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PubMed2005

Theatre as a public engagement tool for health-policy development.

PURPOSE: To explore theatre as a public engagement tool for health-policy development. BACKGROUND: In a justice-based democracy, engagement of a large number of citizens of diverse perspectives is required for legitimate health-policy development. However, all current strategies of citizen participation are limited in their capacity to engage, either by lack of opportunity to educate citizens prior to soliciting their opinions or lack of large numbers of citizens. METHODS: A series of 12 nested case studies was conducted, with each case study consisting of a performance of a 70-min play, specifically written to educate citizens to scientific, clinical, and psychosocial issues of adult predictive genetic testing, and to foster empathy for persons immersed therein; and a 1-h audience discussion that was taped and transcribed for qualitative analysis (modified thematic). The script was based on key informant interviews, literature review, and six script readings for key informants and communities. Audience members were recruited through conference or educational event programs, posters, newsletters, and electronic announcements, as well as newspaper advertisements and other public, community and institutional postings. RESULTS: More than 1,000 citizens were engaged. The analysis indicated that audience members were engaged emotionally and cognitively in the position of the characters and the health-policy issues. Audience members' comments forwarded from personal or professional lived experience confirmed the validity of the script and promoted further emotional and cognitive engagement of other audience members. Audience members offered informed and diverse opinions on policy issues, including resource allocation, patenting of genetic tests, research funding, genetic test-based insurance discrimination, and imperative for public education. The potential for harm to key informants and audience members (and those in relationships with them) were observed, usually related to learning or offering personal information regarding their genetic risk. CONCLUSION: As many citizens can be engaged in theatre-based policy development as surveyed through public opinion polls, and many times the number that can be engaged in strategies that educate citizens prior to soliciting their opinions, likely at a similar cost per citizen engaged.

Community Participation↗
PubMed2000

The decay of linkage disequilibrium under random union of gametes: how to calculate Bennett's principal components.

How rapidly does an arbitrary pattern of statistical association among a set of loci decay under meiosis and random union of gametes? This problem is non-trivial, even in the case of an infinitely large population where selection and other forces are absent. J. H. Bennett (1954, Ann. Hum. Genet. 18, 311-317) found that, for an arbitrary number of loci with an arbitrary linkage map, it is possible to define measures of linkage disequilibrium that decay geometrically with time. He found a recursive method for deriving expressions for these variables in terms of "allelic moments" (the factorial moments about the origin of the "allelic indicators"), and expressions for the allelic moments in terms of his new variables. However, Bennett no where stated his recursive algorithm explicitly, nor did he give a general formula for his measures of linkage disequilibrium, for an arbitrary number of loci. Recursive definitions of Bennett's variables were obtained by Lyubich. However, the expressions generated by these recursions are not the same as those found by Bennett. (They do not express Bennett's variables as functions of the allelic moments.) Lyubich's derivations employ genetic algebras. Here, I present a method for obtaining explicit expressions for Bennett's variables in terms of the allelic moments. I show that the transformation from the allelic moments to Bennett's variables and the inverse transformation always have the form that Bennett claimed. (This transformation and its inverse have essentially the same form.) I present general recursions for calculating the coefficients in the forward transformation and the coefficients in the inverse transformation. My derivations involve combinatorial arguments and ordinary algebra only. The special case of unlinked loci is briefly discussed.

Algorithms↗
PubMed1978

Adenosine kinase as a new selective marker in somatic cell genetics: isolation of adenosine kinase--deficient mouse cell lines and human--mouse hybrid cell lines containing adenosine kinase.

A new selective system for isolating somatic cell hybrids, using adenosine kinase as the selective marker, has been developed. The selective medium for forward selection (to select for cells containing adenosine kinase) contains alanosine, adenosine and uridine. To survive in the presence of alanosine, cells must have adenosine kinase in order to utilize exogenous adenosine as the sole source of AMP. Uridine is added to the selective medium to prevent the toxic effects of adenosine on cultured mammalian cells. The selective medium for reverse selection (to select for cells lacking adenosine kinase) contains 2-fluoroadenosine, an analogue of adenosine, which is converted to a toxic nucleotide by the action of adenosine kinase. Mouse mutant cell lines deficient in adenosine kinase have been derived. Human--mouse hybrid cells containing the kinase have been prepared from one of these mutant lines. Karyotype data of these hygrid lines and their adenosine kinase-minus sublines are consistent with assignment by others of the human gene for adenosine kinase on chromosome 10.

