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Biomedical subjects

Cyrus Cooper

Publications and source records attributed to Cyrus Cooper.

At least 19 recordsLinked to original sources
PubMed2007

Fracture risk with intermittent high-dose oral glucocorticoid therapy.

OBJECTIVE: To evaluate the risk of fracture in patients receiving intermittent therapy with high-dose oral glucocorticoids (GCs). METHODS: The study group comprised 191,752 patients from the UK General Practice Database who were 40 years of age and older and received therapy with GCs. The followup time period was divided into the categories of "current" and "no exposure." The daily dose and cumulative dose for each time period were determined. Relative risks were estimated using Cox proportional hazards models, adjusted for age, sex, body mass index, smoking, disease history, and drug history. Fractures of the radius/ulna, humerus, rib, femur/hip, pelvis, or vertebrae were included in the evaluation. RESULTS: Patients who intermittently received high-dose GCs (daily dose > or =15 mg) and had no or little previous exposure to GCs (cumulative exposure < or =1 gm) had a small increased risk of osteoporotic (but not hip/femur) fracture; this risk increased substantially with increasing cumulative exposure. Among patients who received a daily dose > or =30 mg and whose cumulative exposure was >5 gm, the relative risk (RR) of osteoporotic fracture was 3.63 (95% confidence interval [95% CI] 2.54-5.20), the RR of fracture of the hip/femur was 3.13 (95% CI 1.49-6.59), and the RR of vertebral fracture was 14.42 (95% CI 8.29-25.08). CONCLUSION: Intermittent use of high-dose oral GCs (daily dose > or =15 mg and cumulative exposure < or =1 gm) may result in a small increased risk of osteoporotic fracture. Conversely, patients who receive several courses of high-dose GCs (daily dose > or =15 mg and cumulative exposure >1 gm) have a substantially increased risk of fracture.

Adult↗
PubMed2007

Prevalence and functionality of paucimorphic and private MC4R mutations in a large, unselected European British population, scanned by meltMADGE.

Identification of unknown mutations has remained laborious, expensive, and only viable for studies of selected cases. Population-based "reference ranges" of rarer sequence diversity are not available. However, the research and diagnostic interpretation of sequence variants depends on such information. Additionally, this is the only way to determine prevalence of severe, moderate, and silent mutations and is also relevant to the development of screening programs. We previously described a system, meltMADGE, suitable for mutation scanning at the population level. Here we describe its application to a population-based study of MC4R (melanocortin 4 receptor) mutations, which are associated with obesity. We developed nine assays representing MC4R and examined a population sample of 1,100 subjects. Two "paucimorphisms" were identified (c.307G>A/p.Val103Ile in 27 subjects and c.-178A>C in 22 subjects). Neither exhibited any anthropometric effects, whereas there would have been >90% power to detect a body mass index (BMI) effect of 0.5 kg/m(2) at P=0.01. Two "private" variants were also identified. c.335C>T/p.Thr112Met has been previously described and appears to be silent. A novel variant, c.260C>A/p.Ala87Asp, was observed in a subject with a BMI of 31.5 kg/m(2) (i.e., clinically obese) but not on direct assay of a further 3,525 subjects. This mutation was predicted to be deleterious and analysis using a cyclic AMP (cAMP) responsive luciferase reporter assay showed substantial loss of function of the mutant receptor. This population-based mutation scan of MC4R suggests that there is no severe MC4R mutation with high prevalence in the United Kingdom, but that obesity-causing MC4R mutation at 1 in 1,100 might represent one of the commonest autosomal dominant disorders in man.

Aged↗
PubMed2007

Quantitated transcript haplotypes (QTH) of AGTR1, reduced abundance of mRNA haplotypes containing 1166C (rs5186:A>C), and relevance to metabolic syndrome traits.

