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Biomedical subjects

D Woods

Publications and source records attributed to D Woods.

At least 19 recordsLinked to original sources
PubMed2006

Risk factors for psychological distress following injury.

OBJECTIVES: To identify predictors of psychological morbidity among injured patients admitted to an Emergency Department (ED). DESIGN: A prospective cohort study. PARTICIPANTS: Participants were consecutive male ED attenders. 210 (97.7%) patients consented to participate. At one month, 128 (61.0%) responded, at six months, 114 (54.3%), at eighteen months 96 (45.7%). MAIN OUTCOME MEASURES: Measures immediately following injury were the Hospital Anxiety and Depression Scale, the Eysenck Personality Questionnaire and the McGill pain questionnaire. Recovery at one month was recorded using the SF-36 Health Survey, COPE scale, Perceived Stress Scale and Revised Impact of Events Scale. At six and eighteen months outcome was measured using the General Health Questionnaire (28 items) and Revised Impact of Events Scale. Multivariate analysis identified pre-morbid, accident-related and recovery factors influencing outcome at six and eighteen months. RESULTS: The strongest predictors of outcome were initial levels of anxiety and depression, prior history of mental health problems, early PTSD symptoms and involvement in litigation. These factors predicted between 40-60% of the variance at six months (p<0.001), and 50-60% of the variance in psychological distress at eighteen months (p<0.001). CONCLUSION: Factors identifying individuals at-risk from psychological distress following injury include those related to the immediate response and the recovery phases of injury. Further development is needed to convert identified predictors into a comprehensive screening tool for clinical use.

Adolescent↗
PubMed2005

Adult BMI and fat distribution but not height amplify the effect of low birthweight on insulin resistance and increased blood pressure in 20-year-old South Africans.

AIMS/HYPOTHESIS: We examined whether associations between low birthweight and adult chronic cardio-metabolic disease were dependent upon birthweight alone, or on interactions with BMI, fat accumulation either generally or abdominally, or attained height in young South African adults. METHODS: Blood pressure (BP), lipids, glucose tolerance, insulin sensitivity and secretion (homeostasis model) were measured in 20-year-olds (n = 132) born at full term and with birthweights on or below the tenth centile (underweight for gestational age [UFA]) or between the 25th and 75th centiles for gestational age (appropriate weight for gestational age, [AFA]). Sex-specific median measurements of BMI, waist circumference, percentage body fat and height defined current anthropometric status, providing four groups for each measure: UFA-low or UFA-high and AFA-low or AFA-high. RESULTS: The UFA-high BMI group was more insulin-resistant than both low BMI groups (p < 0.04), but not the AFA-high BMI group. In contrast, plasma triglycerides and systolic BP were higher in the UFA-high than in all other groups (all p < 0.04). When characterised by body fatness, both high percentage (%) body fat groups had higher fasting [insulin] than low percentage (%) body fat groups (p < 0.03), and higher [total cholesterol] and [LDL cholesterol] than the UFA-low percentage (%) body fat group (p < 0.05). The UFA-high group had higher systolic and diastolic BP than all other groups (all at least p < 0.03). A similar pattern was observed when groups were characterised by waist circumference; however, current height status had no effect. CONCLUSIONS/INTERPRETATION: These data indicate that the "fetal origins" expression of the chronic disease phenotype is not dependent on birthweight alone, but on its interaction with subsequent fat accumulation, though not on attained height, in this cohort of young adults.

Adipose Tissue↗
PubMed2004

IL-6-174G/C genotype is associated with the bone mineral density response to oestrogen replacement therapy in post-menopausal women.

A reduction in interleukin-6 (IL-6) activity may contribute to the beneficial effects of hormone replacement therapy (HRT) on the menopausal decline in bone mineral density (BMD). We have examined this hypothesis using a genetic strategy. The -174C (rather than G) IL-6 gene variant is associated with lower IL-6 expression. As such, we might anticipate the C allele to be associated with a greater response to HRT. We have tested this hypothesis. Mean three-site [spine (L1-L4), neck of femur, and Ward's triangle] BMD was measured in 65 women in a 1-year randomised controlled trial of HRT with 0.625 mg oestrogen/day and 0.15 mg norgestrel (n=30). Baseline BMD was genotype-independent for both the control and HRT group. In the control group, the percentage change in BMD after 1 year was similar between genotypes (P=0.45). In contrast, in the HRT group, the rise was genotype-dependent. Those homozygous for the G allele showed a 3.62 (2.14)% increase in BMD compared with 10.44 (4.68)% for the C-homozygous group. Heterozygotes had an intermediate BMD increase of 5.6 (2.82)% [ P=0.006 ( P value for interaction between HRT and genotype was 0.04)] Although the study was limited by its small sample size, these are the first data to demonstrate the importance of IL-6 genotype in determining response to oestrogen therapy, rather than its physiological withdrawal.

