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Objective: In older adults, widespread pain (WP) is common, although its etiology is unclear. This study sought to identify factors associated with an increased risk of developing WP in adults age ≥50 years., Methods: A population-based prospective study was conducted. A baseline questionnaire was administered to subjects to collect data on pain, psychological status, lifestyle and health behaviors, and sociodemographic and clinical factors. Participants free of WP (as defined by the American College of Rheumatology 1990 criteria for fibromyalgia) were followed up for 3 years, and those with new-onset WP at followup were identified. Logistic regression analyses were used to test the relationship between baseline factors and new-onset WP. Multiple imputation was used to test the results for sensitivity to missing data., Results: In this population-based study, 4,326 subjects (1,562 reporting no pain at baseline and 2,764 reporting some pain at baseline) participated at followup. Of these participants, 800 (18.5%) reported a status of new WP at followup (of whom, 121 [7.7%] had reported no pain at baseline and 679 [24.6%] had reported some pain at baseline). The majority of the study factors were associated with new-onset WP. However, only a few factors showed a persistent association with new-onset WP in the multivariate analysis, including age (odds ratio [OR] 0.97, 95% confidence interval [95% CI] 0.96-0.99), baseline pain status (OR 1.1, 95% CI 1.08-1.2), anxiety (OR 1.5, 95% CI 1.01-2.1), physical health-related quality of life (OR 1.3, 95% CI 1.1-1.5), cognitive complaint (OR 1.3, 95% CI 1.04-1.6), and nonrestorative sleep (OR 1.9, 95% CI 1.2-2.8). These associations persisted after adjustment for the presence of diffuse osteoarthritis (OA), which led to a modest increase in model fit (C-statistic 0.738, compared with 0.731 in the model excluding diffuse OA). The results were not sensitive to missing data., Conclusion: Of the factors measured in this study, nonrestorative sleep was the strongest independent predictor of new-onset WP., (© 2014 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

Objectives: To assess the consultation prevalence of musculoskeletal (MSK) conditions as presented in different healthcare systems, and to determine the feasibility of comparing prevalence figures between nations., Methods: The settings were an English regional database (Consultations in Primary Care Archive (CiPCA)) and the Swedish Skåne County Health Care Register. Case definitions, data extraction and analysis procedures were harmonised. The number of people consulting per 10 000 registered population in primary care, and in primary or secondary care, in the year 2010 (annual consultation prevalence) were determined for doctor-diagnosed osteoarthritis (OA), rheumatoid arthritis (RA), low back pain, and spondyloarthritis including psoriatic arthritis and ankylosing spondylitis (AS). Seven-year period consultation prevalences were also determined., Results: Combining primary and secondary care, annual consultation prevalences of any MSK condition (2143 vs 1610/10 000) and low back pain (587 vs 294/10 000) were higher in England than in Sweden, but higher for RA, spondyloarthritis and psoriatic arthritis in Sweden. Annual primary care prevalence figures for OA (176 vs 196/10 000), RA (25 vs 26/10 000), spondyloarthritis (both 8/10 000) and psoriatic arthritis (5 vs 3/10 000) were similar between England and Sweden. AS was rarely recorded in Swedish primary care. These patterns were also observed for 7-year period consultation prevalences., Conclusions: A rigorous methodological approach allowed feasible comparison of MSK consultation prevalence between England and Sweden. Differences in prevalence of inflammatory and unspecific pain conditions may be partially explained by known variations in healthcare systems and recording practice. Routine healthcare data offers potential for investigating variations in occurrence and outcome of MSK conditions between nations.

Objective: The Keele Assessment of Participation (KAP) questionnaire measures person-perceived participation in 11 aspects of life. Participation allows fulfilment of valued life activities and social roles, which are important to older adults. Since we aimed to use the KAP in a larger Dutch cohort, we examined the measurement properties of KAP in a Dutch sample of older adults with joint pain and comorbidity., Design: Cohort study., Setting: A community-based sample in Amsterdam, the Netherlands and North Staffordshire, UK., Participants: Participants were aged 65 years and over, had at least two chronic diseases (identified through general practice consultation) and reported joint pain on most days (questionnaire). The Dutch cohort provided baseline data (n=407), follow-up data at 6 months (n=364) and test-retest data 2 weeks after 6 months (n=122). The UK cohort provided comparable data (n=404)., Outcome Measures: The primary outcome was person-perceived participation, as measured with the KAP. The measurement properties examined were the following: structural validity (factor analysis), internal consistency (Cronbach's α), reliability (intraclass correlation coefficients; ICC), construct validity (hypothesis testing), responsiveness (hypothesis testing and area under the curve) and cross-cultural validity (differential item functioning; DIF)., Results: Factor analysis revealed two domains: KAPd1: 'participation in basic activities' and KAPd2: 'participation in complex activities', with Cronbach's α of 0.74 and 0.57 and moderate test-retest reliability: ICC of 0.63 and 0.57, respectively. Further analyses of KAPd1 showed poor construct validity and responsiveness. Despite the uniform DIF in item 'interpersonal relations', the total KAPd1 score seemed comparable between the Dutch and UK sample., Conclusions: Only KAP domain 'participation in basic activities' showed good internal consistency and sufficient reliability. KAPd2 lacks sufficient measurement properties for application in studies, although items may be used as single items. Further development of the concept 'participation' may help the development and validation of instruments to measure participation.

Purpose: To examine individual and area-level socioeconomic factors that predict the onset of work restriction in employed persons with lower limb joint pain., Methods: Population-based prospective cohort study. Adults were aged 50-59, reported hip, knee, foot pain or a combination and maintained employment through 3 year follow-up (n = 716). Work restriction was measured as inability to participate in work as desired. Multi-level logistic regression was used to assess the associations of work restriction onset with baseline factors: health (severity of knee pain/functional limitation, comorbidity, anxiety, depression, cognitive impairment, abnormal weight), demographic socio-economic, environment and area-level employment deprivation., Results: 108 (15.1 %) reported the onset of work restriction over 3 years. Severe lower limb joint pain and functional limitation, number of affected body sites and area employment deprivation were independently associated with onset. Significant interactions indicated a greater effect of area employment deprivation on older and more depressed workers., Conclusions: Results suggest that effectively preventing work disability in those with OA will require both condition-specific interventions to decrease pain and maintain function, and providing alternative employment opportunities for those with progressive functional limitations. Results in older workers are particularly concerning, as retirement ages are expected to increase in the general population.