Adenosine↗
PubMed1987

Genetic Regulation of Development in Sorghum bicolor: III. Asynchrony of Thermoperiods with Photoperiods Promotes Floral Initiation.

Asynchronous thermo- and photoperiods were observed to hasten floral differentiation (initiation) in the short day plant Sorghum bicolor (L.) Moench. Shifting the 12 hour thermoperiod forward 0.5 or 2.5 hours hastened floral initiation compared to controls with synchronous thermo-and photoperiods. Delaying the day-night temperature change until 2.5 hours after either the dark-light or light-dark transition also hastened floral initiation. Inasmuch as sorghum milo-type maturity genotypes containing the genes designated Ma(1)Ma(2) (class I) were most responsive to asynchrony of the thermo- and photoperiods while those containing ma(3) (R) (class III) were not responsive, the maturity genes appear to control the plant's response to both photoperiod and temperature. Gibberellic acid promoted the effect of thermo- and photoperiod asynchrony on floral initiation. The results suggest that in sorghum both temperature and photoperiod may act as phase setting signals in what has previously been termed photoperiodism.

Journal Article↗
PubMed1995

The prevention of neurogenetic disease.

A significant number of major neurogenetic diseases have been defined at the molecular level in recent years, making it possible to determine precisely the genotype for familial Alzheimer's disease, Huntington's disease, Machado-Joseph disease, dominantly inherited ataxia, Charcot-Marie-Tooth disease, myotonic muscular dystrophy, Duchenne-Becker muscular dystrophy, familial amyotrophic lateral sclerosis, and neurofibromatosis. This information has made it possible to identify the abnormal genotype of at-risk persons for these diseases and for at-risk pregnancies for several of them. Precise molecular diagnoses are thus possible using applied molecular markers. Prevention of disease can be achieved using these molecular markers with genetic counseling and appropriate family planning. Significant progress is being made in this regard with Tay-Sachs disease, Huntington's disease, the dominantly inherited ataxias, and the muscular dystrophies. Further, this molecular genotyping will be of indispensible value to families with these diseases when somatic cell gene therapy becomes available. The field of molecular neurogenetics is moving forward rapidly, and advances in gene identification for these diseases will lead in the near future to the means to prevent many of them.

Alzheimer Disease↗
PubMed1991

Genetic analysis of Aspergillus niger mutants defective in benzoate-4-hydroxylase function.

This study was prompted by the observation that an Aspergillus niger transformant with a multicopy bphA (benzoate-4-hydroxylase gene) insert did not grow on benzoate, whereas a transformant with only one extra copy could grow. Therefore, an extensive survey has been made for other genes involved in the conversion of benzoate into 4-hydroxy-benzoate. A transformant with two copies of the bphA gene was used in part of the mutation experiments in order to avoid the isolation of many bphA mutants. Filtration enrichment was used to isolate mutants defective in the conversion of benzoate. The Bph mutants that have been isolated belong to six complementation groups. Mutants with a defected structural gene (bphA) were again predominantly found but, in addition, five other groups of mutants that could not grow on benzoate were isolated. Genetic analysis of the mutants showed that the six genes were localized in different parts of the genome. This was used as an additional proof that some mutants involved different genes. Diploids with seven copies of the bphA gene and heterozygous for one of the other bph genes were constructed. No indication has been obtained that any one of the mutant classes is responsible for the growth-limiting factor in bphA multicopy transformants. This study shows that the p-hydroxylation of benzoate is very complex, although the metabolic pathway is straight forward.

Aspergillus niger↗
PubMed1987

Implication of active oxygen species in the direct-acting mutagenicity of tea.

