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T Andrew

Publications and source records attributed to T Andrew.

At least 19 recordsLinked to original sources
PubMed2006

ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research.

The product of the ABCB1 gene, P-glycoprotein (PGP), is a transmembrane active efflux pump for a variety of drugs. It is a putative mechanism of multidrug resistance in a range of diseases. It is postulated that ABCB1 polymorphisms contribute to variability in PGP function, and that therefore multidrug resistance is, at least in part, genetically determined. However, studies of ABCB1 genotype or haplotype and PGP expression, activity or drug response have produced inconsistent results. This critical review of ABCB1 genotype and PGP function, including mRNA expression, PGP-substrate drug pharmacokinetics and drug response, highlights methodological limitations of existing studies, including inadequate power, potential confounding by co-morbidity and co-medication, multiple testing, poor definition of disease phenotype and outcomes, and analysis of multiple drugs that might not be PGP substrates. We have produced recommendations for future research that will aid clarification of the association between ABCB1 genotypes and factors related to PGP activity.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2005

Linkage to the FOXC2 region of chromosome 16 for varicose veins in otherwise healthy, unselected sibling pairs.

BACKGROUND: The FOXC2 gene on 16q24 is mutated in lymphoedema distichiasis (LD), in which varicose veins (VV) are a common feature. We hypothesised that this gene might be implicated in the development of VV in the normal population, therefore, after performing a classical twin study, we tested for linkage and association in white women. We also tested for linkage with haemorrhoids (H), as a separate venous anomaly at the same locus. METHODS: A total of 2060 complete female twin pairs aged 18-80 years from the St Thomas' Adult UK Twin registry replied to questions on VV and H as part of a broader postal survey of 6600 twins (62% response rate). Dizygotic female twin pairs were tested for linkage and association to the candidate marker D16S520 (1903 individuals genotyped), which is located about 80 kb from FOXC2. RESULTS: Casewise concordance rates were significantly higher for monozygotic than dizygotic twins for both phenotypes (VV 67% v 45%; p = 2.2x10(-6); H 68% v 59%; p = 0.01; H including during pregnancy 73% v 64%; p = 2.1x10(-4)), corresponding to additive genetic heritabilities in liability of 86% (95% confidence interval (CI) 73% to 99%) for VV and 56-61% for H (95% CI 43% to 73%). The presence of VV and H were significantly correlated. We found significant evidence of linkage to the marker for VV (MLS(ASP) = 1.37, p = 0.01; GLM(ASP/DSP) Z = 3.17 p = 0.002), but no association. Both linkage and association tests were negative for H. The combined phenotype of having VV and H did not show any evidence of linkage or association. CONCLUSION: These results demonstrate VV and H to be heritable, related conditions, and the data strongly suggest FOXC2 to be implicated in the development of VV in the general population.

Adolescent↗
PubMed2003

A genome-screen of a large twin cohort reveals linkage for quantitative ultrasound of the calcaneus to 2q33-37 and 4q12-21.

UNLABELLED: A genome-wide screen was performed on a large cohort of dizygous twin pairs to identify regions of the genome that contain QTL for QUS of bone. Suggestive linkage of QUS parameters to 2q33-37 and 4q12-21 highlighted these regions as potentially important for studies of genes that regulate bone. INTRODUCTION: The genetics of osteoporotic fracture is only partly explained by bone mineral density (BMD). Quantitative ultrasound (QUS) of the calcaneus can also be used for independent clinical assessment of osteoporotic fracture risk. Two specific indices are derived from this assessment: broadband ultrasound attenuation (BUA) and velocity of sound (VOS). Both parameters provide information on fracture risk; however, BUA has been studied more extensively and may be favored because it is thought to have a stronger predictive value for osteoporotic fracture and incorporates aspects of trabecular structure and bone quality as well as BMD. Studies of QUS in twins have shown that both derived parameters are under substantial genetic control, independent of BMD. MATERIALS AND METHODS: To identify regions of the genome that contain quantitative trait loci (QTL) for QUS of bone, we performed a genome-wide screen on a large cohort of dizygous twin pairs. Unselected female dizygous twins from 1067 pedigrees from the St Thomas' UK Adult Twin Registry were genome scanned (737 highly polymorphic microsatellite markers). Multipoint linkage analyses provided maximum evidence of linkage for BUA (LOD 2.1-5.1) to 2q33-37. Linkage for VOS (LOD 2.2-3.4) was maximal at 4q12-21. Potential evidence of linkage in the cohort indicated five other possible locations of QTL (LOD > 2.0) relevant to bone density or structure on chromosomes 1, 2, 13, 14, and X. RESULTS AND CONCLUSIONS: This study has identified eight genomic locations with linkage of LOD > 2.0. This data should be of value in assisting researchers to localize genes that regulate bone mass and microstructure. These results should complement genome screens of BMD and bone structure and serve to enable further targeted positional candidate and positional cloning studies to advance our understanding of genetic control of bone quality and risk of fracture.

