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Biomedical subjects

S Smith

Publications and source records attributed to S Smith.

At least 37 records · Page 2Linked to original sources
PubMed2005

The retinoid anticancer signal: mechanisms of target gene regulation.

Retinoids induce growth arrest, differentiation, and cell death in many cancer cell types. One factor determining the sensitivity or resistance to the retinoid anticancer signal is the transcriptional response of retinoid-regulated target genes in cancer cells. We used cDNA microarray to identify 31 retinoid-regulated target genes shared by two retinoid-sensitive neuroblastoma cell lines, and then sought to determine the relevance of the target gene responses to the retinoid anticancer signal. The pattern of retinoid responsiveness for six of 13 target genes (RARbeta2, CYP26A1, CRBP1, RGS16, DUSP6, EGR1) correlated with phenotypic retinoid sensitivity, across a panel of retinoid-sensitive or -resistant lung and breast cancer cell lines. Retinoid treatment of MYCN transgenic mice bearing neuroblastoma altered the expression of five of nine target genes examined (RARbeta2, CYP26A1, CRBP1, DUSP6, PLAT) in neuroblastoma tumour tissue in vivo. In retinoid-sensitive neuroblastoma, lung and breast cancer cell lines, direct inhibition of retinoid-induced RARbeta2 expression blocked induction of only one of eight retinoid target genes (CYP26A1). DNA demethylation, histone acetylation, and exogenous overexpression of RARbeta2 partially restored retinoid-responsive CYP26A1 expression in RA-resistant MDA-MB-231 breast, but not SK-MES-1 lung, cancer cells. Combined, rather than individual, inhibition of DUSP6 and RGS16 was required to block retinoid-induced growth inhibition in neuroblastoma cells, through phosphorylation of extracellular-signal-regulated kinase. In conclusion, sensitivity to the retinoid anticancer signal is determined in part by the transcriptional response of key retinoid-regulated target genes, such as RARbeta2, DUSP6, and RGS16.

Animals↗
PubMed2005

Fludarabine, melphalan, and alemtuzumab conditioning in adults with standard-risk advanced acute myeloid leukemia and myelodysplastic syndrome.

PURPOSE: This prospective phase II study evaluated toxicity, relapse rate, progression-free survival, and overall survival after allogeneic transplantation and conditioning with fludarabine, melphalan, and alemtuzumab in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Fifty-two consecutive adults with AML and MDS were enrolled onto the study. Median age was 52 years (range, 17 to 71 years) and the majority of patients had high-risk disease, comorbidities, and/or modest reduction in performance status. Fifty-six percent of patients had unrelated or mismatched related donors. RESULTS: After a median follow-up of 18 months (range, 2 to 34 months), 1-year survival was 48% (95% CI, 34% to 61%), progression-free survival was 38% (95% CI, 25% to 52%), relapse rate was 27% (95% CI, 15% to 40%), and treatment-related mortality was 33% (95% CI, 20% to 46%). The cumulative probability of extensive chronic graft-versus-host disease (GVHD) was only 18% (95% CI, 8% to 40%); extensive chronic GVHD was only observed in recipients of unrelated donor transplants. Performance score and disease status were the major predictors of outcome. High-risk disease (ie, active AML or MDS with > 5% blasts) or even modest decreases in performance status were associated with poor outcomes. Patients with standard-risk leukemia (first or second complete remission) or MDS (< 5% blasts) had excellent outcomes despite unfavorable disease characteristics. CONCLUSION: Fludarabine and melphalan combined with in vivo alemtuzumab is a promising transplantation regimen for patients with AML or MDS and low tumor burden. For patients with active disease, this regimen provides at best modest palliation. Despite a low incidence of GVHD, transplantation is still associated with considerable nonrelapse mortality in patients with decreased performance status.

Acute Disease↗
PubMed2005

Risk factors for progression of brain atrophy in aging: six-year follow-up of normal subjects.

