Setting up a home-based business.
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Consultants↗
Biomedical subjects
W C Smith
Publications and source records attributed to W C Smith.
Genetic localization and molecular characterization of the nonS gene required for macrotetrolide biosynthesis in Streptomyces griseus DSM40695.
The macrotetrolides are a family of cyclic polyethers derived from tetramerization, in a stereospecific fashion, of the enantiomeric nonactic acid (NA) and its homologs. Isotope labeling experiments established that NA is of polyketide origin, and biochemical investigations demonstrated that 2-methyl-6,8-dihydroxynon-2E-enoic acid can be converted into NA by a cell-free preparation from Streptomyces lividans that expresses nonS. These results lead to the hypothesis that macrotetrolide biosynthesis involves a pair of enantiospecific polyketide pathways. In this work, a 55-kb contiguous DNA region was cloned from Streptomyces griseus DSM40695, a 6.3-kb fragment of which was sequenced to reveal five open reading frames, including the previously reported nonR and nonS genes. Inactivation of nonS in vivo completely abolished macrotetrolide production. Complementation of the nonS mutant by the expression of nonS in trans fully restored its macrotetrolide production ability, with a distribution of individual macrotetrolides similar to that for the wild-type producer. In contrast, fermentation of the nonS mutant in the presence of exogenous (+/-)-NA resulted in the production of nonactin, monactin, and dinactin but not in the production of trinactin and tetranactin. These results prove the direct involvement of nonS in macrotetrolide biosynthesis. The difference in macrotetrolide production between in vivo complementation of the nonS mutant by the plasmid-borne nonS gene and fermentation of the nonS mutant in the presence of exogenously added (+/-)-NA suggests that NonS catalyzes the formation of (-)-NA and its homologs, supporting the existence of a pair of enantiospecific polyketide pathways for macrotetrolide biosynthesis in S. griseus. The latter should provide a model that can be used to study the mechanism by which polyketide synthase controls stereochemistry during polyketide biosynthesis.
Bacterial Proteins↗
Measuring the costs and benefits of heart disease monitoring.
OBJECTIVE: To evaluate the costs and benefits of alternative systems of coronary heart disease monitoring in Scotland. DESIGN: An option appraisal was conducted to evaluate the costs and benefits of implementing a coronary heart disease monitoring system. This involved a review of existing Scottish datasets and relevant reports, specification of options, definition and weighting of benefit criteria by key stakeholders, assessment of options by experts, and costing of options. The options were assessed by 33 stakeholders (grouped as cardiologists, patient representatives, general practitioners, public health physicians, and policy makers), plus 13 topic experts. SETTING: Scotland (population 5.1 million). RESULTS: Between group mean benefit weights were: mortality rates and case fatality (10.6), quality of life (9.8), patient function (8.8), hospital activity (7.8), primary care activity (9.25), prescribing (5.72), socioeconomic impact (4.0), risk factors (7.4), prevalence (5.0), incidence (6.0), case registration (6.82), international comparability (4.2), breadth of coverage (8.8), and frequency (5.8). Differences between group weights were significant for prevalence (p = 0.048) and international comparability (p = 0.032). Four monitoring options were identified: a community epidemiology model, based on MONICA (monitoring trends and determinants in cardiovascular disease) study methodology applied to a series of eight representative communities, had the highest benefits, at an average annual discounted cost of approximately pound 360,000; models based on the Australian cardiovascular disease monitoring scheme and on enhanced routine data offered fewer benefits at discounted average annual costs ranging from pound 165,000 to pound 195,000; finally, a coronary heart disease registry modelled on the Scottish Cancer Registry scheme would have had fewer benefits and substantially higher costs than the other options. CONCLUSIONS: The most beneficial coronary heart disease monitoring system is the community epidemiology model, based on MONICA methodology. Option appraisal potentially offers an explicit and transparent methodology for evidence based policy development.
Coronary Disease↗
Incidence rates of acute nerve function impairment in leprosy: a prospective cohort analysis after 24 months (The Bangladesh Acute Nerve Damage Study).