The angiotensin II type 1 receptor (AGTR1) is the main target through which angiotensin II influences cardiovascular tone, cell growth, and fluid and electrolyte balance. AGTR1 polymorphism has been reported to associate with hypertension, myocardial infarction (MI), and metabolic traits. Here we describe a novel approach to quantitation of transcript haplotypes (QTH) of AGTR1. To determine relative allelic expression from haplotypes, within-individual-between-allele ratiometric analyses in placental cDNA were developed for the transcribed SNPs rs5182:C>T (encoding p.L191) and rs5186:A>C (3'-noncoding "A1166C"). Additionally, between-individual comparisons were made using TaqMan assays applied to both homozygous and heterozygous genotypes and haplotypes. In conjunction, linkage disequilibrium (LD) and genomic haplotype associations with metabolic syndrome were examined. There was no significant difference of mRNA level for alleles of rs5182:C>T, but allele and mRNA haplotypes carrying 1166C exhibited reduced abundance. The effect was much greater in CC homozygotes than in heterozygotes. The promoter region was confirmed to be in a separate haplotype block from the AGTR1 3' region containing rs5182:C>T and rs5186:A>C. Metabolic syndrome trait associations were strongest for the 3' block generally and for the C allele of rs5186:A>C specifically. All effects were much more prominent in homozygotes, possibly reflecting interallelic interaction through feedback loops of mRNA regulation. Differential abundance of AGTR1 mRNA haplotypes may mediate clinical phenotypic observations of the AGTR1 genotype.

Aged↗
PubMed2007

Use of beta-2 agonists and risk of hip/femur fracture: a population-based case-control study.

INTRODUCTION: Administration of beta-2 agonists decreased bone mineral density in rats. But the association between bronchodilators and fracture risk has not been studied in humans. OBJECTIVES: To examine the association between use of beta-2 agonists and risk of hip/femur fracture. METHODS: We conducted a population-based case-control study (6763 cases) in the Dutch PHARMO database. Current beta-2 agonist use was compared to never use. We adjusted for severity of the underlying respiratory disease and disease and drug history. RESULTS: A hospitalisation for asthma/COPD in the year before index date increased risk of hip/femur fracture: crude OR 2.17 (95% CI, 1.41-3.34). Patients using higher doses of beta-2 agonists had increased risk of hip/femur fracture: crude OR 1.94 (95% CI, 1.41-2.66) for daily dosages of >or=1600 microg albuterol equivalent. The excess fracture risk reduced after adjustment for disease severity (1.46; 95% CI, 1.02-2.08) and after exclusion of oral glucocorticoid users (1.31; 95% CI, 0.80-2.15). Risk of hip/femur fracture was similar between users of beta-2 agonists, inhaled glucocorticoids and anticholinergics. CONCLUSION: We found increases in the risk of hip/femur fracture in patients using higher doses of beta-2 agonists. However, the excess risk of hip/femur fracture substantially reduced after exclusion of oral glucocorticoid users and after adjustment for the underlying disease. Risk of hip/femur fracture was similar between users of beta-2 agonists, inhaled glucocorticoids and anticholinergics. The severity of the underlying disease, rather than the use of beta-2 agonists, may play an important role in the aetiology of hip/femur fractures in patients using beta-2 agonists.

Adrenergic beta-2 Receptor Agonists↗
PubMed2006

Specific associations of insulin resistance with impaired health-related quality of life in the Hertfordshire Cohort Study.

Insulin resistance is a metabolic abnormality that underlies Type 2 diabetes, the metabolic syndrome and cardiovascular disease, but it may also be associated with more global health deficits. This study assessed associations of insulin resistance with health-related quality of life (HRQoL) in different domains of physical and mental health in a large elderly population study. Cross-sectional data of 1212 participants from the Hertfordshire Cohort Study were analysed. Insulin resistance was assessed by the homeostatic model assessment (HOMA-IR), and HRQoL was measured using the SF-36 health survey. Poor HRQoL was defined by a score lower than the sex-specific 10th percentile of each scale, and logistic regressions yielded odds ratios in relation to the HOMA-IR scores. Subsequent analyses adjusted for the influence of age, smoking, alcohol consumption, social class, BMI, coronary heart disease and depression. Results showed an increase in poor HRQoL with an increase in HOMA-IR scores for physical functioning (OR = 2.29; CI: 1.67-3.13), vitality (OR = 1.45; CI: 1.05-2.00), and general health (OR = 1.62; CI: 1.19-2.21). In men, but not in women, associations with physical functioning were independent of confounding variables. The results indicate that insulin resistance is associated with poor HRQoL in domains of physical health, but not in domains of mental health.

