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The Takagi-Sugeno (TS) fuzzy rule system is a widely used data mining technique, and is of particular use in the identification of non-linear interactions between variables. However the number of rules increases dramatically when applied to high dimensional data sets (the curse of dimensionality). Few robust methods are available to identify important rules while removing redundant ones, and this results in limited applicability in fields such as epidemiology or bioinformatics where the interaction of many variables must be considered. Here, we develop a new parsimonious TS rule system. We propose three statistics: R, L, and ω-values, to rank the importance of each TS rule, and a forward selection procedure to construct a final model. We use our method to predict how key components of childhood deprivation combine to influence educational achievement outcome. We show that a parsimonious TS model can be constructed, based on a small subset of rules, that provides an accurate description of the relationship between deprivation indices and educational outcomes. The selected rules shed light on the synergistic relationships between the variables, and reveal that the effect of targeting specific domains of deprivation is crucially dependent on the state of the other domains. Policy decisions need to incorporate these interactions, and deprivation indices should not be considered in isolation. The TS rule system provides a basis for such decision making, and has wide applicability for the identification of non-linear interactions in complex biomedical data.

Background: Latent autoimmune diabetes in adults (LADA) is a slowly developing type 1 diabetes., Objectives: To compare interventions used for LADA., Search Strategy: Studies were obtained from searches of electronic databases, supplemented by handsearches, conference proceedings and consultation with experts. Date of last search was December 2010., Selection Criteria: Randomised controlled trials (RCT) and controlled clinical trials (CCT) evaluating interventions for LADA or type 2 diabetes with antibodies were included., Data Collection and Analysis: Two authors independently extracted data and assessed risk of bias. Studies were summarised using meta-analysis or descriptive methods., Main Results: Searches identified 13,306 citations. Fifteen publications (ten studies) were included, involving 1019 participants who were followed between three months to 10 years (1060 randomised). All studies had a high risk of bias. Sulphonylurea (SU) with insulin did not improve metabolic control significantly more than insulin alone at three months (one study, n = 15) and at 12 months (one study, n = 14) of treatment and follow-up. SU (with or without metformin) gave poorer metabolic control compared to insulin alone (mean difference in glycosylated haemoglobin A1c (HbA1c) from baseline to end of study, for insulin compared to oral therapy: -1.3% (95% confidence interval (CI) -2.4 to -0.1; P = 0.03, 160 participants, four studies, follow-up/duration of therapy: 12, 30, 36 and 60 months; however, heterogeneity was considerable). In addition, there was evidence that SU caused earlier insulin dependence (proportion requiring insulin at two years was 30% in the SU group compared to 5% in conventional care group (P < 0.001); patients classified as insulin dependent was 64% (SU group) and 12.5% (insulin group, P = 0.007). No intervention influenced fasting C-peptide, but insulin maintained stimulated C-peptide better than SU (one study, mean difference 7.7 ng/ml (95% CI 2.9 to 12.5)). In a five year follow-up of GAD65 (glutamic acid decarboxylase formulated with aluminium hydroxide), improvements in fasting and stimulated C-peptide levels (20 μg group) were maintained after five years. Short term (three months) follow-up in one study (n = 74) using Chinese remedies did not demonstrate a significant difference in improving fasting C-peptide levels compared to insulin alone (0.07 µg/L (95% CI -0.05 to 0.19). One study using vitamin D with insulin showed steady fasting C-peptide levels in the vitamin D group but declining fasting C-peptide levels (368 to 179 pmol/L, P = 0.006) in the insulin alone group at 12 months follow-up. Comparing studies was difficult as there was a great deal of heterogeneity in the studies and in their selection criteria. There was no information regarding health-related quality of life, complications of diabetes, cost or health service utilisation, mortality and limited evidence on adverse events (studies on oral agents or insulin reported no adverse events in terms of severe hypoglycaemic episodes)., Authors' Conclusions: Two studies show SU leading to earlier insulin dependence and a meta-analysis of four studies with considerable heterogeneity showed poorer metabolic control if SU is prescribed for patients with LADA compared to insulin. One study showed that vitamin D with insulin may protect pancreatic beta cells in LADA. Novel treatments such as GAD65 in certain doses (20 μg) have been suggested to maintain fasting and stimulated C-peptide levels. However, there is no significant evidence for or against other lines of treatment of LADA.

Background: To understand the key challenges and explore recommendations from teenagers to promote physical activity with a focus on ethnic minority children., Methods: Focus groups with teenagers aged 16-18 of Bangladeshi, Somali or Welsh descent attending a participating school in South Wales, UK. There were seventy four participants (18 Somali, 24 Bangladeshi and 32 Welsh children) divided into 12 focus groups., Results: The boys were more positive about the benefits of exercise than the girls and felt there were not enough facilities or enough opportunity for unsupervised activity. The girls felt there was a lack of support to exercise from their family. All the children felt that attitudes to activity for teenagers needed to change, so that there was more family and community support for girls to be active and for boys to have freedom to do activities they wanted without formal supervision. It was felt that older children from all ethnic backgrounds should be involved more in delivering activities and schools needs to provide more frequent and a wider range of activities., Conclusions: This study takes a child-focused approach to explore how interventions should be designed to promote physical activity in youth. Interventions need to improve access to facilities but also counteract attitudes that teenagers should be studying or working and not 'hanging about' playing with friends. Thus, the value of activity for teenagers needs to be promoted not just among the teenagers but with their teachers, parents and members of the community.

Background: Physical activity is associated with better health. Two sources of activity for children are walking to school and taking part in organised sports and activities. This study uses a large national cohort to examine factors associated with participation in these activities., Methods: The Millennium Cohort study contains 5 year follow-up of 17,561 singleton children recruited between 2000-2002 in the UK. All participants were interviewed in their own homes at 9 months, 3 years and 5 years follow-up and all measures were self reports. Logistic regression and likelihood ratio tests were used., Results: Children are less likely to walk to school as income and parental education increase [Adjusted odds: 0.7 (95%CI: 0.6-0.8) for higher income/education compared to low income/no qualifications]. However, if the parent plays with the child in high income families the child is more likely to walk to school [Adjusted odds: 1.67 (95%CI: 1.3-2.1)]. Children taking part in organised activities are from higher income, higher education families, with a car, in a "good" area with non-working mothers. However, in low socio-economic families where the parent plays with the child the child is more likely to take part in organised activities [Adjusted odds: 2.0 (95% CI: 1.5-2.7)]., Conclusions: Income is an important determinant of the type of activity available to children. Families that report good health behaviours (non-smoking, low TV viewing) and play with their children show higher levels of physical activity. Thus, parenting practice appears to have a strong impact on their child's physical activity.

Background: To examine adiponectin levels in people with Latent Autoimmune Diabetes in Adults using a matched pair case control study., Findings: Patients with LADA (n = 64), were matched for sex with type 2 diabetic and non-diabetic controls. A matched paired T-test was used to examine average adiponectin levels in the LADA patients' versus controls. The average adiponectin level for the LADA patients was 9.96 μg/ml compared to 6.4 μg/ml for Type 2 matched controls and 9.6 μg/ml for non-diabetic controls. Mean difference for the LADA-type 2 comparison was calculated after data was log transformed and showed a difference of 1.58 μg/ml (95%CI: 1.28-1.95, p = 0.0001). There was no significant difference between LADA and non-diabetic controls (p = 0.54)., Conclusions: Adiponectin levels are higher among people with LADA compared to those with type 2 diabetes and are equivalent to levels seen in non-diabetic controls. This suggests that risk of complications in LADA, as with type 1 diabetes may be related more to glycaemic control rather than to factors of the metabolic syndrome.

Background: People with diabetes who experience an acute myocardial infarction (AMI) have a higher risk of death and recurrence of AMI. This study was commissioned by the Department for Transport to develop survival tables for people with diabetes following an AMI in order to inform vehicle licensing., Methods: A cohort study using data obtained from national hospital admission datasets for England and Wales was carried out selecting all patients attending hospital with an MI for 2003-2006 (inclusion criteria: aged 30+ years, hospital admission for MI (defined using ICD 10 code I21-I22). STATA was used to create survival tables and factors associated with survival were examined using Cox regression., Results: Of 157,142 people with an MI in England and Wales between 2003-2006, the relative risk of death or recurrence of MI for those with diabetes (n = 30,407) in the first 90 days was 1.3 (95%CI: 1.26-1.33) crude rates and 1.16 (95%CI: 1.1-1.2) when controlling for age, gender, heart failure and surgery for MI) compared with those without diabetes (n = 129,960). At 91-365 days post AMI the risk was 1.7 (95% CI 1.6-1.8) crude and 1.50 (95%CI: 1.4-1.6) adjusted. The relative risk of death or re-infarction was higher at younger ages for those with diabetes and directly after the AMI (Relative risk; RR: 62.1 for those with diabetes and 28.2 for those without diabetes aged 40-49 [compared with population risk])., Conclusions: This is the first study to provide population based tables of age stratified risk of re-infarction or death for people with diabetes compared with those without diabetes. These tables can be used for giving advice to patients, developing a baseline to compare intervention studies or developing license or health insurance guidelines.