OBJECTIVES: To determine the rate of brain atrophy in neurologically asymptomatic elderly and to investigate the impact of baseline variables including conventional cerebrovascular risk factors, APOE epsilon4, and white matter hyperintensity (WMH) on its progression. METHODS: We assessed the brain parenchymal fraction at baseline and subsequent annual brain volume changes over 6 years for 201 participants (F/M = 96/105; 59.8 +/- 5.9 years) in the Austrian Stroke Prevention Study from 1.5-T MRI scans using SIENA (structural image evaluation using normalization of atrophy)/SIENAX (an adaptation of SIENA for cross-sectional measurement)(www.fmrib.ox.ac.uk/fsl). Hypertension, cardiac disease, diabetes mellitus, smoking, and regular alcohol intake were present in 64 (31.8%), 60 (29.9%), 5 (2.5%), 70 (39.3%), and 40 (20.7%) subjects, respectively. Plasma levels of fasting glucose (93.7 +/- 18.6 mg/dL), glycated hemoglobin A (HbA1c; 5.6 +/- 0.7%), total cholesterol (228.3 +/- 40.3 mg/dL), and triglycerides (127.0 +/- 75.2 mg/dL) were determined. WMH was rated as absent (n = 56), punctate (n = 120), early confluent (n = 14), and confluent (n = 11). RESULTS: The baseline brain parenchymal fraction of the entire cohort was 0.80 +/- 0.02 with a mean annual brain volume change of -0.40 +/- 0.29%. Univariate analysis demonstrated a higher rate of brain atrophy in older subjects (p = 0.0001), in those with higher HbA1c (p = 0.0001), higher body mass index (p = 0.02), high alcohol intake (p = 0.04), severe WMH (p = 0.03), and in APOE epsilon4 carriers (p = 0.07). Multivariate analysis suggested that baseline brain parenchymal fraction, HbA1c, and WMH score explain a major proportion of variance in the rates of brain atrophy in the cohort (corrected R2 = 0.27; p = 0.0001). CONCLUSIONS: Neurologically asymptomatic elderly experience continuing brain volume loss, which appears to accelerate with age. Glycated hemoglobin A (HbA1c) was identified as a risk factor for a greater rate of brain atrophy. Clustering of factors associated with the so-called metabolic syndrome in subjects with high HbA1c suggests a link between this syndrome and late-life brain tissue loss.

Age Distribution↗
PubMed2005

Evaluated fate and effects of atrazine and lambda-cyhalothrin in vegetated and unvegetated microcosms.

Contaminants such as nutrients, metals, and pesticides can interact with constructed wetlands and existing drainage ditches used as agricultural best-management practices. Our research has shown that the presence of macrophytes and a hydrologic regime aid in the transfer and transformation of pesticides associated with agricultural runoff. This study consisted of application of both atrazine (triazine herbicide) and lambda-cyhalothrin (pyrethroid insecticide) to vegetated and unvegetated microcosms in order to measure the fate and effects of pesticides applied at suggested field application rates. Exposures focused on monocultures of Ludwigia peploides (water primrose) and Juncus effusus (soft rush). Pesticide sorption was evident through concentrations of atrazine and lambda-cyhalothrin in plant tissue as high as 2461.4 and 86.50 microg/kg, respectively. Toxicity was measured in water from unvegetated microcosms for 28 days and in Chironomus tentans (midge larvae) exposed to sediment collected from 3 h to 56 days in microcosms receiving the pesticide combination. The comparative survival of test organisms in this study suggests that effective mitigation of pesticides from runoff can depend on the macrophyte contact and vegetative attributes associated with ditches.

Agriculture↗
PubMed2005

The use of allelic expression differences to ascertain functional polymorphisms acting in cis: analysis of MMP1 transcripts in normal lung tissue.

Summary Aberrant expression of matrix metalloproteinase 1 (MMP1) has been implicated in a number of pathological conditions of the lung. In vitro results and analysis of tumours and cell lines suggest that an insertion/deletion polymorphism at position -1607 in the promoter of the gene can influence expression levels. However, whether this polymorphism is associated with differences in expression in normal lung tissue remains to be established. Polymorphisms affecting expression in cis will lead to alleles with different expression levels and will result in unequal expression of both alleles in heterozygous individuals (allelic expression imbalance, AEI). This can be detected using a transcribed marker. Here we follow a new approach and use AEI to ascertain that the -1607 polymorphism is associated with allelic expression differences of MMP1 in normal lung tissue. This approach could be used to map the sites associated with inter-individual expression differences in other genes. This is of particular interest since such sites allow prediction of expression levels, and can be used to test whether genetically determined differences in expression influence inter-individual differences of a phenotype of interest, such as disease predisposition.

Alleles↗
PubMed2005

Developing a service to monitor and improve physical health in people with serious mental illness.

Developing effective models of identifying and managing physical health problems amongst mentally ill populations has become a more pressing issue in recent years as the prescription of Second Generation Antipsychotics (SGAs) has burgeoned. Some of the side effects commonly associated with SGAs such as weight gain and metabolic disorders have potentially devastating effects on health and well-being, increasing cardiovascular risk and the incidence of diabetes. The Well-Being Support Programme (WSP), a nurse-led service, was designed to provide a care delivery system whereby physical problems could be identified and appropriate treatment and monitoring initiated by prompt referral to suitable specialist services or general practitioners, forging strong links between primary and secondary care and ensuring that mentally ill patients with physical health problems were receiving holistic care packages. Other problems such as unhealthy lifestyles and obesity were managed by the Nurse Advisor running the programme. Interventions such as weight counselling and groups, and structured exercise programmes were beneficial in terms of encouraging healthier lifestyles, managing obesity and improving self-esteem. This paper describes the manner in which the service was set up and implemented, demonstrating an effective model for identifying and managing physical health problems in the mentally ill.

