Pain in knee osteoarthritis is associated with variation in the neurokinin 1/substance P receptor (TACR1) gene.

BACKGROUND: Substance P (SP) is a pain- and inflammation-related neuropeptide which preferentially binds to the neurokinin receptor 1 (NK1 ). SP and NK1 receptors have been implicated in joint pain, inflammation and damage in animal models and human studies of osteoarthritis (OA). The aim of this study was to test if genetic variation at the neurokinin 1 receptor gene (TACR1) is associated with pain in individuals with radiographic knee OA. METHODS: Participants from the Genetics of OA and Lifestyle study were used for the discovery group (n = 1615). Genotype data for six SNPs selected to cover most variation in the TACR1 gene were used to test for an association with symptomatic OA. Replication analysis was performed using data from the Chingford 1000 Women Study, Hertfordshire Cohort Study, Tasmanian Older Adult Cohort Study and the Clearwater OA Study. In total, n = 1715 symptomatic OA and n = 735 asymptomatic OA individuals were analysed. RESULTS: Out of six SNPs tested in the TACR1 gene, one (rs11688000) showed a nominally significant association with a decreased risk of symptomatic OA in the discovery cohort. This was then replicated in four additional cohorts. After adjusting for age, gender, body mass index and radiographic severity, the G (minor) allele at rs11688000 was associated with a decreased risk of symptomatic OA compared to asymptomatic OA cases (p = 9.90 × 10-4 , OR = 0.79 95% 0.68-0.90 after meta-analysis). CONCLUSIONS: This study supports a contribution from the TACR1 gene in human OA pain, supporting further investigation of this gene's function in OA. SIGNIFICANCE: This study contributes to the knowledge of the genetics of painful osteoarthritis, a condition which affects millions of individuals worldwide. Specifically, a contribution from the TACR1 gene to modulating pain sensitivity in osteoarthritis is suggested.

Cell therapy for type 1 diabetes.

Cell therapy in the form of human islet transplantation has been a successful form of treatment for patients with type 1 diabetes for over 10 years, but is significantly limited by lack of suitable donor material. A replenishable supply of insulin-producing cells has the potential to address this problem; however to date success has been limited to a few preclinical studies. Two of the most promising strategies include differentiation of embryonic stem cells and induced pluripotent stem cells towards insulin-producing cells and transdifferentiation of acinar or other closely related cell types towards ß-cells. Here, we discuss recent progress and challenges that need to be overcome in taking cell therapy to the clinic.

Changing presentation of prostate cancer in a UK population--10 year trends in prostate cancer risk profiles in the East of England.

BACKGROUND: Prostate cancer incidence is rising in the United Kingdom but there is little data on whether the disease profile is changing. To address this, we interrogated a regional cancer registry for temporal changes in presenting disease characteristics. METHODS: Prostate cancers diagnosed from 2000 to 2010 in the Anglian Cancer Network (n=21,044) were analysed. Risk groups (localised disease) were assigned based on NICE criteria. Age standardised incidence rates (IRs) were compared between 2000-2005 and 2006-2010 and plotted for yearly trends. RESULTS: Over the decade, overall IR increased significantly (P<0.00001), whereas metastasis rates fell (P<0.0007). For localised disease, IR across all risk groups also increased but at different rates (P<0.00001). The most striking change was a three-fold increase in intermediate-risk cancers. Increased IR was evident across all PSA and stage ranges but with no upward PSA or stage shift. In contrast, IR of histological diagnosis of low-grade cancers fell over the decade, whereas intermediate and high-grade diagnosis increased significantly (P<0.00001). CONCLUSION: This study suggests evidence of a significant upward migration in intermediate and high-grade histological diagnosis over the decade. This is most likely to be due to a change in histological reporting of diagnostic prostate biopsies. On the basis of this data, increasing proportions of newly diagnosed cancers will be considered eligible for radical treatment, which will have an impact on health resource planning and provision.

A personalised approach to prostate cancer screening based on genotyping of risk founder alleles.

