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Biomedical subjects

A Weston

Publications and source records attributed to A Weston.

At least 19 recordsLinked to original sources
PubMed2006

The effects of esomeprazole combined with aspirin or rofecoxib on prostaglandin E2 production in patients with Barrett's oesophagus.

BACKGROUND: Reducing mucosal cyclo-oxygenase-2 and prostaglandin E(2) production and suppressing intraoesophageal acid may be effective chemopreventive strategies in patients with Barrett's oesophagus. AIM: To compare the effects of aspirin and rofecoxib when administered with esomeprazole on prostaglandin E(2) production, cyclo-oxygenase-2 expression and proliferating cell nuclear antigen expression in patients with Barrett's oesophagus. METHODS: This exploratory, multicentre, randomized, open-label, four-way crossover study in 45 patients with Barrett's oesophagus evaluated prostaglandin E(2) content, proliferating cell nuclear antigen expression, and cyclo-oxygenase-2 expression after 10 days of sequential treatments with: esomeprazole 40 mg twice daily plus aspirin 325 mg once daily (E40 b.d. + A325); E40 b.d. plus rofecoxib 25 mg once daily (E40 b.d. + R25); E40 b.d.; and rofecoxib 25 mg once daily (R25). RESULTS: Prostaglandin E(2) content reduction in Barrett's oesophagus tissue was significantly greater with E40 b.d. + A325 compared with E40 b.d. + R25, E40 b.d. or R25 (P < 0.05). All treatments containing E40 b.d. significantly decreased proliferating cell nuclear antigen expression from baseline (P < 0.05). None of the treatments significantly reduced cyclo-oxygenase-2 expression. CONCLUSIONS: The combined treatment of esomeprazole 40 mg b.d. and aspirin 325 mg significantly decreased mucosal prostaglandin E(2) content and all treatments containing esomeprazole significantly reduced proliferating cell nuclear antigen expression in patients with Barrett's oesophagus.

Adult↗
PubMed2002

Effects of electrical stimulation-induced leg training on skeletal muscle adaptability in spinal cord injury.

Neuromuscular electrical stimulation has grown in popularity as a therapeutic device for training and an ambulation aid to human paralyzed muscle. Despite its current clinical use, few studies have attempted to concurrently investigate the functional and intramuscular adaptations which occur after electrical stimulation training. Six individuals with a spinal cord injury performed 10 weeks of electrical stimulation leg cycle training (30 min d(-1), 3 d week(-1)). The paralyzed vastus lateralis muscle showed significant alterations in skeletal muscle characteristics after the training, indicated by an improvement in total work output (52-112 kJ; P < 0.05), an increase in fiber cross-sectional area (18 to 41 x 10(2) microm(2); P < 0.05), a reduction in the percentage of type IIX fibers (75% to 12%; P < 0.05), a decrease in myosin heavy chain IIx (68% to 44%; P < 0.05), an increase in capillary density (2-3.5 capillaries around fiber; P < 0.05) and increases in activity levels of citrate synthase (7-16 mU mg(-1) protein) and hexokinase (1.2-2.4 mU mg(-1) protein). This study showed that 10 weeks of electrical stimulation training of human paralyzed muscle induces concurrent improvements in functional capacity and oxidative metabolism.

Adaptation, Physiological↗
PubMed2002

Use of signal-mediated amplification of RNA technology (SMART) to detect marine cyanophage DNA.

Here, we describe the application of an isothermal nucleic acid amplification assay, signal-mediated amplification of RNA technology (SMART), to detect DNA extracted from marine cyanophages known to infect unicellular cyanobacteria from the genus Synechococcus. The SMART assay is based on the target-dependent production of multiple copies of an RNA signal, which is measured by an enzyme-linked oligosorbent assay. SMART was able to detect both synthetic oligonucleotide targets and genomic cyanophage DNA using probes designed against the portal vertex gene (g20). Specific signals were obtained for each cyanophage strain (S-PM2 and S-BnMI). Nonspecific genomic DNA did not produce false signals or inhibit the detection of a specific target. In addition, we found that extensive purification of target DNA may not be required since signals were obtained from crude cyanophage lysates. This is the first report of the SMART assay being used to discriminate between two similar target sequences.

Bacteriophages↗
PubMed2001

Distribution of HER2(V655) genotypes in breast cancer cases and controls in the United States.

The minor variant frequency of a HER2 polymorphism (HER2(V655)) has been determined for 471 United States women enrolled in a multiracial case-control study. Allelic frequencies varied significantly by race. Genotypic distributions showed no excess breast cancer risk associated with inheritance of HER2(V655) either as carriers (OR=1.2, 95% CI=0.8-1.9), heterozygotes (OR=1.2, 95% CI=0.8-1.9), or homozygotes (OR=1.4, 95% CI=0.4-4.2). Nor was there a significant association when each racial group was considered separately. The current study suggests the HER2(V655) allele is not a breast cancer risk factor for Caucasians, African-Americans, or Latinas.

