plasma treated colloids.

What a girl's gotta do: the labor of the biopolitical celebrity in austerity Britain

This article debunks the widespread view that young female celebrities, especially those who rise to fame through reality shows and other forms of media-orchestrated self-exposure, dodge “real” work out of laziness, fatalism, and a misguided sense of entitlement. Instead, the authors argue that becoming a celebrity in a neoliberal economy such as that of the United Kingdom, where austerity measures disproportionately disadvantage the young, women, and the poor, is not as irregular or exceptional a choice as previously thought, especially since the precariousness of celebrity earning power adheres to the current demands of the neoliberal economy on its workforce. What is more, becoming a celebrity involves different forms of labor that are best described as biopolitical, since such labor fully involves and consumes the human body and its capacities as a living organism. Weight gain and weight loss, pregnancy, physical transformation through plastic surgery, physical symptoms of emotional distress, and even illness and death are all photographically documented and supplemented by extended textual commentary, usually with direct input from the celebrity, reinforcing and expanding on the visual content. As well as casting celebrity work as labor, the authors also maintain that the workings of celebrity should always be examined in the context of wider cultural, social and real economies.

Chronic symptoms after vestibular neuritis and the high velocity vestibulo-ocular reflex

Hypothesis: As the anterior and posterior semicircular canals are vital to the regulation of gaze stability, particularly during locomotion or vehicular travel, we tested whether the high velocity vestibulo‐ocular reflex (VOR) of the three ipsilesional semicircular canals elicited by the modified Head Impulse Test would correlate with subjective dizziness or vertigo scores after vestibular neuritis (VN). Background: Recovery following acute VN varies with around half reporting persistent symptoms long after the acute episode. However, an unanswered question is whether chronic symptoms are associated with impairment of the high velocity VOR of the anterior or posterior canals. Methods: Twenty patients who had experienced an acute episode of VN at least three months earlier were included in this study. Participants were assessed with the video head impulse test (vHIT) of all six canals, bithermal caloric irrigation, the Dizziness Handicap Inventory (DHI) and the Vertigo Symptoms Scale short‐form (VSS). Results: Of these 20 patients, 12 felt that they had recovered from the initial episode whereas 8 did not and reported elevated DHI and VSS scores. However, we found no correlation between DHI or VSS scores and the ipsilesional single or combined vHIT gain, vHIT gain asymmetry or caloric paresis. The high velocity VOR was not different between patients who felt they had recovered and patients who felt they had not. Conclusions: Our findings suggest that chronic symptoms of dizziness following VN are not associated with the high velocity VOR of the single or combined ipsilesional horizontal, anterior or posterior semicircular canals.

Absorption coefficient of particulate matter on the south-west coast of Europe: a contribution to the validation of the MERIS-Medium Resolution Imaging Spectrometer sensor

Dissolved oxygen (DO) is one of the most important environmental variables of water quality, especially for marine life. Consequently, oxygen is one of the Chemical Quality Elements required for the implementation of European Union Water Framework Directive. This study uses the example of the Ria Formosa, a meso-tidal lagoon on the south coast of Portugal to demonstrate how monitoring of water quality for coastal waters must be well designed to identify symptoms of episodic hypoxia. New data from the western end of the Ria Formosa were compared to values in a database of historical data and in the published literature to identify long-term trends. The dissolved oxygen concentration values in the database and in the literature were generally higher than those found in this study, where episodic hypoxia was observed during the summer. Analysis of the database showed that the discrepancy was probably related with the time and the sites where the samples had been collected, rather than a long-term trend. The most problematic situations were within the inner lagoon near the city of Faro, where episodic hypoxia (<2 mg dm3 DO) occurred regularly in the early morning. These results emphasise the need for a balanced sampling strategy for oxygen monitoring which includes all periods of the day and night, as well as a representative range of sites throughout the lagoon. Such a strategy would provide adequate data to apply management measures to reduce the risk of more persistent hypoxia that would impact on the ecological, important natural resource. economic and leisure uses of this important natural resource.