Pharmacogenetics: the ethical context.
Explore the source record for details and available documents.
Bioethical Issues↗
Biomedical subjects
S M Thomas
Publications and source records attributed to S M Thomas.
Comparison of a range of green fluorescent protein-tagging vectors for monitoring a microbial inoculant in soil.
Two new transposon-based tagging vectors have been constructed using the gfp marker gene under control of either constitutive or inducible promoters. The two vectors, along with the established pUTminiTn5gfp were used to tag a diesel-degrading Pseudomonas strain. Tagged strains were obtained that were not affected in terms of their growth or ability to use diesel as a carbon source. The transposon tags were stably maintained in the strains without selection and provided visible fluorescence as colonies or single cells in suspension. Tagging did not impede the survival of tagged Pseudomonas aeruginosa GP41B strains in diesel-contaminated soil microcosms. The tagged strains were easily recovered from the microcosms after a 3-month period. The tagging of bacteria with gfp using either native or introduced constitutive/inducible promoters is an effective and easy way to monitor their survival in soil.
Colony Count, Microbial↗
Short-term (30-day) outcome of endovascular treatment of abdominal aortic aneurism: results from the prospective Registry of Endovascular Treatment of Abdominal Aortic Aneurism (RETA).
OBJECTIVES: to assess the early morbidity and mortality of a new treatment, the endovascular repair of abdominal aortic aneurysms, during its introduction into clinical practice. DESIGN: a prospective voluntary registry collecting demographic and risk factor data, details of aneurysm morphology, procedure performed, immediate and 30-day outcomes. SETTING: thirty-one U.K. centres performing endovascular repair submitted data. RESULTS: six hundred and eleven cases were registered in three years of data collection (January 1996 to December 1998). Four per cent of patients received an aortic tube device, 60% an aorto-bi-iliac device and 36% an aorto-uni-iliac device and a crossover graft (AUIC). Conversion to open repair was required in 5% of cases, with more conversions in the AUIC group (OR 2.9 (95% CI: 1.3-6.4)p=0.01). Post procedure complications occurred in 25% of cases. Unfit patients had significantly more complications than fit patients (35% vs 20% for fit patients (OR 1.8 (95% CI: 1.2-2.7)p=0.007)). At 30 days aneurysms were excluded in 90% of cases. Endoleaks were more common in larger aneurysms (2% if aneurysms were <6 cm in diameter vs 10% if >6 cm, OR 5.6 (95% CI: 2.1-14.9)p=0.0006). The overall mortality was 7% but was significantly higher for AUIC devices, (4% for combined aortic tube and bi-iliac devices (AT/BI) vs 12%, OR 2.6 (95% CI: 1.2-5.9 p=0.018)), and unfit patients (4% for fit patients vs 18%, OR 4.3 (95% CI: 2.0-9.5)p<0.001). CONCLUSIONS: endovascular repair is feasible with short-term outcomes comparable to those of conventional surgical repair. In unfit patients the possible benefit in life expectancy gain must be balanced against the morbidity and mortality of the procedure.
Adult↗
The cytoplasmic domain of the integrin alpha9 subunit requires the adaptor protein paxillin to inhibit cell spreading but promotes cell migration in a paxillin-independent manner.
The integrin alpha9 subunit forms a single heterodimer, alpha9beta1. The alpha9 subunit is most closely related to the alpha4 subunit, and like alpha4 integrins, alpha9beta1 plays an important role in leukocyte migration. The alpha4 cytoplasmic domain preferentially enhances cell migration and inhibits cell spreading, effects that depend on interaction with the adaptor protein, paxillin. To determine whether the alpha9 cytoplasmic domain has similar effects, a series of chimeric and deleted alpha9 constructs were expressed in Chinese hamster ovary cells and tested for their effects on migration and spreading on an alpha9beta1-specific ligand. Like alpha4, the alpha9 cytoplasmic domain enhanced cell migration and inhibited cell spreading. Paxillin also specifically bound the alpha9 cytoplasmic domain and to a similar level as alpha4. In paxillin(-/-) cells, alpha9 failed to inhibit cell spreading as expected but surprisingly still enhanced cell migration. Further, mutations that abolished the alpha9-paxillin interaction prevented alpha9 from inhibiting cell spreading but had no effect on alpha9-dependent cell migration. These findings suggest that the mechanisms by which the cytoplasmic domains of integrin alpha subunits enhance migration and inhibit cell spreading are distinct and that the alpha9 and alpha4 cytoplasmic domains, despite sequence and functional similarities, enhance cell migration by different intracellular signaling pathways.
Amino Acid Motifs↗
Cloning and characterization of a gene cluster for cyclododecanone oxidation in Rhodococcus ruber SC1.