Breast Neoplasms↗
PubMed2001

Specific detection of DNA and RNA targets using a novel isothermal nucleic acid amplification assay based on the formation of a three-way junction structure.

The formation of DNA three-way junction (3WJ) structures has been utilised to develop a novel isothermal nucleic acid amplification assay (SMART) for the detection of specific DNA or RNA targets. The assay consists of two oligonucleotide probes that hybridise to a specific target sequence and, only then, to each other forming a 3WJ structure. One probe (template for the RNA signal) contains a non-functional single-stranded T7 RNA polymerase promoter sequence. This promoter sequence is made double-stranded (hence functional) by DNA polymerase, allowing T7 RNA polymerase to generate a target-dependent RNA signal which is measured by an enzyme-linked oligosorbent assay (ELOSA). The sequence of the RNA signal is always the same, regardless of the original target sequence. The SMART assay was successfully tested in model systems with several single-stranded synthetic targets, both DNA and RNA. The assay could also detect specific target sequences in both genomic DNA and total RNA from Escherichia coli. It was also possible to generate signal from E.coli samples without prior extraction of nucleic acid, showing that for some targets, sample purification may not be required. The assay is simple to perform and easily adaptable to different targets.

Cystic Fibrosis Transmembrane Conductance Regulato↗
PubMed2001

Association of tumor necrosis factor-alpha and interleukin-1 gene polymorphisms with silicosis.

Silicosis, an interstitial lung disease prevalent among miners, sand blasters, and quarry workers, is manifested as a chronic inflammatory response leading to severe pulmonary fibrotic changes. Proinflammatory cytokines, such as TNFalpha and IL-1, produced in the lung by type II epithelial cells and alveolar macrophages, have been strongly implicated in the formation of these lesions. Recently, a number of single nucleotide polymorphisms (SNPs), which quantitatively affect mRNA synthesis, have been identified in the TNFalpha promoter and IL-1 gene cluster and their frequency is associated with certain chronic inflammatory diseases. To assess the role of these SNPs in silicosis, we examined their frequency in 325 ex-miners with moderate and severe silicosis and 164 miners with no lung disease. The odds ratio of disease for carriers of the minor variant, TNFalpha (-238), was markedly higher for severe silicosis (4.0) and significantly lower for moderate silicosis (0.52). Regardless of disease severity, the odds ratios of disease for carriers of the IL-1RA (+2018) or TNFalpha (-308) variants were elevated. There were no significant consistent differences in the distribution of the IL-1alpha (+4845) or IL-1beta (+3953) variants with respect to disease status. In addition, several significant gene-gene and gene-gene-environment interactions were observed. Different associations between moderate cases and controls versus severe cases and controls were also observed in a number of these multigene comparisons. These studies suggest that gene-environment interactions involving cytokine polymorphisms play a significant role in silicosis by modifying the extent of and susceptibility to disease.

Adult↗
PubMed2000

Association between GSTM1*0 and squamous dysplasia of the esophagus in the high risk region of Linxian, China.

Individuals with specific phase I and phase II enzyme polymorphisms may be at increased risk for squamous cell carcinoma of the esophagus. However, to our knowledge there has been only one previous report that evaluates a potential role for these polymorphisms in increasing risk for preneoplastic squamous lesions of the esophagus. To explore this further, we examined polymorphisms in CYP1A1, CYP2E1, GSTM1 and GSTT1, both independently and in combination, for potential associations with the risk of biopsy-proven squamous dysplasia of the esophagus in asymptomatic adults from Linxian, a high risk region in China. Cases consisted of 56 individuals from an esophageal cancer screening study with an endoscopic biopsy diagnosis of mild or moderate squamous dysplasia. Each case was matched on age (+/- 1 year) and gender to a control. Controls were defined as screening study participants with an endoscopic biopsy diagnosis of normal mucosa or esophagitis. DNA was extracted from frozen cell samples obtained by cytologic balloon examination and genotyped using standard methods. Individuals who were GSTM1 null (homozygous for GSTM1*0) were found to have a tendency for an increased risk of esophageal squamous dysplasia (odds ratio=2.6, 95% CI, 0.9-7.4). No excess risks were observed for inheritance of other putative at risk genotypes CYP1A1*2B, CYP2E1*6 or GSTT1*0. The risk associated with the inheritance of combined genotypes was not significantly different than the risk estimates from the univariate analysis. These results are consistent with the notion that exposure to environmental carcinogens that are detoxified by GSTM1, such as polycyclic aromatic hydrocarbons, may contribute to the etiology of esophageal cancer in Linxian.

