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Biomedical subjects

J Young

Publications and source records attributed to J Young.

At least 73 records · Page 4Linked to original sources
PubMed2001

Methylation of O-6-methylguanine DNA methyltransferase characterizes a subset of colorectal cancer with low-level DNA microsatellite instability.

The significance of low-level DNA microsatellite instability (MSI-L) is not well understood. K-ras mutation is associated with MSI-L colorectal cancer and with the silencing of the DNA repair gene O-6-methylguanine DNA methyltransferase (MGMT) by methylation of its promoter region. MGMT methylation was studied in sporadic colorectal cancers stratified as DNA microsatellite instability-high (n = 23), MSI-L (n = 44), and microsatellite-stable (n = 23). Methylation-specific PCR was used to detect MGMT-promoter hypermethylation in 3 of 23 (13%) microsatellite instability-high, in 28 of 44 (64%) MSI-L, and in 6 of 23 (26%) microsatellite-stable cancers (P = 0.0001). K-ras was mutated in 20 of 29 (69%) methylated MSI-L cancers and in 2 of 15 (13%) unmethylated MSI-L cancers (P = 0.001), indicating a relationship between MGMT-methylation and mutation of K-ras. Loss of nuclear expression of MGMT was demonstrated immunohistochemically in 23 of 31 (74%) cancers with methylated MGMT and in 10 of 49 (20%) cancers with nonmethylated MGMT (P < 0.0001). Loss of expression of MGMT was also demonstrated in 9 of 31 serrated polyps. Silencing of MGMT may predispose to mutation by overwhelming the DNA mismatch repair system and occurs with greatest frequency in MSI-L colorectal cancers.

Colorectal Neoplasms↗
PubMed2001

HPP1: a transmembrane protein-encoding gene commonly methylated in colorectal polyps and cancers.

Adenomas are the precursors of most colorectal cancers. Hyperplastic polyps have been linked to the subset of colorectal cancers showing DNA microsatellite instability, but little is known of their underlying genetic etiology. Using a strategy that isolates differentially methylated sequences from hyperplastic polyps and normal mucosa, we identified a 370-bp sequence containing the 5' untranslated region and the first exon of a gene that we have called HPP1. Rapid amplification of cDNA ends was used to isolate HPP1 from normal mucosa. Using reverse transcription-PCR, HPP1 was expressed in 28 of 30 (93%) normal colonic samples but in only seven of 30 (23%) colorectal cancers (P < 0.001). The 5' region of HPP1 included a CpG island containing 49 CpG sites, of which 96% were found to be methylated by bisulfite sequencing of DNA from colonic tumor samples. By COBRA analysis, methylation was detected in six of nine (66%) adenomas, 17 of 27 (63%) hyperplastic polyps, and 46 of 55 (84%) colorectal cancers. There was an inverse relationship between methylation level and mRNA expression in cancers (r = -0.67; P < 0.001), and 5-aza-2-deoxycytidine treatment restored HPP1 expression in two colorectal cancer cell lines. In situ hybridization of HPP1 indicated that expression occurs in epithelial and stromal elements in normal mucosa but is silenced in both cell types in early colonic neoplasia. HPP1 is predicted to encode a transmembrane protein containing follistatin and epidermal growth factor-like domains. Silencing of HPP1 by methylation may increase the probability of neoplastic transformation.

Amino Acid Sequence↗
PubMed2001

Information provision for stroke patients and their caregivers.

BACKGROUND: The provision of information has been recommended as a key component of service provision after stroke. However, research suggests that patients' understanding of stroke and associated issues remains poor. We determined to undertake a systematic review of information provision strategies for patients and their carers after stroke. OBJECTIVES: To examine the effectiveness of an information and/or education strategy to improve the outcome of stroke patients and/or their identified caregivers. SEARCH STRATEGY: Relevant trials were identified in the Cochrane Stroke Group Specialised Trials Register (last searched: June 2000). Additional intervention-based search strategies were developed for: The Cochrane Controlled Trials Register (CENTRAL/CCTR) Medline; Embase; CINAHL; ISI citation index; Science and Social Science Citation Indexes; ISI Web of Science Service; Aslib Index to UK theses; Dissertation Abstracts International, ASSIA and Psychlit/PsycINFO. We also searched the Journal of Advanced Nursing, bibliographies of retrieved papers, relevant articles and books. SELECTION CRITERIA: Two or three investigators independently assessed trials and abstracts identified for eligibility, methodological quality and other participant characteristics. DATA COLLECTION AND ANALYSIS: Data were extracted independently using piloted data extraction forms. The primary outcomes were knowledge about stroke and stroke services, and impact on health, specifically mood. MAIN RESULTS: We identified 152 abstracts, of which 36 studies were potentially relevant to this review. The current analysis includes nine completed trials, a further eight studies are ongoing. Of the nine trials, three evaluated a programme of lectures and the remaining trials evaluated the provision of information. There is some evidence that information combined with educational sessions improved knowledge and was more effective than providing information only. Information provision only had no effect on mood, perceived health status or quality of life for patients or carers. Two trials used an objective measure of satisfaction and no significant differences were found between groups. One trial reported that information and education sessions for carers improved 'family functioning'. REVIEWER'S CONCLUSIONS: The results of the review are limited by the variable quality of the trials and the wide range of outcome measures used. The general effectiveness of information provision has not been conclusively demonstrated. Future work should address the expressed needs of patients and carers and seek to identify appropriate teaching strategies which can be successfully implemented within clinical practice.