BACKGROUND: To evaluate whether genotyping for 18 prostate cancer founder variants is helpful in identifying high-risk individuals and for determining optimal screening regimens. METHODS: A serum PSA level was measured and a digital rectal examination (DRE) was performed on 2907 unaffected men aged 40-90. Three hundred and twenty-three men with an elevated PSA (≥4 ng ml⁻¹) or an abnormal DRE underwent a prostate biopsy. All men were genotyped for three founder alleles in BRCA1 (5382insC, 4153delA and C61G), for four alleles in CHEK2 (1100delC, IVS2+1G>A, del5395 and I157T), for one allele in NBS1 (657del5), for one allele in HOXB13 (G84E), and for nine low-risk single-nucleotide polymorphisms (SNPs). RESULTS: On the basis of an elevated PSA or an abnormal DRE, prostate cancer was diagnosed in 135 of 2907 men (4.6%). In men with a CHEK2 missense mutation I157T, the cancer detection rate among men with an elevated PSA or an abnormal DRE was much higher (10.2%, P=0.0008). The cancer detection rate rose with the number of SNP risk genotypes observed from 1.2% for men with no variant to 8.6% for men who carried six or more variants (P=0.04). No single variant was helpful on its own in predicting the presence of prostate cancer, however, the combination of all rare mutations and SNPs improved predictive power (area under the curve=0.59; P=0.03). CONCLUSION: These results suggest that testing for germline CHEK2 mutations improves the ability to predict the presence of prostate cancer in screened men, however, the clinical utility of incorporating DNA variants in the screening process is marginal.

Incident knee pain in the Nottingham community: a 12-year retrospective cohort study.

OBJECTIVES: To determine the community incidence of knee pain and associated risk factors over a 12-year period in people over the age of 40 years. METHOD: A cohort study of knee pain was undertaken in 2156 people from four general practices in North Nottinghamshire, UK. Knee pain was defined as 'pain around the knee for most days of at least a month'. Cumulative incidence over 12 years and person-year incidence rate of knee pain were estimated. Survival analysis was undertaken for time to the onset of knee pain. Hazard ratio (HR) and 95% confidence interval (CI) were estimated for relative risk between exposure and non-exposure. Cox regression model was used to adjust for confounding factors. RESULTS: The 12-year cumulative incidence of knee pain was 34.4% (32% for men and 35% for women), corresponding to an average incidence rate of 32 (31 for men and 34 for women)/1000 person-years. Incident knee pain was associated with female gender (HR 1.27, 95% CI 1.08, 1.49), obesity (1.80; 95% CI 1.37, 2.38), varus (1.68, 95% CI 1.15, 2.47) and valgus (1.83, 95% CI 1.05, 3.20) mal-alignment, and knee injury (2.37, 95% CI 2.98, 2.85). CONCLUSIONS: For people over age 40, one in three will develop knee pain within 12 years. On average, the risk of knee pain was 32/1000 person-years. This risk is associated with a variety of constitutional and environmental biomechanical insults to the knee. Some of these could be modified to possibly reduce the incidence of the condition.

Lifetime body mass index, other anthropometric measures of obesity and risk of knee or hip osteoarthritis in the GOAL case-control study.

OBJECTIVE: To examine the risk of large joint osteoarthritis (OA) in those becoming overweight during early adult life, and to assess the risks associated with high body mass index (BMI) and other anthropometric measures of obesity. METHODS: BMI, waist and hip circumference were measured in the GOAL case-control study comprising hip OA cases (n=1007), knee OA cases (n=1042) and asymptomatic controls (n=1121). Retrospective estimates of lifetime weight, body shape and other risk factors were collected using an interview-lead questionnaire. Odds ratios (ORs), adjusted OR (aOR), 95% confidence intervals (CIs) and P values were calculated using logistic regression analysis. RESULTS: BMI was associated with knee OA (aOR 2.68, 95% CI 2.33-3.09, P-trend<0.001) and hip OA (aOR 1.65, 95% CI 1.46-1.87, P-trend<0.001). Those who became overweight earlier in adulthood showed higher risks of lower limb OA (P-trend<0.001 for knee OA and hip OA). Self-reported body shape was also associated with knee OA and hip OA, following a similar pattern to current and life-course BMI measures. Waist:hip ratio (WHR) at time of examination did not associate with OA independently of BMI, except in women-only analysis. Waist circumference was associated with lower limb OA risk. CONCLUSIONS: Becoming overweight earlier in adult life increased the risks of knee OA and hip OA. Different distribution patterns of adiposity may be related to OA risk in women.

