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Determining the chemical and structural modifications occurring within a protein during fundamental processes such as ligand or substrate binding is essential to building up a complete picture of biological function. Currently, significant unanswered questions relate to the way in which protein structural dynamics fit within the structure-function relationship and to the functional role, if any, of bound water molecules in the active site. Addressing these questions requires a multidisciplinary approach and complementary experimental techniques that, in combination, enhance our understanding of the complexities of protein chemistry. We exemplify this philosophy by applying both physical and biological approaches to investigate the active site chemistry that contributes to the inhibition of the Corynebacterium glutamicum catalase enzyme by nitric oxide. Ultrafast two-dimensional infrared spectroscopy (2D-IR) experiments exploit the NO ligand as a local probe of the active site molecular environment and shows that catalase displays a dynamically-restricted, 'tight,' structure. X-ray crystallography studies of C. glutamicum catalase confirm the presence of a conserved chain of hydrogen-bonded bound water molecules that link the NO ligand and the protein scaffold. This combination of bound water and restricted dynamics stands in stark contrast to other haem proteins, such as myoglobin, that exhibit ligand transport functionality despite the presence of a similar distal architecture in close proximity to the ligand. We conclude not only that the bound water molecules in the catalase active site play an important role in molecular recognition of NO but also may be part of the mechanistic operation of this important enzyme.

Background: Rapid access chest pain clinics have facilitated the early diagnosis and treatment of patients with coronary heart disease and angina. Despite this important service provision, coronary heart disease continues to be under-diagnosed and many patients are left untreated and at risk. Recent advances in imaging technology have now led to the widespread use of noninvasive computed tomography, which can be used to measure coronary artery calcium scores and perform coronary angiography in one examination. However, this technology has not been robustly evaluated in its application to the clinic., Methods/design: The SCOT-HEART study is an open parallel group prospective multicentre randomized controlled trial of 4,138 patients attending the rapid access chest pain clinic for evaluation of suspected cardiac chest pain. Following clinical consultation, participants will be approached and randomized 1:1 to receive standard care or standard care plus ≥64-multidetector computed tomography coronary angiography and coronary calcium score. Randomization will be conducted using a web-based system to ensure allocation concealment and will incorporate minimization. The primary endpoint of the study will be the proportion of patients diagnosed with angina pectoris secondary to coronary heart disease at 6 weeks. Secondary endpoints will include the assessment of subsequent symptoms, diagnosis, investigation and treatment. In addition, long-term health outcomes, safety endpoints, such as radiation dose, and health economic endpoints will be assessed. Assuming a clinic rate of 27.0% for the diagnosis of angina pectoris due to coronary heart disease, we will need to recruit 2,069 patients per group to detect an absolute increase of 4.0% in the rate of diagnosis at 80% power and a two-sided P value of 0.05. The SCOT-HEART study is currently recruiting participants and expects to report in 2014., Discussion: This is the first study to look at the implementation of computed tomography in the patient care pathway that is outcome focused. This study will have major implications for the management of patients with cardiovascular disease., Trial Registration: ClinicalTrials.gov Identifier: NCT01149590.

The ultrafast equilibrium fluctuations of the Fe(III)-NO complex of a single point mutation of Myoglobin (H64Q) have been studied using Fourier Transform 2D-IR spectroscopy. Comparison with data from wild type Myoglobin (wt-Mb) shows the presence of two conformational substates of the mutant haem pocket where only one exists in the wild type form. One of the substates of the mutant exhibits an almost identical NO stretching frequency and spectral diffusion dynamics to wt-Mb while the other is distinctly different in both respects. The remarkably contrasting dynamics are largely attributable to interactions between the NO ligand and a nearby distal side chain which provides a basis for understanding the roles of these side chains in other ferric haem proteins.

