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(1998)Journal ArticleThe first results obtained using a SOI device for microdosimetry applications are presented. Microbeam and broadbeam spectroscopy methods are used for determining minority carrier lifetime and radiation damage constants. A spectroscopy model is presented which includes the majority of effects that impact spectral resolution. Charge collection statistics were found to substantially affect spectral resolution. Lateral diffusion effects significantly complicate charge collection
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(1996)Conference PaperThe Mungi single address space operating system provides a protected procedure call mechanism named protection domain extension (PDX). The PDX call executes in a protection domain which is the union of (a subset of) the caller`s, and a fixed domain associated with the procedure. On return, the caller`s original protection domain is reestablished. Extensive caching of validation data allows amortisation of setup costs over a possibly large number of invocations. The PDX mechanism forms the basis for object support in Mungi, particularly encapsulation. It is also used for accessing devices, and to implement user-level page fault handlers.
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(2008)Journal ArticlePurpose: Despite the established importance of the role of family history in prostate cancer, relatively little research encompasses the psychosocial issues relevant to unaffected men with a family history of prostate cancer. To determine the completeness and quality of available literature on the issues faced by men with a high risk of prostate cancer, we conducted a multidisciplinary review of the literature to provide some guidance on the information that clinicians might provide to men who are concerned about family history. Materials and Methods: A structured literature search was conducted by a multidisciplinary team of clinicians and researchers who reviewed the medical and psychosocial literature, and identified 21 relevant studies. Results: Research suggests that many high risk patients are concerned about the risk of prostate cancer, and some may significantly overestimate that risk. Several studies have shown high screening rates among high risk patients and high levels of interest in genetic testing for prostate cancer risk should it become available, yet many men also report a desire for more information about their personal risk and risk management options. Conclusions: Given the lack of clear data on the efficacy of prostate cancer screening among high risk patients, clinicians could consider providing men who are concerned about family history with information on their personal risk, help them to clarify the potential benefits, limitations and harms of prostate cancer screening in their situation, and then support their choice regarding the management of prostate cancer risk.
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(2008)Journal ArticleDespite rapid advancements in molecular genetics research, little is known about the psychological experiences of individuals with a family history of melanoma. The present study aimed to identify factors contributing to psychological distress among affected and unaffected individuals with a strong family history of melanoma. A total of 121 adults who had recently been informed of the identification of a family-specific mutation in the CDKN2A melanoma susceptibility gene, completed a self-report questionnaire assessing cancer-specific and generalized distress, and a variety of potential predictors. Having a personal history of melanoma (OR = 3.37, p = 0.033), perceiving greater family implications of melanoma (OR = 2.52, p < 0.0001), and the tendency to monitor for threatening information (OR = 3.12, p = 0.008) were associated with melanoma-specific distress. Being childless (beta = 2.09, p = 0.007), perceiving sun exposure as an important cause of melanoma (beta = 1.15, p = 0.015), and perceiving greater family implications of melanoma (beta = 1.02, p = 0.002) were associated with greater generalized anxiety, while monitoring moderated the relationship between endorsement of a genetic model of melanoma and generalized anxiety (p = 0.005). As in other common familial cancers, distress was relatively uncommon in this familial melanoma cohort, even after notification of the presence of a family mutation. Participants do not contemplate their melanoma risk in isolation, but evaluate their risk vis-a-vis the experiences of their relatives.
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(2008)Journal ArticleObjectives: This study assesses interest in genetic testing for gene variations associated with bipolar disorder and associated information needs. Methods: Two hundred individuals (95 unaffected and 105 affected with either bipolar disorder, schizoaffective disorder-manic type, or recurrent major depression) from families with multiple cases of bipolar disorder were assessed, using mailed, self-administered questionnaires. Results: The percentage of participants reporting interest in genetic testing was associated with the degree of certainty with which any test would indicate the development of bipolar disorder. Interest in genetic testing, given a 25% lifetime risk scenario, was lowest (with 77% of participants indicating interest), and highest for the 100% lifetime risk scenario (92%). Eighty percent of participants indicated interest in genetic testing of their own children; of these 30% reported wanting their children tested at birth, and 33% in early childhood. Forty-one percent of participants reported that they would be interested in preimplantation genetic diagnosis, and 54% in prenatal testing. Limitations: The possibility of ascertainment bias cannot be ruled out. Interest in hypothetical genetic testing for bipolar disorder may not necessarily translate into actual utilization. Conclusions: These results indicate that uptake of genetic testing for genotyping for low-risk alleles related to bipolar disorder is likely to be lower than for testing for high-penetrance gene mutations that follow Mendelian inheritance. The discrepancy between the desired age of testing children and the accepted current practice may be a source of distress and conflict for parents and health professionals alike.