Background: Health is a result of influences operating at multiple levels. For example, inadequate housing, poor educational attainment, and reduced access to health care are clustered together, and are all associated with reduced health. Policies which try to change individual people's behaviour have limited effect when people have little control over their environment. However, structural environmental change and an understanding of the way that influences interact with each other, has the potential to facilitate healthy choices irrespective of personal resources. The aim of Environments for Healthy Living (EHL) is to investigate the impact of gestational and postnatal environments on health, and to examine where structural change can be brought about to optimise health outcomes. The baseline assessment will focus on birth outcomes and maternal and infant health., Methods/design: EHL is a longitudinal birth cohort study. We aim to recruit 1000 pregnant women in the period April 2010 to March 2013. We will examine the impact of the gestational environment (maternal health) and the postnatal environment (housing and neighbourhood conditions) on subsequent health outcomes for the infants born to these women. Data collection will commence during the participants' pregnancy, from approximately 20 weeks gestation. Participants will complete a questionnaire, undergo anthropometric measurements, wear an accelerometer, compile a food diary, and have environmental measures taken within their home. They will also be asked to consent to having a sample of umbilical cord blood taken following delivery of their baby. These data will be complemented by routinely collected electronic data such as health records from GP surgeries, hospital admissions, and child health and development records. Thereafter, participants will be visited annually for follow-up of subsequent exposures and child health outcomes., Discussion: The baseline assessment of EHL will provide information concerning the impact of gestational and postnatal environments on birth outcomes and maternal and infant health. The findings can be used to inform the development of complex interventions targeted at structural, environmental factors, intended to reduce ill-health. Long-term follow-up of the cohort will focus on relationships between environmental exposures and the later development of adverse health outcomes, including obesity and diabetes.

Background: Weight at age 5 is a predictor for future health of the individual. This study examines risk factors for childhood obesity with a focus on ethnicity., Methods: Data from the Millennium Cohort study were used. 17,561 singleton children of White/European (n = 15,062), Asian (n = 1,845) or African (n = 654) background were selected. Logistic regression and likelihood ratio tests were used to examine factors associated with obesity at age 5. All participants were interviewed in their own homes. The main exposures examined included; Birth weight, sedentary lifestyle, family health behaviours, ethnicity, education and income., Results: Children with a sedentary lifestyle, large at birth, with high risk family health behaviours (overweight mothers, smoking near the child, missing breakfast) and from a family with low income or low educational attainment, were more likely to be obese regardless of ethnicity. Feeding solid food before 3 months was associated with obesity in higher income White/European families. Even when controlling for socioeconomic status, ethnic background is an important independent risk factor for childhood obesity [Odds ratio of obesity; was 1.7 (95%CI: 1.2-2.3) for Asian and 2.7 (95%CI: 1.9-3.9) for African children, compared to White/European]. The final adjusted model suggests that increasing income does not have a great impact on lowering obesity levels, but that higher academic qualifications are associated with lower obesity levels [Odds of obesity: 0.63 (95%CI: 0.52-0.77) if primary carer leaves school after age 16 compared at age 16]., Conclusions: Education of the primary carer is an important modifiable factor which can be targeted to address rising obesity levels in children. Interventions should be family centred supporting and showing people how they can implement lifestyle changes in their family.

Preoperative chemoradiotherapy is used in locally advanced rectal cancer to reduce local recurrence and improve operability, however a proportion of tumors do not undergo significant regression. Identification of predictive markers of response to chemoradiotherapy would improve patient selection and may allow response modification by targeting of specific pathways. The aim of this study was to determine whether expression of glucose transporter-1 (GLUT-1) and p53 in pretreatment rectal cancer biopsies was predictive of tumor response to chemoradiotherapy. Immunohistochemical staining for GLUT-1 and p53 was performed on 69 pretreatment biopsies and compared to tumor response in the resected specimen as determined by the tumor regression grade (TRG) scoring system. GLUT-1 expression was significantly associated with reduced response to chemoradiotherapy and increasing GLUT expression correlated with poorer response (p=0.02). GLUT-1 negative tumors had a 70% probability of good response (TRG3/4) compared to a 31% probability of good response in GLUT-1 positive tumors. GLUT-1 may be a useful predictive marker of response to chemoradiotherapy in rectal cancer., (Copyright (c) 2009 UICC.)

Background: Childhood obesity levels are rising with estimates suggesting that around one in three children in Western countries are overweight. People from lower socioeconomic status and ethnic minority backgrounds are at higher risk of obesity and subsequent CVD and diabetes. Within this study we examine the prevalence of risk factors for CVD and diabetes (obesity, hypercholesterolemia, hypertension) and examine factors associated with the presence of these risk factors in school children aged 11-13., Methods and Design: Participants will be recruited from schools across South Wales. Schools will be selected based on catchment area, recruiting those with high ethnic minority or deprived catchment areas. Data collection will take place during the PE lessons and on school premises. Data will include: anthropometrical variables (height, weight, waist, hip and neck circumferences, skinfold thickness at 4 sites), physiological variables (blood pressure and aerobic fitness (20 metre multi stage fitness test (20 MSFT)), diet (self-reported seven-day food diary), physical activity (Physical Activity Questionnire for Adolescents (PAQ-A), accelerometery) and blood tests (fasting glucose, insulin, lipids, fibrinogen (Fg), adiponectin (high molecular weight), C-reactive protein (CRP) and interleukin-6 (IL-6)). Deprivation at the school level will be measured via information on the number of children receiving free school meals. Townsend deprivation scores will be calculated based on the individual childs postcode and self assigned ethnicity for each participating child will be collected. It is anticipated 800 children will be recruited. Multilevel modeling will be used to examine shared and individual factors associated with obesity, stratified by ethnic background, deprivation level and school., Discussion: This study is part of a larger project which includes interviews with older children regarding health behaviours and analysis of existing cohort studies (Millennium cohort study) for factors associated with childhood obesity. The project will contribute to the evidence base needed to develop multi-dimensional interventions for addressing childhood obesity.

Background: Latent autoimmune diabetes in adults [LADA] is a type 1 diabetes that is slowly developing. This means many people are treated as having type 2 diabetes at diagnosis as they are adults who are not immediately insulin dependent. LADA can be distinguished from type 2 diabetes by antibody tests. Patients who are antibody positive have an autoimmune reaction which is similar to that of type 1 diabetes and is not found in type 2 diabetes. We would like to examine the best way of treating LADA in the early phase of the conditions, with tablets (similar to type 2 diabetes) or with insulin (similar to type 1 diabetes)., Methods/design: This is an open parallel group prospective randomised trial. Participants need to have a GAD antibody test results of 101 WHO units or more and a diagnosis of diabetes not requiring insulin at diagnosis. Participants will need to have been diagnosed within 12 months and not treated with insulin at study entry. They will be randomised to receive either insulin (NovoMix 30) or tablets (diet treated followed by metformin followed by glitazone (with or without metformin) followed by insulin). Primary outcome assessment will be for change in HbA1c and change in fasting C-peptide over 24 months. Secondary outcome measures will include Quality of life, GAD antibody levels, adverse events, inflammatory markers, insulin resistance, and markers of the metabolic syndrome., Discussion: This study seeks the best treatment for early LADA in terms of maintaining glycaemic control and maintaining natural insulin production., Trial Registration: ISRCTN63815121.

Objective: Latent autoimmune diabetes in adults is type 1 diabetes presenting as non-insulin dependent diabetes. One feature of the selection criteria is time independent of insulin treatment. We examine the validity of this criterion., Research Design and Methods: Patients were recruited in nine European centers, and clinicians reported on criteria for initiating insulin. All patients were tested for GAD antibodies (GADAs) in a central laboratory. We examined time to insulin treatment for GADA-positive patients in six participating centers., Results: There was intercenter variation in the criteria used to initiate insulin. Median time to insulin was 16.15 months (interqartile range 6.7-25.5) in centers with GADA testing compared with 45.6 months (29.5-61.8) in centers without routine GADA testing (P < 0.002)., Conclusion: Time to insulin should not be used to define patients with LADA because it is dependent on local clinical judgment and the use of laboratory tests for GADA.