Objective: This study examined the role of time perspective in explaining inequalities in colorectal cancer screening attendance. We tested a path model predicting that (a) socioeconomic status (SES) would be associated with consideration of future consequences (CFC), (b) CFC would be associated with perceived benefits/barriers, and (c) barriers and benefits would be associated longitudinally with screening attendance., Method: Data for these analyses came from the control arm (n = 809) of an intervention to increase screening uptake. Participants between 55 and 64 years were offered screening as part of the U.K. Flexible Sigmoidoscopy (FS) Trial. They completed a questionnaire that included demographic and psychological variables. Subsequent screening attendance was recorded., Results: There was clear evidence of SES differences in attendance, with 56% in the most deprived tertile attending their FS appointment, compared with 68% in the middle tertile and 71% in the least deprived tertile (p < .01). Lower SES was associated with lower CFC, higher perceived barriers, and lower perceived benefits (p < .05 for all). Higher CFC, higher perceived benefits, and lower perceived barriers were associated with attendance (p < .01 for all). CFC mediated the association between SES and perceived benefits/barriers, while perceived benefits/barriers mediated the association between CFC and attendance., Conclusion: SES differences in CFC contribute to SES differences in the perceived barriers and benefits of screening, which, in turn, contribute to differences in attendance. Interventions that take CFC into account, for example, by emphasizing short-term benefits, could promote equality in screening participation., (PsycINFO Database Record (c) 2011 APA, all rights reserved.)

The toxic free radical NO (nitric oxide) has diverse biological roles in eukaryotes and bacteria, being involved in signalling, vasodilation, blood clotting and immunity, and as an intermediate in microbial denitrification. The predominant biological mechanism of detecting NO is through the formation of iron nitrosyl complexes, although this is a deleterious process for other iron-containing enzymes. We have previously applied techniques such as UV-visible and EPR spectroscopy to the analysis of protein Fe-NO complex formation in order to study how NO controls the activity of the bacterial transcriptional regulators NorR and NsrR. These studies have analysed NO-dependent biological activity both in vitro and in vivo using diverse biochemical, molecular and spectroscopic methods. Recently, we have applied ultrafast 2D-IR (two-dimensional IR) spectroscopy to the analysis of NO-protein interactions using Mb (myoglobin) and Cc (cytochrome c) as model haem proteins. The ultrafast fluctuations of Cc and Mb show marked differences, indicating altered flexibility of the haem pockets. We have extended this analysis to bacterial catalase enzymes that are known to play a role in the nitrosative stress response by detoxifying peroxynitrite. The first 2D-IR analysis of haem nitrosylation and perspectives for the future are discussed.

Doreen McCullough OBE, who has died aged 90, was one of Northern Ireland's best known and most successful nurses.

Background: Qualitative studies implicate knowledge of cancer symptoms and attitudes towards help-seeking as important factors in patient delay. The present study uses quantitative data from a population-based survey to test the hypotheses that (a) a greater knowledge of early cancer symptoms is associated with a higher likelihood of having appraised a symptom as possibly due to cancer, and (b) more negative attitudes towards help-seeking are associated with a lower likelihood of having sought medical advice for that symptom., Methods: Two thousand and seventy-one adults were asked whether they had experienced a symptom that they worried might be cancer in the past 3 months, and if so, whether they had seen a doctor. Respondents also completed the Cancer Awareness Measure (CAM) assessing symptom knowledge and barriers to help-seeking., Results: Two hundred and thirty-six (11.4%) respondents reported having experienced a possible cancer symptom. In logistic regression analyses controlling for age, sex, and self-rated health, higher CAM symptom knowledge scores were associated with a greater likelihood of having experienced a possible cancer symptom (odds ratio = 1.09; 95% confidence interval, 1.01-1.17). Of those who had experienced a symptom, 75% (177/236) had seen a doctor. Higher scores on the CAM barriers scale were associated with being less likely to have seen a doctor (odds ratio, 0.74; 95% confidence interval, 0.63-0.87)., Conclusions: Better knowledge of the signs and symptoms of cancer might help people recognize possible cancer symptoms and therefore reduce appraisal delay, whereas more positive attitudes towards help-seeking might reduce behavioral delay., Impact: Campaigns to educate the public about cancer symptoms and reduce help-seeking barriers could play a role in promoting early diagnosis., ((c)2010 AACR.)