Objective: To determine why multimorbidity causes participation restriction in adults ages ≥50 years who consult primary care with lower extremity osteoarthritis (OA)., Methods: This was a population-based prospective cohort study of 1,053 consulters for lower extremity OA who were free of participation restriction at baseline. Path analysis was used to test proposed mechanisms by examining for mediation of the association between multimorbidity at baseline, defined by self-report and consultation data separately, and incident participation restriction at 3 years by lower extremity pain severity, obesity, locomotor disability, and depression., Results: Multimorbidity was associated with incident participation restriction (adjusted odds ratio [OR] 2.83, 95% confidence interval [95% CI] 2.03-3.94 for multimorbidity [self-report]; OR 1.59, 95% CI 1.15-2.21 for multimorbidity [consultation data]). The extent of mediation of the association of baseline multimorbidity, defined by self-report, and incident participation restriction was greater for severe lower extremity pain than obesity (standardized beta coefficients for indirect effect 0.032 [SE 0.015] and 0.020 [SE 0.019], respectively). The addition of depression and locomotor disability increased the amount of mediation (0.115 [SE 0.028]) and reduced the proportion explained by severe lower extremity pain (0.014 [SE 0.015]) and obesity (0.006 [SE 0.010]). Locomotor disability was the strongest mediator., Conclusion: The additional impact on participation in social and domestic life that multimorbidity places on individuals with lower extremity OA appears to be mediated through further restriction of locomotor disability, as well as through depression. The results suggest that the effect of multimorbidity on the daily lives of people with lower extremity OA will be ameliorated by active management of depression and locomotor disability., (Copyright © 2013 by the American College of Rheumatology.)

Objective: Chronic musculoskeletal pain is common in older adults but the nature of its relationship with ageing is unclear. The objective for this study was to test the hypothesis that the onset of widespread pain would be associated with a decrease in healthy ageing., Methods: Population-based prospective cohort study. A "healthy ageing" index was constructed across biomedical, physical, psychosocial and lay components. Analysis was performed with 2949 adults aged 50 years and over who had complete index scores at baseline, 3 and 6-year follow-ups., Results: At three and six year follow-up, 365 (16.8%) and 259 (14.3%) experienced the onset of widespread pain. The onset of widespread pain during the six-year period was associated with a 25% and a 46% decrease in healthy ageing index scores; this decrease was independent of age, sex, education, social networks, smoking status, alcohol consumption and physical inactivity. The decrease in healthy ageing attenuated to 20% and 39% following adjustment for diagnosed musculoskeletal conditions and analgesic and non-steroidal use., Conclusions: The onset of widespread pain was associated with a decrease in healthy ageing throughout the six-year period. When pain increased over time, the markers of unhealthy ageing increased also. Strong analgesia was associated with unhealthy ageing. Research could now usefully test whether early identification, improved treatment and prevention of pain prior to old age may facilitate healthy ageing.

The impact of musculoskeletal disorders on work is demanding more attention from clinicians. For many rheumatologists, inflammatory arthritis is the most frequently encountered condition that interferes with work. However, the cumulative burden of non-inflammatory arthropathies and disorders such as back pain, osteoarthritis and limb pain as a whole results in a much greater economic and human cost to society than inflammatory disease. New conceptual approaches and research results support the view that work loss does not need to be a frequent consequence of a musculoskeletal disorder or disability. This is often accomplished through a biopsychosocial and interdisciplinary approach, involving interaction between those with a musculoskeletal condition, their clinicians and employers. This review outlines the challenges and draws on the results of empirical studies to highlight potential opportunities to promote sustained ability for patients to successfully remain on the job. It also outlines future research opportunities., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The transcription factors Nanog and Oct4 regulate pluripotency in the pre-implantation epiblast and in derivative embryonic stem cells. During post-implantation development, the precise timing and mechanism of the loss of pluripotency is unknown. Here, we show that in the mouse, pluripotency is extinguished at the onset of somitogenesis, coincident with reduced expression and chromatin accessibility of Oct4 and Nanog regulatory regions. Prior to somitogenesis expression of both Nanog and Oct4 is regionalized. We show that pluripotency tracks the in vivo level of Oct4 and not Nanog by assessing the ability to reactivate or maintain Nanog expression in cell culture. Enforced Oct4 expression in somitogenesis-stage tissue provokes rapid reopening of Oct4 and Nanog chromatin, Nanog re-expression and resuscitates moribund pluripotency. Our data suggest that decreasing Oct4 expression is converted to a sudden drop in competence to maintain pluripotency gene regulatory network activity that is subsequently stabilized by epigenetic locks.

Purpose:  Job lock, one form of restricted job mobility that often prevents older workers from retiring, is linked to existing health and work place problems. This study explored (i) the rate of change in work limitation for job locked and non-job locked older workers and (ii) the factors associated with these changes over a 12-month period following a work injury., Methods:  Prospective observational cohort study of adults aged  ≥55 years. Data were collected using self-completed questionnaires. Individual growth modelling was used to examine the pre- and post- injury influences on work limitation., Results: Work limitation was greater in the job locked older workers pre-injury. Both job-locked and non-job locked respondents had initial post-injury decreases in work limitations, suggesting a positive impact of temporary post-injury accommodations. However, both groups had increases in work limitations over time, but the increases were greater in the non-job locked group. In those with job lock, return to work problems were associated with increases in work limitations; in those without job lock, greater increases were associated only with low education., Conclusions: These results suggest that job accommodations may be important in moderating increasing work limitation in job-locked older workers. Results support prior findings that job-locked older workers have unique characteristics, perhaps requiring more tailored interventions to maintain them in the workforce.

Mice deficient in the runt homology domain transcription factor Runx1/AML1 fail to generate functional clonogenic hematopoietic cells and die in utero by embryonic day 12.5. We previously generated Runx1 reversible knockout mice, in which the Runx1 locus can be restored by Cre-mediated recombination. We show here that selective restoration of the Runx1 locus in the Tie2 cell compartment rescues clonogenic hematopoietic progenitors in early Runx1-null embryos and rescues lymphoid and myeloid lineages during fetal development. Furthermore, fetal liver cells isolated from reactivated Runx1 embryos are capable of long-term multilineage lymphomyeloid reconstitution of adult irradiated recipients, demonstrating the rescue of definitive hematopoietic stem cells. However, this rescue of the definitive hematopoietic hierarchy is not sufficient to rescue the viability of animals beyond birth, pointing to an essential role for Runx1 in other vital developmental processes.