Background: Globally and nationally large numbers of people are injured each year, yet there is little information on the impact of these injuries on people's lives, on society and on health and social care services. Measurement of the burden of injuries is needed at a global, national and regional level to be able to inform injured people of the likely duration of impairment; to guide policy makers in investing in preventative measures; to facilitate the evaluation and cost effectiveness of interventions and to contribute to international efforts to more accurately assess the global burden of injuries., Methods/design: A prospective, longitudinal multi-centre study of 1333 injured individuals, atttending Emergency Departments or admitted to hospital in four UK areas: Swansea, Surrey, Bristol and Nottingham. Specified quotas of patients with defined injuries covering the whole spectrum will be recruited. Participants (or a proxy) will complete a baseline questionnaire regarding their injury and pre-injury quality of life. Follow up occurs at 1, 4, and 12 months post injury or until return to normal function within 12 months, with measures of health service utilisation, impairment, disability, and health related quality of life. National estimates of the burden of injuries will be calculated by extrapolation from the sample population to national and regional computerised hospital in-patient, emergency department and mortality data., Discussion: This study will provide more detailed data on the national burden of injuries than has previously been available in any country and will contribute to international collaborative efforts to more accurately assess the global burden of injuries. The results will be used to advise policy makers on prioritisation of preventive measures, support the evaluation of interventions, and provide guidance on the likely impact and degree of impairment and disability following specific injuries.

Background: Latent autoimmune diabetes in Adults (LADA) is a slowly developing type 1 diabetes which presents as non-insulin dependent diabetes and progresses to insulin dependence. However, the best treatment strategy for LADA is unclear., Objectives: To compare interventions used for LADA., Search Strategy: Studies were obtained from searches of electronic databases (including MEDLINE, EMBASE), supplemented by hand searches, conference proceedings and consultation with experts., Selection Criteria: Selection was in duplicate by two independent reviewers. RCT and controlled clinical trials evaluating interventions for LADA or type 2 diabetes with antibodies were included., Data Collection and Analysis: Two reviewers independently extracted data and assessed study quality. Studies were summarised in a descriptive manner., Main Results: Searches identified 8067 citations. Eight publications (seven studies) were included, involving 735 participants. All studies had high risk of bias. There were no data on use of metformin or glitazones alone. Rosiglitazone or sulphonylurea (SU) with insulin did not improve metabolic control significantly more than insulin alone. SU alone gave either poorer (one study, mean difference in HbA1c 2.8% (95% confidence interval (CI) 0.9 to 4.7) or equivalent metabolic control compared to insulin alone (two studies). There was evidence that SU caused earlier insulin dependence (insulin treated at two years: 60% (SU) and 5% (conventional care) (P < 0.001); classified insulin dependent: 64% (SU) and 12.5% (insulin group) (P = 0.007)). No interventions influenced fasting C-peptide, but insulin maintained stimulated C-peptide better than SU (one study, mean difference 7.7 ng/ml (95% CI 2.9 to 12.5) and insulin with rosiglitazone was superior to insulin alone (one study) at maintaining stimulated C-peptide. A pilot study showed better metabolic control at six months with subcutaneously administered glutamic acid decarboxylase (GAD) GAD65, a major autoantigen in autoimmune diabetes, compared to placebo. There was no information regarding quality of life, mortality, complications or costs in any of the publications. Time from diagnosis varied between recruitment at diagnosis to recruitment at nine years of disease duration and there was a great deal of variation in the selection criteria for LADA patients, making it difficult to generalise findings from these studies., Authors' Conclusions: There are few studies on this topic and existing studies have a high risk of bias. However, there does seem to be an indication that SU should not be a first line treatment for antibody positive type 2 diabetes. There is no significant evidence for or against other lines of treatment of LADA.

Latent autoimmune diabetes iln adults (LADA) is the term used for patients with non-insulin dependent diabetes who progress to insulin dependency as their pancreatic secretion of insulin fails. Diagnosis is based on adult age at the time of diabetes, the presence of serum autoantibodies to pancreatic antigens and the absence of a requirement for insulin at diagnosis. High titres of serum glutamic acid decarboxylase (GAD) antibodies act as a marker for LADA. Serum C-peptide concentrations are also lower in autoimmune diabetic patients. The best treatment for patients with LADA is not clear, but early insulin treatment may prevent pancreatic beta-cell failure.

A total of 22 individuals participated in this benchmark study to characterize the thermodynamics of small-molecule inhibitor-enzyme interactions using Biacore instruments. Participants were provided with reagents (the enzyme carbonic anhydrase II, which was immobilized onto the sensor surface, and four sulfonamide-based inhibitors) and were instructed to collect response data from 6 to 36 degrees C. van't Hoff enthalpies and entropies were calculated from the temperature dependence of the binding constants. The equilibrium dissociation and thermodynamic constants determined from the Biacore analysis matched the values determined using isothermal titration calorimetry. These results demonstrate that immobilization of the enzyme onto the sensor surface did not alter the thermodynamics of these interactions. This benchmark study also provides insights into the opportunities and challenges in carrying out thermodynamic studies using optical biosensors.

Background: Injury in the home is extremely common, accounting for around a third of all injuries. The majority of injuries of children under five and people aged 75 and over, occur at home. Multifactorial injury prevention interventions have been shown to reduce injuries in the home. However, few studies have focused specifically on the impact of physical adaptations to the home environment and the effectiveness of such interventions needs to be ascertained., Objectives: To review the evidence for the effect on injuries of modification of the home environment with a primary focus on interventions to reduce physical hazards., Search Strategy: We searched The Cochrane Library, MEDLINE, EMBASE, National Research Register and other specialised databases. We also scanned conference proceedings and reference lists. In addition, we contacted experts and trialists in the field. The searches were not restricted by language or publication status. The searches were last updated in December 2004., Selection Criteria: Randomised controlled trials., Data Collection and Analysis: All abstracts were screened by two authors for relevance, outcome and design. Two authors independently assessed methodological quality and extracted data from each eligible study., Main Results: We found 18 published and one unpublished trials. Trials were not sufficiently similar to allow pooling of data by statistical analyses, so this review takes a narrative form. Studies were divided into three groups based on the primary population sample; children (five studies), older people (14 studies) and the general population/mixed age group (no studies). None of the studies focusing on children demonstrated a reduction in injuries that might have been due to environmental adaptation in the home; one study reported a reduction in injuries and in hazards but the two could not be linked. Of the 14 included studies in older people, none demonstrated a reduction in injuries due to hazard reduction, although two demonstrated a reduction in falls that could be due to hazard reduction., Authors' Conclusions: There is insufficient evidence to determine the effects of interventions to modify environmental home hazards. Further interventions to reduce hazards in the home should be evaluated by adequately designed randomised controlled trials measuring injury outcomes. Recruitment of large study samples to measure effect must be a major consideration for future trials.

Objective: To determine the prevalence of painful diabetic peripheral neuropathy (PDPN) in a population-based sample and to estimate its severity and impact., Research Design and Methods: A cross-sectional descriptive study consisting of two phases: phase 1, a postal survey to patients with type 2 diabetes (an initial screening questionnaire including one question about pain); phase 2, neurological history and examination using the Toronto Clinical Scoring System. Subjects with PDPN or mixed (PDPN and nonneuropathic) pain completed the Neuropathic Pain Scale and Neuroqol to assess severity and nature of the pain and impact on quality of life. Those without PDPN completed the Neuroqol only., Results: In phase 1, there was a 92.7% response (n = 326), with 208 (63.8%) subjects reporting pain. In phase 2, 269 (82.5%) subjects attended and 51 (19.0%) were found to have PDPN: 99 (36.8%) nonneuropathic pain, 20 (7.4%) mixed pain, and 99 (36.8%) no pain (PDPN prevalence 26.4%). Of those with PDPN, 80% stated that their pain was moderate or severe. Those affected had poorer quality of life than those with no pain (difference in mean scores 3.6 [95% CI 2.5-4.6%]) compared with those with nonneuropathic pain (1.7 [0.4-2.9%]). Both pain and neuropathy score were independently associated with quality of life, and subjects with PDPN had significantly higher neuropathy scores., Conclusions: Our study showed a prevalence of PDPN of 26.4%. Having PDPN has a significant negative effect on quality of life, and increasing neuropathy is associated with an increasing risk of developing PDPN.