Adolescent↗
PubMed2005

Repair of obstetric brachial plexus palsy: results in 100 children.

This is a prospective study of 107 repairs of obstetric brachial plexus palsy carried out between January 1990 and December 1999. The results in 100 children are presented. In partial lesions operation was advised when paralysis of abduction of the shoulder and of flexion of the elbow persisted after the age of three months and neurophysiological investigations predicted a poor prognosis. Operation was carried out earlier at about two months in complete lesions showing no sign of clinical recovery and with unfavourable neurophysiological investigations. Twelve children presented at the age of 12 months or more; in three more repair was undertaken after earlier unsuccessful neurolysis. The median age at operation was four months, the mean seven months and a total of 237 spinal nerves were repaired. The mean duration of follow-up after operation was 85 months (30 to 152). Good results were obtained in 33% of repairs of C5, in 55% of C6, in 24% of C7 and in 57% of operations on C8 and T1. No statistical difference was seen between a repair of C5 by graft or nerve transfer. Posterior dislocation of the shoulder was observed in 30 cases. All were successfully relocated after the age of one year. In these children the results of repairs of C5 were reduced by a mean of 0.8 on the Gilbert score and 1.6 on the Mallett score. Pre-operative electrodiagnosis is a reliable indicator of the depth of the lesion and of the outcome after repair. Intra-operative somatosensory evoked potentials were helpful in the detection of occult intradural (pre-ganglionic) injury.

Age Factors↗
PubMed2004

Monocyte chemotactic protein-1 expression is increased in human gestational tissues during term and preterm labor.

OBJECTIVE: Microarray analysis was used to characterize the labor-selective transcriptome of the human myometrium during labor. One highly up-regulated transcript, monocyte chemotactic protein-1 (MCP-1), was further characterized. METHODS: Expression of MCP-1 was evaluated in the myometrium, the placenta, the gestational membranes (GM) and the amniotic fluid (AF) by real time RT-PCR, Northern blot analysis and ELISA. The level of immunoreactive (IR) MCP-1 content of primary myometrial cultures treated with inflammatory cytokines was quantified by ELISA. RESULTS: Up-regulation of the myometrial MCP-1 transcript in term laboring patients was demonstrated by microarray and confirmed by real time (RT)-PCR and Northern blot analysis. Increased MCP-1 transcripts were demonstrated in GM during term labor. The IR content of myometrial MCP-1 was increased during term labor and in the AF from patients experiencing preterm delivery. Levels of IR MCP-1 increased in myometrial cultures in response to interleukin 1-beta. CONCLUSION: The expression of myometrial MCP-1 was significantly increased during term labor and was similarly increased in vitro in response to interleukin 1-beta, a pro-inflammatory substance known to play a role in preterm birth. The increased IR content of MCP-1 within the AF preceding preterm delivery may render this protein a useful predictor of preterm birth.

Adult↗
PubMed2004

Factors influencing time from presentation to treatment of colorectal and breast cancer in urban and rural areas.

Stage at diagnosis and survival from cancer vary according to where people live, suggesting some may have delays in diagnosis. The aim of this study was to determine if time from presentation to treatment was longer for colorectal and breast cancer patients living further from cancer centres, and identify other important factors in delay. Data were collected on 1097 patients with breast and 1223 with colorectal cancer in north and northeast Scotland. Women with breast cancer who lived further from cancer centres were treated more quickly than those living closer to cancer centres (P=0.011). Multilevel modelling found that this was largely due to them receiving earlier treatment at hospitals other than cancer centres. Breast lump, change in skin contour, lymphadenopathy, more symptoms and signs, and increasing age predicted faster treatment. Screen detected cancers and private referrals were treated more quickly. For colorectal cancer, time to treatment was similar for people in rural and urban areas. Quicker treatment was associated with palpable rectal or abdominal masses, tenesmus, abdominal pain, frequent GP consultations, age between 50 and 74 years, tumours of the transverse colon, and iron medication at presentation. Delay was associated with past anxiety or depression. There was variation between general practices and treatment appeared quicker at practices with more female general practitioners.

Adult↗
PubMed2004

Achievement of ultralow emittance beam in the accelerator test facility damping ring.