In this paper, the incidence rates and cumulative incidence of nerve function impairment (NFI) and leprosy reactions over 24 months follow-up of the prospective cohort of 2664 new leprosy cases are presented. Graphs showing the cumulative incidence of NFI relative to time since registration are presented. Hazard ratios (HRs) for the development of NFI for four variables are given. The majority of patients who developed NFI after registration did so in the first year (67% of multibacillary (MB) patients, and 91% of paucibacillary (PB) patients who developed NFI). Thirty-three percent of all MB patients who developed NFI after registration did so in the second year of follow-up. No PB patients developed NFI for the first time in the last 6 months of follow-up. However, seven NFI events occurred amongst PB patients in that period, amongst those who had already had one NFI event. The incidence rate (IR) of NFI amongst MB patients was 24/100 person-years at risk (PYAR), and amongst PB patients was 1.3/100 PYAR. The HR for the development of NFI amongst MB patients compared with PB patients was 16 using univariate analysis. Amongst patients who had long-standing NFI present at registration, the IR was 27/100 PYAR compared with 1.7/100 PYAR amongst those who did not have long-standing NFI. The HR for developing acute NFI amongst those with long-standing NFI present at registration compared with those without was 14 using univariate analysis. When multivariate regression analysis is applied, the apparently significant univariate HRs for sex and age disappeared. The resultant multivariate HR for leprosy group is 8.8, and 6.1 for the presence/absence of long-standing NFI at registration. In all, 142/166 (86%) of all new NFI events were silent, underlining the need for regular nerve function testing. IRs are presented for the four 6-month periods of the 24-month follow-up. They show a clear stepwise reduction over the total period. The IRs amongst MB patients and those with long-standing NFI present at registration are very high at 34 and 41/100 PYAR, respectively, for the first 6 months of follow-up. Even during the final 6-month period, the IR is maintained at a moderately high level (18 and 15/100 PYAR, respectively).
Adult↗
The treatment of acute nerve function impairment in leprosy: results from a prospective cohort study in Bangladesh.
In this paper, the outcome of 132 patients having acute nerve function impairment (NFI) is reported at 4 and 12 months after the start of prednisolone treatment. In all, 68% of sensory nerves and 67% of motor nerves showed improvement at 12 months, with no statistical difference in responsiveness of various nerves to prednisolone. Duration and severity of impairment were not found significant predictors of treatment outcome. A core of 32% of impaired nerves did not respond to prednisolone, and 12% of impaired nerves had functional deterioration despite treatment. The mean eye-hand-foot (EHF) score improved from 2.02 to 1.33 in the treatment group (median score improved from 2 to 1). Approximately one-third of all patients requiring prednisolone treatment did not receive it, an important reason being that some patients developed new NFI against a background of chronic impairment, and were thus overlooked. The 'unjustly untreated' group of patients had a spontaneous sensory nerve function improvement rate of 62% and a motor nerve function improvement rate of 33% at 12 months from onset of NFI. The EHF score showed no statistically significant improvement.
Adult↗
Implementing guidelines for socio-economic rehabilitation.
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Female↗
Review of current research in the prevention of nerve damage in leprosy.
Nerve damage and the consequences of nerve damage set leprosy apart from other diseases. The irreversible motor and sensory impairments caused by leprosy lead to increasing secondary impairments long after the disease process has been arrested. Interventions that prevent, reverse or limit the impairments resulting from leprosy are, therefore, of the highest priority. Self-care has been demonstrated to be an effective means of preventing secondary tissue damage, and its implementation must now be encouraged within the framework of basic health care. Currently, a comprehensive effort has been made to address all dimensions of impairment of nerve function and its consequences, from prevention of both primary and secondary impairments to interventions in long-term nerve damage. The BANDS prospective study of a cohort of 2664 previously untreated leprosy patients in Bangladesh has provided both a valuable baseline and insight into the epidemiology of nerve damage in leprosy. This work has defined the numbers of patients who present with acute nerve damage, the numbers who are not treated, and the importance of the MB classification, and has described the simple clinical prediction rule. This study also provided the basis for the development of the three TRIPOD randomized clinical trials in Nepal and Bangladesh. Follow-up of the BANDS cohort, which is continuing, will yield more data on the natural history of nerve damage. The encouraging results from the TRIPOD trials of low-dose prophylactic steroids will be followed up, to see whether the effect is sustained over time. The TRIPOD trials are to be completed, a trial of three steroid regimens in reversal reaction is to be completed, and a number of specific research topics within the ILEP programme, INFIR, are to be developed.
Bangladesh↗
Cloning and functional characterization of salamander rod and cone arrestins.