Purpose: To bring to the attention of health care professionals a framework and set of ideas for conceptualising a typical patient's experience and ways to respond out of a subjective inner quality called personal excellence., Design/methodology/approach: This paper essays the viewpoint of the author on a selection of his experiences as a patient over 19 hospital admissions during his lifetime. He integrates these findings with his understanding of personal construct psychology, the psychology of change and the Greek philosophical concept of "arete" or excellence., Findings: The paper offers a theory that patients experience three kinds of emotions or anguish when admitted to hospitals called threat, fear and anxiety. These three ways of interpreting an experience of change are based on the diagnostic constructs of transition from the psychology of personal constructs or the psychology of change. The paper asserts that a holistic approach is more likely to be delivered by health care staff with a calling than those who are merely doing a job or pursuing a career., Originality/value: This paper is significant in that it draws on authentic experiences of a patient that are conceptualised into a coherent framework and linked to a well-accepted theory within the science of psychology. Further it offers an alternative to essays on quality that are confined to objective features only. It offers a way, via the philosophical concept of "arete" to tap into the subjective attitudinal dimension of quality that is often the lever or more often the impediment to enabling quality improvement programmes to be effective.

The proportion of the population over the age of retirement has risen in many countries, and this means there is a corresponding rise in the incidence of hip fractures. However, in order to reliably investigate the ability of interventions to prevent fracture, there needs to be a reliable measure of the incidence of hip fracture. The purpose of this study was to examine the inclusion and exclusion criteria used to identify hip fracture from hospital admission data and to examine the impact that these criteria have on estimated incidence of hip fracture. We examine the influence of: individual compared to consultant episode data; primary data compared to any diagnosis of hip fracture; emergency compared to elective admissions; and the influence of type and rate of surgery on incidence estimates. The results showed that classifying hip fractures by use of consultant episodes overestimated the rate of hip fracture by 6-31%, and this overestimation has increased in recent years. The use of primary diagnosis as opposed to any diagnosis underestimates hip fracture by 5%. Two percent (2%) of the people studied had an operation for a hip fracture but did not have a hip fracture diagnosis (many had a multiple fracture diagnosis), and 5.5% of the people studied had an elective admission for the hip fracture (perhaps falling in hospital during an elective admission). We conclude that the selection criteria can have a great influence on the number of hip fractures identified using routine data. There should be a standardized selection procedure for the identification of hip fracture, as this would enable interventions and preventive measures to be evaluated over time and facilitate comparisons of rates in different regions and countries, in order to examine factors associated with hip fracture.

Injury indicators can be used to give policy makers an estimate of the scale of injuries and their long-term effects. They can help compare injury levels in different areas and countries and can be used to help measure the effectiveness of interventions. Work on severity related indicators is promising. However there are no perfect indicators to date as many are hampered with difficulties in case definition and under reporting. For example, mortality rates are affected by improvements in care even if the incidence of an injury remains the same, the abbreviated injury scale (AIS) takes 10-20 minutes to code and so is not used in health service databases, surveys have problems with recall bias, definition of injury and response rates. If we accept that we need to make the best out of imperfect indicators and imperfect data then we should use multiple sources of data and accept that no one indicator can be used universally but needs to be selected for the purpose. For example, one possible new indicator of the incidence of non-fatal injury might be fracture data in the emergency department. Fractures are painful and so nearly always end up with a hospital attendance. This might give a means to compare incidence of non-fatal injury in different areas and countries. In conclusion, we need injury indicators to progress in injury prevention. Imperfect indicators can be used for targeting and evaluating interventions as long as we know and adjust for their limitations.

Objective: The minimum clinically important difference (MCID) is the minimum level of change of an outcome measure that is considered to be clinically relevant. This prospective study was conducted to establish the minimum level of change in the Bath Ankylosing Spondylitis (BAS) indices that is meaningful for both the patient and the clinician., Methods: The BAS questionnaires [i.e., Bath Ankylosing Spondylitis Functional Index (BASFI); Bath Ankylosing Spondylitis Disease Activity Index (BASDAI); and Bath Ankylosing Spondylitis patient Global score (BAS-G)] were administered to 125 patients with ankylosing spondylitis (AS) at baseline and at the end of a 2-week intensive physiotherapy program. Together with the final assessment, a global validated rating scale was used to examine each domain. Receiver operating characteristic (ROC) curves were plotted to determine the BAS change score that most accurately classified patients with respect to a clinically meaningful change. This analysis was repeated to investigate whether the estimate of change was dependent upon the patients' baseline scores., Results: According to analyses of ROC curves, the MCID are 7 mm or 17.5% for BASFI: sensitivity = 0.60/specificity = 0.85; 10 mm or 22.5% for BASDAI: sensitivity = 0.65/specificity = 0.82; and 15 mm or 27.5% for BAS-G: sensitivity = 0.61/specificity = 0.74. MCID values were independent of the patients' baseline scores (p = 0.09 to 0.72) by regression analysis., Conclusion: This prospective study gives MCID values for BASFI, BASDAI, and BAS-G that allow translation from the BAS indices to readily understood values for both patients and clinicians.

Introduction: Perianal manifestations occur in almost half of patients with Crohn's disease and often respond poorly to conventional therapies. The introduction of anti-tumour necrosis factor alpha agents (e.g. infliximab) has altered the management of patients who fail first and second line medical and surgical therapies., Methods: We performed a literature search of the PubMed database using the Medical Search Headings infliximab, perianal Crohn's disease, fistulae, cost and safety. We also performed a manual search using references from these articles, review articles and proceedings from major gastroenterology meetings., Results: Use of infliximab, at a dose of 5mg/kg at intervals of 0, 2 and 6 weeks, results in significant improvement in disease in approximately 70% of patients with fistulae. Prior examination under anaesthesia with placement of non-cutting seton sutures in fistula tracks is a useful adjunct in many patients. Preliminary results show a benefit from maintenance infliximab therapy and from concomitant use of immunosuppressants such as azathioprine. No clinical or biochemical markers have been identified which predict non-response to infliximab, although its use is contraindicated in patients with strictures. Acute infusion reactions are the most common side-effect of infliximab therapy and they are usually mild. Despite initial fears, the incidence of opportunistic infection is low. There is inadequate information, at present, regarding a possible increase in incidence of lymphoma with infliximab therapy. Infliximab is expensive compared with established therapies and its use will increase the lifetime cost of treating Crohn's disease., Conclusion: While infliximab is a useful adjunct in selected patients, the cornerstones of management of perianal Crohn's are essentially unchanged.

Objective: The heritability of disease activity and function in ankylosing spondylitis (AS) have been estimated at 0.51 and 0.63 (i.e., 51% and 63%), respectively. We examined the concordance of disease severity among family members in terms of disease activity, function, radiological change, prevalence of iritis, and juvenile onset., Methods: Disease activity and functional impairment due to AS were studied using the Bath AS Disease Activity Index (BASDAI) and Functional Index (BASFI) self-administered questionnaires; radiographic involvement was measured using the Bath AS Radiology Index (BASRI) scale. Familial correlation of BASDAI and BASFI was assessed in 406 families with 2 or more cases, using the program PAP. Parent-child and sibling-sibling concordance for iritis and juvenile AS were also studied in these families. Heritability of radiological disease severity based on the BASRI was assessed in 29 families containing 60 affected individuals using the program SOLAR., Results: Correlations between parent-child pairs for disease activity and function were 0.07 for both. Correlations between sibling pairs for disease activity and function were 0.27 and 0.36, respectively. The children of AS parents with iritis were more likely to develop iritis [27/71 (38%)] than children of non-iritis AS parents [13/70 (19%)] (p = 0.01). Parents with JAS were more likely to have children with JAS [17/30 (57%) compared to non-JAS parents 34/111 (30%)] (p = 0.002). The heritability of radiological disease severity based on the BASRI was 0.62., Conclusion: While correlation in severity between parent and child is poor, siblings do resemble each other in terms of severity, supporting the findings of segregation studies indicating significant genetic dominance in the heritable component of disease activity. Significant parent-child concordance for iritis and juvenile disease onset suggest that there are genetic risk factors for these traits independent of those determining the risk of AS itself. The finding of significant heritability of radiological change (BASRI) provides support using an objective measure for the observed heritability of the questionnaire-assessed disease severity scores, BASDAI and BASFI.

Objective: To determine whether visual analog scales (VAS) can be used over the Internet to assess the patient with ankylosing spondylitis (AS) accurately or if the use of this different medium will affect the results., Methods: Patients with AS (n = 50) attending a physiotherapy/educational course completed both an Internet based and a paper based version of the Bath Ankylosing Spondylitis Functional Index (BASFI) that uses VAS. The Internet version was completed twice to assess intrarespondent variation reliability and compared with the paper version to assess interrespondent variation reliability. Patients were also asked to assess ease of use and to suggest changes to the Internet version., Results: The interclass coefficient of intra- and interrespondent reliability were 0.989 (p < 0.001) and 0.976 (p < 0.001), respectively. There was a 3% difference in assessments carried out over the Internet compared to those on paper and a 2% difference in repeatability of Internet assessed questionnaires. Bland and Altman plots showed a mean difference between paper compared to the Internet version was 0.0156 with 95% limits of agreement at -1.07 to 1.03. More than half the participants reported that the Internet version was easier to complete than the paper version (96% rated usability as 1 on a scale of 1-10, with 1 being extremely easy and 10 being impossible)., Conclusion: Assessment of disease severity by VAS may be accurately carried out over the Internet. This means that the evaluation of disease status and the longterm followup of people in different countries and perhaps in different languages may now be possible, using the Internet.