Background: Participation restriction is defined as "problems an individual may experience in involvement in life situations" and refers to the personal and societal consequences of health conditions. There is a growing interest in participation restriction because (i) problems with work or looking after others may be more concerning to individuals than the signs and symptoms of health conditions and (ii) even when poor health persists, participation may still be maintained. The natural history of participation restriction in the general population is unknown and the aim of this report is to describe change in status of person-perceived participation restriction over three years in community-dwelling adults aged 50 years and over., Method: Prospective cohort study (baseline and 3-year follow-up) using postal questionnaires mailed to a population-based sample of older adults. Responders were included in this study if they completed all items of the Keele Assessment of Participation at baseline (n = 6965). Estimates of onset and persistence of person-perceived participation restriction at 3-year follow-up were calculated for any and for each aspect of life in the sample as a whole, and then by age and gender using attrition re-weighted logistic regression to take account of sample attrition., Results: In the whole sample of 6965 persons, overall participation status at three years was unchanged in 69%, and changed in 31%. Of 3431 persons with no restriction at baseline, it is estimated that 29.8% (95% confidence interval: 27.6%, 32.0%) would report restriction in at least one aspect of life at 3-year follow-up. Of 3534 persons who had baseline restriction, it is estimated that 68.8% (66.2%, 71.3%) would report continuing restriction in at least one aspect of life after 3 years. Onset and persistence both increased with age, and were most frequently recorded for restricted mobility outside the home., Conclusion: Although most older persons do not change their overall participation status during a three-year period, change does occur which implies that population approaches to improving participation can be sought. Both onset and persistence of person-perceived participation restriction are more common the older the age-group.

Pain is common in adult life, and the extent to which pain interferes with daily activities rises with age. Little is known about the social factors associated with disabling pain. The objective was to determine the individual and neighbourhood social factors that predict pain that interferes with daily activities. This was a prospective cohort study set within the North Staffordshire Osteoarthritis Project (NorStOP). People aged 50 and over registered with six general practices were sent baseline and 3-year questionnaires. Individual predictors of the onset of pain interference were determined through multilevel modelling. Neighbourhood impact was examined using measures of deprivation taken from the UK Index of Multiple Deprivation 2004. 19% of the 3644 people without pain interference at baseline reported it at follow-up. Baseline social factors were weaker predictors than baseline age, multiple-site pain and anxiety or depression. However, perceived financial strain was a significant predictor (OR 1.5; 95% CI: 1.2, 1.8). Onset of pain interference varied by local area deprivation status. Those living in areas of high health deprivation had an increased risk of developing pain interference (OR 1.6; 95% CI: 1.1, 2.3). Whilst the onset of pain which disrupts daily life is influenced mainly by the characteristics of the pain and by the psychological factors, there are links with the social factors, particularly individual measures of perceived income adequacy. The onset of disabling pain is also influenced by the place where one lives. Policies to prevent disabling pain need to consider the contribution of neighbourhood deprivation and income inequalities to the extent of the problem.

Mobility limitation is the most common disability in the general population, and pain is a frequent symptom at older ages. We have investigated the association of different patterns of pain and mobility limitation in a large sample of older adults. A cross-sectional postal survey of all adults aged 50 years and over registered with eight general practices in North Staffordshire, UK, resulted in 18,497 respondents (adjusted response=70.8%). Information on demographics, recent pain and the self-reported level of mobility limitation was collected. Associations between pain and mobility limitation were assessed using a partial proportional odds model, taking into account age, gender and socio-economic status. Limitation in walking 100 yards was reported by 29% of respondents. Limitation increased sharply with age, and was higher in the female and lower socio-economic groups. Persons reporting pain were significantly more likely to report limitation. The relationship between mobility limitation and pain was stronger in the youngest age group, but proportionally more people in the oldest age groups have mobility limitation associated with pain. Lower limb and multiple pains present a potential target for the prevention of mobility limitation up to the oldest age groups.

In the World Health Organization's International Classification of Functioning, Disability and Health, participation restriction--the social and personal consequences of health conditions and their environment--is an important component of the concept of disability. The cross-sectional associations between perceived participation restriction and health, demographic and socio-economic factors were examined in 7,878 community-dwelling adults aged 50 years and over in North Staffordshire, UK who responded to a postal survey. All health conditions, impairments, activity limitations, demographic and socio-economic factors were associated with participation restriction, after adjusting for age and gender in a logistic regression analysis. Health and disability factors most strongly and independently associated with participation restriction in a multivariate analysis were the number of peripheral joint pains, the number of health conditions, cognitive impairment, anxiety, depression, and activity limitation. Perceived adequacy of income, employment status and occupational class were also significantly associated with participation restriction after adjusting for health and disability factors. In conclusion, perceived participation restriction is associated with a range of health and socio-economic factors. Although further prospective research is needed to identify the direction of causal association, these factors represent potential targets for intervention to prevent or reduce participation restriction in older adults in the community.

Pain that interferes with daily life appears to be strongly age-related in cross-sectional studies, although the nature of this relationship over time has not been established. We have investigated the onset and persistence of pain and pain interference over a 3-year period to determine their association with age in older people. A 3-year follow-up postal survey was conducted of adults aged 50 years and over (n=5366) who had previously been recruited as part of the North Staffordshire Osteoarthritis Project. Four thousand two-hundred and thirty-four completed questionnaires were received (adjusted response 84.7%). The occurrence of pain interference at 3 years was 19.7% in persons free of such pain at baseline, higher in females than males (6.0% difference; 95% CI: 2.6%, 9.3%), and showed a clear age-related trend with a more than twofold increase from 50 to 59 years (16.0%) to the 80+ years (35%). Any pain at follow-up was reported by 48% of those pain-free at recruitment, and this figure was similar for males and females, and across 10-year age-groups. Persistence of pain interference (72.1%) at 3 years was high. In adults aged 50 years and over, the onset of pain that interferes with life shows a clear gender difference and a consistent rise with age into the oldest age-group. This was in strong contrast to the onset of pain which showed no gender or age-related trends. The implications for public health, as for the treatment of the individual, are twofold, relating to efforts to prevent disabling pain from occurring and to understand the factors that accelerate the impact which pain has on everyday life when people reach the oldest ages.