PURPOSE: To clone, localize, and determine functional binding characteristics of rod and cone arrestins from the retina of the tiger salamander (Ambystoma tigrinum). METHODS: Two arrestins from salamander retina were cloned on the basis of their homology to known arrestins from other species. The expression pattern of these arrestins (SalArr1 and SalArr2) in the retina was determined by immunocytochemistry and in situ hybridization. SalArr1 and SalArr2 were expressed and functionally characterized. RESULTS: Both immunocytochemistry and in situ hybridization show that SalArr1 and SalArr2 localized specifically to rod and cone photoreceptors, respectively. SalArr1 demonstrated a characteristic high selectivity for light-activated phosphorylated rhodopsin (P-Rh*) and significant species selectivity, binding preferentially to amphibian rhodopsin over bovine rhodopsin. Mutant constitutively active forms of SalArr1 demonstrated a 2- to 4-fold increase in P-Rh* binding (compared with wild-type protein) and an even more dramatic (up to 25-fold) increase in binding to unphosphorylated Rh* and dark P-Rh. Constitutively active SalArr1 mutants also showed a reduced specificity for amphibian rhodopsin. The ability of Escherichia coli-expressed SalArr1, SalArr2, and an SalArr1-3A (L369A,V370A,F371A) mutant to bind to frog Rh* and P-Rh* and to compete with tritiated SalArr1 for amphibian P-Rh* was compared. SalArr1 and its mutant form bound to amphibian P-Rh* with high affinity (Ki = 179 and 74 nM, respectively), whereas the affinity of SalArr2 for P-Rh* was substantially lower (Ki = 9.1 microM). CONCLUSIONS: SalArr1 and SalArr2 are salamander rod and cone arrestins, respectively. Crucial regulatory elements in SalArr1 are conserved and play functional roles similar to those of their counterparts in bovine rod arrestin. Rod and cone arrestins are relatively specific for their respective receptors.
Ambystoma↗
The epidemiology of chronic pain in the community.
BACKGROUND: Chronic pain is recognised as an important problem in the community but our understanding of the epidemiology of chronic pain remains limited. We undertook a study designed to quantify and describe the prevalence and distribution of chronic pain in the community. METHODS: A random sample of 5036 patients, aged 25 and over, was drawn from 29 general practices in the Grampian region of the UK and surveyed by a postal self-completion questionnaire. The questionnaire included case-screening questions, a question on the cause of the pain, the chronic pain grade questionnaire, the level of expressed needs questionnaire, and sociodemographic questions. FINDINGS: 3605 questionnaires were returned completed. 1817 (50.4%) of patients self reported chronic pain, equivalent to 46.5% of the general population. 576 reported back pain and 570 reported arthritis; these were the most common complaints and accounted for a third of all complaints. Backward stepwise logistic-regression modelling identified age, sex, housing tenure, and employment status as significant predictors of the presence of chronic pain in the community. 703 (48.7%) individuals with chronic pain had the least severe grade of pain, and 228 (15.8%) the most severe grade. Of those who reported chronic pain, 312 (17.2%) reported no expressed need, and 509 (28.0%) reported the highest expressed need. INTERPRETATION: Chronic pain is a major problem in the community and certain groups within the population are more likely to have chronic pain. A detailed understanding of the epidemiology of chronic pain is essential for efficient management of chronic pain in primary care.
Adult↗
Sulfhydryl reactivity demonstrates different conformational states for arrestin, arrestin activated by a synthetic phosphopeptide, and constitutively active arrestin.
The sulfhydryl groups of the three cysteines in bovine arrestin react with DTNB very slowly (over a period of several hours). In the presence of the synthetic phosphopeptide comprising the fully phosphorylated carboxyl-terminal 19 amino acids of bovine rhodopsin, the reactivity of one of the sulfhydryls was enhanced while that of another was greatly reduced. Since this synthetic peptide was shown to activate arrestin with respect to its binding to unphosphorylated, light-activated rhodopsin, the reactivity of the sulfhydryl groups of a constitutively active R175Q arrestin mutant was examined. All three of the sulfhydryl groups of the mutant arrestin R175Q reacted rapidly with DTNB, but not as rapidly as with SDS-denatured arrestin. The arrestin mutant R175Q bound to light-activated, unphosphorylated rhodopsin in ROS disk membranes. The arrestin mutant R175Q also inhibited the light-activated PDE activity with an IC50 of 1.3 microM under the experimental conditions that were used. These data indicate that each of these forms of arrestin is a different conformation. The activated conformation of arrestin that binds to phosphorylated rhodopsin in vivo may be yet another conformation. We conclude that arrestin is a flexible molecule that is able to attain several different conformations, all of which are able to attain the activated functional state of arrestin.