Objectives: In the past, treatment options for ankylosing spondylitis (AS) have been limited, and the introduction of new treatments such as infliximab will have a noticeable impact on health-care budgets. The objective of this study was therefore to assess the current burden of the disease and estimate the cost-effectiveness of infliximab treatments., Methods: A cross-sectional retrospective observational study of resource consumption and utility related to disease severity was performed in patients who had participated in a population survey between 1992 and 1994 at the University of Bath and patients regularly followed at the Royal National Hospital for Rheumatic Diseases in Bath for up to 9 years. Mean costs and utility were estimated using a regression model including age, gender, disease duration, disease activity and functional status, and disease development was expressed as annual progression of functional disability. Cost-effectiveness of infliximab was modelled using a 3-month placebo-controlled clinical trial with open 1-yr extension in 70 patients, over a total time frame of 2 yr. In the model, costs and utility controlled for disease severity and age from the observational study were assigned to individual patients. The effect of long-term treatment was evaluated in a hypothetical model over 30 yr., Results: Fifty-seven per cent of patients answered the questionnaires. The mean age was 57 (s.d. 11.2) yr, 74% were male and mean disease duration was 30.2 (11.7) yr. Mean total costs were estimated at pound 6765 (s.d. pound 166). Indirect costs represented 57.9% and non-medical costs such as investments and informal care accounted for 16.5% of total costs. Mean utility was 0.67 (0.21). In the main model, mean costs for untreated patients are estimated at pound 25,128. For the infliximab group, mean costs (excluding treatment) are estimated at pound 17,240, a reduction of 31%. Thus, part of the treatment cost was offset by savings in other resources ( pound 7888), leaving an incremental cost of pound 6214. Treatment increased the number of quality-adjusted live years (QALYs) by 0.175 QALYs, leading to a cost per QALY gained of pound 35,400 for the first year of treatment. When treatment is assumed to continue for the full 2 yr, the cost per QALY is pound 32,800. When infliximab infusions are given every 8 weeks instead of every 6 weeks, the cost per QALY is reduced to pound 17,300. In the long-term model, the cost per QALY is estimated at pound 9600., Conclusions: Non-medical costs and production losses dominate costs in AS, and economic evaluation must therefore adopt a societal perspective. The cost of treatment with infliximab is partly offset by reductions in the cost of the disease and patients' quality of life is increased, leading to a cost per QALY gained in the vicinity of pound 30,000 to pound 40,000 in the short term, but potentially below pound 10,000 in the long term.

Objectives: To determine whether genetic polymorphisms in or near the transforming growth factor beta1 (TGFB1) locus were associated with susceptibility to or severity of ankylosing spondylitis (AS)., Methods: Five intragenic single-nucleotide polymorphisms (SNP) and three microsatellite markers flanking the TGFB1 locus were genotyped. Seven hundred and sixty-two individuals from 184 multiplex families were genotyped for the microsatellite markers and two of the promoter SNPs. One thousand and two individuals from 212 English and 170 Finnish families with AS were genotyped for all five intragenic SNPs. A structured questionnaire was used to assess the age of symptom onset, disease duration and disease severity scores, including the BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and BASFI (Bath Ankylosing Spondylitis Functional Index)., Results: A weak association was noted between the rare TGFB1 +1632 T allele and AS in the Finnish population (P = 0.04) and in the combined data set (P = 0.03). No association was noted between any other SNPs or SNP haplotype and AS, even among those families with positive non-parametric linkage scores. The TGFB1 +1632 polymorphism was also associated with a younger age of symptom onset (English population, allele 2 associated with age of onset greater by 4.2 yr, P = 0.05; combined data set, allele 2 associated with age of onset greater by 3.2 yr, P = 0.02). A haplotype of coding region SNPs (TGFB1 +869/+915+1632 alleles 2/1/2) was associated with age of symptom onset in both the English parent-case trios and the combined data set (English data set, haplotype 2/1/2 associated with age of onset greater by 4.9 yr, P = 0.03; combined data set, haplotype 2/1/2 associated with greater age of onset by 4.2 yr, P = 0.006). Weak linkage with AS susceptibility was noted and the peak LOD score was 1.3 at distance 2 cM centromeric to the TGFB1 gene. No other linkage or association was found between quantitative traits and the markers., Conclusion: This study suggests that the polymorphisms within the TGFB1 gene play at most a small role in AS and that other genes encoded on chromosome 19 are involved in susceptibility to the disease.

Objective: To examine the evidence that families, where the mother has disease, carry more heritable factors and investigate the effect of maternal/paternal inheritance on phenotypic expression of disease in terms of (a) severity and outcome and (b) additional co-disorders. The children of women with ankylosing spondylitis (AS) develop the disease more often than the children of men. This suggests that either women with disease carry more susceptibility factors than men or that the uterine environment/breast feeding may play a role in AS., Methods: The number of second degree relatives (i.e., grandparent, aunt/uncle) was calculated for those index patients with a mother with disease as opposed to a father. Outcome measures were compared and prevalence of secondary disorders (i.e., psoriasis, iritis, inflammatory bowel disease) was examined in patients with an AS mother as opposed to an AS father., Results: The affected offspring of maternal cases had more second degree relatives with disease [20% vs 9%, respectively, p = 0.012, odds ratio (OR): 2.3, 95% confidence interval (CI): 1.2, 4.5] than did children of affected men. The affected children of a mother with AS were comparable in terms of disease activity, function, and radiology to children of a father with disease. Inflammatory bowel disease was more prevalent among children of AS mothers than AS fathers (15% vs 5%, respectively, p = 0.009, OR: 2.9, 95% CI: 1.3, 6.3). Psoriasis was less prevalent among sons of AS mothers than among sons of AS fathers (9% vs 22%, respectively, p = 0.03, OR: 0.4, 95% CI: 0.2, 0.9)., Conclusion: The inherited susceptibility load is strongly linked to the sex of the parent with AS. Women with disease carry higher heritability (which is associated with inflammatory bowel disease) than do men. There is a male sex impact on susceptibility to psoriasis (when AS is present). However, there is no evidence that the susceptibility load has an effect on outcome or severity of disease (as measured by disease activity, function, and radiology), or that outcome is influenced by transmission of maternal as opposed to paternal factors.

Objective: To identify genomic regions linked with determinants of age at symptom onset, disease activity, and functional impairment in ankylosing spondylitis (AS)., Methods: A whole genome linkage scan was performed in 188 affected sibling pair families with 454 affected individuals. Traits assessed were age at symptom onset, disease activity assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and functional impairment assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI). Parametric and nonparametric quantitative linkage analysis was performed using parameters defined in a previous segregation study., Results: Heritabilities of the traits studied in this data set were as follows: BASDAI 0.49 (P = 0.0001, 95% confidence interval [95% CI] 0.23-0.75), BASFI 0.76 (P = 10(-7), 95% CI 0.49-1.0), and age at symptom onset 0.33 (P = 0.005, 95% CI 0.04-0.62). No linkage was observed between the major histocompatibility complex (MHC) and any of the traits studied (logarithm of odds [LOD] score <1.0). "Significant" linkage (LOD score 4.0) was observed between a region on chromosome 18p and the BASDAI. Age at symptom onset showed "suggestive" linkage to chromosome 11p (LOD score 3.3). Maximum linkage with the BASFI was seen at chromosome 2q (LOD score 2.9)., Conclusion: In contrast to the genetic determinants of susceptibility to AS, clinical manifestations of the disease measured by the BASDAI, BASFI, and age at symptom onset are largely determined by a small number of genes not encoded within the MHC.