Large-scale meta-analysis of interleukin-1 beta and interleukin-1 receptor antagonist polymorphisms on risk of radiographic hip and knee osteoarthritis and severity of knee osteoarthritis.

OBJECTIVE: To clarify the role of common genetic variation in the Interleukin-1ß (IL1B) and Interleukin-1R antagonist (IL1RN) genes on risk of knee and hip osteoarthritis (OA) and severity of knee OA by means of large-scale meta-analyses. METHODS: We searched PubMed for articles assessing the role of IL1B and IL1RN polymorphisms/haplotypes on the risk of hip and/or knee OA. Novel data were included from eight unpublished studies. Meta-analyses were performed using fixed- and random-effects models with a total of 3595 hip OA and 5013 knee OA cases, and 6559 and 9132 controls respectively. The role of ILRN haplotypes on radiographic severity of knee OA was tested in 1918 cases with Kellgren-Lawrence (K/L) 1 or 2 compared to 199 cases with K/L 3 or 4. RESULTS: The meta-analysis of six published studies retrieved from the literature search and eight unpublished studies showed no evidence of association between common genetic variation in the IL1B or IL1RN genes and risk of hip OA or knee OA (P>0.05 for rs16944, rs1143634, rs419598 and haplotype C-G-C (rs1143634, rs16944 and rs419598) previously implicated in risk of hip OA). The C-T-A haplotype formed by rs419598, rs315952 and rs9005, previously implicated in radiographic severity of knee OA, was associated with reduced severity of knee OA (odds ratio (OR)=0.71 95%CI 0.56-0.91; P=0.006, I(2)=74%), and achieved borderline statistical significance in a random-effects model (OR=0.61 95%CI 0.35-1.06 P=0.08). CONCLUSION: Common genetic variation in the Interleukin-1 region is not associated with prevalence of hip or knee OA but our data suggest that IL1RN might have a role in severity of knee OA.

A meta-analysis of interleukin-6 promoter polymorphisms on risk of hip and knee osteoarthritis.

OBJECTIVE: Interleukin-6 is a pro-inflammatory cytokine involved in the pathogenesis of osteoarthritis (OA). We investigated the role of two single nucleotide polymorphisms (SNPs) mapping to the promoter of the IL-6 gene on genetic susceptibility to hip and knee OA. METHODS: The -174G/C (rs1800795) and -597G/A (rs1800797) SNPs, implicated in the literature in risk of hip and hand OA, were genotyped in 2511 controls, 1101 hip OA cases and 1904 knee OA cases from four cohorts from the UK and Estonia. Data were analysed in conjuntion with published data on rs1800797 from the Genetics of OA and Lifestyle study (UK) on 791 controls, 1034 knee and 997 hip OA cases and rs1800795 data on 75 hip OA cases and 96 controls from Italy. Cases included both radiographic OA only and radiographic and symptomatic OA. Fixed and random-effects meta-analysis models were tested. RESULTS: No significant association was found with hip OA or knee OA with either SNP nor with the haplotypes formed by them. For individual SNPs the smallest P-value for hip OA was observed using a random-effects model for rs1800795 OR(Gallele)=1.066 (95% CI 0.89-1.28) P<0.49, and significant heterogeneity between cohorts (I(2)=65%, P<0.034) was detected. For knee OA the smallest P-value was seen for rs1800797 OR(Aallele)=1.055 (95%CI 0.98-1.12) P<0.18, no significant heterogeneity was observed (I(2)=0%, P<0.68). CONCLUSIONS: Our data do not support a role for the -174 and -597 IL-6 promoter polymorphisms in genetic susceptibility to knee or hip OA in Caucasian populations.

Attempt to replicate published genetic associations in a large, well-defined osteoarthritis case-control population (the GOAL study).