Animals↗
Identification of regions of arrestin that bind to rhodopsin.
Arrestin facilitates phototransduction inactivation through binding to photoactivated and phosphorylated rhodopsin (RP). However, the specific portions of arrestin that bind to RP are not known. In this study, two different approaches were used to determine the regions of arrestin that bind to rhodopsin: panning of phage-displayed arrestin fragments against RP and cGMP phosphodiesterase (PDE) activity inhibition using synthetic arrestin peptides spanning the entire arrestin protein. Phage display indicated the predominant region of binding was contained within amino acids 90-140. A portion of this region (residues 95-140) expressed as a fusion protein with glutathione S-transferase is capable of binding to rhodopsin regardless of the activation or phosphorylation state of the receptor. Within this region, the synthetic peptide of residues 109-130 was shown to completely inhibit the binding of arrestin to rhodopsin with an IC50 of 1.1 mM. The relatively high IC50 of this competition suggests that this portion of the molecule may be only one of several regions of binding between arrestin and RP. A survey of synthetic arrestin peptides in the PDE assay indicated that the two most effective inhibitors of PDE activity were peptides of residues 111-130 and 101-120. These results indicate that at least one of the principal regions of binding between arrestin and RP is contained within the region of residues 109-130.
3',5'-Cyclic-GMP Phosphodiesterases↗
Isolation of developmental mutants of the ascidian Ciona savignyi.
Ascidians have been used extensively as model animals for experimental embryology. We report here the results of a pilot study with the aim of developing genetic methods for the ascidian Ciona savignyi. The chemical mutagen N-ethyl-N-nitrosourea (ENU) was used to induce point mutations. F1 animals, produced by using sperm from ENU-treated animals to fertilize untreated eggs, were grown to reproductive age. Sperm and eggs collected from the hermaphrodite F1 adults were used to generate self-fertilized F2 broods, which were then screened for recessive, zygotically acting mutations. Animals carrying potential mutations were outcrossed to wild type to test for the heritability of the phenotypes. We report on a number of mutants isolated using this method, including several with abnormalities in tail and notochord development.
Animals↗
TGF beta inhibitors. New and unexpected requirements in vertebrate development.
Analysis of embryonic induction has pointed to the importance of the antagonistic roles played by secreted inducing factors and their soluble inhibitory binding proteins. These interactions have been particularly well characterized in patterning the primary axes of insects and vertebrates. New results implicate similar antagonistic relationships in numerous later events of embryogenesis.
Animals↗
Relationship between the chronic pain grade and measures of physical, social and psychological well-being.
Chronic pain is an important cause of suffering, disability and loss of productivity within the community. Chronic pain can also be viewed as a multidimensional phenomenon, and may be associated with increased suffering of a social and psychological nature, as well as physical suffering. In this paper, the severity of the chronic pain gradings (CPG) is defined in terms of physical, social and psychological well-being, as measured by the SF36 and Glasgow Pain Questionnaire. Although previous work has shown the chronic pain grade to be a valid measure of chronic pain severity, little is known of the relationship between this and other health measures. A random sample of 5036 individuals, representative of the general population, stratified for age and sex, was drawn. A further sample of 4175 patients was drawn from a list of patients enrolled for repeat prescriptions for analgesic medication. A questionnaire survey was carried out, and response rates of 82 and 87% were achieved, respectively. The comparisons described confirm the widespread impact of chronic pain on all aspects of health, supporting the multidimensional view. These findings are important in addressing the management of chronic pain patients, and in particular, the social and psychological well-being of a patient needs to be addressed in parallel with the physical well-being in order to successfully reduce the suffering associated with chronic pain.
Adult↗
A retrospective cohort study of post mastectomy pain syndrome.
Post mastectomy pain syndrome is a condition which can occur following breast surgery and has until recently been regarded as uncommon. Recent reports have suggested that it may affect 20% or more of women following mastectomy. The symptoms are distressing and may be difficult to treat however treatment for neuropathic pain can be successful. This paper reports a retrospective cohort of consecutive mastectomy cases over a six year period in one region of whom 511 survivors were traced and eligible for survey. A total of 408 completed a questionnaire survey which revealed that 175 (43%) had ever suffered from postmastectomy pain syndrome and 119 (29%) reported current symptoms although the majority were decreasing in intensity. A striking finding was the very high cumulative prevalence in younger women (65%) decreasing to 26% in the over 70 year group. The details of the onset, frequency and intensity of symptoms are described along with their natural history. The age effect on the frequency of the syndrome influences the marital status, employment status, housing, and educational status of those who report typical symptoms. Body weight and height are also associated with the frequency of post mastectomy pain syndrome. Relationship between the frequency of post mastectomy pain syndrome and radiotherapy, chemotherapy and the use of tamoxifen are difficult to unravel because of the combinations of pre and post operative treatments received confounded by age. The implications of a much higher frequency of post mastectomy pain are discussed with regard to management and counselling. The high frequency of the syndrome in the younger women is important and possible explanations are explored.