Objective: To determine predictors of longterm outcome in ankylosing spondylitis (AS)., Methods: Data were collected retrospectively on constitutional and environmental factors that may predict outcome in AS in 311 patients (252 men, 81%). Univariate statistics and multivariable linear regression analyses were used to identify factors correlated with disease outcome, which was defined in terms of radiological (Bath AS Radiology Index, BASRI) and functional status (Bath AS Functional Index, BASFI)., Results: Disease duration, sex, and iritis are independently associated with BASRI and account for 23% (p < 0.001) of variation in radiological scores (BASRI-t), a measure that includes the hip joint in the score. Radiological hip involvement is significantly associated with higher scores of spinal radiological change (BASRI-s) (p < 0.001). Cigarette smoking, radiological status, and Bath AS Disease Activity Index score (BASDAI) are independently associated with and account for 50% of variability in functional status (p < 0.001)., Conclusion: Much of the variability in disease severity in AS remains unexplained. All but one of the factors associated with outcome in this study are inherent. This suggests that genetic factors have a greater influence than environmental factors on radiological progression and disability in AS. It may, however, be possible to improve longterm functional outcome in AS by targeting high risk individuals early in the disease course with more aggressive management strategies and encouraging smoking cessation in all patients with AS.

Objective: Radiological status is an important objective endpoint in the assessment of ankylosing spondylitis (AS). We investigated the disease development of AS using radiological change., Methods: The existing radiographs (n = 2,284) of 571 AS patients attending the Royal National Hospital for Rheumatic Diseases were scored retrospectively using the Bath Ankylosing Spondylitis Radiology Index. (1) Progression of disease was initially examined cross sectionally. Univariate analysis was used to examine factors associated with joint involvement. (2) Progression of disease was then examined longitudinally for patients with films at time of symptom onset. (3) Rate of progression of radiological change was calculated using longitudinal data of 2 sets of radiographs taken 10 years apart (patient number = 54). The results from this were used to extrapolate backwards to age at first radiological change., Results: (1) Progression to cervical spine disease was a function of: disease duration, severity of hip and lumbar involvement, and a history of iritis (p < 0.001). Lumbar involvement was associated with disease duration, age now, and severity of cervical and hip involvement (p < 0.001). Hip involvement was a marker for cervical disease and associated with disease duration (p < 0.001). (2) Longitudinal analysis revealed marked variation among patients with a slow general rate of progression. (3) The progression of AS over any 10 year period is linear [first 10 years = 30% (SD 0.3) of potential change, 10-20 yrs = 40% (SD 0.3) change, 20-30 yrs = 35% (SD 0.4) change (p = 0.5)]. Backward extrapolation suggests that the approximate time of first radiological change is at the age of 8 years. CONCLUSION. (1) AS is a linearly progressive disease with about 35% change every 10 years. Spinal involvement is largely an expression of disease duration while the hips become involved in about 25% of individuals and may predict a more severe outcome for the cervical spine. (2) Backward extrapolation shows that the disease process may start as young as 8 years of age. However, the time interval between the disease trigger and radiological change remains unknown.

Objective: To investigate the role of the gene NOD2 in susceptibility to, and clinical manifestations of, ankylosing spondylitis (AS)., Methods: A case-control study of NOD2 polymorphisms known to be associated with Crohn's disease (CD) (Pro(268)Ser, Arg(702)Trp, Gly(908)Arg, and Leu(1007)fsinsC) was performed in 229 cases of primary AS with no diagnosed inflammatory bowel disease (IBD), 197 cases of AS associated with IBD (referred to as colitic spondylarthritis; comprising 78 with CD and 119 with ulcerative colitis [UC]), and 229 ethnically matched, healthy controls. Associations between NOD2 polymorphisms and several clinical features of AS, including disease severity assessed by questionnaire and age at spondylarthritis onset, were also investigated. Exclusion linkage mapping of chromosome 16 was performed in a separate group of 185 multicase families with AS., Results: An association was identified between Gly(908)Arg and UC spondylarthritis (P = 0.016, odds ratio [OR] 4.6, 95% confidence interval [95% CI] 1.3-16), and a nonsignificant trend with a similar magnitude was observed in association with CD spondylarthritis (P = 0.08, OR 3.9, 95% CI 0.8-18). The Pro(268)Ser variant was inversely associated with UC spondylarthritis (P = 0.003, OR 0.55, 95% CI 0.37-0.82), but not with CD spondylarthritis. No association was demonstrated between NOD2 variants and primary AS, or between other variants of NOD2 and either UC or CD spondylarthritis. Carriage of the Pro(268)Ser polymorphism was associated with greater disease activity as measured by the Bath Ankylosing Spondylitis Disease Activity Index (P = 0.002). Although patients with CD had a younger age at spondylarthritis onset than did those with UC (22.4 years versus 26.4 years; P = 0.01), no association was noted between the NOD2 variants linked with CD and age at spondylarthritis onset. In primary AS, the presence of a gene with a magnitude of association >2.0 was excluded (exclusion logarithm of odds score less than -2.0), and no association was observed with the microsatellite D16S3136., Conclusion: NOD2 variants do not significantly affect the risk of developing primary AS, but may influence susceptibility to, and clinical manifestations of, colitic spondylarthritis.

Objective: Ankylosing spondylitis (AS) is a systemic disorder occurring in genetically predisposed individuals. The disease course appears to be characterized by bouts of partial remission and flares. However, we have little understanding of what is a flare, why they occur, and what lasting effects they have on the patient. We examine the patient's perception of the factors important in defining flare., Methods: Twenty group meetings of 7-12 participants were held over a one year period. A summary statement was written at the end of each discussion and patients were asked to sign the statement if they considered it to be an accurate summary of their answers, or to amend the statement where they disagreed., Results: There were 214 patients questioned (169 men, 45 women; average disease duration 25 years; age of disease onset 22 years). Data show that the main symptoms of flare are pain (100% of groups), immobility (90%), fatigue (80%), and emotional symptoms (depression, withdrawal, anger) (75%). There are 2 types of flare: (1) localized: during which the symptoms affect one area; and (2) generalized: this is a severe event including all the above symptoms and a flu-like illness (fever, sweating) with hot, burning joints, muscle spasm, and increased sensitivity. All patients experience between one and 5 localized flares per year. Fifty-five percent of groups contained patients (n = 85) who experienced a generalized flare. The main perceived triggers of flare were stress (80%) and "overdoing it" (50%). Patients reported that a flare may last anywhere from a few days to a few weeks and relief from flare can be gained by analgesic injections (including opiates) from a doctor, relaxation, sleep, and cannabis (3 individuals). Three-quarters of the groups agreed that there was no longterm effect on the AS following a flare., Conclusion: There are 2 forms of flare: (1) localized to one area or (2) throughout the entire body. Examining the differences between these types of flares may aid our understanding of the biological mechanism of the disease process of AS and allow us to help relieve the symptoms of flare, a highly painful and often depressing phenomenon.

Objective: In the HLA-B27 transgenic mouse model the first litters have been shown to have a higher percentage of diseased offspring than later litters. First-born children (n = 162) have also been shown to have a higher risk of ankylosing spondylitis (AS) than later-born children. We examined this effect of birth order using similar methods but larger numbers., Methods: Patients from the Bath AS database (n = 4517; M:F = 2.5:1) were examined according to position of birth within the family. Chi-squared analysis was used to examine if AS was more prevalent among first-born than later-born children., Results: The first-born child was not significantly more likely to have AS than later-born children (p = 0.295). [Observed compared to expected: 1607 (36%) compared to 1641.13 (36%) for first-born children and 2910 (64%) compared to 2876.3 (64%) for later-born children, respectively.] There was no biological gradient (i.e., inverse correlation between birth order and disease risk)., Conclusion: There was no statistically significant effect of birth order based on our data. Findings suggesting a birth order effect may be skewed, as it is possible that those parents who do have AS will be less likely to have a large family and yet it is their offspring who will be at greatest risk of developing disease. This will affect the data, as those children born into a large family (i.e., high birth order children) will be at a lower risk of AS than any child born into a small but family-history-positive unit.