Biological oxidation of cyclic ketones normally results in formation of the corresponding dicarboxylic acids, which are further metabolized in the cell. Rhodococcus ruber strain SC1 was isolated from an industrial wastewater bioreactor that was able to utilize cyclododecanone as the sole carbon source. A reverse genetic approach was used to isolate a 10-kb gene cluster containing all genes required for oxidative conversion of cyclododecanone to 1,12-dodecanedioic acid (DDDA). The genes required for cyclododecanone oxidation were only marginally similar to the analogous genes for cyclohexanone oxidation. The biochemical function of the enzymes encoded on the 10-kb gene cluster, the flavin monooxygenase, the lactone hydrolase, the alcohol dehydrogenase, and the aldehyde dehydrogenase, was determined in Escherichia coli based on the ability to convert cyclododecanone. Recombinant E. coli strains grown in the presence of cyclododecanone accumulated lauryl lactone, 12-hydroxylauric acid, and/or DDDA depending on the genes cloned. The cyclododecanone monooxygenase is a type 1 Baeyer-Villiger flavin monooxygenase (FAD as cofactor) and exhibited substrate specificity towards long-chain cyclic ketones (C11 to C15), which is different from the specificity of cyclohexanone monooxygenase favoring short-chain cyclic compounds (C5 to C7).
Amino Acid Sequence↗
Techniques for the production of point-light and fully illuminated video displays from identical recordings.
Illumination of only a few key points on a moving human body or face is enough to convey a compelling perception of human motion. A full understanding of the perception of biological motion from point-light displays requires accurate comparison with the perception of motion in normal, fully illuminated versions of the same images. Traditionally, these two types of stimuli (point-light and fully illuminated) have been filmed separately, allowing the introduction of uncontrolled variation across recordings. This is undesirable for accurate comparison of perceptual performance across the two types of display. This article describes simple techniques, using proprietary software, that allow production of point-light and fully illuminated video displays from identical recordings. These techniques are potentially useful for many studies of motion perception, by permitting precise comparison of perceptual performances across point-light displays and their fully illuminated counterparts with accuracy and comparative ease.
Computer Terminals↗
Effects of horizontal viewing angle on visual and audiovisual speech recognition.
The authors investigated the effects of changes in horizontal viewing angle on visual and audiovisual speech recognition in 4 experiments, using a talker's face viewed full face, three quarters, and in profile. When only experimental items were shown (Experiments 1 and 2), identification of unimodal visual speech and visual speech influences on congruent and incongruent auditory speech were unaffected by viewing angle changes. However, when experimental items were intermingled with distractor items (Experiments 3 and 4), identification of unimodal visual speech decreased with profile views, whereas visual speech influences on congruent and incongruent auditory speech remained unaffected by viewing angle changes. These findings indicate that audiovisual speech recognition withstands substantial changes in horizontal viewing angle, but explicit identification of visual speech is less robust. Implications of this distinction for understanding the processes underlying visual and audiovisual speech recognition are discussed.
Humans↗
A comparison of a printed patient summary document with its electronic equivalent: early results.
Clinicians are always searching for efficient access to clinical data. The Regenstrief Medical Record System has a printed report that fills this niche: Pocket Rounds. Handheld computers may offer an alternative, but it is unclear how effectively a handheld computer can display such data. We surveyed residents and students on the general medicine services for their opinions regarding Pocket Rounds. Those with handheld computers were given access to an electronic version of Pocket Rounds-e-Rounds. We surveyed the subjects who used e-Rounds for their opinions on the electronic format and how it compared to paper. Users overall satisfaction with Pocket Rounds was 5.8 on a seven-point scale. User s overall satisfaction for e-Rounds was 5.6 on a seven-point scale. The most useful function was retrieval of lab data for both modalities. The results suggest that the electronic format is a viable alternative to paper. Further evaluation is needed, and we plan a prospective controlled trial to study this further.
Hospital Information Systems↗
Plasma interleukin-6, tumour necrosis factor alpha and blood cytokine production in type 2 diabetes.