The present study shows that the L-arabinose resistance test with Salmonella typhimurium detects that freshly infused tea is highly mutagenic in the absence of mammalian microsomal activation. Both the mutagenesis protocol (preincubation test) and the additional genetic characteristics of the bacterial tester strain (excision repair deficiency, normal lipopolysaccharide barrier and the presence of plasmid pKM101) were critical factors in the optimal induction by tea of forward mutations to L-arabinose resistance. The TA104 strain--a histidine auxotroph specific to oxidative mutagens--was the most sensitive tester strain of the Ames test to the direct-acting mutagenicity of tea. In comparison with strain TA104, the sensitivity of the Ara forward mutation test was 18 times higher, one cup of tea (200 ml) inducing 3 X 10(6) AraR mutants. More than 90% of the mutagenicity of 150 microliter of a fresh tea infusion, or that of the equivalent amount (1.32 mg) of the corresponding lyophilized residue, was suppressed by 10 units of catalase. In contrast to catalase, superoxide dismutase was rather ineffective. These results indicate that hydrogen peroxide is produced in tea solutions, playing an essential role in its mutagenicity. In comparison, the role of superoxide anion seems negligible. Like catalase, the chelating agent DETAPAC showed a protective effect with respect to the mutagenicity of tea, suggesting the additional implication of hydroxyl radicals.

Arabinose↗
PubMed2002

4th International Meeting on Single Nucleotide Polymorphism and Complex Genome Analysis. Various uses for DNA variations.

At the 4th International Meeting on Single Nucleotide Polymorphism and Complex Genome Analysis (Stockholm, Sweden, 10th-14th October 2001), approximately 100 scientists from more than 20 nations undertook a probing review of latest developments in the field. Despite impressive and still ongoing activities towards SNP discovery and validation, plus efforts towards haplotype exploitation, it was clear that supporting technologies for genotyping are way behind where they need to be. Innate complexity and large variances in aspects of genome function together pose immense challenges that are difficult to surmount in the human situation. In contrast, studies in simpler organisms and population/evolutionary genetics studies are yielding important new insights. Breakthroughs that are being made in understanding the genetic etiology of complex disease tend to involve genes of larger effect or extremely well merited candidates. Linkage studies and proximal phenotypes are being recommended, though the best way forward is still hotly debated. Consequently, many diverse and ambitious projects are underway, from which the data itself will eventually show what is and is not possible.

Genome, Human↗
PubMed1994

Case report: developmental characterization of skeletal Class III malocclusion.

Skeletal Class III malocclusion is usually characterized by a steep mandibular plane angle, obtuse gonial angle, overdeveloped mandible, underdeveloped maxilla, and a small cranial base angle which may displace the glenoid fossa anteriorly to cause a forward positioning of the mandible. These factors are generally thought to contribute to the development of skeletal malocclusion as well as facial deformities, and are believed to originate from genetic and/or environmental factors. The posterior discrepancy is an important etiological factor in the development of a skeletal Class III malocclusion because it affects the occlusal plane. This idea must be amended for an appropriate clinical approach to the treatment of Class III malocclusion.

Adolescent↗
PubMed2001

Neurotoxic Abeta peptides increase oxidative stress in vivo through NMDA-receptor and nitric-oxide-synthase mechanisms, and inhibit complex IV activity and induce a mitochondrial permeability transition in vitro.

Beta amyloid (Abeta) peptides accumulate in Alzheimer's disease and are neurotoxic possibly through the production of oxygen free radicals. Using brain microdialysis we characterized the ability of Abeta to increase oxygen radical production in vivo. The 1-40 Abeta fragment increased 2,3-dehydroxybenzoic acid efflux more than the 1-28 fragment, in a manner dependent on nitric oxide synthase and NMDA receptor channels. We then examined the effects of Abeta peptides on mitochondrial function in vitro. Induction of the mitochondrial permeability transition in isolated rat liver mitochondria by Abeta(25-35) and Abeta(35-25) exhibited dose dependency and required calcium and phosphate. Cyclosporin A prevented the transition as did ruthenium red, chlorpromazine, or N-ethylmaleimide. ADP and magnesium delayed the onset of mitochondrial permeability transition. Electron microscopy confirmed the presence of Abeta aggregates and swollen mitochondria and preservation of mitochondrial structure by inhibitors of mitochondrial permeability transition. Cytochrome c oxidase (COX) activity was selectively inhibited by Abeta(25-35) but not by Abeta(35-25). Neurotoxic Abeta peptide can increase oxidative stress in vivo through mechanisms involving NMDA receptors and nitric oxide sythase. Increased intracellular Abeta levels can further exacerbate the genetically driven complex IV defect in sporadic Alzheimer's disease and may precipitate mitochondrial permeability transition opening. In combination, our results provide potential mechanisms to support the feed-forward hypothesis of Abeta neurotoxicity.