Objective: To explore the nature of the interrelationship between inflammatory disease of the spine/joints, skin, eye, and bowel [i.e., ankylosing spondylitis (AS), psoriasis, iritis, inflammatory bowel disease (IBD)]., Methods: The study used 4 approaches: (1) analysis of the prevalence of secondary disorders within the AS individual (chi-square and matched pair analysis); (2) study of the temporal relationship between the onset of the different conditions; (3) evaluation of the prevalence of disease among first degree relatives; and (4) influence of secondary disorders on outcome of AS., Results: 1. Among 3287 patients with AS, more than expected had either spondylitis associated with multiple co-disorders or pure AS (with no co-diseases); fewer than expected had AS plus a single co-disease (chi-square = 32.2, p < 0.001). In a matched pair analysis, patients with AS and a secondary disorder were more likely to have an additional concomitant disease, e.g., IBD-AS (n = 335) patients had a higher prevalence of iritis [45.4% vs 36.7%; OR 1.4 (1.1-2.0)] or psoriasis [23.9% vs 14.3%; OR 1.9 (1.3-2.8)] than controls. 2. Among our database subjects, the symptomatic onset of the spinal disease precedes or is contemporaneous with gut, skin, and eye involvement (matched pair t test, p < 0.001). 3. Patients with multiple disorders predict the highest prevalence of co-diseases (i.e., psoriasis, IBD, iritis, or AS) within family members, followed by those AS patients with only IBD, psoriasis, or iritis in descending order. 4. Both psoriasis and IBD increase severity in terrms of function and disease activity of AS in the patient. Radiological change is greatest for those AS subjects with iritis., Conclusion: There is a striking overlap within patients and family members of rheumatological, dermatological, and gastroenterological diseases. The susceptibility genes of these co-disorders appear to overlap with each other and with AS: 1. A patient with 2 inflammatory conditions is at an increased risk of developing an additional related inflammatory disorder. 2. Those with enteropathic spondylarthritis would appear to carry the greatest genetic load in terms of first degree relatives developing inflammatory conditions (including psoriasis and iritis that are not seen in the index IBD-AS patient). 3. The secondary disorders do not precede AS (arguing against psoriasis and IBD allowing for an environmental conduit to pathogenic triggers in AS). The susceptibility factors for these inflammatory conditions may be additive or have a synergistic effect on each other. There is evidence for a shared gene hypothesis.

Objective: Ankylosing spondylitis (AS) is a chronic inflammatory disorder with symptom onset generally occurring in the late teens/mid-twenties. In women, a younger age at onset enhances disease susceptibility in the next generation. We examined the influence of age at symptom onset on phenotypic expression., Methods: Patients were divided into cohorts according to age of symptom onset. The primary outcome measure was radiological progression (by Bath AS Radiology Index, BASRI). Secondary measures were disease activity (Bath AS Disease Activity Index, BASDAI), function (Bath AS Functional Index, BASFI), numbers undergoing AS related surgery, and percentage with secondary disorders., Results: Age at onset had no significant effect on radiological progression (young onset vs late onset, 8.0, 8.6, respectively) disease activity (young vs late, 4.4, 4.4), need for non-hip surgical intervention (9%, 8%, respectively), or prevalence of secondary disorders (iritis, 40%, 41%; psoriasis, 20%, 19%; inflammatory bowel disease, 7.5%, 8.9%). By contrast, there was a striking increase in prevalence of total hip replacement in those with juvenile onset (18%, 8%, respectively; p < 0.001). Regardless of age at onset, spinal progression determined radiologically was greater in those with hip arthritis compared to those without (young onset hip involvement vs non-hip involvement, 9.7 (2.4), 7.2 (3.0) (p < 0.001); late onset hip involvement vs non-hip involvement, 10.1 (2.5), 7.1 (3.0), respectively]. Function deteriorates with age (young onset vs late onset, 3.7, 4.5, respectively; p < 0.01)., Conclusion: (1) Hip disease (young or late onset) is a major prognostic marker for longterm severe disease (patients with hip disease have a spinal score increased by 2.5-3 points or 35-40% more change). (2) Hip involvement is more prevalent among patients with young age at onset. (3) Young onset patients without hip involvement do not have more severe disease. Thus, age at onset, itself, does not influence disease severity. (4) Since hip involvement and not age at onset is associated with worse outcome, patients with a young age at onset may be assumed to have an increased susceptibility load (i.e., genetic component or environmental trigger) rather than more severity genes. The lack of association between severity and age at onset implies that the determinants of susceptibility and severity are independent.

Objective: To assess the role of genes and the environment in determining the severity of ankylosing spondylitis., Methods: One hundred seventy-three families with >1 case of ankylosing spondylitis were recruited (120 affected sibling pairs, 26 affected parent-child pairs, 20 families with both first- and second-degree relatives affected, and 7 families with only second-degree relatives affected), comprising a total of 384 affected individuals. Disease severity was assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and functional impairment was determined using the Bath Ankylosing Spondylitis Functional Index (BASFI). Disease duration and age at onset were also studied. Variance-components modeling was used to determine the genetic and environmental components contributing to familiality of the traits examined, and complex segregation analysis was performed to assess different disease models., Results: Both the disease activity and functional capacity as assessed by the BASDAI and the BASFI, respectively, were found to be highly familial (BASDAI familiality 0.51 [P = 10(-4)], BASFI familiality 0.68 [P = 3 x 10(-7)]). No significant shared environmental component was demonstrated to be associated with either the BASDAI or the BASFI. Including age at disease onset and duration of disease as covariates made no difference in the heritability assessments. A strong correlation was noted between the BASDAI and the BASFI (genetic correlation 0.9), suggesting the presence of shared determinants of these 2 measures. However, there was significant residual heritability for each measure independent of the other (BASFI residual heritability 0.48, BASDAI 0.36), perhaps indicating that not all genes influencing disease activity influence chronicity. No significant heritability of age at disease onset was found (heritability 0.18; P = 0.2). Segregation studies suggested the presence of a single major gene influencing the BASDAI and the BASFI., Conclusion: This study demonstrates a major genetic contribution to disease severity in ankylosing spondylitis. As with susceptibility to ankylosing spondylitis, shared environmental factors play little role in determining the disease severity.

Ankylosing spondylitis (AS) is a common inflammatory arthritis predominantly affecting the axial skeleton. Susceptibility to the disease is thought to be oligogenic. To identify the genes involved, we have performed a genomewide scan in 185 families containing 255 affected sibling pairs. Two-point and multipoint nonparametric linkage analysis was performed. Regions were identified showing "suggestive" or stronger linkage with the disease on chromosomes 1p, 2q, 6p, 9q, 10q, 16q, and 19q. The MHC locus was identified as encoding the greatest component of susceptibility, with an overall LOD score of 15.6. The strongest non-MHC linkage lies on chromosome 16q (overall LOD score 4.7). These results strongly support the presence of non-MHC genetic-susceptibility factors in AS and point to their likely locations.

Individuals with neurofibromatosis 1 (NF1) develop low-grade astrocytomas at an increased frequency. To gain insight into the function of the Nf1 gene product as a growth regulator for astrocytes, we examined mice heterozygous for a targeted Nf1 mutation. In our previous studies, we demonstrated increased numbers of proliferating astrocytes in Nf1 heterozygote (Nf1+/-) mice in vivo. We now show that cultured Nf1+/- astrocytes exhibit a cell-autonomous growth advantage in vitro associated with increased p21-ras pathway activation. Furthermore, we demonstrate that Nf1+/-;wild-type N-ras mice have a similar astrocyte growth advantage in vitro and in vivo as either oncogenic N-ras or Nf1+/-; oncogenic N-ras mice. Lastly, mice heterozygous for targeted defects in both Nf1 and p53 as well as Nf1 and Rb exhibit 3- and 2.5-fold increases in astrocyte proliferation in vivo, respectively, suggesting that abnormalities in Nf1- and p53/Rb-regulated pathways cooperate in the heterozygous state to confer a growth advantage for brain astrocytes. Collectively, these results provide evidence for a cell-autonomous growth advantage in Nf1+/- astrocytes and suggest that some of the brain pathology in individuals with NF1 might result from reduced, but not absent, NF1 gene function., (Copyright 2001 Wiley-Liss, Inc.)

Objective: To develop a simple but reproducible radiological scoring system for the hip in ankylosing spondylitis (AS)., Methods: A consensus approach was used to develop a grading system whereby hip radiographs of 470 patients with AS were scored from 0 to 4 (normal, suspicious, mild, moderate, and severe), producing the Bath Ankylosing Spondylitis Radiology Hip Index ( BASRI-hip or BASRI-h). The system was designed to be specific for AS radiographic change at the hip and includes circumferential joint space narrowing, osteophytes, erosions, and protrusio acetabulae. This score can then be added to the BASRI-spine, forming the grading system BASRI-total, scored 2-16. Radiographs of 134 patients were used to test reproducibility. Blinded radiographs of 100 non-AS patients were included randomly to assess disease specificity. Sensitivity to change was determined using 438 radiographs from 122 patients, over 219 time intervals., Results: Inter and intraobserver variation for the right and left hip showed 83-84% and 94-96% complete agreement, respectively. Disease specificity was 0.76. If non-AS patients with a total hip replacement were excluded, disease specificity was 0.83. Sensitivity to change became apparent at one year (p < 0.001). Grading the hips using a single radiograph takes seconds., Conclusion: BASRI-h is a reliable method for grading hip radiographic change in AS. It is disease-specific, sensitive to change, simple to use, and rapid to perform.