Objective: To estimate the prevalence, nature and distribution of person-perceived participation restriction, in community-dwelling older adults., Method: Population based cross-sectional postal survey of 11,055 adults aged 50 years and over in North Staffordshire, United Kingdom. Person-perceived participation restriction was measured using the Keele Assessment of Participation which covers 11 different aspects of life mapped to the World Health Organization's International Classification of Functioning. Four-week period prevalence was calculated for restriction in any, multiple and for each aspect separately. Prevalence estimates were calculated for the total sample, and for each age and gender stratum., Results: A total of 7,878 subjects responded (adjusted response--71.3%). The 4-week period prevalence of any participation restriction was 51.8%; 3.3% had substantial restriction. Participation restriction increased with age (p<0.001) and, for moderate and substantial restriction, was more frequent in women. The prevalence of restricted participation in individual aspects of life ranged from 3.8% (work) to 25.9% (mobility outside the home)., Conclusion: Some restriction of participation 'as and when we want it' is common in the general population and increases with age, although severe restriction only affects a minority. The distribution of person-perceived participation restriction is similar to that of impairments and activity limitation in community-dwelling older adults.

Objective: This study estimated the inter- and intraobserver reliability of a set of noninstrumented physical examination measures for knee pain in older adults., Study Design and Setting: Forty-five patients from primary care, and 13 patients from secondary care, were each examined by two out of a team of three physical therapists, and were reexamined by one of these observers 1 month later. The examination items were standardized and included dichotomous, ordinal and continuous variables considered relevant to a primary care context., Results: For individual dichotomous items, median interobserver and intraobserver agreement (kappa) was 0.22 (interquartile range IQR=0.12-0.35) and 0.41 (IQR=0.28-0.56) respectively. For ordinally rated variables, weighted kappa ranged from -0.08 to 0.43 for interobserver agreement, and from 0.00 to 0.79 for intraobserver agreement. The median intraclass correlation coefficient for continuous examination variables was 0.80 (range 0.68-0.89) for interobserver agreement, and 0.84 (range 0.67-0.95) for intraobserver agreement., Conclusion: For trained but nonexpert examiners, agreement was generally poor for dichotomous and ordinal examination items; however, kappa-values are liable to be depressed by the low prevalence of clinical signs in this sample. Agreement on continuous variables was notably better.

Background: Selective non-participation at baseline (due to non-response and non-consent) and loss to follow-up are important concerns for longitudinal observational research. We investigated these matters in the context of baseline recruitment and retention at 18 months of participants for a prospective observational cohort study of knee pain and knee osteoarthritis in the general population., Methods: Participants were recruited to the Knee Clinical Assessment Study-CAS(K)--by a multi-stage process involving response to two postal questionnaires, consent to further contact and medical record review (optional), and attendance at a research clinic. Follow-up at 18-months was by postal questionnaire. The characteristics of responders/consenters were described for each stage in the recruitment process to identify patterns of selective non-participation and loss to follow-up. The external validity of findings from the clinic attenders was tested by comparing the distribution of WOMAC scores and the association between physical function and obesity with the same parameters measured directly in the target population as whole., Results: 3106 adults aged 50 years and over reporting knee pain in the previous 12 months were identified from the first baseline questionnaire. Of these, 819 consented to further contact, responded to the second questionnaire, and attended the research clinics. 776 were successfully followed up at 18 months. There was evidence of selective non-participation during recruitment (aged 80 years and over, lower socioeconomic group, currently in employment, experiencing anxiety or depression, brief episode of knee pain within the previous year). This did not cause significant bias in either the distribution of WOMAC scores or the association between physical function and obesity., Conclusion: Despite recruiting a minority of the target population to the research clinics and some evidence of selective non-participation, this appears not to have resulted in significant bias of cross-sectional estimates. The main effect of non-participation in the current cohort is likely to be a loss of precision in stratum-specific estimates e.g. in those aged 80 years and over. The subgroup of individuals who attended the research clinics and who make up the CAS(K) cohort can be used to accurately estimate parameters in the reference population as a whole. The potential for selection bias, however, remains an important consideration in each subsequent analysis.

The World Health Organization has proposed participation restriction to reflect the societal consequences of health conditions. Despite its importance, participation restriction appears to be inconsistently represented or absent from the content of many health status instruments. This paper describes the development and testing of a new self-complete measure of participation restriction from the conceptual basis of participation as an individual's perception of their actual involvement in life situations. The psychometric properties (face, content and construct validity, responder burden, performance and repeatability) of the instrument were examined using qualitative and quantitative methods. Person-perceived participation restriction did not reflect the frequency of participation but was associated with participants' expectations, aspirations, and needs, as well as contextual factors. We conclude that the instrument can provide estimates of person-perceived participation restriction in population surveys.

Background: Joint pain is common in community-dwelling older adults. Osteoarthritis is the most likely cause and the most common diagnosis made in this age group by GPs. However, the level of agreement between patients and their GPs in this diagnosis is questionable and may have important implications for clinical care., Objectives: Our aim was to determine the level of agreement between GP diagnosis of knee osteoarthritis and patients' own attribution of osteoarthritis in older adults consulting their GP with knee pain., Methods: Forty-five patients aged > or =50 years were recruited retrospectively from consecutive knee pain attenders at two general practices in North Staffordshire. All patients were assessed by trained research physiotherapists using standardized assessment procedures. Patients' attribution was assessed by the open-ended question "What do you think is the matter with your knee now?" Blind to the findings of the assessment, a researcher extracted the most recent knee-related Read code recorded by the patient's GP from the medical records to determine GP diagnosis. The physiotherapists also classified patients as osteoarthritis or non-osteoarthritis according to the American College of Rheumatology's clinical classification criteria., Results: Agreement between GP diagnosis of 'knee osteoarthritis' or 'osteoarthritis NOS' and patient diagnostic attribution of knee 'arthritis' or 'osteoarthritis' was poor [kappa=-0.03; 95% confidence interval (CI) -0.32 to 0.26]. Neither the GP diagnosis nor the patient diagnostic attribution was strongly related to clinical classification using standard criteria (kappa=0.28; 95% CI -0.01 to 0.56; and kappa=-0.39; 95% CI -0.66 to -0.13, respectively)., Conclusions: The level of agreement between a GP diagnostic code of osteoarthritis and patients' use of the term '(osteo)arthritis' is no greater than would be expected by chance alone. Discordance may be high in the use of the label osteoarthritis but is not direct evidence of a lack of shared understanding of this condition.