Adolescent↗
PubMed2003

Association of birth weight with osteoporosis and osteoarthritis in adult twins.

OBJECTIVES: Twin studies present a unique opportunity to examine the association of birth weight with adult life phenotypes in a design that naturally accounts for maternal factors and a range of early environmental factors, which might potentially bias the association. In this study, we explored the association of birth weight with osteoporosis (OP) and osteoarthritis (OA), in a large national cohort of female twins. METHODS: Intra-pair differences between the reported birth weight of the twins (n=4008) were examined for an association with: (i) intra-pair differences in bone mineral density (BMD) and bone mineral content (BMC) at the lumbar spine, hip and forearm using linear regression; and (ii) osteoarthritis status in pairs discordant for radiographic disease at the hand, hip and knee using matched logistic regression. The confounding influences of height and weight were taken into account. RESULTS: The mean age of the twins was 47.5+/-12.3 yr. Intra-pair differences in birth weight were significantly associated with BMD at the spine (P=0.047), total hip (P=0.016) and femoral neck (P<0.001), but not at the forearm (P=0.245). These were entirely explained by the birth weight association with height and weight. The associations of intra-pair differences in birth weight and BMC were highly significant (P<0.001) at all sites, but were partly explained by adjustment for adult height and weight. We found no clear association between intra-pair birth weight differences and OA in twins discordant for any of the radiographic OA phenotypes at any site. CONCLUSIONS: Bone mass and especially BMC are highly associated with birth weight. These associations are accounted for mainly by environmental factors that are independent of maternal factors such as gestational age, maternal smoking and nutrition, and are largely mediated by skeletal size and particularly adult height. Birth weight does not appear to be a major influence on the later development of radiographic OA in women.

Adult↗
PubMed2002

Linkage and association for bone mineral density and heel ultrasound measurements with a simple tandem repeat polymorphism near the osteocalcin gene in female dizygotic twins.

In this confirmatory candidate gene study, we investigated possible linkage and association for bone density, heel ultrasound and bone turnover with the osteocalcin gene using the nearby (50-180kb) microsatellite marker D1S3737. Non-identical twin sisters aged 18-75 years at first interview were recruited for the study from the St Thomas' UK Adult Twin Registry with 1366 women being genotyped for marker D1S3737. Linkage, allelic association and joint linkage and association tests were carried out using quantitative transmission disequilibrium tests (QTDT), along with post-hoc multivariate tests of linkage and association. Phenotypes tested were bone mineral density (BMD) at the spine, left forearm and left total hip; quantitative ultrasound measurements of the heel including velocity of ultrasound (VOS) and broadband ultrasound attenuation (BUA); and bone turnover markers, urine deoxypyridinoline (DPD), serum osteocalcin, bone specific and total alkaline phosphatase (ALP). BMD and ultrasound variables showed evidence of pleiotropic linkage ( p = 0.05) and association ( p = 0.02) with the marker in postmenopausal women. Bone markers showed little or no evidence of linkage and association for any age group. Evidence for pleiotropic linkage appeared to be strongest for BUA and spine BMD in postmenopausal women. The univariate test statistic for BUA was chi(2)(1)=12.8 ( p = 0.0003), equivalent to a LOD score of 2.8. DPD showed borderline evidence of linkage to the marker for women of all ages. Multivariate model-fitting showed allele 10 to be negatively associated with BMD, VOS and BUA via a common pathway, suggesting the putative functional polymorphism affects both bone content and structure through shared underlying metabolic pathways. It is likely that the alleles are in linkage disequilibrium with functional polymorphism(s) in or nearby the osteocalcin gene, which may contribute to the onset of osteoporosis.