Objectives: It has long been suspected that susceptibility to ankylosing spondylitis (AS) is influenced by genes lying distant to the major histocompatibility complex. This study compares genetic models of AS to assess the most likely mode of inheritance, using recurrence risk ratios in relatives of affected subjects., Methods: Recurrence risk ratios in different degrees of relatives were determined using published data from studies specifically designed to address the question. The methods of Risch were used to determine the expected recurrence risk ratios in different degrees of relatives, assuming equal first degree relative recurrence risk between models. Goodness of fit was determined by chi(2) comparison of the expected number of affected subjects with the observed number, given equal numbers of each type of relative studied., Results: The recurrence risks in different degrees of relatives were: monozygotic (MZ) twins 63% (17/27), first degree relatives 8.2% (441/5390), second degree relatives 1.0% (8/834), and third degree relatives 0. 7% (7/997). Parent-child recurrence risk (7.9%, 37/466) was not significantly different from the sibling recurrence risk (8.2%, 404/4924), excluding a significant dominance genetic component to susceptibility. Poor fitting models included single gene, genetic heterogeneity, additive, two locus multiplicative, and one locus and residual polygenes (chi(2) >32 (two degrees of freedom), p<10(-6) for all models). The best fitting model studied was a five locus model with multiplicative interaction between loci (chi(2)=1.4 (two degrees of freedom), p=0.5). Oligogenic multiplicative models were the best fitting over a range of population prevalences and first degree recurrence risk rates., Conclusions: This study suggests that of the genetic models tested, the most likely model operating in AS is an oligogenic model with predominantly multiplicative interaction between loci.

Background: Ankylosing spondylitis is a genetically determined and commonly familial disorder. Men and women differ in their susceptibility to ankylosing spondylitis, with about 2.5 men affected for every woman with the disease. We investigated the influence of the sex of the index case on disease penetrance within families., Methods: The ages at which 50% and 75% of patients were diagnosed with ankylosing spondylitis were ascertained from a database of 4400 cases. Index patients with children or siblings who were old enough to have obtained a diagnosis (50% and 75% rates) were assessed for prevalence of disease among relatives. Confirmation of diagnosis for affected relatives was sought for all offspring and a random 25% selection of siblings., Findings: Ankylosing spondylitis was more prevalent among children (odds ratio 1.9 [95% CI 1.2-3.0], p<0.005) and siblings (1.5 [1.2-1.9], p<0.0001) of female index cases than among those of male cases. Analyses restricted to index cases with a young age at onset (< or = 21 years) indicated that children of women had an even higher incidence of ankylosing spondylitis (7.2 [1.5-34], p=0.013) than did children of men at similar age at onset. 38% of children of female cases had disease compared with 8% of male cases. There was no difference in sex distribution among affected children or siblings of female patients with ankylosing spondylitis. By contrast, the sons and brothers of male patients had a higher prevalence of the disease (odds ratio 2.6 [1.4-5.2], p=0.003) than did daughters and sisters (1.7 [1.3-2.2], p<0.0001)., Interpretation: The influence of female sex is greater than that of male sex in determining increased susceptibility to ankylosing spondylitis in children. The striking maternal effect is greatest for women with young age at onset, which is not seen in men. The sex ratio of affected children depends on the sex of the affected parent.

Our aim was to develop a reproducible and simple radiological scoring system for ankylosing spondylitis (AS) to use in cross sectional and prospective studies. Regarding validation of the BASRI (Bath Ankylosing Spondylitis Radiology Index), radiographs of 470 patients with AS were scored using the New York criteria for the sacroiliac joints. The lumbar and cervical spine, and hips were similarly graded 0-4. These scores were added together to give BASRI-t (total) and if the hips are excluded to give BASRI-s (spine). Radiographs of 188 patients were used to test reproducibility. Blinded radiographs of 89 non-AS patients were included randomly to assess disease specificity. Sensitivity to change was assessed using 177 radiographs from 40 patients. Regarding the cross sectional study, 2200 radiographs of 550 (104 F:446 M) patients were randomly selected and scored using BASRI. The frequency distribution of BASRI-t and BASRI-s were plotted using a probit plot. Inter and intraobservation showed between 73 and 82% and 73 and 88% complete agreement, with specificity of 0.78-0.89, suggesting scores are disease-specific. Sensitivity to change became apparent at 2 years (p<0.05). Scoring required 30 seconds to complete. BASRI-t was found to be normally distributed using a probit plot. The mean BASRI scores (total, spinal, hip) increased with disease duration. The correlation, however, was poor (r=0.293, 0.347, 0.263, respectively). Those with hip involvement had more severe spinal disease (p<0.0001). Men had more severe spinal disease than women (p<0.0001). We conclude BASRI is a reliable and rapid method to grade radiographic changes in AS. Using this scoring system it can be seen that AS is a slowly progressive disease with much individual variation. Hip patients have more severe spinal disease than those without hip involvement and men have more severe spinal disease than women.

1. It has been widely accepted that the rat aortic depressor nerve contains only baroreceptors. However, the experiments which have provided these negative data have employed whole aortic nerve recording. In the present study, the technical difficulties associated with recording single fibres in vivo, from the rat aortic nerve (diameter 25-50 microm), have been surmounted using a small tip, glass suction electrode technique. 2. Upon switching from normocapnic hyperoxia to hypercapnic hypoxia, irregularly firing units (n = 13) appeared and these were significantly excited by intravenous injections of sodium cyanide (20 microg) but not by rises in arterial blood pressure induced by methoxamine (an alpha1-adrenoreceptor agonist; 10 microg). Inhalation of 100 % oxygen rapidly and reversibly silenced, or profoundly reduced, ongoing activity. 3. Intravenous injection of phenylbiguanide (PBG; a 5-HT3 receptor agonist; 8 microg) strongly stimulated the chemoreceptors and was followed by a period of chemodepression (3-21 s). In contrast none of the single fibre baroreceptors recorded (n = 15) were excited by PBG but all significantly increased their discharge in response to the increases in arterial blood pressure associated with methoxamine and cyanide. Both the excitatory and inhibitory effects of PBG on the chemoreceptor fibres were abolished by ondansetron (a 5-HT3 receptor antagonist: 1 mg kg-1 i.v.; n = 5 animals) whilst the chemoexcitatory action of cyanide was preserved. 4. It is concluded that there are chemoreceptor afferents contained in the aortic nerve of the Sprague-Dawley rat. The 5-HT3 receptor appears not to be a pre-requisite for aortic body chemoexcitation.

Objective: To develop a reproducible and simple radiologic scoring system for the spine in patients with ankylosing spondylitis (AS): the Bath Ankylosing Spondylitis Radiology Index for the spine (BASRI-s)., Methods: Radiographs of 470 patients with AS were scored using the New York criteria for the sacroiliac joints and, similarly, grading the lumbar and cervical spine on a scale of 0-4 (for normal, suspicious, mild, moderate, and severe). These 3 scores were added together to produce the BASRI-s score (scored 2-12). Radiographs of 188 patients were used to test reproducibility. Blinded radiographs of 89 non-AS patients were included, randomly, to assess disease specificity. Sensitivity to change was assessed using 177 radiographs from 58 AS patients., Results: Intra- and interobserver variation showed 75-86% and 73-79% complete agreement at all sites, respectively. Specificities of 0.83-0.89 suggested that the lumbar and cervical spine BASRI scores were disease specific. Sensitivity to change became apparent at 2 years (P < 0.001). Using a lateral view and an anteroposterior view of the lumbar spine was more sensitive than using a lateral view alone. Grading a set of radiographs (sacroiliac joints, lumbar spine, and cervical spine) took 30 seconds., Conclusion: BASRI is a reliable method for grading radiographic changes in patients with AS. It is disease specific, sensitive to change, valid, simple, and rapid to perform.

Objective: To evaluate how much exercise patients with ankylosing spondylitis perform on a regular basis, to analyze demographic and clinical variables that might influence adherence to exercise, and to determine the effect of exercise on disease activity and function., Methods: We analyzed 4282 patients who completed a self-administered questionnaire regarding physical exercise. To determine the relationship between exercise, demographic data, and clinical variables, patients who exercise 2 to 4 hours and 10 or more hours per week were compared to nonexercising controls matched for age, sex, and disease duration., Results: Most of the patients reported 2 to 4 hours of exercise or no exercise. The group who performed moderate exercise had improved function and lower disease activity (p < 0.001, p < 0.015, respectively). The group who performed intensive exercise had improved function, but no difference in disease activity was found (p=0.033, p=0.394, respectively). Adherence to a regular exercise regime is associated with rheumatologist followup, beliefs in the benefits of exercise, and a higher education level., Conclusion: This study suggests there is an optimum duration for exercise performed over a weekly period. Consistency, rather than quantity, is of most importance. Individuals most likely to follow this regime attend a rheumatologist, believe that exercise is of benefit, and are in the higher education category. Those who are less educated and followed by general practitioners should be targeted.