Bone Density↗
PubMed2004

Assay for ubiquitin ligase activity: high-throughput screen for inhibitors of HDM2.

An assay for the autoubiquitination activity of the E3 ligase HDM2 (Mdm2) was developed and adapted to a high-throughput format to identify inhibitors of this activity. The assay can also be used to measure the activity of other E3s and may be useful in finding both inhibitors and activators of a wide range of different ubiquitin ligases.

Animals↗
PubMed2001

Bradykinin B2BKR receptor polymorphism and left-ventricular growth response.

Angiotensin-converting-enzyme (ACE) activity regulates left-ventricular growth. The deletion (D), rather than the insertion (I), ACE gene variant is associated with increased ACE activity and kinin degradation, and the absence (-) rather than the presence (+) of a 9 bp deletion in the gene encoding the bradykinin 2 receptor (B2BKR) is associated with greater gene expression. We determined the ACE and B2BKR genotype of 109 male army recruits, and measured their physiological left-ventricular growth response to a 10-week physical training programme. Mean left-ventricular growth was 15.7 g (SE 3.5) in those with ACE genotype D/D and B2BKR genotype +9/+9, but -1.37 g (4.1) in those with ACE genotype I/I and B2BKR genotype -9/-9 (p=0.003 for trend across genotypes). These results suggest that kinins regulate left-ventricular growth, mediating some of the effects of ACE in this regard.

Adult↗
PubMed2001

Elite swimmers and the D allele of the ACE I/D polymorphism.

A polymorphism of the human angiotensin-1-converting enzyme (ACE) gene has been identified in which the presence (insertion, I allele) of a 287-bp fragment rather than the absence (deletion, D allele) is associated with lower ACE activity. Several recent studies have shown an association of the I allele with endurance performance, it being found with excess frequency in elite distance runners, rowers and mountaineers. Other workers using heterogeneous cohorts of athletes from mixed sporting disciplines have found no such association. An increasing linear trend of I allele frequency with the distance run amongst Olympic runners and an excess of the D allele amongst sprinters led us to examine whether the ratio of I and D alleles in swimmers competing over different distances would also vary. Swimmers (n=120) from the European and Commonwealth championships and an American college team had their ACE genotype determined and their gene and allele frequencies compared with several control groups, the most closely age-matched of which were 1,248 military recruits. Of the 103 Caucasians, there was a significant excess of the D allele compared with this control group only in the truly elite swimmers of the European and Commonwealth championships (P=0.004). This association remained in those competing over shorter distances (P=0.005 for 400 m and below) but not in the longer events. These findings were confirmed in three further large control groups. A population association study testing whether a genetic marker (the ACE I/D polymorphism) occurs more frequently in cases (elite athletes) than in controls therefore requires a homogeneous cohort of subjects from the same sporting discipline.

Adolescent↗
PubMed2001

Identification of the acid phosphatase (acpA) gene homologues in pathogenic and non-pathogenic Burkholderia spp. facilitates TnphoA mutagenesis.

Burkholderia pseudomallei and Burkholderia mallei are pathogens responsible for disease in both humans and animals. Burkholderia thailandensis, while phylogenetically similar, is considered avirulent in comparison. These three species exhibit phosphatase activity when grown on media containing chromogenic substrates such as 5-bromo-4-chloro-3-indolyl phosphate (XP). Tn5-OT182 mutagenesis has been utilized to isolate mutants of B. pseudomallei and B. thailandensis unable to hydrolyse XP. Sequence analysis of these mutants revealed an ORF of 1734 nucleotides demonstrating a high degree of homology to the acpA gene product of Francisella tularensis. PCR primers were designed based on the B. pseudomallei acpA gene sequence and were used to amplify an acpA homologue from B. mallei. The predicted amino acid sequence of B. pseudomallei AcpA differed from those of the predicted B. thailandensis AcpA and B. mallei AcpA by 15 and 3 amino acids, respectively. Allelic exchange was used to construct DeltaacpA mutants in each of these Burkholderia spp. These mutants were shown to be devoid of phosphatase activity and have subsequently allowed for the implementation of phoA fusion transposon mutagenesis systems. Two such systems have been successfully utilized in Burkholderia spp. for the identification of several genes encoding exported proteins.