Aged↗
PubMed2006

Grip strength, body composition, and mortality.

BACKGROUND: Several studies in older people have shown that grip strength predicts all-cause mortality. The mechanisms are unclear. Muscle strength declines with age, accompanied by a loss of muscle mass and an increase in fat, but the role that body composition plays in the association between grip strength and mortality has been little explored. We investigated the relation between grip strength, body composition, and cause-specific and total mortality in 800 men and women aged 65 and over. METHODS: During 197374 the UK Department of Health and Social Security surveyed random samples of men and women aged 65 and over living in eight areas of Britain to assess the nutritional state of the elderly population. The survey included a clinical examination by a geriatrician who assessed grip strength and anthropometry. We used Cox proportional hazards models to examine mortality over 24 years of follow-up. RESULTS: Poorer grip strength was associated with increased mortality from all-causes, from cardiovascular disease, and from cancer in men, though not in women. After adjustment for potential confounding factors, including arm muscle area and BMI, the relative risk of death in men was 0.81 (95% CI 0.700.95) from all-causes, 0.73 (95% CI 0.600.89) from cardiovascular disease, and 0.81 (95% CI 0.660.98) from cancer per SD increase in grip strength. These associations remained statistically significant after further adjustment for fat-free mass or % body fat. CONCLUSION: Grip strength is a long-term predictor of mortality from all-causes, cardiovascular disease, and cancer in men. Muscle size and other indicators of body composition did not explain these associations.

Adipose Tissue↗
PubMed2006

Knee pain, knee osteoarthritis, and the risk of fracture.

OBJECTIVE: Patients with osteoarthritis (OA) have increased bone mineral density; however, the association between knee OA and fracture is controversial. Few data exist on the association between knee pain and fracture. We examined the association of knee OA and knee pain with fracture and falls in elderly men and women. METHODS: The study group comprised 6,641 men and women ages > or =75 years who participated in a 3-year randomized controlled trial of intramuscular vitamin D therapy. Patients completed a questionnaire about knee pain and OA. Fracture and fall data were collected prospectively every 6 months. RESULTS: Knee pain prevalence and a clinician diagnosis of knee OA were 35.2% and 6.8%, respectively. A total of 436 incident nonvertebral fractures were reported, and 3,992 patients sustained a fall. Prevalent knee pain was associated with an increased risk of falls (hazard ratio [HR] 1.26, 95% confidence interval [95% CI] 1.17-1.36) and hip fracture (HR 2.0, 95% CI 1.18-3.37). Increasing severity of knee pain was associated with a greater risk of falls and hip fracture. Clinician diagnosis of knee OA was associated with an increased risk of nonvertebral fractures (HR 1.61, 95% CI 1.09-2.36). The increased risk of fracture was not substantially reduced by adjusting for falls, but was attenuated by adjustment for the use of walking aids. CONCLUSION: Patients with a clinical diagnosis of knee OA and with knee pain have an increased risk of nonvertebral and hip fracture. This is not explained by the increased risk of falls, but is more likely to be due to the severity of falls sustained. Knee pain and OA should be regarded as independent risk factors for fracture.

Aged↗
PubMed2006

Falls, sarcopenia, and growth in early life: findings from the Hertfordshire cohort study.

Recent studies have shown that people whose early growth is poor have an increased risk of sarcopenia. Sarcopenia is an important risk factor for falls, but it is not known whether poor early growth is related to falls. The authors investigated this association in the Hertfordshire Cohort Study (1998-2004), where 2,148 participants from the United Kingdom provided their history of falls. Grip strength was used as a marker of sarcopenia. Birth weight, weight at 1 year, and conditional infant growth were analyzed in relation to history of falls. The prevalence of any fall in the last year was 14.3% for men and 22.5% for women. Falls in the last year were inversely related to adult grip strength, height, and walking speed in men and women as well as to lower conditional infant growth in men (odds ratio = 1.27, 95% confidence interval: 1.04, 1.56 per standard deviation decrease in conditional infant growth; p = 0.02). This association was attenuated after adjustment for grip strength. These findings support an association between poor early growth and falls in older men that appears to be mediated partly through sarcopenia. The lack of a relation with birth weight suggests that postnatal rather than prenatal influences on muscle growth and development may be important regarding the risk of falls in later life.