Adult↗
PubMed2001

Genetic variation in bone mineral density and calcaneal ultrasound: a study of the influence of menopause using female twins.

The aim of the study was to determine whether the genetic variance in bone mineral density (BMD) and calcaneal ultrasound differs in pre- and postmenopausal women and to establish whether the genes operating before the menopause are the same as those after the menopause. Twins aged 18-75 years were recruited from the St Thomas' UK Adult Twin Registry. Quantitative model fitting techniques were used to test for differences in genetic influences in pre- and postmenopausal twins of several BMD sites and calcaneal ultrasound measures accounting for age. BMD and heel ultrasound variables were measured in 2490 female twins: 360 monozygotic pairs and 885 dizygotic pairs. The heritability in the group overall ranged from 19% to 76%. A significant increase in total variance was seen for most BMD sites after the menopause. The proportion of total variance explained by genetic influence was higher premenopausally at all sites except the femoral neck. For example, the genetic proportion of total variance for spine BMD was 88% premenopausally and 77% postmenopausally. In contrast there was no significant difference in total variance of ultrasound measures with menopause. There was no indication that traits are influenced by different genes before and after menopause. This study demonstrates that genetic and environmental influences differ significantly in pre- and postmenopausal groups for BMD, but not for calcaneal ultrasound. The total variance in BMD is greater postmenopausally, but there is evidence that the same genes are involved. These data stress the importance of accounting for menopause-gene interactions in the genetic analysis of data on osteoporosis.

Adolescent↗
PubMed2001

Resistance studies with daptomycin.

We studied the in vitro emergence of resistance to daptomycin using three methods: spontaneous resistance incidence, serial passage in the presence of increasing drug concentrations, and chemical mutagenesis. No spontaneously resistant mutants were obtained for any organism tested (<10(-10) for Staphylococcus aureus, <10(-9) for Staphylococcus epidermidis, <10(-9) for Enterococcus faecalis, <10(-9) for Enterococcus faecium, <10(-8) for Streptococcus pneumoniae). Population analysis demonstrated that bacterial susceptibility to daptomycin is heterogeneous. Assay results were sensitive to calcium concentration and culture density, both of which can affect apparent resistance rates. Stable S. aureus mutants were isolated by both serial passage in liquid media and chemical mutagenesis. The daptomycin MICs for these isolates were 8- to 32-fold higher than for the parental strain. Many mutants with high MICs (>12.5 microg/ml) had significant growth defects but did not display phenotypes typical of S. aureus small colony variants. The voltage component (Delta psi) of the bacterial membrane potential was increased in three independent resistant isolates. In vivo data showed that some daptomycin-resistant mutants had lost significant virulence. For other mutants, the degree of in vitro resistance was greater than the change in in vivo susceptibility. These results suggest that infection with some daptomycin-resistant organisms may still be easily treatable.

Animals↗
PubMed2001

Are twins and singletons comparable? A study of disease-related and lifestyle characteristics in adult women.

The classic twin study is sometimes described as "the perfect natural experiment" for the investigation of the aetiology of complex disease, but assumptions of the twin design need to be empirically tested if their results are to be considered unbiased and representative of singleton populations. In this study comparisons of disease and prevalence of lifestyle characteristics have been made between twin participants in the St Thomas' Hospital UK adult twin registry, the largest twin volunteer register in the UK for the study of diseases of ageing, and a parallel population-based study of singleton women. The only differences found were for weight, where monozygotic (MZ) twins were lighter and had a smaller variance than dizygotic (DZ) twins and singletons. For the other variables studied, volunteer twins were not found to differ from age-matched singleton women in distribution or prevalence of: bone mineral density, osteoarthritis, blood pressure, hypertensive drug use, height, history of hysterectomy and ovariectomy, menopausal status and current alcohol and overall tobacco consumption. We conclude that the results of twin studies can be generalised to singleton populations for these measures and disease outcomes.