Objective: This discussion document about the management of cancer pain is written from the pain specialists' perspective in order to provoke thought and interest in a multimodal approach to the management of cancer pain, not just towards the end of life, but pain at diagnosis, as a consequence of cancer therapies, and in cancer survivors. It relates the science of pain to the clinical setting and explains the role of psychological, physical, interventional and complementary therapies in cancer pain., Methods: This document has been produced by a consensus group of relevant healthcare professionals in the United Kingdom and patients' representatives making reference to the current body of evidence relating to cancer pain. In the second of two parts, physical, invasive and complementary cancer pain therapies; treatment in the community; acute, treatment-related and complex cancer pain are considered., Conclusions: It is recognized that the World Health Organization (WHO) analgesic ladder, whilst providing relief of cancer pain towards the end of life for many sufferers world-wide, may have limitations in the context of longer survival and increasing disease complexity. To complement this, it is suggested that a more comprehensive model of managing cancer pain is needed that is mechanism-based and multimodal, using combination therapies including interventions where appropriate, tailored to the needs of an individual, with the aim to optimize pain relief with minimization of adverse effects.

Objective: This discussion document about the management of cancer pain is written from the pain specialists' perspective in order to provoke thought and interest in a multimodal approach to the management of cancer pain, not just towards the end of life, but pain at diagnosis, as a consequence of cancer therapies, and in cancer survivors. It relates the science of pain to the clinical setting and explains the role of psychological, physical, interventional and complementary therapies in cancer pain., Methods: This document has been produced by a consensus group of relevant health care professionals in the United Kingdom and patients' representatives making reference to the current body of evidence relating to cancer pain. In the first of two parts, pathophysiology, oncological, pharmacological, and psychological treatment are considered., Conclusions: It is recognized that the World Health Organization (WHO) analgesic ladder, while providing relief of cancer pain towards the end of life for many sufferers worldwide, may have limitations in the context of longer survival and increasing disease complexity. To complement this, it is suggested that a more comprehensive model of managing cancer pain is needed that is mechanism-based and multimodal, using combination therapies including interventions where appropriate, tailored to the needs of an individual, with the aim to optimize pain relief with minimization of adverse effects.

Objective: The aim of the study was to examine awareness of the three National Cancer Screening Programmes (breast, cervical, bowel) among white and ethnic minority groups in the UK., Setting: Data were from two surveys in which the screening questions were added: (i) the Office of National Statistics (ONS) Opinions Survey, carried out in September and October 2008; and (ii) the Ethnibus™ survey of the main ethnic minority groups in England, conducted in October and November 2008., Methods: The ONS sample consisted of 2216 adults selected using stratified probability sampling to obtain a population-representative sample. The Ethnibus™ sample was obtained by quota sampling and included 1500 adults from the six largest ethnic minority groups in England (Indian, Pakistani, Bangladeshi, Caribbean, African and Chinese). Participants completed questions on awareness of cancer screening programmes as part of the wider Cancer Awareness Measure (CAM) in home-based, face-to-face interviews., Results: Awareness of breast and cervical cancer screening was high in the white ONS participants (89% breast and 84% cervical), lower in the ONS ethnic minority sample (74% for both breast and cervical) and lowest in the Ethnibus™ sample (69% breast and 66% cervical). Ethnic disparities persisted after controlling for age, gender and occupational group. In both groups, knowledge of breast and cervical screening was lower among men and more socioeconomically deprived groups. Awareness of the new bowel cancer screening programme was less than 30% in both white and ethnic minority groups., Conclusions: Ethnic disparities in knowledge of breast and cervical cancer screening should be addressed. Strategies to engage ethnic minority and socioeconomically deprived groups in bowel cancer screening should be instigated to avoid the emergence of disparities.