Accidental Falls↗
PubMed2006

Osteoporosis.

Osteoporosis is a serious public health issue. The past 10 years have seen great advances in our understanding of its epidemiology, pathophysiology, and treatment, and further advances are rapidly being made. Clinical assessment will probably evolve from decisions mainly being made on the basis of bone densitometry, to use of algorithms of absolute fracture risk. Biochemical markers of bone turnover are also likely to become more widely used. Bisphosphonates will probably remain the mainstay of therapy, but improved understanding of the optimum amount of remodelling suppression and duration of therapy will be important. At the same time, other diagnostic and therapeutic approaches, including biological agents, are likely to become more widespread.

Aged↗
PubMed2006

Developmental origins of midlife physical performance: evidence from a British birth cohort.

The authors hypothesized that 1) physical growth, as a marker of the early development of muscle fibers, and 2) advanced childhood motor and cognitive abilities, as markers of central nervous system development, would be positively related to midlife standing balance and chair rising, independently of later life experiences. They tested these hypotheses in a representative British sample of 1,374 men and 1,410 women aged 53 years in 1999 with prospective childhood measures of heights and weights, age at first standing and walking, cognitive ability, and motor coordination. Weight gain before age 7 years was positively related to adult performance in men but not women, independently of later body size, social class, physical activity, and health status. Attainment of motor milestones at the modal age and higher scores on tests of cognitive ability and motor coordination were associated with better performance, independently of other factors. This study is the first to show that childhood growth and development affect midlife performance; prevention of disability and frailty in later life may need to start early.

Adolescent↗
PubMed2006

Is grip strength associated with health-related quality of life? Findings from the Hertfordshire Cohort Study.

OBJECTIVE: to investigate the relationship between grip strength and health-related quality of life (HRQoL). DESIGN: cross-sectional survey within a cohort study design. SETTING: the county of Hertfordshire in the UK. PARTICIPANTS: a total of 2,987 community-dwelling men and women aged 59-73 years of age. MEASUREMENTS: grip strength was used as a marker of sarcopaenia and measured using a Jamar dynamometer. HRQoL was assessed using the eight domain scores of the Short Form-36 (SF-36) questionnaire, and subjects in the lowest sex-specific fifth of the distribution were classified as having 'poor' status for each domain. RESULTS: men and women with lower grip strength were significantly more likely to report a poor as opposed to excellent to fair overall opinion of their general health (GH) [odds ratio (OR) per kilogram decrease in grip strength = 1.13, 95% CI = 1.06-1.19, P < 0.001 in men, 1.13, 95% CI = 1.07-1.20, P < 0.001 in women]. Among men, after adjustment for age, size, physical activity and known co-morbidity, decreased grip strength was associated with increased prevalence of poor SF-36 scores for the physical functioning (PF) (OR per kilogram decrease in grip strength = 1.03, 95% CI = 1.01-1.06, P = 0.007) and GH domains (OR = 1.03, 95% CI = 1.01-1.05, P = 0.01). Similar associations were seen in women. CONCLUSIONS: our findings suggest that lower grip strength is associated with reduced HRQoL in older men and women. This does not appear to be explained by age, size, physical activity or co-morbidity and may reflect the link between sarcopaenia and generalised frailty. Individuals with sarcopaenia may benefit from interventions to improve muscle mass and strength before the onset of chronic disorders usually associated with impaired HRQoL.

Accidental Falls↗
PubMed2006

Risk factors for specific upper limb disorders as compared with non-specific upper limb pain: assessing the utility of a structured examination schedule.