Type 2 diabetes is associated with increased circulating concentrations of markers of the acute-phase response and interleukin-6 (IL-6). An augmented acute-phase response may be a mechanism which explains many of the clinical and biochemical features of type 2 diabetes and its complications. We sought to confirm that circulating concentrations of the cytokine acute-phase mediators IL-6 and tumour necrosis factor alpha [TNFalpha] are elevated in type 2 diabetes, and investigated blood as a source of cytokines in type 2 diabetes. Blood samples from 20 type 2 diabetic and 17 age-matched healthy subjects were incubated in vitro for 24 hr with and without lipopolysaccharide (LPS) stimulation and secreted cytokines measured. Plasma IL-6 and TNFalpha were significantly increased in type 2 diabetes compared to normal subjects. However, basal production of IL-6 and TNFalpha in cultured diabetic blood was markedly depressed in comparison with non-diabetic samples. IL-6 and TNFalpha production was increased in blood in response to LPS, reaching similar levels in diabetic and non-diabetic subjects, though IL-6 was slightly but significantly higher in controls. We conclude that circulating levels of IL-6 and TNFalpha are increased in type 2 diabetes but there is downregulation of basal cytokine production in blood cells in type 2 diabetes. Blood has the capacity to produce cytokines in diabetes which contribute to the augmented acute-phase response, but the main source of the increased plasma IL-6 and TNFalpha concentrations may be from non-circulating cells.
Acute-Phase Reaction↗
Presentation of intravascular lymphomatosis as lumbosacral polyradiculopathy.
A 53-year-old man developed progressive sensory disturbance and weakness in the legs, sphincter disturbance, back pain, systemic symptoms, and pancytopenia. Electrophysiological tests indicated a widespread lumbosacral polyradiculopathy. Spinal magnetic resonance imaging and routine cerebrospinal fluid analysis showed minor nonspecific abnormalities. Bone marrow and liver biopsies showed hemophagocytosis; and polymerase chain reaction of cerebrospinal fluid, bone marrow, and serum suggested active infection with human herpesvirus-6. Autopsy revealed that his neurological symptoms resulted from intravascular lymphomatosis (angiotropic large cell lymphoma), a rare variant of lymphoma with predilection for the nervous system.
Diagnosis, Differential↗
Is it possible to predict diabetic kidney disease?
Explore the source record for details and available documents.
Adult↗
Minority recruitment in the prostate cancer prevention trial.
PURPOSE: African American men have a higher prostate cancer risk profile than that of other men in the United States. The purpose of this manuscript is to summarize the challenges associated with enrolling and randomizing African American and other minority participants in the Prostate Cancer Prevention Trial (PCPT). METHODS: The PCPT is a randomized trial of finasteride versus placebo for preventing prostate cancer in healthy men age 55 years and older; it is coordinated by the Southwest Oncology Group. The manuscript describes demographic and lifestyle characteristics of the PCPT randomized sample (18,882 men) by four racial and ethnic groups (Caucasian, African American, Hispanic, and other). African American men comprised 4% of the total randomized sample compared to our goal of 8%. Minority recruitment was emphasized through the Study Manual and training that occurred at trial activation. Supplemental minority recruitment activities were initiated a year after study activation and continued through the end of the accrual period. Minority recruitment was emphasized as follows: minority recruitment presentations at PCPT training seminars (held during twice yearly Southwest Oncology Group meetings); distribution of additional minority recruitment materials; engagement of four consultants for minority recruitment; production of a Minority Recruitment Manual; and a small pilot study involving minority outreach recruiters at five PCPT sites. RESULTS: The consultants were helpful in implementing the pilot project and in suggesting and reviewing materials for minority recruitment. The five-site pilot project did not increase either enrollment or randomization of minorities (with a possible exception at one site). CONCLUSIONS: We suggest that a long-term perspective is required for successful recruitment of minority participants in clinical trials. Likewise, extensive minority recruitment efforts must be ready to implement at trial activation.
Aged↗
Signalling by adhesion receptors.
Over the past twenty years, intensive research has enabled us to identify components of specific signalling pathways downstream of an array of adhesion and growth-factor receptors. The first Gordon Research Conference on 'Signalling by Adhesion Receptors', which took place in Newport, Rhode Island, USA (23-28 July 2000), focused on these findings.
Animals↗
Searching for new coronary heart disease risk factors.
Explore the source record for details and available documents.
Albuminuria↗
Rhizosphere competitiveness of trichloroethylene-degrading, poplar-colonizing recombinant bacteria.
Indigenous bacteria from poplar tree (Populus canadensis var. eugenei 'Imperial Carolina') and southern California shrub rhizospheres, as well as two tree-colonizing Rhizobium strains (ATCC 10320 and ATCC 35645), were engineered to express constitutively and stably toluene o-monooxygenase (TOM) from Burkholderia cepacia G4 by integrating the tom locus into the chromosome. The poplar and Rhizobium recombinant bacteria degraded trichloroethylene at a rate of 0.8 to 2.1 nmol/min/mg of protein and were competitive against the unengineered hosts in wheat and barley rhizospheres for 1 month (colonization occurred at a level of 1.0 x 10(5) to 23 x 10(5) CFU/cm of root). In addition, six of these recombinants colonized poplar roots stably and competitively with populations as large as 79% +/- 12% of all rhizosphere bacteria after 28 days (0.2 x 10(5) to 31 x 10(5) CFU/cm of root). Furthermore, five of the most competitive poplar recombinants (e.g., Pb3-1 and Pb5-1, which were identified as Pseudomonas sp. strain PsK recombinants) retained the ability to express TOM for 29 days as 100% +/- 0% of the recombinants detected in the poplar rhizosphere expressed TOM constitutively.