Objective: The aim of this study was is to examine uptake of population-based, flexible sigmoidoscopy (FS) screening delivered by nurses in a socioeconomically and ethnically diverse area of London, England., Methods: All adults aged 58 and 59 years registered at 34 general practices in North London (n = 2260) were mailed an invitation to attend FS screening at the local hospital., Results: In total, 45% (1024/2260) accepted the invitation and attended, 5% (114/2260) accepted the invitation but failed to attend, 5% (111/2260) accepted the invitation but were unable to attend within the time-frame of the pilot study, 7% (165/2260) declined the offer, 27% (602/2260) did not respond, and 11% (244/2260) were ineligible or did not receive the invitation. Among those eligible to be screened, the uptake rate was 51% (1024/2016). Uptake did not differ by gender, but people living in the most affluent quintile of areas had a substantially higher uptake rate (63%) than those living in the most deprived quintile (38%)., Conclusion: Uptake of FS screening delivered as a population-based programme was over 50% among the eligible population in a socioeconomically and ethnically diverse area of London. Disparities in uptake should be addressed to avoid exacerbating health inequalities.

ROBB K. & EWER-SMITH C. (2010) European Journal of Cancer Care19, 5 The role of therapies in managing cancer-related pain Cancer pain is complex and multi-dimensional and requires a multi-disciplinary team approach. Therapists have an important role in the assessment and management of patients with cancer-related pain, but the challenge remains to practise in an evidence-based way.

Background: Low cancer awareness contributes to delay in presentation for cancer symptoms and may lead to delay in cancer diagnosis. The aim of this study was to review the evidence for the effectiveness of interventions to raise cancer awareness and promote early presentation in cancer to inform policy and future research., Methods: We searched bibliographic databases and reference lists for randomised controlled trials of interventions delivered to individuals, and controlled or uncontrolled studies of interventions delivered to communities., Results: We found some evidence that interventions delivered to individuals modestly increase cancer awareness in the short term and insufficient evidence that they promote early presentation. We found limited evidence that public education campaigns reduce stage at presentation of breast cancer, malignant melanoma and retinoblastoma., Conclusions: Interventions delivered to individuals may increase cancer awareness. Interventions delivered to communities may promote cancer awareness and early presentation, although the evidence is limited.

Objective: To assess public awareness of cancer warning signs, anticipated delay and perceived barriers to seeking medical advice in the British population., Methods: We carried out a population-based survey using face-to-face, computer-assisted interviews to administer the cancer awareness measure (CAM), a newly developed, validated measure of cancer awareness. The sample included 2216 adults (970 males and 1246 females) recruited as part of the Office for National Statistics Opinions Survey using stratified probability sampling., Results: Awareness of cancer warning signs was low when open-ended (recall) questions were used and higher with closed (recognition) questions; but on either measure, awareness was lower in those who were male, younger, and from lower socio-economic status (SES) groups or ethnic minorities. The most commonly endorsed barriers to help seeking were difficulty making an appointment, worry about wasting the doctor's time and worry about what would be found. Emotional barriers were more prominent in lower SES groups and practical barriers (e.g. too busy) more prominent in higher SES groups. Anticipated delay was lower in ethnic minority and lower SES groups. In multivariate analysis, higher symptom awareness was associated with lower anticipated delay, and more barriers with greater anticipated delay., Conclusions: A combination of public education about symptoms and empowerment to seek medical advice, as well as support at primary care level, could enhance early presentation and improve cancer outcomes.

Objective: Little is known about ethnic differences in awareness of cancer-warning signs or help-seeking behaviour in Britain. As part of the National Awareness and Early Diagnosis Initiative (NAEDI), this study aimed to explore these factors as possible contributors to delay in cancer diagnosis., Methods: We used quota sampling to recruit 1500 men and women from the six largest minority ethnic groups in England (Indian, Pakistani, Bangladeshi, Caribbean, African and Chinese). In face-to-face interviews, participants completed the newly developed cancer awareness measure (CAM), which includes questions about warning signs for cancer, speed of consultation for possible cancer symptoms and barriers to help seeking., Results: Awareness of warning signs was low across all ethnic groups, especially using the open-ended (recall) question format, with lowest awareness in the African group. Women identified more emotional barriers and men more practical barriers to help seeking, with considerable ethnic variation. Anticipated delay in help seeking was higher in individuals who identified fewer warning signs and more barriers., Conclusions: The study suggests the need for culturally sensitive, community-based interventions to raise awareness and encourage early presentation.