OBJECTIVE: Published studies have tested over 90 genes for association with osteoarthritis (OA), but few positives reported have been independently replicated. Using a new case-control study, our aim was to attempt the replication of findings from 12 genes reported to have significant genetic association with OA and to further examine the role of genetic variation in six of these genes. METHODS: A case-control study was undertaken in Nottingham, UK. Hospital-referred index cases with symptomatic, radiographic OA (ROA) of the knee (n=1040) or hip (n=1004) were recruited. Asymptomatic controls (n=1123) were recruited from intravenous urography waiting lists and screened for radiographic hip and knee OA. Sixty-eight polymorphisms were genotyped in IL1A, IL1B, IL1RN, IL4R, IL6, COL2A1, ADAM12, ASPN, IGF1, TGFB1, ESR1 and VDR. Statistical analysis compared allele or genotype frequencies of these polymorphisms in all asymptomatic controls and the subset of controls without ROA vs all OA, knee OA and hip OA. The analyses were adjusted for age, gender and body mass index. RESULTS: We were unable to replicate any of the published genetic associations investigated. Our extended exploratory analyses identified some associations between polymorphisms in TGFB1, IGF1 and IL1RN and OA; but the strength of evidence varied with the control group used. CONCLUSION: Lack of replication is common and could be due to differences in study design, phenotype, populations examined or the occurrence of false positives in the initial study. Variants within TGFB1, IGF1 and IL1RN could have a role in OA susceptibility; however, replication of these findings is required in an independent study.

Index to ring finger length ratio and the risk of osteoarthritis.

OBJECTIVE: To determine the relationship between the index to ring finger (2D:4D) length ratio and the risk of knee and hip osteoarthritis (OA). METHODS: We conducted a case-control study, in which cases with persistent symptoms and radiographic evidence of knee or hip OA were compared with controls with no symptoms and no radiographic evidence of knee or hip OA. Hand radiographs were visually classified as type 1 (index finger longer than the ring finger), type 2 (index finger equal to the ring finger), or type 3 (index finger shorter than the ring finger). The 2D:4D phalangeal and metacarpal length ratios were measured separately. The odds ratio (OR) and 95% confidence interval (95% CI) were calculated and adjusted for possible confounding factors using a logistic regression model. RESULTS: Of 2,049 cases, 1,013 had radiographic evidence of knee OA and 995 had hip OA. Of 1,123 controls, 836 had no knee OA and 1,050 had no hip OA. The type 3 finger pattern was associated with knee OA (OR 1.94, 95% CI 1.54-2.44), and the risk was greater in women (OR 3.05, 95% CI 2.08-4.47) than in men (OR 1.45, 95% CI 1.08-1.95). There was a dose-response relationship between both 2D:4D phalangeal and metacarpal length ratios and the risk of knee OA. The risk of hip OA was inconsistent. CONCLUSION: Compared with types 1 and 2, the type 3 "male" pattern 2D:4D length ratio is associated with OA, especially knee OA. The risk is independent of other major OA risk factors.

Dietary zinc intake and brain cancer in adults: a case-control study.

Little is known about the aetiology of brain tumours. One putative factor suggested from animal models is a protective effect of dietary Zn. We tested the hypothesis that increased compared with low dietary Zn intake is protective against brain tumour development. We conducted a population-based case-control study in the UK, of adults aged 18-69 years, between 2001 and 2004 aiming to identify possible risk factors. Dietary information was collected from 637 cases diagnosed with a glioma or meningioma, and 876 controls. Data were obtained from a self-completed FFQ. Multivariate logistic regression analysis was conducted, adjusting for socio-demographic factors, season of questionnaire return, multivitamin supplementation and energy intake. Although a weak protective effect was observed for the third quartile of intake (normal compared with low intake) in the meningioma group, this was limited to the specific brain tumour subtype and quartile, and was not significant after also adjusting for intake of other elements. Overall there was no significant effect of Zn intake. No association or dose-response relationship was observed between increased compared with low Zn intake and risk of glioma or meningioma.

Radiographic assessment of the index to ring finger ratio (2D:4D) in adults.