Caregivers↗
PubMed2001

Validation and development of fluorescence two-dimensional differential gel electrophoresis proteomics technology.

Fluorescence two-dimensional differential gel electrophoresis (2-D DIGE*) is a new development in protein detection for two-dimensional gels. Using mouse liver homogenates (control and paracetamol (N-acetyl-p-aminophenol, APAP)-treated), we have determined the quantitative variation in the 2-D DIGE process and established statistically valid thresholds for assigning quantitative changes between samples. Thresholds were dependent on normalised spot volume, ranged from approximately 1.2 fold for large volume spots to 3.5 fold for small volume spots and were not markedly affected by the particular cyanine dye combination or by multiple operators carrying out the dye labelling reaction. To minimise the thresholds, substantial user editing was required when using ImageMaster 2D-Elite software. The difference thresholds were applied to the test system and quantitative protein differences were determined using replicate gels of pool samples and single gels from multiple individual animals (control vs treated in each gel). Throughout, the differences revealed with a particular cyanine dye combination were mirrored almost without exception when the dye combination was reversed. Both pool and individual sample analyses provided unique data to the study. The inter-animal response variability in inbred mice was approximately nine times that contributed by the 2-D DIGE process. A number of the most frequently observed protein changes resulting from APAP-treatment were identified by mass spectrometry. Several of these can be rationalised based on available data on the mechanism of APAP hepatotoxicity but others cannot, indicating that proteomics can provide further insights into the biochemical basis of APAP toxicity.

Acetaminophen↗
PubMed2001

Quantitative proteomic analysis of mouse liver response to the peroxisome proliferator diethylhexylphthalate (DEHP).

Peroxisome proliferators (PPs) are a diverse group of chemicals that cause hepatic proliferation, suppression of apoptosis, peroxisome proliferation and liver tumours in rodents. The biochemical response to PPs involves changes in the expression of peroxisomal beta-oxidation enzymes and fatty acid transport proteins such as acyl-CoA oxidase and liver fatty acid binding protein. The response to PPs is mediated by the peroxisome proliferator-activated receptor alpha (PPARalpha) and the livers of PPARalpha-null transgenic mice do not develop tumours in response to PPs. In order to identify the molecular pathways underlying the adverse effects of PPs in rodent liver, we carried out two-dimensional differential gel electrophoresis to provide quantitative proteomic analyses of diethylhexylphthalate (DEHP)-treated wild-type or PPARalpha-null mouse livers. Since tumourigenesis is both PP- and PPARalpha-dependent, analyses were focused on these changes. Fifty-nine proteins were identified where altered expression was both PPARalpha- and PP-dependent. In addition, six proteins regulated by the deletion of PPARalpha were identified, possibly indicating an adaptive change in response to the loss of this receptor. The proteins that we identified as being regulated by PPARalpha are known to be involved in lipid metabolism pathways, but also in amino acid and carbohydrate metabolism, mitochondrial bioenergetics and in stress responses including several genes not previously reported to be regulated by PPARalpha. These data provide novel insights into the pathways utilised by PPs and may assist in the identification of early markers rodent nongenotoxic hepatocarcinogenesis.

Animals↗
PubMed2001

Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings: parallel pathways of tumorigenesis.

High-level microsatellite instability (MSI-H) is demonstrated in 10 to 15% of sporadic colorectal cancers and in most cancers presenting in the inherited condition hereditary nonpolyposis colorectal cancer (HNPCC). Distinction between these categories of MSI-H cancer is of clinical importance and the aim of this study was to assess clinical, pathological, and molecular features that might be discriminatory. One hundred and twelve MSI-H colorectal cancers from families fulfilling the Bethesda criteria were compared with 57 sporadic MSI-H colorectal cancers. HNPCC cancers presented at a lower age (P < 0.001) with no sporadic MSI-H cancer being diagnosed before the age of 57 years. MSI was less extensive in HNPCC cancers with 72% microsatellite markers showing band shifts compared with 87% in sporadic tumors (P < 0.001). Absent immunostaining for hMSH2 was only found in HNPCC tumors. Methylation of hMLH1 was observed in 87% of sporadic cancers but also in 55% of HNPCC tumors that showed loss of expression of hMLH1 (P = 0.02). HNPCC cancers were more frequently characterized by aberrant beta-catenin immunostaining as evidenced by nuclear positivity (P < 0.001). Aberrant p53 immunostaining was infrequent in both groups. There were no differences with respect to 5q loss of heterozygosity or codon 12 K-ras mutation, which were infrequent in both groups. Sporadic MSI-H cancers were more frequently heterogeneous (P < 0.001), poorly differentiated (P = 0.02), mucinous (P = 0.02), and proximally located (P = 0.04) than HNPCC tumors. In sporadic MSI-H cancers, contiguous adenomas were likely to be serrated whereas traditional adenomas were dominant in HNPCC. Lymphocytic infiltration was more pronounced in HNPCC but the results did not reach statistical significance. Overall, HNPCC cancers were more like common colorectal cancer in terms of morphology and expression of beta-catenin whereas sporadic MSI-H cancers displayed features consistent with a different morphogenesis. No individual feature was discriminatory for all HNPCC cancers. However, a model based on four features was able to classify 94.5% of tumors as sporadic or HNPCC. The finding of multiple differences between sporadic and familial MSI-H colorectal cancer with respect to both genotype and phenotype is consistent with tumorigenesis through parallel evolutionary pathways and emphasizes the importance of studying the two groups separately.