Alcohol Drinking↗
PubMed2000

Outcome of referral to social services departments for people with cognitive impairment.

The objective of this study was to determine how the entry into long term care of people assessed by their local social services department (SSD) under the National Health Service and Community Care Act 1990 is predicted by the severity of their cognitive impairment, care provided by family members, and the receipt of community care services. The design involved a cohort study of people over one and a half years following referral (min-max: 1-2 years) from three SSDs (county council, metropolitan and inner London boroughs). Consecutive recruitment of 141 people with cognitive impairment aged 65 and over took place over a 4 month period. The main outcome measure was survival analysis of time taken from referral to entering long term care at follow-up. The receipt and intensity of community care services increased the probability of remaining at home. People with mild or moderate cognitive impairment were more likely to remain at home if they had a spouse or daughter carer. Analysis of the interaction between three main effects predicting entry to long term care (severity of cognitive impairment, access to a carer, and the receipt of home care or day care) suggests that while carers are central in determining whether older people with cognitive impairment are able to remain living in the community, there are limits to the care they can provide.

Aged↗
PubMed2000

The genetic contribution to radiographic hip osteoarthritis in women: results of a classic twin study.

OBJECTIVE: To assess the genetic contribution to radiographic hip osteoarthritis (OA) by measuring the distribution of disease features in monozygotic (MZ) and dizygotic (DZ) twins. METHODS: A population-based, cross-sectional study was conducted of 135 MZ and 277 DZ healthy female twin pairs, 50 years of age and older, who were recruited into the St. Thomas' UK Adult Twin Registry. Pelvic radiographs were read by a single observer who was blinded to the pairing and zygosity of the twins. The films were assessed for overall OA grade using a modification of the Kellgren and Lawrence scheme, and assessed for individual radiographic features. RESULTS: There was evidence of significant familial clustering for grade I and grade II OA changes, with an excess concordance in MZ twins compared with DZ twins, suggesting a genetic effect. The MZ versus DZ excess was also apparent for those classified as having more severe disease, although the number of pairs with these disease features was small. Familial clustering attributable to genetic factors was evident for joint space narrowing of <2.5 mm. Familial, but not genetic, clustering was seen for subchondral sclerosis. The number of pairs concordant for definite osteophytes in the sample was too low to assess this feature alone. These results translate into a significant heritability of 58% for OA overall and 64% for joint space narrowing. The heritability estimates decreased a little when the potential confounding influences of age, body mass index, and hip bone density were taken into account. CONCLUSION: Genetic factors have a significant contribution to OA at the hip in women and account for approximately 60% of the variation in population liability to the disease.

Adult↗
PubMed2000

A randomized controlled trial of vitamin D supplementation on preventing postmenopausal bone loss and modifying bone metabolism using identical twin pairs.

Vitamin D supplementation, when given with calcium, has been shown to increase bone mineral density (BMD) and reduce the incidence of hip fracture in elderly subjects. Despite its widespread use, the benefits of vitamin D supplementation in younger women and as a single agent are less clear. We performed a randomized co-twin, placebo-controlled, double-blind trial over 2 years to measure the effect of vitamin D3 supplementation on bone density and bone metabolism in young postmenopausal women. Seventy-nine monozygotic (MZ) twin pairs (mean age, 58.7 years; range, 47-70 years) were recruited. For each twin pair, one was randomized to 800 IU cholecalciferol/day for 2 years and the other was randomized to placebo. BMD was measured at the spine and hip and heel ultrasound at baseline, 12, 18, and 24 months. Samples were collected at 0, 3, and 6 months to measure serum calcium, 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), osteocalcin, and urinary deoxypyridinoline (DPD). In total, 64 pairs completed the study. No differences in baseline characteristics were seen between the groups. At 6 months, the treatment group had an increase in serum vitamin D [mean +/- SEM intrapair difference, 14.1+/-2.4 microg/liter (p < 0.001)]. There were no significant differences in other serum measurements or bone markers at 3 months or 6 months. At 24 months, no significant treatment effect was seen on BMD or calcaneal ultrasound change within pairs. Subanalysis of treatment response by vitamin D receptor (VDR) genotype revealed no significant difference in effect on BMD variables with treatment. On the basis of these results, vitamin D supplementation, on its own, cannot be recommended routinely as an osteoporosis prevention for healthy postmenopausal women with normal vitamin D levels under the age of 70 years.