The smaller index to ring finger (2D:4D) ratio has been considered as a 'male finger pattern' and is associated with sporting ability and a number of conditions. However, the ratio may vary according to what is measured, the hand selected and the method used. This study aimed to determine: (1) which bones (phalanges, metacarpals or both) account for variation in the 2D:4D ratio; (2) whether the ratio shows right-left symmetry or relates to hand dominance; and (3) the correlation between visual classification and measured determinations of the ratio based on radiographs. Hand radiographs obtained as part of a large osteoarthritis genetic study were examined. Each hand was classified visually into three types according to the relative length of the index and ring finger: Type 1 (index longer than ring), Type 2 (index = ring) and Type 3 (index shorter than ring). For both index and ring fingers we measured (1) from base of proximal to tip of distal phalanx and (2) metacarpal length. Reproducibility of the classification and measurements were examined using kappa and intraclass correlation coefficient; symmetry between left and right hands was examined using Bland and Altman's agreement analysis; and correlation between visual classification and 2D:4D ratio data was analysed using the anova linearity test. Data were obtained from 3172 radiographs (1636 men, 1536 women; mean age 67 +/- 7.9 years, range 45-86 years). Prevalence of Type 3 hand was 61% in men and 37% in women (P < 0.001). Men had smaller 2D:4D ratios than women for phalanges (0.908 versus 0.922, P < 0.01), metacarpals (1.152 versus 1.157, P < 0.01) and the sum of phalanges plus metacarpals (1.005 versus 1.015, P < 0.01). The mean difference between right and left was -0.001 (95% limit of agreement -0.035, 0.032) for the phalangeal ratio and 0.003 (95% limit of agreement -0.051 to 0.057) for the metacarpal ratio. The 2D:4D ratio did not associate with handedness or age. There was a linear trend between the visual classification of hand type and the 2D:4D ratio data (P < 0.001). More technical difficulties (due to positioning, finger trauma, osteoarthritis) were encountered with the phalangeal ratio and visual categorization than with the metacarpal ratio: the latter could be measured in 98.7% of the study population. We concluded that measured 2D:4D ratios and visual categorization can be derived from hand radiographs. The phalanges and metacarpals both contribute to the variation in 2D:4D ratio with smaller ratios observed in men than in women. The ratio is symmetrical with only very small differences between right and left hands. Visual classification may be a useful simple tool for future epidemiological studies but is more prone to bias from positioning than direct measurement. If radiographs are used for this purpose, we recommend the metacarpal ratio with measurement of a single index hand or an average of both as it is least affected by bias from malpositioning, trauma or common joint disease.

Thymidylate synthase polymorphisms, folate and B-vitamin intake, and risk of colorectal adenoma.

The effects of polymorphisms in genes coding for key folate metabolism enzymes such as thymidylate synthetase (TS) on colorectal neoplasia risk are likely to be influenced by gene-gene and gene-nutrient interactions. We investigated the combined effects of three polymorphisms in the TS gene region, TSER, TS 3R G>C, and TS 1494del6, dietary intakes of folate and other B vitamins, and genotype for other folate metabolism variants, in a colorectal adenoma (CRA) case-control study. Individuals homozygous for TS 1494del6 del/del were at significantly reduced CRA risk compared to those with either ins/del or ins/ins genotypes (odds ratio 0.52; 95% confidence interval: 0.31-0.85, P=0.009). We also observed evidence of interactions between TS 1494del6 genotype and intake of folate, and vitamins B6 and B12, and MTHFR C677T genotype, with the reduction in risk in del/del homozygotes being largely confined to individuals with high nutrient intakes and MTHFR 677CC genotype (P interaction=0.01, 0.006, 0.03, and 0.07, respectively). TSER genotype, when considered either alone or in combination with TS 3R G>C genotype, did not significantly influence CRA risk. These findings support a role for TS in colorectal carcinogenesis, and provide further evidence that functional polymorphisms in folate metabolism genes act as low-risk alleles for colorectal neoplasia and participate in complex gene-gene and gene-nutrient interactions.

The relationship between body mass index and health-related quality of life: comparing the EQ-5D, EuroQol VAS and SF-6D.