Adaptor Proteins, Signal Transducing↗
PubMed2001

A database generator for human brain imaging.

Sharing scientific data containing complex information requires new concepts and new technology. NEUROGENERATOR is a database generator for the neuroimaging community. A database generator is a database that generates new databases. The scientists submit raw PET and fMRI data to NEUROGENERATOR, which then processes the data in a uniform way to create databases of homogeneous data suitable for data sharing, met-analysis and modelling the human brain at the systems level. These databases are then distributed to the scientists.

Brain↗
PubMed2001

Aspartyl proteinase genes from apicomplexan parasites: evidence for evolution of the gene structure.

Aspartyl proteinases are a widely distributed family of enzymes. All vertebrate aspartyl proteinases share a conserved nine-exon gene structure, but in other organisms the structure of aspartyl proteinase genes varies considerably. The exon-intron patterns generally reflect phylogeny based on amino acid sequences. However, close comparison of these gene structures reveals some striking features, such as the conservation of intron positions and intron phases between aspartyl proteinases from nematodes and apicomplexans. Here, we discuss the implications of gene structure for the possible evolution of the aspartyl proteinase family, with particular reference to the plasmepsins of Plasmodium falciparum and eimepsin from Eimeria tenella.

Amino Acid Sequence↗
PubMed2001

Elevated dentine-lead levels in deciduous teeth collected from remote first nation communities located in the western James Bay region of northern Ontario, Canada.

Teeth were collected from First Nation schoolchildren inhabiting the remote western James Bay region of northern Ontario, Canada. Lead levels in dentine chips were determined by graphite furnace atomic absorption spectrometry, for naturally exfoliated deciduous teeth. Within exfoliated teeth (one tooth supplied per person), no significant differences in lead concentrations between tooth type were found (P = 0.36). The mean lead concentration of exfoliated teeth of 9.2 microg g(-1) dry weight (N = 61) from this remote region was comparable to levels reported by others for children inhabiting urban centers or residing near smelters. Further, 24.6% (N = 15) had elevated dentine-lead levels ( > 10 microg g(-1)). Lead levels in soil, water, and air have been reported as being low and unimportant sources of exposure for people of the western James Bay area. Evidence is reviewed suggesting that lead contaminated game meat was one source of environmental lead exposure. Consumption data indicate that wildlife is still an important food source for First Nation people of the western James Bay region; 98% (46/47) of the children surveyed consumed some type of wild meat.

Animals↗
PubMed2001

An evaluation of invasive and non-invasive tests for the diagnosis of Helicobacter pylori infection in Chinese.

BACKGROUND: Different tests are available for diagnosing Helicobacter pylori infection. AIM: To compare the most commonly used tests either alone or in combination in Chinese patients with respect to routine clinical use or research purpose. METHODS: A total of 294 consecutive dyspeptic patients without previous H. pylori treatment were recruited. During upper endoscopy, biopsies were taken from the antrum and corpus, for a commercially available CLO-test, an in-house rapid urease test, culture, polymerase chain reaction and histological examination. Patients then received a 13C-urea breath test. The H. pylori status of each patient was determined by a concordance of test results. RESULTS: For routine clinical use, histology (antral plus corpus biopsies) had an accuracy of 100%, whilst the rapid urease test had an accuracy of 99.7%. The 13C-urea breath test was equally reliable, with an accuracy of 94.5%. Combinations of two tests did not confer additional advantage over the most accurate single test. For research purposes, the accuracy of using the criteria of two positives out of three diagnostic tests was 100% and equivocal results were not found. CONCLUSION: Histology with or without a rapid urease test was highly accurate for routine clinical use. Alternatively, the 13C-urea breath test was an equally reliable non-invasive test. The two positives out of three tests approach was highly reliable in predicting H. pylori status of untreated Chinese patients in a research setting.

Biopsy↗