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- De Koning, H. J., et al.
(författare)
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Large-scale randomized prostate cancer screening trials : Program performances in the european randomized screening for prostate cancer trial and the prostate, lung, colorectal and ovary cancer trial
- 2002
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 97:2, s. 237-244
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Tidskriftsartikel (refereegranskat)abstract
- Two large-scale randomized screening trials, the Prostate, Lung, Colorectal and Ovary (PLCO) cancer trial in the USA and the European Randomized Screening for Prostate Cancer (ERSPC) trial in Europe are currently under way, aimed at assessing whether screening reduces prostate cancer mortality. Up to the end of 1998, 102,691 men have been randomized to the intervention arm and 115,322 to the control arm (which represents 83% of the target sample size) from 7 European countries and 10 screening centers in the USA. The principal screening method at all centers is determination of serum prostate-specific antigen (PSA). The PLCO trial and some European centers use also digital rectal examination (DRE) as an ancillary screening test. In the core age group (55-69 years), 3,362 of 32,486 men screened (10%) had a serum PSA concentration of 4 ng/ml or greater, which is I cut-off for biopsy (performed in 84%). An additional 6% was referred for further assessment based on other criteria, with much less efficiency. Differences in PSA by country are largely attributable to the age structure of the study population. The mean age-specific PSA levels are lower in the PLCO trial (1.64 ng/ml [in the age group 55-59 years], 1.80 [60-64 years] and 2.18 [65-69 years) than in the ERSPC trial (1.28-1.71 [55-59], 1.75-2.87 [60-64] and 2.48-3.06 [65-69 years]). Detection rates at the first screen in the ERSPC trial range from II to 42/1,000 men screened and reflect underlying differences in incidence rates and screening procedures. In centers with consent to randomization design, adherence in the screening arm is 91%, but less than half of the men in the target population are enrolled in the trial. In population-based centers in which men were randomized prior to consent, all eligible subjects are enrolled, but only about two-thirds of the men in the intervention arm undergo screening. Considerable progress has been made in both trials. Enrollment will be completed in 2001. A substantial number of early prostate cancers have been detected. The differences between countries seem to reflect both underlying prostate cancer incidence and screening policy. The trials have the power to show definitive results in 2005-2008.
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- Lewis, Cathryn M, et al.
(författare)
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Genome scan meta-analysis of schizophrenia and bipolar disorder, part II : Schizophrenia
- 2003
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Ingår i: American Journal of Human Genetics. - 0002-9297 .- 1537-6605. ; 73:1, s. 34-48
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.
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- Lind, Monica, et al.
(författare)
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Abnormal bone composition in female juvenile American alligators from a pesticide-polluted lake (Lake Apopka, Florida)
- 2004
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Ingår i: Journal of Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 112:3, s. 359-362
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Tidskriftsartikel (refereegranskat)abstract
- Reproductive disorders have been found in pesticide-exposed alligators living in Lake Apopka, Florida (USA). These disorders have been hypothesized to be caused by exposure to endocrine- disruptive estrogen-like contaminants. The aim of this study was to expand our analysis beyond previous studies by investigating whether bone tissue, known to be affected by sex steroid hormones, is a potential target of endocrine disruptors. Long bones from 16 juvenile female alligators from Lake Apopka (pesticide-contaminated lake) and Lake Woodruff (control lake) were evaluated by peripheral quantitative computed tomography. We observed significant differences in bone composition, with female alligators from the contaminated lake having greater trabecular bone mineral density (BMD), total BMD, and trabecular mineral content compared with females from the control lake (p < 0.05). Increased trabecular and total BMD measurements suggest that juvenile female alligators from Lake Apopka were exposed to contaminants that created an internal environment more estrogenic than that normally observed. This estrogenic environment could be caused by both natural and anthropogenic compounds. Effects on BMD indicate interference with bone homeostasis. We hypothesize that contaminants present in the lake inhibit the natural and continuous resorption of bone tissue, resulting in increased bone mass. Although this is the only study performed to date examining effects of environmental estrogenic compounds on alligator bones, it supports previous laboratory-based studies in rodents. Further, this study is important in demonstrating that the alterations in morphology and physiology induced in free-ranging individuals living in environments contaminated with endocrine-active compounds are not limited to a few systems or tissues; rather, effects can be observed in many tissues affected by these hormones.
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- Louis, M, et al.
(författare)
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Creatine supplementation has no effect on human muscle protein turnover at rest in the postabsorptive or fed states
- 2003
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 284:4, s. E764-E770
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Tidskriftsartikel (refereegranskat)abstract
- Dietary creatine supplementation is associated with increases in muscle mass, but the mechanism is unknown. We tested the hypothesis that creatine supplementation enhanced myofibrillar protein synthesis (MPS) and diminished muscle protein breakdown (MPB) in the fed state. Six healthy men (26 ± 7 yr, body mass index 22 ± 4 kg/m2) were studied twice, 2–4 wk apart, before and after ingestion of creatine (21 g/day, 5 days). We carried out two sets of measurements within 5.5 h of both MPS (by incorporation of [1-13C]leucine in quadriceps muscle) and MPB (as dilution of [1-13C]leucine or [2H5]phenylalanine across the forearm); for the first 3 h, the subjects were postabsorptive but thereafter were fed orally (0.3 g maltodextrin and 0.083 g protein · kg body wt−1 · h−1). Creatine supplementation increased muscle total creatine by ∼30% ( P < 0.01). Feeding had significant effects, doubling MPS ( P < 0.001) and depressing MPB by ∼40% ( P < 0.026), but creatine had no effect on turnover in the postabsorptive or fed states. Thus any increase in muscle mass accompanying creatine supplementation must be associated with increased physical activity.