BACKGROUND: No other studies have compared the relationship between body mass index (BMI) and health-related quality of life (HRQL) on more than one utility measure. Estimating the HRQL effects of obesity on a (common) utility scale enables the relative cost-effectiveness of interventions designed to alleviate obesity to be estimated. OBJECTIVE: To examine the relationship between BMI and HRQL according to the EQ-5D, EuroQol visual analogue scale (EQ-VAS) and SF-6D. METHODS: Patients aged >/=45 years at one UK general practice were asked to complete the EQ-5D, EQ-VAS, SF-36 questionnaire (used to derive the SF-6D), and information on their characteristics and co-morbidity. Body mass index was categorized according to the World Health Organization (WHO) recommendations. Regression analysis was used to compare the HRQL of normal BMI patients to the HRQL of patients in other BMI categories, while controlling for patient characteristics and co-morbidity. RESULTS: A total of 1865 patients responded (67%), mean BMI 26.0 kg/m(2), 16% obese (BMI>/=30). Patients with back pain, hip pain, knee pain, asthma, diabetes or osteoarthritis were also significantly more likely to be obese. After controlling for other factors, compared to normal BMI patients, obese patients had a lower HRQL according to the EQ-5D (P<0.01), EQ-VAS (P<0.001) and SF-6D (P<0.001). Pre-obese patients were not estimated to have a significantly lower HRQL, and underweight patients were only estimated to have a significantly lower HRQL according to the SF-6D. These results arose because, on the EQ-5D, obese patients were found to have significantly more problems with mobility and pain, compared to physical functioning, social functioning and role limitations on the SF-6D. Whereas, according to the SF-6D, underweight patients had significantly more problems on the dimension of role limitation. CONCLUSION: The EQ-5D, EQ-VAS and SF-6D were in agreement that, relative to a normal BMI, obesity is associated with a lower HRQL, even after controlling for patient characteristics and co-morbidity. These three measures are thereby sensitive to the HRQL effects of obesity and can be used to estimate the cost-effectiveness of interventions designed to alleviate obesity.

History of allergic disease and risk of meningioma.

Epidemiologic studies have consistently shown inverse associations of allergic disease with risk of glioma, but it is unclear whether this association also applies to meningioma. The authors conducted a pooled analysis of meningioma risk in relation to a history of allergic disease based on data from two population-based, case-control studies with 475 cases and 1,716 controls in the United Kingdom (2001-2004). Meningioma risk was significantly reduced in relation to self-reported, physician-diagnosed allergic disease (odds ratio = 0.76, 95% confidence interval (CI): 0.61, 0.96) but was nonsignificantly reduced for individual conditions: asthma (odds ratio = 0.85, 95% CI: 0.61, 1.18), hay fever (odds ratio = 0.81, 95% CI: 0.62, 1.06), and eczema (odds ratio = 0.72, 95% CI: 0.51, 1.02). Risk reductions were greatest for asthma (odds ratio = 0.43, 95% CI: 0.21, 0.89) and hay fever (odds ratio = 0.50, 95% CI: 0.25, 1.00) with an early age at onset (<10 years) and for eczema (odds ratio = 0.46, 95% CI: 0.21, 1.07) with an onset at ages 10-19 years; they were near unity for onset in adulthood. This study suggests an inverse association between a history of allergies and meningioma risk, but with smaller risk reductions than for glioma. The reasons for this association need clarification, as well as an etiologic explanation. Consideration also needs to be given to confounding or bias.

Assigning exposure to pesticides and solvents from self-reports collected by a computer assisted personal interview and expert assessment of job codes: the UK Adult Brain Tumour Study.

OBJECTIVES: To compare assignment of occupational pesticide and solvent exposure using self-reported data collected by a computer assisted personal interview (CAPI) with exposure based on expert assessment of job codes. To discuss the advantages and disadvantages of using a CAPI to collect individual occupational exposure data. METHODS: Between 2001 and 2004, 1495 participants were interviewed using a CAPI for a case-control study of adult brain tumours and acoustic neuromas. Two types of occupational data were collected: (1) a full history, including job title from which a job code was assigned from the Standard Occupational Classification; and (2) specific details on pesticide and solvent exposure reported by participants. Study members' experiences of using the CAPI were recorded and advantages and disadvantages summarised. RESULTS: Of 7192 jobs recorded, the prevalence of self-reported exposure was 1.3% for pesticides and 11.5% for solvents. Comparing this with exposure expertly assessed from job titles showed 53.6% and 45.8% concordance for pesticides and solvents respectively. Advantages of the CAPI include no data entry stage, automatic input validation, and a reduction in interviewer bias. Disadvantages include an adverse effect on study implementation as a consequence of resources required for programming and difficulties encountered with data management prior to analysis. CONCLUSIONS: Different methods of exposure assessment derive different exposure levels for pesticide and solvent exposure at work. Agreement between self-reported and expert assessment of exposure was greater for pesticides compared to solvents. The advantages of using a CAPI for the collection of complex data outweigh the disadvantages for interviewers and data quality but using such a method requires extra resources at the study outset.