Adult↗
Influence of socioeconomic conditions on growth in infancy: the 1921 Aberdeen birth cohort.
OBJECTIVES: To identify environmental influences on infant growth using data from a birth cohort established in 1921. DESIGN: A longitudinal cohort study. SETTING: Aberdeen 1921-22. SUBJECTS: Five hundred and sixteen individuals (263 boys and 253 girls) born in Aberdeen during 1921. Health visitor assessments ranged from two to 40 (47% received at least 10 visits). No records were available for infants who died. Individuals were grouped as those who did not breast feed, those who breast fed initially but not at 6 months, and those who were continuing to breast feed at 6 months. MAIN OUTCOME MEASURE: Rate of weight gain over the 1st year of life. A random effects model was used to identify environmental factors and conditions contributing to rate of weight gain in the 1st year of life. RESULTS: Breast feeding rates were about 80% and 50% at 10 days and 6 months, respectively. Breast fed infants were significantly heavier than bottle fed infants at 28 days but this difference disappeared by 12 months. Significant negative effects on rate of weight gain, independent of initial body weight, were found for overcrowding in family homes and maternal parity, whereas social class had no effect. CONCLUSION: Studies based on historical cohorts that have controlled socioeconomic variables only in terms of social class (derived from parental occupation) may have been subject to residual confounding. Growth in the 1st year of life is likely to reflect a number of environmental influences, some of which may continue to have effects throughout early life and beyond.
Aged↗
Mutations affecting tail and notochord development in the ascidian Ciona savignyi.
Ascidians are among the most distant chordate relatives of the vertebrates. However, ascidians share many features with vertebrates including a notochord and hollow dorsal nerve cord. A screen for N-ethyl-N-nitrosourea (ENU)-induced mutations affecting early development in the ascidian Ciona savignyi resulted in the isolation of a number of mutants including the complementing notochord mutants chongmague and chobi. In chongmague embryos the notochord fails to develop, and the notochord cells instead adopt a mesenchyme-like fate. The failure of notochord development in chongmague embryos results in a severe truncation of tail, although development of the tail muscles and caudal nerve tracts appears largely normal. Chobi embryos also have a truncation of the tail stemming from a disruption of the notochord. However, in chobi embryos the early development of the notochord appears normal and defects occur later as the notochord attempts to extend and direct elongation of the tail. We find in chobi tailbud embryos that the notochord is often bent, with cells clumped together, rather than extended as a column. These results provide new information on the function and development of the ascidian notochord. In addition, the results demonstrate how the unique features of ascidians can be used in genetic analysis of morphogenesis.
Animals↗
Spatial and temporal properties of ventral blood island induction in Xenopus laevis.
Questions of dorsoventral axis determination and patterning in Xenopus seek to uncover the mechanisms by which particular mesodermal fates, for example somite, are specified in the dorsal pole of the axis while other mesoderm fates, for example, ventral blood island (VBI), are specified at the ventral pole. We report here that the genes Xvent-1, Xvent-2, and Xwnt-8 do not appear to be in the pathway of VBI induction, contrary to previous reports. Results from the selective inhibition of bone morphogenetic protein (BMP) activity, a key regulator of VBI induction, by ectopic Noggin, Chordin, or dominant negative BMP ligands and receptors suggest an alternative route of VBI induction. Injection of noggin or chordin RNA into animal pole blastomeres effectively inhibited VBI development, while marginal zone injection had no effect. Cell autonomous inhibition of BMP activity in epidermis with dominant negative ligand dramatically reduced the amount of (&agr;)T3 globin expression. These results indicate that signaling activity from the Spemann Organizer alone may not be sufficient for dorsoventral patterning in the marginal zone and that an inductive interaction between presumptive VBIs and ectoderm late in gastrulation may be crucial. In agreement with these observations, other results show that in explanted blastula-stage marginal zones a distinct pattern develops with a restricted VBI-forming region at the vegetal pole that is independent of the patterning activity of the Spemann Organizer.
Actins↗