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| 9. |
- Noaksson, Erik, 1972-
(författare)
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Environmental Monitoring of Refuse Dump Leachate Toxicity in Fish
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The global economy is driven by the consumption of goods and materials. Used products are often deposited on refuse dumps, making them potential point sources for all man-made chemicals. Water soaking through landfill waste results in a wastewater termed leachate. The collection and treatment of leachate is generally inadequate, but leachate toxicity is a surprisingly neglected area of research. This thesis covers six consecutive years (1996-2001) of environmental monitoring of toxicological effects and reproductive status in perch (Perca fluviatilis) from two Swedish lakes: Lake Molnbyggen, located within the same drainage area as a municipal refuse dump at Lindbodarna, and the reference Lake Djursjön. Toxicological and reproductive effects have been monitored also in fish from several other leachate-contaminated waters, including the stream Vadbäcken which drains the dump area and empties into Molnbyggen, and Lake Siljan, a recipient for the sewage treatment plant (STP) which processes some of the leachate from Lindbodarna. Unusually high frequencies of fin erosion and unique open body sores were found on Molnbyggen perch in 1996. They also had increased hepatic activities of catalase and glutathione-S-transferase. A weak induction of ethoxyresorufin O-deethylase (EROD) and low levels of DNA adducts indicated that the undersized gonads, observed in both sexes, were caused by pollutants specifically targeting gametogenesis. Later samplings revealed exceptionally low ratios of sexually mature (SM) females among both perch from Molnbyggen and brook trout (Salvelinus fontinalis) from Vadbäcken. Together with low gonadosomatic index (GSI), low brain aromatase (P450arom) activity, and low circulating levels of testosterone (T) and 17β-estradiol (E2) in both species, these results suggested a similar exposure to endocrine disrupting substances (EDSs) present in the refuse dump leachate. It was hypothesised that the aromatase activity could be inhibited by these EDSs, thereby disturbing the conversion of androgens into estrogens. An analysis of progesterone and 17α-hydroxyprogesterone indicated, however, that the low T levels in female perch and brook trout could result from a disturbance in its synthesis and that the low aromatase activity most likely was a result of down-regulation at the mRNA and/or protein level rather than a result of inhibition. In vitro studies of aromatase inhibition by chemical extracts of Molnbyggen sediments supported this conclusion. Mechanistic studies covering a single reproductive cycle further demonstrated that the disturbed synthesis of androgens could be a possible mechanism behind the reproductive failures, since too low T levels might be insufficient to activate the reproductive axis in leachate-exposed females. Analysis of 17α,20β-dihydroxy-4-pregnen-3-one (17α,20β-P) showed for the first time that it is the maturation-inducing hormone in this species. Three out of the four additional leachate-contaminated lakes investigated had low ratios of SM female perch. In Lake Nedre Vättern, the low ratio of SM females was associated with the same open body sores as in Molnbyggen, low GSI, low levels of T and E2, and high EROD activity, suggesting that the effects found in Molnbyggen and Vadbäcken are not unique. In Siljan, however, the low ratios of SM female perch found outside the STP were not associated with endocrine disruption. The EDSs responsible for the reproductive failures and endocrine disruption still remain unknown, thus the results of this thesis imply that the inappropriate handling of leachate from Swedish refuse dumps constitutes a serious environmental problem with unforeseeable consequences for wildlife and future generations.
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| 10. |
- Oresic, Matej, 1967-, et al.
(författare)
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Phenotype characterisation using integrated gene transcript, protein and metabolite profiling
- 2004
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Ingår i: Applied bioinformatics. - : Adis International Ltd.. - 1175-5636. ; 3:4, s. 205-217
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Tidskriftsartikel (refereegranskat)abstract
- Multifactorial diseases present a significant challenge for functional genomics. Owing to their multiple compartmental effects and complex biomolecular activities, such diseases cannot be adequately characterised by changes in single components, nor can pathophysiological changes be understood by observing gene transcripts alone. Instead, a pattern of subtle changes is observed in multifactorial diseases across multiple tissues and organs with complex associations between corresponding gene, protein and metabolite levels. This article presents methods for exploratory and integrative analysis of pathophysiological changes at the biomolecular level. In particular, novel approaches are introduced for the following challenges: (i) data processing and analysis methods for proteomic and metabolomic data obtained by electrospray ionisation (ESI) liquid chromatography-tandem mass spectrometry (LC/MS); (ii) association analysis of integrated gene, protein and metabolite patterns that are most descriptive of pathophysiological changes; and (iii) interpretation of results obtained from association analyses in the context of known biological processes. These novel approaches are illustrated with the apolipoprotein E3-Leiden transgenic mouse model, a commonly used model of atherosclerosis. We seek to gain insight into the early responses of disease onset and progression by determining and identifying--well in advance of pathogenic manifestations of disease--the sets of gene transcripts, proteins and metabolites, along with their putative relationships in the transgenic model and associated wild-type cohort. Our results corroborate previous findings and extend predictions for three processes in atherosclerosis: aberrant lipid metabolism, inflammation, and tissue development and maintenance.
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