Although pain is experienced at all ages, there is uncertainty about the pattern of its occurrence in older people. We have investigated the prevalence of three aspects of self-reported pain-occurrence of any recent pain, number and location of pain sites, and interference with daily life-to determine their association with age in older people. A cross-sectional postal survey of all adults aged 50 years and over registered with three general practices (n = 11230) in North Staffordshire using self-complete questionnaires was conducted. Respondents' gender, age, employment status, socio-economic classification, and general health status were gathered to characterise the population under study. The location of any recent pain (past 4 weeks) was recorded on a full-body manikin and pain interference was based on a single question. Completed questionnaires were received from 7878 respondents (adjusted response of 71.3%). The 4-week prevalence of any pain was 72.4%; similar across 10-year age-groups, and higher in females than males. In those with pain the median number of painful areas (from 44) was 6, and 12.5% of the responding population were classified as having widespread pain, both figures similar across age-groups. Most regional pains showed a decline in prevalence in the older age-groups, the exceptions being the lower limb regions (hip, knee, foot). Pain that interfered with daily activities was reported by 3002 (38.1%) respondents overall. There was a clear age-related rise in this prevalence with age up to and including the oldest group. Within each regional pain subgroup, the proportion of people who also reported pain interference rose with age. Our study has provided evidence that increasing age in the elderly population is not associated with any change in the overall prevalence of pain, although, as previous studies have suggested, the pattern of pain prevalence in different body regions does change with age. More importantly the extent to which pain interferes with everyday life increases incrementally with age up to the oldest age-group in the community-dwelling general population.

Background: Knee pain affects an estimated 25% of the adult population aged 50 years and over. Osteoarthritis is the most common diagnosis made in older adults consulting with knee pain in primary care. However, the relationship between this diagnosis and both the current disease-based definition of osteoarthritis and the regional pain syndrome of knee pain and disability is unclear. Expert consensus, based on current evidence, views the disease and the syndrome as distinct entities but the clinical usefulness of these two approaches to classifying knee pain in older adults has not been established. We plan to conduct a prospective, population-based, observational cohort study to investigate the relative merits of disease-based and regional pain syndrome-based approaches to classification and prognosis of knee pain in older adults., Methods: All patients aged 50 years and over registered with three general practices in North Staffordshire will be invited to take part in a two-stage postal survey. Respondents to this survey phase who indicate that they have experienced knee pain within the previous 12 months will be invited to attend a research clinic for a detailed assessment. This will consist of clinical interview, physical examination, digital photography, plain x-rays, anthropometric measurement and a brief self-complete questionnaire. All consenting clinic attenders will be followed up by (i) general practice medical record review, (ii) repeat postal questionnaire at 18-months.

Background: The clinical syndrome of joint pain and stiffness in older people is the commonest cause of disability and health care consultation in this age group. Yet there have been few prospective studies of its course over time and its impact on personal and social life. We plan a cohort study in the general population aged 50 years and over to determine the course and prognosis of hand, hip, knee and foot pain, and the impact of these syndromes on participation levels and health care use., Methods: All patients aged 50 years and over registered with 3 local general practices are to be recruited to a population-based cohort study through the use of a two-stage mailing process. Participants will initially complete a "Health Survey" questionnaire. This will collect information on several areas of life including socio-demographics, general health, physical function, participation, and bodily pain. Those who state that they have experienced any hand problem or any pain in their hands, hips, knees, or feet in the previous 12 months, and also give permission to be re-contacted, will be mailed a "Regional Pains Survey" questionnaire which collects detailed information on the four selected body regions (hand, hips, knees, feet). Follow-up data for the three-year period subsequent to cohort recruitment will be collected through two sources: i) general practice medical records and ii) repeat mailed survey.

Ehox is an X-linked paired like homeobox gene identified from a differentiating embryonic stem (ES) cell cDNA library and is expressed at low levels in the preimplantation blastocyst and in ES cells in vitro. In embryos at 6.5 days post coitum (dpc), Ehox expression was restricted to the extraembryonic ectoderm which correlates with high-level expression in cultures of trophoblast stem cells. Extraembryonic expression becomes further restricted to the chorion and by 15.5 dpc Ehox is expressed in chorionic trophoblast of the labyrinth and spongiotrophoblast layers of the placenta. Ehox expression in the embryo proper first appears at 8.5 dpc in the anterior foregut endoderm and by 9.5 dpc is visible in pharyngeal pouches 2-4. By 10.5 dpc, Ehox expression becomes restricted to the ventral end of pouches 2 and 3. The data presented here is the first description of Ehox expression during embryogenesis and suggests a dual role for Ehox: (1) in trophoblast stem cells and compartments of the developing placenta, and (2) during development of the pharyngeal pouches, possibly delineating the area to become thymus., (Copyright 2003 Wiley-Liss, Inc.)

Background and Objectives: Clinical history and examination remain the cornerstones of diagnosis, prognosis, estimates of severity, and treatment selection in primary care for older adults presenting with knee pain. In this study we investigated the extent and cause of inter- and intraobserver variability of the clinical history using a structured, quantitative, clinical interview (KNE-SCI)., Methods: 58 patients aged 50 years and over with current knee pain were independently interviewed by two trained observers and again by one of these observers a month later., Results: Interobserver and intraobserver variability were found to be generally low [median agreement beyond chance (kappa)=0.71 (range: -0.03-1.00) and 0.58 (range: -0.03-1.00), respectively]. However, 9 of the 57 items demonstrated high inter- and intraobserver variability: notably subjective reports of swelling and specific aspects of pain experience and functional limitation., Conclusion: Structured interview can reliably quantify certain clinically relevant aspects of the clinical history in older adults with knee pain, including those felt to be indicative of osteoarthritis. Its usefulness requires further investigation.

The contribution of retinal flow (RF), extraretinal (ER), and egocentric visual direction (VD) information in locomotor control was explored. First, the recovery of heading from RF was examined when ER information was manipulated; results confirmed that ER signals affect heading judgments. Then the task was translated to steering curved paths, and the availability and veracity of VD were manipulated with either degraded or systematically biased RF. Large steering errors resulted from selective manipulation of RF and VD, providing strong evidence for the combination of RF, ER, and VD. The relative weighting applied to RF and VD was estimated. A point-attractor model is proposed that combines redundant sources of information for robust locomotor control with flexible trajectory planning through active gaze.