Acid Phosphatase↗
PubMed2001

Induction of beta3-integrin gene expression by sustained activation of the Ras-regulated Raf-MEK-extracellular signal-regulated kinase signaling pathway.

Alterations in the expression of integrin receptors for extracellular matrix (ECM) proteins are strongly associated with the acquisition of invasive and/or metastatic properties by human cancer cells. Despite this, comparatively little is known of the biochemical mechanisms that regulate the expression of integrin genes in cells. Here we demonstrate that the Ras-activated Raf-MEK-extracellular signal-regulated kinase (ERK) signaling pathway can specifically control the expression of individual integrin subunits in a variety of human and mouse cell lines. Pharmacological inhibition of MEK1 in a number of human melanoma and pancreatic carcinoma cell lines led to reduced cell surface expression of alpha6- and beta3-integrin. Consistent with this, conditional activation of the Raf-MEK-ERK pathway in NIH 3T3 cells led to a 5 to 20-fold induction of cell surface alpha6- and beta3-integrin expression. Induced beta3-integrin was expressed on the cell surface as a heterodimer with alphav-integrin; however, the overall level of alphav-integrin expression was not altered by Ras or Raf. Raf-induced beta3-integrin was observed in primary and established mouse fibroblast lines and in mouse and human endothelial cells. Consistent with previous reports of the ability of the Raf-MEK-ERK signaling pathway to induce beta3-integrin gene transcription in human K-562 erythroleukemia cells, Raf activation in NIH 3T3 cells led to elevated beta3-integrin mRNA. However, unlike immediate-early Raf targets such as heparin binding epidermal growth factor and Mdm2, beta3-integrin mRNA was induced by Raf in a manner that was cycloheximide sensitive. Surprisingly, activation of the Raf-MEK-ERK signaling pathway by growth factors and mitogens had little or no effect on beta3-integrin expression, suggesting that the expression of this gene requires sustained activation of this signaling pathway. In addition, despite the robust induction of cell surface alphavbeta3-integrin expression by Raf in NIH 3T3 cells, such cells display decreased spreading and adhesion, with a loss of focal adhesions and actin stress fibers. These data suggest that oncogene-induced alterations in integrin gene expression may participate in the changes in cell adhesion and migration that accompany the process of oncogenic transformation.

3T3 Cells↗
PubMed2001

Angiotensin-I converting enzyme genotype-dependent benefit from hormone replacement therapy in isometric muscle strength and bone mineral density.

Low bone mineral density (BMD) and muscle weakness are major risk factors for postmenopausal osteoporotic fracture. Hormone replacement therapy (HRT) reverses the menopausal decline in maximum voluntary force of the adductor pollicis and reduces serum angiotensin-I converting enzyme (ACE) levels. The insertion (I) allele of the ACE gene polymorphism is associated with lower ACE activity and improved muscle efficiency in response to physical training. Therefore, we examined whether the presence of the I allele in postmenopausal women would affect the muscle response to HRT. Those taking HRT showed a significant gain in normalized muscle maximum voluntary force slope, the rate of which was strongly influenced by ACE genotype (16.0 +/- 1.53%, 14.3 +/- 2.67%, and 7.76 +/- 4.13%, mean +/- SEM for II, ID, and DD genotype, respectively; P = 0.017 for gene effect, P = 0.004 for I allele effect). There was also a significant ACE gene effect in the response of BMD to HRT in Ward's triangle (P = 0.03) and a significant I allele effect in the spine (P = 0.03), but not in the neck of femur or total hip. These data suggests that low ACE activity associated with the I allele confers an improved muscle and BMD response in postmenopausal women treated with HRT.

Bone Density↗
PubMed2001

The flexion-adduction test: an early sign of hip disease.