Biodegradation, Environmental↗
Simultaneous identification of two cyclohexanone oxidation genes from an environmental Brevibacterium isolate using mRNA differential display.
The technique of mRNA differential display was used to identify simultaneously two metabolic genes involved in the degradation of cyclohexanone in a new halotolerant Brevibacterium environmental isolate. In a strategy based only on the knowledge that cyclohexanone oxidation was inducible in this strain, the mRNA population of cells exposed to cyclohexanone was compared to that of control cells using reverse transcription-PCR reactions primed with a collection of 81 arbitrary oligonucleotides. Three DNA fragments encoding segments of flavin monooxygenases were isolated with this technique, leading to the identification of the genes of two distinct cyclohexanone monooxygenases, the enzymes responsible for the oxidation of cyclohexanone. Each monooxygenase was expressed in Escherichia coli and characterized. This work validates the application of mRNA differential display for the discovery of new microbial metabolic genes.
Amino Acid Sequence↗
Genetic analysis of a gene cluster for cyclohexanol oxidation in Acinetobacter sp. Strain SE19 by in vitro transposition.
Biological oxidation of cyclic alcohols normally results in formation of the corresponding dicarboxylic acids, which are further metabolized and enter the central carbon metabolism in the cell. We isolated an Acinetobacter sp. from an industrial wastewater bioreactor that utilized cyclohexanol as a sole carbon source. A cosmid library was constructed from Acinetobacter sp. strain SE19, and oxidation of cyclohexanol to adipic acid was demonstrated in recombinant Escherichia coli carrying a SE19 DNA segment. A region that was essential for cyclohexanol oxidation was localized to a 14-kb fragment on the cosmid DNA. Several putative open reading frames (ORFs) that were expected to encode enzymes catalyzing the conversion of cyclohexanol to adipic acid were identified. Whereas one ORF showed high homology to cyclohexanone monooxygenase from Acinetobacter sp. strain NCIB 9871, most of the ORFs showed only moderate homology to proteins in GenBank. In order to assign functions of the various ORFs, in vitro transposon mutagenesis was performed using the cosmid DNA as a target. A set of transposon mutants with a single insertion in each of the ORFs was screened for cyclohexanol oxidation in E. coli. Several of the transposon mutants accumulated a variety of cyclohexanol oxidation intermediates. The in vitro transposon mutagenesis technique was shown to be a powerful tool for rapidly assigning gene functions to all ORFs in the pathway.
Acinetobacter↗
Completeness of excision and follow up cytology in patients treated with loop excision biopsy.
AIMS: To assess the relation between the grade and the status of follow up cytology, the completeness of loop excision biopsies with cervical intraepithelial neoplasia (CIN), and the findings at follow up cytology, as well as the differences between complete and incomplete exclusion, using the odds ratio. Treatment failure was assessed. METHODS: 1600 women with CIN (290 CIN1, 304 CIN2, 1006 CIN3) were followed for a minimum of six months and a maximum of 10 years. A database was created and comparisons performed. The mean age of the patients was 37 years. RESULTS: Excision was complete in over 84% of loops. Residual disease and recurrence of high grade dyskaryosis was more common in women with CIN 3 than CIN 2 or 1. No high grade dyskaryosis was seen in the fifth follow up smear in patients with CIN 1 and CIN 2. Residual, recurrent, and persistent disease was most common in patients with incompletely excised CIN at ectocervical and endocervical margins and deep margins of resection than in patients with completely excised CIN. The odds ratios were significantly higher in the women who had incomplete excision of CIN at ectocervical, endocervical, both ecto- and endocervical, and deep margins of resection compared with those with apparent complete excision of CIN lesions. One patient developed invasive squamous cell carcinoma 44 months after loop excision which showed CIN 3 invading endocervical crypts and extending to both ectocervical and endocervical margins of resection. CONCLUSIONS: At long term follow up, patients with CIN who have residual disease are at increased risk of persistent disease and should therefore be followed up regularly with cytology and colposcopy. The findings support national policy of returning women with treated CIN of any grade to normal recall after five years except for cases of CIN3 where excision was incomplete or equivocal. In these cases follow up with annual smear for 10 years is recommended.
Adolescent↗