We report on nine children with Shwachman-Diamond syndrome (SDS), eight of whom had clonal abnormalities of chromosome 7. Seven children had an isochromosome 7 [i(7)(q10)] and one a derivative chromosome 7, all with an apparently identical (centromeric) breakpoint. Children with SDS are predisposed to myelodysplasia (MDS) and acute myeloid leukaemia (AML) often with chromosome 7 abnormalities. Allogeneic transplants have been used to treat these children, however, they are a high-risk transplant group and require careful evaluation. Three of the children were transplanted but only one survived, who to our knowledge remains the longest surviving SDS transplant patient (4.5 years +). The six non-transplanted children are well. In classic MDS, chromosome 7 abnormalities are associated with rapid progression to acute leukaemia; however, we present evidence to suggest that isochromosome 7q may represent a separate disease entity in SDS children. This is a particularly interesting finding given that the SDS gene has recently been mapped to the centromeric region of chromosome 7. Our studies indicate that i(7)(q10) is a relatively benign rearrangement and that it is not advisable to offer allogeneic transplants to SDS children with i(7)(q10) alone in the absence of other clinical signs of disease progression.

The authors describe two pediatric cases of large granular lymphocytosis presenting early in the second decade of life with neutropenia and sepsis. They are among the youngest described in the literature. This report focuses on the advantages of detailed immunophenotypic and molecular analysis and highlights some of the controversies and uncertainties in the management of these patients, particularly the choice of immunosuppressive therapy. Immunosuppressive therapy in the two children described in this report resulted in improvement of neutropenia and clinical status, but this was not accompanied by the disappearance of the clonal population.

Inadvertent positive end-expiratory pressure (PEEP) is a potential cause of lung overdistension and impaired gas exchange in ventilated infants. It can be extremely difficult to diagnose clinically and if unrecognized can be life-threatening. Measurement of lung function can lead to the recognition of inadvertent PEEP, allowing appropriate ventilator adjustment with immediate substantial improvement in clinical state. Lung function measurements can help to optimize ventilation and may improve clinical outcome.

This study describes the effect of acidic and basic fibroblast growth factor (FGF) on DNA synthesis in chick satellite cells in vitro and interactions with insulin-like growth factor-I (IGF-I) and exogenous heparin. Basic bFGF stimulated incorporation of [3H]thymidine into DNA with a half-maximum concentration (ED50) of 3.23 +/- 0.33 pmol/l, more than 500-fold more potent than acidic FGF (ED50 = 2.13 +/- 0.5 nmol/l). Both bFGF and IGF-I allowed the cells to traverse the cell cycle with an approximate length of the G1 phase of 12 h. When cells were incubated with bFGF and IGF-I together their effects on DNA synthesis were additive rather than synergistic throughout the full concentration range. Incubation of satellite cells with low concentrations of heparin (ng/ml) to mimic the effect of endogenous heparan sulphate proteoglycan caused a small increase in DNA synthesis, whereas higher concentrations (microgram/ml) inhibited DNA synthesis in a dose-related manner. A low concentration of heparin increased DNA synthesis at the highest concentration of bFGF, but high doses of heparin inhibited the response to bFGF throughout the dose-response curve but without altering the ED50. RNAse protection assay showed the expression of bFGF mRNA in proliferating cells which appeared to decrease on differentiation. The results suggest that aspects of neonatal muscle development are regulated by interactions between autocrine/paracrine growth factors such as IGF-I and bFGF, perhaps IGF-I derived from the circulation, and components of the extracellular matrix. Concentrations of the matrix components may change throughout the neonatal period and into adulthood and have an important effect on the regulatory role played by the growth factors.

Objective: To assess the reliability of estimates of static respiratory system compliance (Crs) made by junior hospital doctors caring for ventilated newborn infants., Design: A prospective comparison of junior doctors' estimates of Crs to the Crs measured immediately afterwards., Setting: A regional neonatal intensive care nursery in Edinburgh, Scotland., Patients: 46 ventilated newborn infants., Measurements and Results: Crs was estimated by three grades of junior doctor (Senior House Officer, Registrar and Research Fellow) using two different methods, (i) based on visual assessment of tidal volume in relation to inflation pressure (optical Crs) and (ii) directly using a visual analogue scale (analogue Crs). The Crs was then measured immediately afterwards using the single breath passive expiratory flow technique. The differences between the estimates and the measurements were calculated for each grade of observer and plotted against the corresponding measurements. The relationship between estimates and measurements was also expressed in terms of the coefficients of determination r2 calculated by least squares regression. With both methods of estimation observers tended to overestimate the Crs of infants with lower measured Crs and underestimate that of infants with higher measured Crs with many estimates differing from the measurements by more than 50%. Values of r2 ranged from 0.086 to 0.481 indicating a weak relationship between the estimates and the measurements., Conclusions: Junior doctors' estimates of Crs were unreliable and did not represent a useful method of assessing respiratory function. The clinical use of compliance measurements merits wider evaluation.

1. Plasma concentrations of growth hormone (GH) and insulin-like growth factor I(IGF-I) were determined in individually caged broiler breeder females from 17 to 30 weeks of age. The birds were fed ad libitum or restricted during rearing in a randomised block design. Restricted birds were fed ad libitum after laying an egg and egg production was recorded to 54 weeks. 2. GH concentrations were higher in restricted compared with ad libitum-fed birds at 17 to 21 weeks of age and were similar thereafter. Plasma IGF-I concentrations were higher in restricted compared with ad libitum-fed birds throughout the sampling period of the experiment. 3. The age at first egg was delayed by about two weeks in restricted birds. At 54 weeks of age they had laid 114 compared with 67 eggs in birds fed ad libitum throughout and had produced less than half the number of eggs with defective shells. 4. It was suggested that differences in egg production between ad libitum and restricted broiler breeder females could be related to changes in the pattern of GH and/or IGF-I secretion.