BACKGROUND: Few community-based epidemiological investigations of upper limb disorders (ULDs) have classified cases by validated procedures involving a structured clinical examination. AIM: To compare risk factor profiles for different diagnostic categories of ULD using one such examination scheme. METHODS: A questionnaire about upper limb pain and demographic, occupational and psychosocial risk factors was mailed to 10,264 adults from two English general practices, followed by standardized physical examination in those with arm or neck pain. Logistic regression was used to compare those with specific ULDs and non-specific arm pain with those who had no neck or arm symptoms. RESULTS: There was a 59% response rate. A total of 1,197 subjects with arm or neck pain underwent standardized physical examination and were classified as having one or more of 11 specific ULDs or non-specific regional pain. Among these, 250 subjects with specific ULDs and 176 with only non-specific arm pain were compared with 2,248 subjects who had no neck or arm symptoms. Certain physical risk factors were more strongly associated with specific disorders than with non-specific pain. In comparison with pain-free subjects, the odds ratios (ORs) in keyboard users (>or=1 h versus <1 h/day) were 3.1 (95% CI 1.3, 7.8) for hand-wrist tendonitis but 1.3 (0.8, 2.1) for non-specific hand-wrist pain. Other differential associations were found with age, sex, manual versus non-manual employment and smoking. Unexpectedly, low vitality was similarly associated with both specific disorders and non-specific pain. CONCLUSION: These findings suggest that the schedule may usefully distinguish disorders that differ in their association with physical risk factors.

Adult↗
PubMed2006

Infant growth influences proximal femoral geometry in adulthood.

UNLABELLED: The relationship between early growth and adult femoral geometry has not been studied previously. In 333 adults, we were able to show that infant weight predicts femoral width and cross-sectional moment of inertia but not femoral neck length. These results support the hypothesis that growth in early life leads to persisting differences in proximal femoral geometry. INTRODUCTION: Both femoral geometry and bone mass have been shown independently to predict both hip strength and fracture risk. Whereas growth during intrauterine and early postnatal life has been shown to influence adult bone mass, the relationship between growth in early life and adult femoral geometry has not been described previously. MATERIALS AND METHODS: We studied the relationship between growth during early life, adult hip geometry, and proximal femur bone mass in a sample of 333 men and women (60-75 years of age), for whom birth weight and weight at 1 year of age were recorded. Hip geometry was derived using Hip Structure Analysis software from proximal femur DXA scans (Hologic QDR 1000). RESULTS: There were significant (p < 0.002) relationships between weight at age 1 year and measures of femoral width as well as intertrochanteric (IT) cross-sectional moment of inertia (CSMI), but not with femoral neck length. The relationships with measures of femoral width but not CSMI remained after adjusting for adult body weight and were independent of proximal femoral BMC. CONCLUSIONS: These results support the hypothesis that different patterns of growth in utero and during the first year of life lead to persisting differences in proximal femoral geometry, thereby mediating in part the effects of early growth on risk of hip fracture in adulthood.

Aged↗
PubMed2006

Evaluation of human bone marrow stromal cell growth on biodegradable polymer/bioglass composites.

Bone tissue engineering using human bone marrow mesenchymal stem cells (HBMCs) and biocompatible materials provides an attractive approach to regenerate bone tissue to meet the major clinical need. The aim of this study was to examine the effects of novel porous biodegradable composite materials consisting of a bioactive phase (45S5 Bioglass, 0, 5, and 40 wt%) incorporated within a biodegradable poly(dl-lactic acid) matrix, on HBMCs growth. Cell adhesion, spreading, and viability was examined using Cell Tracker Green/Ethidium Homodimer-1. Bone formation was assessed using scaffolds seeded with stro-1 positive HBMCs in nude mice. In vitro biochemistry indicated that with minimal scaffold pre-treatment osteoblast activity falls with increasing Bioglass content. However, 24h scaffold pre-treatment with serum resulted in a significant increase in alkaline phosphatase specific activity in 5 wt% Bioglass composites relative to the 0 and 40 wt% Bioglass groups. In vivo studies indicate significant new bone formation throughout all the scaffolds, as evidenced by immunohistochemistry.

Absorbable Implants↗
PubMed2006

Prevalence and clinical features of Paget's disease of bone in Japan.