Aged↗
PubMed1994

Death and survival in a cohort of heroin addicts from London clinics: a 22-year follow-up study.

Data are presented on the 43 people who died over a 22-year follow-up period of a cohort of 128 heroin addicts drawn in 1969 from the newly opened London clinics. The main causes of death were drug-related, with 18 deaths specifically determined as due to overdose, of which the great majority were among people being prescribed opiates at the time. The mortality rate was a mean of 1.84% annually, and the excess mortality ratio was 11.9. This excess was highest at the beginning and varied over the period of study, appearing higher at the opening of the clinics and again in the mid-1980s. No sex differences in mortality rates were demonstrated but the excess mortality was concentrated at younger ages. No prediction of the 85 survivors could be made on the basis of length of heroin use prior to study intake, nor on age at intake.

Adolescent↗
PubMed1993

Hyaluronic acid regulates the function and distribution of sulfated glycosaminoglycans in bone marrow stromal cultures.

Treatment with steroid is necessary for adult human bone marrow-derived stroma to support hemopoiesis in vitro. We have investigated the effect of the steroid methylprednisolone on the glycosaminoglycans produced by adult bone marrow stroma. Methylprednisolone did not significantly alter the amount of sulfated glycosaminoglycans produced but the amount of the nonsulfated glycosaminoglycan, hyaluronic acid (HA), was dramatically decreased by the steroid. Culturing methylprednisolone-treated stroma with exogenous HA reduced the proportion of sulfated glycosaminoglycans incorporated into the cell layer and increased the proportion secreted into the medium. It also reduced the capacity of the stroma to bind and stimulate blast colony-forming cells. In fetal liver stroma, methylprednisolone did not decrease the amount of HA or alter the type of heparan sulfate produced. Thus, the ability of stroma cells to respond to steroid and the amount of HA in the extracellular matrix may vary in different marrow microenvironments. This may have functional consequences regarding their abilities to support hemopoiesis.

Adult↗
PubMed1985

Growth arrest for progressive scoliosis. Combined anterior and posterior fusion of the convexity.

A review is presented of 13 young patients with congenital scoliosis who were treated by epiphysiodesis of part of the vertebral bodies combined with posterior fusion, both on the convex side; the plan was to arrest growth on the convexity which, combined with growth of the concave side, would result in progressive correction of the curve. The first patient was operated on at the age of four years and has now reached skeletal maturity with complete correction of her curve. Several others, still growing, are showing progressive correction. Only three curves, in which kyphosis was more severe than scoliosis, have deteriorated since operation. Although full assessment must await skeletal maturity of all the patients, this approach appears to have sufficient potential to justify an early report.

Adolescent↗
PubMed1979

Gutter treatment for ingrowing toenails.

The gutter treatment for ingrowing toenails consists of introducing a small guard along the side of the toenail and requires only three outpatient attendances. The gutter is left in place for eight to 12 weeks and then removed by the patient. Two studies were carried out to establish the long-term results of the method. In one, a preliminary retrospective study, 13 out of 25 patients who had received the gutter treatment were cured after one year compared with five out of 15 patients in whom the toenail had been avulsed. In a randomised prospective study 20 out of 36 patients (56%) treated by the gutter method were cured after one year compared with 27 out of 32 (84%) in whom the wedge resection procedure had been used. The gutter treatment demands little skill and may be carried out in general practice. It gives an excellent cosmetic result with immediate pain relief and does not compromise further surgery should this be required, thus fulfilling the main requirements for the primary treatment of choice.

Adolescent↗