Cost effectiveness of a two-year home exercise program for the treatment of knee pain.

OBJECTIVE: To assess the cost effectiveness of a 2-year home exercise program for the treatment of knee pain. METHODS: A total of 759 adults aged > or = 45 years were randomized to receive exercise therapy, monthly telephone contact, exercise therapy and telephone contact, or no intervention. Efficacy was measured using self-reported knee pain at 2 years. Costs to both the National Health Service and to the patient were included. RESULTS: Exercise therapy was associated with higher costs and better effectiveness. Direct costs for the interventions were pound 112 for the exercise program and pound 61 for the monthly telephone support. Participants allocated to receive exercise therapy were significantly more likely to incur higher medical costs than those in the no-exercise groups (mean difference pound 225; 95% confidence interval pound 218, pound 232; P < 0.001). CONCLUSION: Exercise therapy is associated with improvements in knee pain, but the cost of delivering the exercise program is unlikely to be offset by any reduction in medical resource use.

The role of occupational and environmental exposures in the aetiology of acquired severe aplastic anaemia: a case control investigation.

Aplastic anaemia is a rare but serious disorder with a high morbidity and mortality rate. The causes of aplastic anaemia are, for the most part, unknown. We report on the hypothesis that aplastic anaemia may be caused by occupational and/or environmental exposures to certain chemicals. The UK Aplastic Anaemia Study was an interview-based case-control study covering the whole of Great Britain. Those patients diagnosed between 1 July 1993 and 20 October 1997, aged < or =75 years and born and diagnosed in the UK were eligible for the study. Two hundred eligible cases of aplastic anaemia were compared with 387 age- and sex-matched controls. A number of occupational exposures showed increases in risk. In a multivariate model of these exposures the odds ratios (ORs) for solvents/degreasing agents, pesticides and radiation were >2 and statistically significant. Reported chemical treatment of houses within 5 years of diagnosis had a significantly raised risk for adults [OR = 2.51, 95% confidence interval (CI) 1.02-12.01], particularly for woodworm treatment (OR = 5.1, 95% CI 1.5-17.4). This study identified significant risks associated with self-reported exposure to solvents, radiation and pesticides in the workplace. Self-reported chemical treatment of houses was also associated with an increased risk of developing aplastic anaemia, in keeping with previous literature.

Home based exercise programme for knee pain and knee osteoarthritis: randomised controlled trial.

OBJECTIVES: To determine whether a home based exercise programme can improve outcomes in patients with knee pain. DESIGN: Pragmatic, factorial randomised controlled trial of two years' duration. SETTING: Two general practices in Nottingham. PARTICIPANTS: 786 men and women aged >/=45 years with self reported knee pain. INTERVENTIONS: Participants were randomised to four groups to receive exercise therapy, monthly telephone contact, exercise therapy plus telephone contact, or no intervention. Patients in the no intervention and combined exercise and telephone groups were randomised to receive or not receive a placebo health food tablet. MAIN OUTCOME MEASURES: Primary outcome was self reported score for knee pain on the Western Ontario and McMaster universities (WOMAC) osteoarthritis index at two years. Secondary outcomes included knee specific physical function and stiffness (scored on WOMAC index), general physical function (scored on SF-36 questionnaire), psychological outlook (scored on hospital anxiety and depression scale), and isometric muscle strength. RESULTS: 600 (76.3%) participants completed the study. At 24 months, highly significant reductions in knee pain were apparent for the pooled exercise groups compared with the non-exercise groups (mean difference -0.82, 95% confidence interval -1.3 to -0.3). Similar improvements were observed at 6, 12, and 18 months. Regular telephone contact alone did not reduce pain. The reduction in pain was greater the closer patients adhered to the exercise plan. CONCLUSIONS: A simple home based exercise programme can significantly reduce knee pain. The lack of improvement in patients who received only telephone contact suggests that improvements are not just due to psychosocial effects because of contact with the therapist.