The present study aimed to evaluate the prevalence and clinical presentation of Paget's disease of bone (PDB) in Japan. As PDB is a very rare disease in Japan, a nationwide mail survey was conducted targeting doctors in the specialty most frequently diagnosing and treating PDB patients in Japan. First, the literature for all case reports in Japan published between January 1990 and December 2002 was reviewed to determine who was diagnosing and treating PDB in Japan. This literature review for all case reports in Japan revealed that 72.1% of cases in Japan were reported from departments of orthopedic surgery. A nationwide two-phase mail survey was conducted for the departments of orthopedic surgery of 2,320 general hospitals accredited by the Japanese Orthopaedic Association. Phase 1 involved determining how many patients with PDB were followed at each hospital. If the answer was one or more, phase 2 of the survey gathered information on the clinical presentation of current patients. The mail survey yielded a final response rate of 75.4% for phase 1 and 87.6% for phase 2. Phase 1 indicated that the prevalence of PDB in Japan is about 2.8 cases per million capita. Phase 2 revealed a slight female predominance, lower frequency of familial clustering, higher frequency of femoral fracture in the affected femur, and a higher ratio of symptomatic PDB in Japan compared with findings in countries displaying a higher prevalence of PDB. The present epidemiological study revealed that the disorder is extremely rare in Japanese individuals, and that some differences exist with regard to the clinical features of PDB between Japanese patients and patients from high-prevalence countries.

Adult↗
PubMed2006

Risk factors for knee osteoarthritis in Japanese men: a case-control study.

Risk of knee osteoarthritis (OA) was assessed in a population-based case-control study of Japanese men. The study covered three health districts in Wakayama and Osaka prefectures, Japan. Subjects were male individuals >or=45 years old diagnosed radiographically with knee OA, and who did not display any established causes of secondary OA. Controls selected randomly from the general population were individually matched to cases for age, sex, and residential district. Subjects were interviewed using structured questionnaires to determine medical history, physical activity, socio-economic factors, and occupation. Interviews were obtained from 37 cases and 37 controls. In univariate analysis, heaviest weight in the past and physical work such as factory, construction, agricultural, or fishery work as the principal occupation significantly raised the risk of male knee OA (P<0.05). Odds ratios (OR) were determined using conditional logistic regression analysis mutually adjusted for potential risk factors using the results of univariate analysis. Heaviest weight in the past (OR 6.01, 95% confidence interval (CI) 1.18-30.5, P<0.05), past knee injury (OR 6.25, 95% CI 1.13-34.5, P<0.05), and physical work as the principal occupation (OR 6.20, 95% CI 1.40-27.5, P<0.05) represented independent factors associated with knee OA after controlling for other risk factors. Physical work is associated with knee OA, demonstrating the influence of working activity on the development of OA. The present study suggests that risk factors for knee OA in men resemble those in women.

Aged↗
PubMed2006

Replication of IGF2-INS-TH*5 haplotype effect on obesity in older men and study of related phenotypes.

Interindividual variation of the IGF2-INS-TH region influences risk of a variety of diseases and complex traits. Previous studies identified a haplotype (designated IGF2-INS-TH(*)5 and tagged by allele A of IGF2 ApaI, allele 9 of TH01 and class I alleles of INS VNTR) associated with low body mass index (BMI) in a cohort of UK men. We aimed here both to study whether previous findings relating (*)5 with weight are replicated in a different cohort of men (East Hertfordshire) characterised in more phenotypic detail and to test the effect of this haplotype on related subphenotypes. The PHASE program was used to identify (*)5 and not(*)5 haplotypes. A total of 490 haplotypes were derived from 131 men and 114 women, the frequency of (*)5 being around 9%. Specific tests of (*)5 haplotype (vs not(*)5 haplotypes) conducted included Student's t-test and multiple regression analyses. We observed replication of weight effect for the (*)5 haplotype in men: significant associations with lower BMI (-1.81 kg/m(2), P=0.009), lower waist circumference (-6.3 cm, P=0.001) and lower waist-hip ratio (-5%, P<0.001). This haplotype also marks nearly two-fold lower 120 min insulin (P=0.004) as well as low baseline insulin (-11.02 pmol/l, P=0.043) and low 30 min insulin (-64.44 pmol/l, P=0.072) in a glucose tolerance test. No association between (*)5 and these traits was found in women. Our results, taken together with other data on IGFII levels and TH activity, point to the importance of (*)5 as an integrated polygenic haplotype relevant to obesity and insulin response to glucose in men.

Aged↗