Carcinoma, Squamous Cell↗
PubMed2000

Catecholamine sensitivity in the rat femoral artery after microvascular anastomosis.

Tissue can demonstrate vasospastic instability after microvascular anastomosis. This study investigates the in vitro effect of increasing concentrations of phenylephrine on the rat femoral artery after microvascular anastomosis. Bilateral groin flaps based on the inferior epigastric artery were raised on 55 Wistar male rats. On the test side, a microvascular anastomosis was performed, but not on the control side. On days 2-12 postoperatively, the rats were sacrificed and the femoral arteries harvested and suspended in increasing concentrations of phenylephrine. The vascular tone on the test and control sides were recorded and compared. Increased sensitivity was found on the test side as compared with the control side (P = 0.000). This supersensitivity to phenylephrine was blocked by the addition of phentolamine and it is believed to be the result of sympathetic denervation, which occurs when the sympathetic fibers are cut during the harvesting of the flap. The resulting vascular instability is believed to contribute to flap failure.

Adrenergic alpha-Agonists↗
PubMed2000

Organochlorine exposures and breast cancer risk in New York City women.

A hospital-based case-control study of breast cancer risk related to organochlorine (OC) exposure was conducted in a multiethnic setting in New York City. We enrolled 175 breast cancer patients and 355 control patients. The overall racial/ethnic distribution was 57% Caucasian, 21% Hispanic, 22% African-American; cases and controls were frequency-matched by age and race/ethnicity. Tumor markers (estrogen and progesterone receptors, p53, erbB-2) were assessed and organochlorines (DDE, DDT, trans-nonachlor, and higher (HPCB) and lower (LPCB) chlorinated biphenyls) were measured in blood serum. Tumors among minority women were of slightly higher stage than among Caucasians, but tumor markers were similar across the racial/ethnic groups. DDE levels were highest among African-American and Hispanic women; DDT was highest among Hispanics; HPCBs were highest among African-Americans; LPCBs were lowest among Hispanics; and trans-nonachlor was highest among African-Americans. However, OC levels were not associated with risk for breast cancer, nor did OCs differ with respect to tumor stage or tumor markers. Higher DDE levels were associated with increasing body mass index (BMI), but with decreasing level of education, frequency of nulliparity, and frequency of family history of breast cancer. HPCB levels decreased with BMI and were not correlated with breast cancer risk factors. These relationships can be attributed to historical patterns of exposure and to metabolic differences in OCs related to BMI.

Black People↗
PubMed2000

Carcinogen macromolecular adducts and their measurement.

Damage to DNA induced by carcinogenic chemicals reflects exposure and is directly related to tumor formation, whereas modification of protein provides relatively precise dosimetry for stable adducts of proteins with a known half-life. Sophisticated methods for the detection and quantitation of DNA and protein adducts have been developed during the last approximately 25 years. For DNA adducts the most widely used methods include electrochemical detection, mass spectrometry, fluorescence and phosphorescence spectroscopy, immunoassays and immunohistochemistry and (32)P-post-labeling. Detection limits for quantitative assays are typically in the range of 1 adduct in 10(7) or 10(9) nucleotides. However, accelerator mass spectrometry, which is highly sophisticated but less accessible, has a detection limit of approximately 1 adduct in 10(12) nucleotides. Methods for the determination of protein adducts include immunoassay and a variety of elegant high-resolution mass spectrometry approaches. The detection limit of approximately 0.1 fmol for protein adducts, is based primarily on method specificity and the availability of large quantities of sample material. Using these highly sensitive methods a major achievement has been the biomonitoring of chemically exposed human populations. Validation of macromolecular adduct formation in humans has been predicated on studies in animal models. Adduct formation in humans appears to be indicative of molecular dosimetry and suggestive of increased human cancer risk. However, despite the large body of literature documenting DNA and protein adduct molecular dosimetry for many carcinogen exposures, the relationship between adduct formation and human cancer risk has been defined for only a few carcinogens. Thus, elucidation of this association remains a compelling challenge. For the future, integration of DNA and protein adduct measurements together with documentation of correlative and subsequent events, and host susceptibility factors, within the context of valid molecular epidemiologic study designs, will further our understanding of human disease mechanisms.

Biotransformation↗
PubMed1999

Determination of benzo[a]pyrene-DNA adducts by solid-matrix phosphorescence.