For high luminosity in electron-positron linear colliders, it is essential to generate low vertical emittance beams. We report on the smallest vertical emittance achieved in single-bunch-mode operation of the Accelerator Test Facility, which satisfies the requirement of the x-band linear collider. The emittances were measured with a laser-wire beam-profile monitor installed in the damping ring. The bunch length and the momentum spread of the beam were also recorded under the same conditions. The smallest vertical rms emittance measured at low intensity is 4 pm at a beam energy of 1.3 GeV, which corresponds to the normalized emittance of 1.0x1.0(-8) m. It increases by a factor of 1.5 for a bunch intensity of 10(10) electrons. The measured data agreed to the calculation of intrabeam scattering within much better than a factor of 2.

Journal Article↗
PubMed2004

Evaluating acute toxicity of methyl parathion application in constructed wetland mesocosms.

Wetland ecosystems have reduced ambient levels of various organic and metallic compounds, although their effectiveness on agricultural pesticides is not well documented. Five stations within each of two 10 x 50 m constructed wetlands (two vegetated, two nonvegetated) were selected to measure the fate and effects of methyl parathion (MeP). Following a simulated storm event (0.64 cm of rainfall), aqueous, sediment, and plant samples were collected and analyzed spatially (5, 10, 20, and 40 m from the inlet) and temporally (after 3-10 days) for MeP concentrations and for the impact of those concentrations on the aquatic fauna. Aqueous toxicity to fish decreased spatially and temporally in the vegetated mesocosm. Pimephales promelas survival was significantly reduced, to 68%, at the 10-m station of the nonvegetated wetlands (3 h postapplication), with pesticide concentrations averaging 9.6 microg MeP/L. Ceriodaphnia in both the vegetated and nonvegetated wetlands was sensitive (i.e., a significant acute response to MeP occurred) to pesticide concentrations through 10 days postapplication. Mean MeP concentrations in water ranged from 0.5 to 15.4 microg/L and from 0.1 to 27.0 microg/L in the vegetated and nonvegetated wetlands, respectively. Hyalella azteca aqueous tests resulted in significant mortality in the 5-m vegetated segment 10 days after exposure to MeP (2.2 microg/L). Solid-phase (10-day) sediment toxicity tests showed no significant reduction in Chironomus tentans survival or growth, except for the sediments sampled 3 h postapplication in the nonvegetated wetland (65% survival). Thereafter, midge survival averaged >87% in sediments sampled from both wetlands. These data suggest that wetlands play a significant role in mitigating the effect of MeP exposure in sensitive aquatic biota.

Agriculture↗
PubMed2004

Evaluating toxicity of Asana XL (esfenvalerate) amendments in agricultural ditch mesocosms.

Agricultural ditches primarily serve to remove and store excess water associated with irrigation and storm events. The ability of these ecosystems to mitigate potential contaminants is not well understood. Five sites along a 650-m agricultural ditch located in the Mississippi Delta Management Systems Evaluation Area (MDMSEA) were used to measure fate and effects of an esfenvalerate (insecticide) exposure. Following a 0.64-cm simulated storm event, samples were collected from water and sediments and analyzed spatially from five sites and temporally from 0.5 h to 56 d. Results of aqueous toxicity bioassays indicated that lethality progressed downstream throughout all sampling intervals, while sediment toxicity bioassays only elicited biological responses at the point of pesticide application to the ditch (0 m). Significant reductions in survival of Ceriodaphnia dubia and Pimephales promelas in water were measured at the 0-, 20-, and 80-m sites following application. Ten-day solid phase sediment testing of Chironomus tentans indicated persistent toxicity only at the point of application (0 m) and throughout 56 d (mean=14.4% survival). No lethality or significant reduction in midge growth was measured for remaining downstream sites. These measurements were used to evaluate the potential of agricultural ditches to reduce potential deleterious effects of contaminants in agricultural drainage systems that precede receiving streams.

Agriculture↗
PubMed2004

A comparison of enamel erosion by a new sports drink compared to two proprietary products: a controlled, crossover study in situ.

OBJECTIVE: The aim of the study was to measure the erosive potential of a prototype sports drink on enamel in a model in situ. METHODS: The study was a single centre, single blind, randomised crossover design balanced for residual effects involving 18 subjects. The drinks were the prototype formulation containing calcium and maltodextrin (test), two sports drink products containing sugars (drink with calcium and positive control) and water (negative control). During each 15-day study period, subjects wore a palatal removable appliance carrying two flat human enamel specimens. Drinks were imbibed as 250 ml volumes over 10 min 4 times per day. Loss of enamel was measured on days 5, 10 and 15 using a contacting profilometer. RESULTS: Very little erosion occurred with the test, drink with calcium and negative control drinks and differences between the test and negative control only reached significance at day 15. The positive control produced progressive erosion over time and significantly more than the test or negative control at all time points. CONCLUSION: The technology of adding calcium with appropriate pH adjustment, which has been applied previously to soft and carbonated drinks to markedly reduce erosive potential, can be applied to sports drinks to the same end. Significant variation in the carbohydrate composition does not influence this outcome.

Adult↗