Amyloid beta-Peptides↗
PubMed2001

Cytotoxic and genotoxic consequences of heat stress are dependent on the presence of oxygen in Saccharomyces cerevisiae.

Lethal heat stress generates oxidative stress in Saccharomyces cerevisiae, and anaerobic cells are several orders of magnitude more resistant than aerobic cells to a 50 degrees C heat shock. Here we characterize the oxidative effects of this heat stress. The thermoprotective effect in anaerobic cells was not due to expression of HSP104 or any other heat shock gene, raising the possibility that the toxicity of lethal heat shock is due mainly to oxidative stress. Aerobic but not anaerobic heat stress caused elevated frequencies of forward mutations and interchromosomal DNA recombination. Oxidative DNA repair glycosylase-deficient strains under aerobic conditions showed a powerful induction of forward mutation frequencies compared to wild-type cells, which was completely abolished under anaerobiosis. We also investigated potential causes for this oxygen-dependent heat shock-induced genetic instability. Levels of sulfhydryl groups, dominated mainly by the high levels of the antioxidant glutathione (reduced form) and levels of vitamin E, decreased after aerobic heat stress but not after anaerobic heat stress. Aerobic heat stress also led to an increase in mitochondrial membrane disruption of several hundredfold, which was 100-fold reduced under anaerobic conditions.

Anaerobiosis↗
PubMed2005

Unraveling the chromosomal aberrations of head and neck squamous cell carcinoma: a review.

Information from the genetic analysis of head and neck cancer has grown enormously in the last 20 years. The advent of high-resolution genetic analysis techniques such as microarray technology will further expand this field in the future. Here we review the data on chromosomal aberrations of head and neck squamous cell carcinoma, focusing on the data generated by comparative genomic hybridization analysis, and suggest how such findings will be taken forward over the next decade. With the search engine PUBMED, the key words "comparative genomic hybridisation," "head and neck," "oral," "hypopharyngeal," "laryngeal," and "squamous cell carcinoma" were used. Publications unavailable in English were excluded.

Carcinoma, Squamous Cell↗
PubMedDate not supplied

[The role of reaper-dependent apoptosis in radiation-induced life-span alterations in Drosophila melanogaster].

This is the result of studying on a problem of radio-induced ageing. From the point of view of radiation genetics it is perspective to investigate influence of low doze irradiation on individuals with the mutant phenotypes that allows to assume a role of separate genes and mechanisms controllable by them in determination of life span and ageing. The role of a reaper-dependent way of apoptosis regulation in the induced change of life span is shown. The assumption is put forward that apoptosis has the important role during ageing an animal organism.

Aging↗
PubMed1978

Mutagenicity of industrial compounds. VII. Styrene and styrene oxide: II. Point mutations, chromosome aberrations and DNA repair induction analyses.

The possible genetic effects produced by styrene have been investigated by means of different methodologies in several biological organisms: (a) the induction of point mutation has been investigated in Salmonella typhimurium (reverse mutation), in the yeast Schizosaccharomyces pombe (forward mutation), both in vitro and in vivo, in the host-mediated assay of mice, and in the Chinese hamster cell line grown in vitro (V-79) (forward mutation); (b) the induction of chromosome mutation has been investigated in vivo, in mice, through the analysis of the presence of chromosome aberrations in bone marrow cells of treated animals; (c) the production of DNA (deoxyribonucleic acid) damage and the stimulation of DNA repair synthesis have been evaluated from measurements of unscheduled DNA synthesis in a heteroploid human cell line (EUE) and gene-conversion produced in the yeast Saccharomyces cerevisiae treated in vitro and in vivo (host-mediated assay). All the in vitro studies have been developed by the testing of the styrene in the presence of a metabolic activating system obtained with a mouse liver microsomal preparation. Styrene oxide, one of the in vivo metabolites of styrene with electrophilic properties towards DNA molecules, have also been tested in similar systems. Styrene was not mutagenic in all the systems tested; styrene oxide, on the contrary, was shown to be an active mutagen, independently of the genetic system under evaluation.