It has been demonstrated for the first time that linear relationships can be obtained between the solid-matrix phosphorescence (SMP) and the percent modification of benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE)-DNA adducts. The samples of DNA were modified with BPDE at levels of 5.0 x 10(-3), 1.0 x 10(-3), 5.0 x 10(-4), 1.0 x 10(-4), 5.0 x 10(-5), and 1.0 x 10(-5%). In addition, the changes in the SMP intensities of a given percentage of DNA adduct were investigated as a function of sample size, and linear relationships were also acquired. With the different percentages of modified DNA, very good reproducibility of the SMP signals was obtained. Data were acquired with both Whatman 1PS paper and 30% TlNO3/sodium acetate as solid matrixes. The limit of detection for the BPDE-DNA adducts was 2 adducts in 10(7) bases for both Whatman 1PS paper and 30% TlNO3/sodium acetate. In addition, it was shown that it would be important to develop a standard procedure for the preparation of the BPDE-DNA samples if different batches of DNA were used in the preparation procedure.

Benzo(a)pyrene↗
PubMed1999

Molecular epidemiological study of non-small-cell lung cancer from an environmentally polluted region of Poland.

The p53 mutation spectrum can generate hypotheses linking carcinogen exposure to human cancer. Although it is well-documented that tobacco smoking is a major cause of lung cancer, the contribution of air pollution is less well-established. We determined the molecular and immunohistochemical changes (p53 gene mutations, p53 protein accumulation and WAF1 protein expression) and genetic polymorphisms of GSTM1, CYP1A1 and CYP2D6 genes in a case series of non-small-cell lung cancers from Silesia. This region of southern Poland is highly industrialized with considerable environmental pollution. More than 50% of lung cancers (90/164) contained p53 mutations and 75% showed the combined alteration of the p53 gene and protein accumulation. Males occupationally exposed to coal-derived substances showed a relatively high frequency of squamous and large-cell carcinomas, relatively frequent mutations in codon 298 of p53 and a low frequency of p53 immunohistochemically positive tumours. Codon 298 GAG-->TAG mutations have rarely been found in lung cancers in other populations. We found no correlation between WAF1 protein expression and mutations in the p53 gene or p53 protein accumulation. No statistically significant relationship was found between p53 mutations and GSTM1, CYP1A1, CYP2D6 genotypes. Never smokers with lung cancers from Silesia had a higher frequency of G:C-->T:A transversions than previously reported of the p53 mutation spectrum in never smokers (6/15 vs 4/34; P = 0.06 by chi2). These data are a tentative indication that occupational and environmental exposure to polycyclic aromatic hydrocarbons, such as benzo(a)pyrene, in polluted air contributes to the molecular pathogenesis of lung cancer in never smokers.

Air Pollution↗
PubMed1999

Effect of targeted expression of clusterin in photoreceptor cells on retinal development and differentiation.

Clusterin expression is increased in tissues undergoing apoptosis, including neurodegenerative retina, but the causal relationships remain to be clarified. To test the hypothesis that overexpression of clusterin could induce apoptosis in neurons, transgenic mice were generated in which rat clusterin transgene was expressed in photoreceptor cells under the transcriptional control of the human interphotoreceptor retinoid-binding protein (IRBP) promoter. Photoreceptor cell death in the resulting transgenic mice was examined by histology and TUNEL techniques. The expression of the clusterin transgene was confirmed by in situ hybridization in the photoreceptor cells, and results in a complex pattern of clusterin protein distribution in the retina. A reduction in apoptotic staining in the transgenic retinas was observed from birth to postnatal day 15. These results suggest that clusterin is not causally involved in apoptotic mechanisms of photoreceptor cell death, but may relate to cytoprotective functions.

Age Factors↗
PubMed1998

High intensity exercise: a cause of lymphocyte apoptosis?

Post exercise lymphocytopenia is well documented and attributed to egress of lymphocytes from the vascular compartment. Recent studies have reported exercise induced DNA damage in leukocytes and have questioned a possible link to apoptosis. Eleven subjects underwent a ramped treadmill test to exhaustion. Venous blood samples were taken before, immediately post exercise, and 24 and 48 hours after exercise. Single cell gel electrophoresis revealed evidence of single strand DNA damage in 10% of lymphocytes immediately after exercise, but not at other times. Fluorescent microscopy showed three patterns of DNA distribution, similar to those seen in apoptosis, at all times after exercise. Three subjects underwent the same exercise protocol, and lymphocytes were prepared for flow cytometry to determine apoptosis using the TUNEL method. Flow cytometry revealed lymphocyte apoptosis in 63% of lymphocytes immediately after exercise and 86.2%, 24 hours after exercise. Lymphocyte apoptosis is documented for the first time after exercise and may in part account for exercise induced lymphocytopenia and reduced immunity.

Apoptosis↗