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(2006)Journal ArticleWe have used a bioinformatics approach to evaluate the completeness and functionality of the reported human immunoglobulin heavy-chain IGHD gene repertoire. Using the hidden Markov-model-based iHMMune-align program, 1,080 relatively unmutated heavy-chain sequences were aligned against the reported repertoire. These alignments were compared with alignments to 1,639 more highly mutated sequences. Comparisons of the frequencies of gene utilization in the two databases, and analysis of features of aligned IGHD gene segments, including their length, the frequency with which they appear to mutate, and the frequency with which specific mutations were seen, were used to determine the reliability of alignments to the less commonly seen IGHD genes. Analysis demonstrates that IGHD4-23 and IGHD5-24, which have been reported to be open reading frames of uncertain functionality, are represented in the expressed gene repertoire; however, the functionality of IGHD6-25 must be questioned. Sequence similarities make the unequivocal identification of members of the IGHD1 gene family problematic, although all genes except IGHD1-14*01 appear to be functional. On the other hand, reported allelic variants of IGHD2-2 and of the IGHD3 gene family appear to be nonfunctional, very rare, or nonexistent. Analysis also suggests that the reported repertoire is relatively complete, although one new putative polymorphism (IGHD3-10*p03) was identified. This study therefore confirms a surprising lack of diversity in the available IGHD gene repertoire, and restriction of the germline sequence databases to the functional set described here will substantially improve the accuracy of IGHD gene alignments and therefore the accuracy of analysis of the V-D-J junction.
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(2008)Journal ArticleThe concept that macrophages can become foam cells as a result of a disturbed balance between the uptake of cholesterol from lipoproteins and cholesterol efflux is generally accepted. ABCA1 and ABCG1 are two cholesterol transporters that may act sequentially to remove cellular cholesterol, but currently their combined role in vivo is unknown. We report here that targeted disruption of both ABCA1 and ABCG1 in mice, despite severe plasma hypocholesterolemia, leads to massive lipid accumulation and foam cell formation of tissue macrophages. A complete ablation of cellular cholesterol efflux in vitro is observed, whereas in vivo macrophage-specific reverse cholesterol transport to the feces is markedly decreased. Despite the massive foam cell formation of tissue macrophages, no lipid accumulation was observed in the vascular wall, even in mice of 1 year old, indicating that the double knockout mice, possibly because of their hypocholesterolemia, lack the trigger to attract macrophages to the vessel wall. In conclusion, even under hypocholesterolemic conditions macrophages can be converted into foam cells, and ABCA1 and ABCG1 play an essential role in the prevention of foam cell formation.
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(2008)Journal ArticleFire activity has varied globally and continuously since the last glacial maximum (LGM) in response to long-term changes in global climate and shorter-term regional changes in climate, vegetation, and human land use. We have synthesized sedimentary charcoal records of biomass burning since the LGM and present global maps showing changes in fire activity for time slices during the past 21,000 years (as differences in charcoal accumulation values compared to pre-industrial). There is strong broad-scale coherence in fire activity after the LGM, but spatial heterogeneity in the signals increases thereafter. In North America, Europe and southern South America, charcoal records indicate less-than-present fire activity during the deglacial period, from 21,000 to ∼11,000 cal yr BP. In contrast, the tropical latitudes of South America and Africa show greater-than-present fire activity from ∼19,000 to ∼17,000 cal yr BP and most sites from Indochina and Australia show greater-than-present fire activity from 16,000 to ∼13,000 cal yr BP. Many sites indicate greater-than-present or near-present activity during the Holocene with the exception of eastern North America and eastern Asia from 8,000 to ∼3,000 cal yr BP, Indonesia and Australia from 11,000 to 4,000 cal yr BP, and southern South America from 6,000 to 3,000 cal yr BP where fire activity was less than present. Regional coherence in the patterns of change in fire activity was evident throughout the post-glacial period. These complex patterns can largely be explained in terms of large-scale climate controls modulated by local changes in vegetation and fuel load.