Objective: We aimed to develop and validate a measurement tool to assess cancer awareness in the general population: the cancer awareness measure (CAM)., Methods: Items assessing awareness of cancer warning signs, risk factors, incidence, screening programmes and attitudes towards help seeking were extracted from the literature or generated by expert groups. To determine reliability, the CAM was administered to a university participant panel (n=148), with a sub-sample (n=94) completing it again 2 weeks later. To establish construct validity, CAM scores of cancer experts (n=12) were compared with those of non-medical academics (n=21). Finally, university students (n=49) were randomly assigned to read either a cancer information leaflet or a leaflet with control information before completing the measure, to ensure the CAM was sensitive to change., Results: Cognitive interviewing indicated that the CAM was being interpreted as intended. Internal reliability (Cronbach's alpha=0.77) and test-retest reliability (r=0.81) were high. Scores for cancer experts were significantly higher than those for non-medical academics (t(31)=6.8, P<0.001). CAM scores were higher among students who received an intervention leaflet than the control leaflet (t(47)=4.8, P<0.001)., Conclusions: These studies show the psychometric properties of the CAM and support its validity as a measure of cancer awareness in the general population.

Colorectal cancer (CRC) accounts for 9% of all new cancer cases worldwide and affects over 1 million people each year. Screening can reduce the mortality associated with the disease, yet participation rates are suboptimal. Compliers with CRC screening are less deprived; they have higher education than noncompliers and tend to be male, white and married. Likely reasons for nonparticipation encompass several 'modifiable' factors that could be targeted in interventions aimed at increasing participation rates. Successful intervention strategies include organizational changes, such as increasing access to fecal occult blood test (FOBT) kits, providing reminders to healthcare providers or users about screening opportunities, and educational strategies to improve awareness and attitudes towards CRC screening. Multifactor interventions that target more than one level of the screening process are likely to have larger effects. The biggest challenge for future research will be to reduce inequalities related to socio-economic position and ethnicity in the uptake of screening.

Cancer-related pain is complex and multi-dimensional; yet, the mainstay of cancer pain management has been the biomedical approach. There is a need for nonpharmacological and innovative pain management strategies. Transcutaneous electrical nerve stimulation (TENS) may have a role. The aim of this systematic review was to determine the effectiveness of TENS for cancer-related pain in adults. The Cochrane Library, MEDLINE, EMBASE, CINAHL, PsychINFO, AMED, and PEDro databases were searched for randomized controlled trials (RCTs) investigating the use of TENS for the management of cancer-related pain in adults. Once relevant studies were identified, two pairs of reviewers assessed eligibility for inclusion in the review based on a study eligibility form and using the 5-point Oxford Quality Scale. Two RCTs met the study eligibility criteria (these involved 64 patients). These studies were heterogeneous with respect to study population, methodology, and outcome measures. This prevented meta-analysis. In one RCT, there were no significant differences between TENS and placebo in women with chronic pain secondary to breast cancer treatment. In the other RCT, there were no significant differences between acupuncture-like TENS (AL-TENS) and sham in palliative care patients; this study was significantly underpowered. There is insufficient available evidence to determine the effectiveness of TENS in treating cancer-related pain. Further research is needed to help guide clinical practice, and large multi-center RCTs are required to assess the value of TENS in the management of cancer-related pain in adults.

A randomized trial of in-home psychotherapy for depressive symptoms that targeted low-income mothers of infants and toddlers used innovative design features to reduce stigma and enhance acceptability. Despite these features, advanced practice psychiatric mental health nurses used specialized, relationship-based strategies to engage and retain these high-risk mothers in the intervention. Data revealed that the nurses needed to diligently maintain contact, provide encouragement, use empathy for rapid assessment and response, and control the intensity of the relationship-based contacts in order to retain mothers.