Static respiratory system compliance (Crs) was measured by a single breath passive expiratory flow technique in 73 newborn infants treated with exogenous surfactant. The first 39 received Curosurf, a natural porcine surfactant. The other 34 received Exosurf Neonatal, a synthetic surfactant. All had a diagnosis of respiratory distress syndrome with an arterial/alveolar oxygen ratio < 0.22. Static Crs and arterial blood gases were measured shortly before, and at three and 12 hours after the first dose of surfactant. In 32 infants treated with Curosurf with initial static Crs < 1.8 ml/cm H2O/m body length, which is consistent with surfactant deficiency, static Crs improved by 18% at three hours and by 39% at 12 hours along with a median reduction in fractional inspired oxygen (FIO2) at three hours by 0.32. In 26 infants treated with Exosurf with initial Crs < 1.8 ml/cm H2O/m, Crs did not improve three and 12 hours after treatment and oxygenation improved less than after Curosurf, with a median reduction in FIO2 at three hours of 0.11. Fifteen of the 73 (21%) infants had initial static Crs of > or = 1.8 ml/cm H2O/m, not consistent with surfactant deficiency. Thirteen of these 15 infants showed a fall in static Crs after surfactant treatment, raising the question whether exogenous surfactant did them more harm than good. Initial static Crs and surfactant type both appear to determine the early response to the first dose of surfactant. Only a considerably larger, randomised study can show which surfactant is more effective in reducing adverse clinical outcome.

Static respiratory system compliance (Crs) and lecithin/sphingomyelin (L/S) ratios in tracheal aspirates were estimated in two independent groups of mechanically ventilated infants. Crs was measured rapidly at the cotside using a passive expiratory flow technique and L/S ratios were estimated in the laboratory by high performance liquid chromatography. In the reference group of 22 infants, Crs < 1.8 ml/cm H2O/m predicted surfactant deficiency with a positive predictive value of 100% and a negative predictive value of 92%. In the validation group of 23 infants, Crs < 1.8 ml/cm H2O/m predicted surfactant deficiency with a positive predictive value of 94% and a negative predictive value of 83%. Measurement of static Crs is a rapid, non-invasive technique which may usefully supplement current methods of selecting infants at high risk of respiratory distress syndrome.

Accurate measures of the severity of respiratory disease are important, both clinically and epidemiologically. The apparent prognostic value of static respiratory system compliance (Crs) on the first day and mean appropriate fractional inspired oxygen (FIO2) in the first 12 hours of life were compared in 48 infants who received mechanical ventilation in a regional neonatal unit. Their median (range) gestation was 30 (25-41) weeks and they were representative of all 140 newborn infants born to residents of a geographically defined area who received mechanical ventilation over a 30 month period. Using the best cut off value (< or = 0.6 ml/cm H2O/m corrected for body length), static Crs predicted hospital death with 98% accuracy, 80% sensitivity, and 100% specificity. Using the best cut off value (> 0.60), mean FIO2 in the first 12 hours predicted hospital death with 81% accuracy, 80% sensitivity, and 81% specificity. Static Crs appeared to be a more accurate measure of respiratory function and disease severity than mean FIO2, perhaps because static Crs is less dependent on ventilator management than routine indices based on blood gases. Static Crs now merits wider evaluation, both as an aid to routine clinical management and as a prognostic index in comparative studies.

This study compared the clinical behavior of a glass ionomer silver cermet (Ketac-Silver), a posterior resin composite (Visio-Molar) used with the "sandwich" technique, and a high-copper amalgam (Dispersalloy) for restoring conventional Class I occlusal cavity preparations. Two dentists placed 116 restorations in the posterior permanent teeth of 35 adults treated at a dental hospital. Restorations were assessed at 6-month intervals over 2 years for bulk loss of material and occlusal wear, surface voids, roughness and cracking, surface and marginal staining, and marginal fracture. Losses of material and surface voids were obvious with the cermet material, with surface crazing or cracking being present in 33% of the restorations. The cermet cannot be recommended as a long-term permanent restorative material if the restorations are likely to be subjected to heavy occlusal stresses and abrasive wear.

This study compared the clinical behavior of a glass ionomer (polyalkenoate) silver cermet, a posterior resin composite used with the "tunnel" technique, a posterior resin composite used with the "closed sandwich" technique, and a high-copper amalgam for restoring small, proximal surface carious lesions. Two dentists placed 86 restorations in the posterior permanent teeth of 26 adults treated at a dental hospital. Restorations were assessed at 6-month intervals over 2 years for gingivitis adjacent to them, the tightness of proximal contacts, occlusal wear, surface voids, roughness and cracking, surface and marginal staining, and marginal fracture. Small filling defects, surface voids and occlusal wear were obvious with the cermet material, with surface crazing and cracking present in 48% of the tunnel restorations. Two of the posterior resin composites, but none of the amalgam restorations, also failed. The cermet cannot be recommended as a long-term permanent restorative material in situations where it is likely to be subjected to heavy occlusal stresses and abrasive wear.

This limited study examined differences in pharmacists' competencies through self-assessment. By using self-assessment with specified objectives, pharmacists can target areas for CE programs. Pharmacists can then improve and maintain their competencies in these specific areas. A future study could focus on discovering the reasons some pharmacists do not feel comfortable in giving advice/information to other healthcare professionals.

Early respiratory mechanics have been reported to predict outcome in newborns with respiratory failure. However, it remains unknown whether measurements of pulmonary function add significantly to the predictive value of more readily available variables The present study was designed to answer this question. Passive respiratory system mechanics were measured by an airway occlusion technique in 104 ventilator-dependent premature infants between 6 and 48 hours of life and corrected for infant size. A ventilation index [FiO2 x mean airway pressure (MAP)] was calculated at the time of pulmonary function testing. Poor outcome was defined as death from respiratory failure or need for supplemental oxygen at 28 days. Stepwise logistic function regression examined whether ventilation index and respiratory mechanics added predictive power over and above birthweight. Five infants died, and 45 patients required supplemental oxygen at 28 days. Birthweight was a strong predictor and would have entered the logistic model first in any case. Ventilation index added significantly to the predictive model (P = 0.038). Respiratory system conductance (P = 0.15) and compliance (P = 0.93) entered on the third and last step, respectively. We conclude that in premature infants with respiratory failure, birthweight is a strong predictor of outcome. Early ventilator requirements but not respiratory system mechanics, add significantly to this predictive model.