This report introduces the flexion-adduction test as an additional diagnostic technique for hip pathology in children and young adults. Losses of flexion-adduction, internal rotation, abduction and total flexion arc are all individually assessed in patients with confirmed hip pathology. The findings suggest that the "flexion-adduction" test is a simple, but sensitive, clinical procedure to detect the early signs of hip disease in older children and young adults. Although abduction and internal rotation are reportedly the most commonly restricted movements in frequent hip pathologies such as irritable hip, Legg-Calve-Perthes disease and slipped epiphysis, we believe that the loss of flexion-adduction is often the first affected range of movement. A statistical analysis of 87 cases from 1994 to 1997 is presented wherein the clinical loss of flexion-adduction provided the initial suggestion of underlying hip pathology, and concludes that the loss of internal rotation, abduction and flexion arc are not statistically reliable tests for clinically diagnosing pathology individually. Often, despite a positive flexion-adduction test, the other ranges of movements remained unaffected or minimally affected in children and young adults with varying hip diseases, later confirmed through subsequent physical examinations or investigations. A thorough explanation of the flexion-adduction test is provided.

Adult↗
PubMed2000

Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p19ARF.

Mdm2 acts as a major regulator of the tumor suppressor p53 by targeting its destruction. Here, we show that the mdm2 gene is also regulated by the Ras-driven Raf/MEK/MAP kinase pathway, in a p53-independent manner. Mdm2 induced by activated Raf degrades p53 in the absence of the Mdm2 inhibitor p19ARF. This regulatory pathway accounts for the observation that cells transformed by oncogenic Ras are more resistant to p53-dependent apoptosis following exposure to DNA damage. Activation of the Ras-induced Raf/MEK/MAP kinase may therefore play a key role in suppressing p53 during tumor development and treatment. In primary cells, Raf also activates the Mdm2 inhibitor p19ARF. Levels of p53 are therefore determined by opposing effects of Raf-induced p19ARF and Mdm2.

Animals↗
PubMed2000

Synaptic targeting and localization of discs-large is a stepwise process controlled by different domains of the protein.

BACKGROUND: Membrane-associated guanylate kinases (MAGUKs) assemble ion channels, cell-adhesion molecules and components of second messenger cascades into synapses, and are therefore potentially important for co-ordinating synaptic strength and structure. Here, we have examined the targeting of the Drosophila MAGUK Discs-large (DLG) to larval neuromuscular junctions. RESULTS: During development, DLG was first found associated with the muscle subcortical compartment and plasma membrane, and later was recruited to the postsynaptic membrane. Using a transgenic approach, we studied how mutations in various domains of the DLGprotein affect DLG targeting. Deletion of the HOOK region-the region between the Src homology 3 (SH3) domain and the guanylate-kinase-like (GUK) domain-prevented association of DLG with the subcortical network and rendered the protein largely diffuse. Loss of the first two PDZ domains led to the formation of large clusters throughout the plasma membrane, with scant targeting to the neuromuscular junction. Proper trafficking of DLG missing the GUK domain depended on the presence of endogenous DLG. CONCLUSIONS: Postsynaptic targeting of DLG requires a HOOK-dependent association with extrasynaptic compartments, and interactions mediated by the first two PDZ domains. The GUK domain routes DLG between compartments, possibly by interacting with recently identified cytoskeletal-binding partners.

Animals↗
PubMed2000

Rapsynoid/partner of inscuteable controls asymmetric division of larval neuroblasts in Drosophila.

Asymmetric cell division generates daughter cells with different developmental fates. In Drosophila neuroblasts, asymmetric divisions are characterized by (1) a difference in size between the two daughter cells and (2) an asymmetric distribution of cell fate determinants, including Prospero and Numb, between the two daughter cells. In embryonic neuroblasts, the asymmetric localization of cell fate determinants is under the control of the protein Inscuteable (Insc), which is itself localized asymmetrically as an apical crescent. Here, we describe a new Drosophila protein, Rapsynoid (Raps), which interacts in a two-hybrid assay with the signal transduction protein Galpha(i). We show that Raps is localized asymmetrically in dividing larval neuroblasts and colocalizes with Insc. Moreover, in raps mutants, the asymmetric divisions of neuroblasts are altered: (1) Insc is no longer asymmetrically localized in the dividing neuroblast; and (2) the neuroblast division produces two daughter cells of similar sizes. However, the morphologically symmetrical divisions of raps neuroblasts still lead to daughter cells with different fates, as shown by differences in gene expression. Our data show that Raps is a novel protein involved in the control of asymmetric divisions of neuroblasts.

Amino Acid Motifs↗