Study Objective: To examine the completion rate, internal reliability, and external validity of a home affluence scale based on adolescents' reports of material circumstances in the home as a measure of family socioeconomic status., Design: Cross sectional survey., Setting: Data were collected from a school based study in seven schools in the north of England Cheshire over a five month period from September 1999 to January 2000., Participants: 1824 students (1248 girls, 567 boys) aged 13-15 years who were attending normal classes in Years 9 and 10 in 7 schools on the days of data collection., Main Results: Comparatively poor completion rates were found for questions on parental education and occupation while material deprivation items had much higher completion rates. There was evidence that students with poorer material circumstances were less able to report parental education and occupation whereas material based questions showed less bias. A home affluence scale composed of material items was found to have adequate internal reliability and good external validity., Conclusions: A home affluence scale based on material markers provides a useful alternative in assessing family affluence in adolescents. Additionally, it prevents exclusion of those less materially well off adolescents who fail to complete conventional socioeconomic status items.

Our objective was to review the available evidence of the precision and accuracy of the clinical examination for abnormal systolic murmurs. We conducted a MEDLINE search, manually reviewed all reference lists, and contacted authors of published studies. Each study was independently reviewed by 2 observers and graded for methodologic quality. We found that most studies were conducted using cardiologist examiners. In the clinical setting, the reliability of detecting systolic murmurs was fair (kappa, 0.30-0.48). The most useful findings for ruling in aortic stenosis are a slow rate of rise of the carotid pulse (positive likelihood ratio, 2.8-130), mid to late peak intensity of the murmur (positive likelihood ratio, 8.0-101), and decreased intensity of the second heart sound (positive likelihood ratio, 3.1-50). The most useful finding for ruling out aortic stenosis is the absence of murmur radiation to the right carotid artery (negative likelihood ratio, 0.05-0.10). Smaller, lower-quality studies indicate that cardiologists can accurately rule in and rule out mitral regurgitation, tricuspid regurgitation, hypertrophic cardiomyopathy, and echocardiographic mitral valve prolapse. We conclude that the clinical examination by cardiologists is accurate for detecting various causes of abnormal systolic murmurs. Studies of the clinical examination by noncardiologists are needed.

Functional electrical stimulation (FES) may improve recovery after stroke. We studied its effects in 38 postcerebral infarct patients. Twenty were randomly assigned to receive FES producing ankle dorsiflexion on the affected side and physical therapy. The remaining 18 received physical therapy only. Subjects were evaluated prior to commencing therapy, at its completion after 4 weeks, and again 4 weeks later using functional and electrophysiological measures. Functional deficit in most patients improved (p < 0.01). Although no significant differences were observed when those treated with FES and those not treated were compared at 4 and 8 weeks, there was significant improvement in the rate of recovery using an ambulation score (p < 0.05), and there was a similar trend in the Barthel Index for FES-treated patients (p < 0.1). Our results indicate that FES may confer additional benefit in acute stroke rehabilitation. Further studies are needed to delineate how best to use it., (Copyright © 1994 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

The alien hand syndrome has been associated with different descriptions of abnormal motor behavior. We report on two patients with transient left hemiparesis who remained with limb apraxia and were particularly impaired by a variety of involuntary skilled movements of their apractic limb. After the report and a review of the literature, we discuss the presence of one type of abnormal movement observed in this syndrome. These movements resemble the mirror movements seen in the normal development of motor control and in some pathologic conditions later. Their appearance in the alien hand syndrome seems to demand both intrahemispheric and interhemispheric motor pathway damage.

The clinical clerkship in Canadian Medical Schools is intended to provide senior medical students with opportunities to gain practical knowledge of clinical medicine, develop technical skills, learn to use judgement and experience first-hand clinical decision making. Assessment of rotations in internal medicine were undertaken in order to understand more fully the nature of medical clerkship experiences. We found that medical clerks in our programme were exposed to a high proportion of undifferentiated problems and an adequate case mix. They performed a wide range of technical procedures. There were, however, certain gaps in the clerks' experiences both in the specialty areas, and in therapeutic and technical procedures. Recognition of these gaps in the clerkship experiences suggest that further deliberation of goals and objectives is required and issues of achievement of competencies need to be addressed.