Insulin-like growth factors-I and -II (IGF-I and IGF-II) stimulate proliferation, differentiation, nutrient uptake and protein accretion in muscle cells. These effects are thought to be mediated through the type-I IGF receptor although a role for the type-II IGF receptor cannot be ruled out, since it has been found in most cells studied so far. Current evidence suggests that the chicken does not have a type-II IGF receptor and therefore provides a good model to study the function of IGF peptides. We have compared the effects of insulin and insulin-like growth factors on DNA synthesis with the binding of these peptides to receptors in primary chicken muscle satellite cells. Human IGF-I (hIGF-I), hIGF-II and porcine insulin increased thymidine incorporation into DNA by threefold in muscle satellite cells prepared from neonatal chickens. IGF-I and -II were almost equipotent, with half-maximum effective concentrations of 10 micrograms/l, and were 1000-fold more potent than insulin. A combination of maximum effective concentrations of all three peptides was not additive, suggesting that their effect was mediated by the same receptor. Receptor binding studies on satellite cells demonstrated the presence of specific IGF receptors. Human IGF-I inhibited the binding of 125I-labelled hIGF-I with a much higher potency than insulin, as usually observed for a type-IIGF receptor. However, unlabelled hIGF-II exhibited a higher potency than hIGF-I in displacing 125I-labelled hIGF-I. Affinity cross-linking of 125I-labelled hIGF-I and -II, followed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis, showed that hIGF-I and -II bound to a receptor with the structural characteristics of a type-I IGF receptor and confirmed the lack of a type-II IGF receptor in these cells. The concentrations of IGF-I, -II and insulin required for biological action and to displace 125I-labelled hIGF-I binding were similar, and support the hypothesis that their effects on proliferation were mediated exclusively through a type-I IGF receptor.

Objectives: To investigate (a) which clinical variables and physiological measures of disease severity best predict death in very low birthweight infants and (b) their use in comparing mortality between two neonatal units., Design: Retrospective study of two cohorts of very low birthweight infants from overlapping time periods who received mechanical ventilation., Setting: Two neonatal intensive care units (hospitals A and B)., Subjects: 262 Very low birthweight infants, 130 in hospital A, 132 in hospital B., Main Outcome Measure: Death in hospital., Results: In hospital A the mean level of oxygenation in the first 12 hours of life, whether measured as inspired oxygen requirement (FIO2), arterial/alveolar oxygen (a/AO2) ratio, or alveolar-arterial oxygen difference (A-aDO2), was more closely associated with death than any of four "traditional" risk factors: low birth weight, short gestation, the diagnosis of respiratory distress syndrome, and male sex. Mean pH in the first 12 hours was as strongly associated with death as birth weight. Multiple logistic regression models were derived in infants from hospital A using the four traditional risk factors with measures of oxygenation and pH. The validity of each model was then tested in infants from hospital B. The model based on the four traditional risk factors alone predicted death in hospital B with only 31% sensitivity. Adding mean a/AO2 ratio and mean pH increased its sensitivity to 75%, and when mean a/AO2 ratio was replaced by mean FIO2 its sensitivity increased further to 81%. Based on crude mortality rates alone, the odds of death in hospital A versus hospital B were 0.67 (95% confidence interval 0.37 to 1.23). After correcting for traditional risk factors and mean FIO2 and mean pH, however, the odds of death in hospital A increased to 3.27 (1.35 to 7.92; p less than 0.01). This increased risk persisted after adjusting for the time difference between each cohort., Conclusions: Crude comparisons of hospital mortality can be highly misleading. Reliable assessment of neonatal outcome is impossible without correcting for major risk factors, particularly initial disease severity. International agreement on a minimum core dataset of clinical and physiological information could improve neonatal audit and help to identify effective treatments and policies.

A pair of monozygotic twins discordant for Wiedemann-Beckwith syndrome is described. The probability of monozygosity is 0.995. This observation suggests that the syndrome is unlikely to be under single gene control and genetic counselling should be based on multifactorial inheritance.

The concentrations of circulating insulin-like growth factor I, growth hormone, insulin and thyroid hormones were measured in broilers selected for an increase in growth, broilers in which selection pressure was relaxed and in White Leghorns. Growth hormone levels increased in all lines between 3 and 4 weeks of age followed by a decline to adult levels. The lines with the slowest rate of growth had the highest growth hormone concentrations. Insulin-like growth factor I concentrations increased significantly in all three lines of birds during the 10 weeks of study and was significantly correlated with the increase in body weight. There were no consistent differences in plasma IGF-1 levels between the lines. Thyroxine levels increased consistently throughout the study but the levels of triiodothyronine decreased between 5 and 6 weeks of age in all lines. There were no consistent changes in plasma insulin levels. The highest rate of growth in these animals is accompanied by an increase in growth hormone concentration followed by an increase in plasma IGF-1. However, despite differences in plasma growth hormone, plasma concentrations of IGF-1 are not different between lines and are not related to between line differences in growth rate.

Epidural venography is a relatively simple, safe and highly accurate method of diagnosing lumbar disc herniations. Good opacification of the epidural venous plexus can be obtained by selective catheterization of the ascending lumbar vein or pre-sacral branches of the internal iliac veins. Experience with 100 cases of lumbar disc herniations is described. The authors think that epidural venography is a more sensitive technique than myelography, particularly with lateral disc herniation at the L5-S1 level. It is not associated with the morbidity or complications of myelography and can be performed as an outpatient procedure. Epidural venography is recommended as the examination of choice in patients with suspected lumbar disc herniation.

Uncommonly, pancreatic cysts are complicated by the erosion of certain adjacent arteries and serious gastrointestinal haemorrhage. This diagnosis should be entertained in any patient with chronic pancreatitis who presents with unexplained gastrointestinal blood loss, whether acute or chronic, a pulsatile mass in the epigastrium, and an associated bruit. Selective caeliac axis angiography may not only confirm the diagnosis, but provide precise anatomical information as a guide to the surgeon in planning treatment. The surgical treatment of choice is transcystic ligation of the bleeding vessel, followed by internal cyst drainage.

Using the Wolfe breast pattern classification, a study was conducted to test the reproducibility of this classification in view of its likely significance for breast screening and rescreening programs. The results are highly encouraging, and there was good agreement. Reclassification from low risk occurred in 1% of the cases; reclassification from high risk to low risk occurred in 1.4%. There was a variance of 2.4% in the low-risk group and 0.6% in the high-risk group.