Animals↗
PubMed1994

Forward-mutation tests on the antitumor agent ICR-170 in Neurospora crassa demonstrate that it induces gene/point mutations in the ad-3 region and an exceptionally high frequency of multiple-locus ad-3 mutations with closely linked sites of recessive lethal damage.

The mutagenicity of the antitumor agent ICR-170 (2-methoxy-6-chloro-9-[(ethyl-2-chloroethyl)amino propylamino] acridine dihydrochloride) in the adenine-3 (ad-3) region was studied with a two-component heterokaryon (H-12) of Neurospora crassa. The objective was to characterize the genetic damage produced by this acridine nitrogen mustard derivative to determine in a lower eukaryotic organism the basis for its potent activity against ascites tumors in mice. As in higher eukaryotes, specific-locus mutations in the ad-3 region of strain H-12 result from gene/point mutations, multiple-locus mutations, and multilocus deletion mutations at the closely linked ad-3A and ad-3B loci. Six different treatments of conidial suspensions of H-12 with ICR-170 were used to obtain dose-response curves for inactivation of conidia as well as the overall induction of ad-3 forward mutations using a direct method based on pigment accumulation rather than a requirement for adenine. These experiments demonstrated that: (1) the slope of the dose-response curve for ICR-170-induced specific-locus mutations in the ad-3 region was 1.97 +/- 0.02, and (2) ICR-170 is a potent mutagen (maximum forward-mutation frequency between 1000 and 10,000 ad-3 mutations per 10(6) survivors) for the induction of specific-locus mutations in the ad-3 region. Both biochemical and classical genetic tests were used to characterize the ICR-170-induced ad-3 mutations from each of the six treatments to distinguish the different genotypic classes and subclasses. The overall data base demonstrates that ICR-170-induced ad-3 mutations result exclusively from gene/point mutations at the ad-3A and ad-3B loci and not multilocus deletion mutations. In addition, the frequency of multiple-locus ad-3 mutations resulting from gene/point mutations at the ad-3A and ad-3B loci with a separate site of recessive lethal damage elsewhere in the genome increases as a function of dose. However, an exceptionally high frequency of multiple-locus ad-3 mutations consisting of gene/point mutations at the ad-3A and ad-3B loci with a separate site of closely linked recessive lethal damage was found at all doses. Comparison of the dose-response curves for the major classes and subclasses of ICR-170-induced ad-3 mutations demonstrates that the gene/point ad-3 mutations and multiple-locus ad-3 mutations with a separate site of recessive lethal damage elsewhere in the genome have different induction kinetics.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenine↗
PubMed1996

Iridoschisis: high frequency ultrasound imaging. Evidence for a genetic defect?

AIMS: To elucidate changes in the anatomy of the anterior chamber associated with iridoschisis, a rare form of iris atrophy, and their potential contribution to angle closure glaucoma. METHODS: Both eyes of a 71-year-old woman with bilateral iridoschisis and fibrous dysplasia and her asymptomatic 50-year-old daughter were scanned with a very high frequency (50 MHz) ultrasound system. RESULTS: The symptomatic patient exhibited diffuse changes in the iris stoma with an intact posterior iris pigmented layer in both eyes. These changes were clinically compatible with the lack of iris transillumination defects. Additionally, iris bowing with a resultant narrowing of the angle occurred. The asymptomatic daughter showed discrete, but less severe iris stromal changes. CONCLUSION: This is the first detailed study of high frequency ultrasonic imaging of the iris in iridoschisis. The observed structural changes suggest angle narrowing by forward bowing of the anterior iris stroma may be a mechanism of IOP elevation in this condition. The ultrasonic detection of iris changes in the asymptomatic daughter of the symptomatic patient and the association of iridoschisis with fibrous dysplasia suggest a possible genetic component in the pathogenesis of this condition.

Aged↗