Biomedical subjects

William Davies

Publications and source records attributed to William Davies.

13 recordsLinked to original sources

PubMed2007

Detection of Vibrio cholerae by real-time nucleic acid sequence-based amplification.

A multitarget molecular beacon-based real-time nucleic acid sequence-based amplification (NASBA) assay for the specific detection of Vibrio cholerae has been developed. The genes encoding the cholera toxin (ctxA), the toxin-coregulated pilus (tcpA; colonization factor), the ctxA toxin regulator (toxR), hemolysin (hlyA), and the 60-kDa chaperonin product (groEL) were selected as target sequences for detection. The beacons for the five different genetic targets were evaluated by serial dilution of RNA from V. cholerae cells. RNase treatment of the nucleic acids eliminated all NASBA, whereas DNase treatment had no effect, showing that RNA and not DNA was amplified. The specificity of the assay was investigated by testing several isolates of V. cholerae, other Vibrio species, and Bacillus cereus, Salmonella enterica, and Escherichia coli strains. The toxR, groEL, and hlyA beacons identified all V. cholerae isolates, whereas the ctxA and tcpA beacons identified the O1 toxigenic clinical isolates. The NASBA assay detected V. cholerae at 50 CFU/ml by using the general marker groEL and tcpA that specifically indicates toxigenic strains. A correlation between cell viability and NASBA was demonstrated for the ctxA, toxR, and hlyA targets. RNA isolated from different environmental water samples spiked with V. cholerae was specifically detected by NASBA. These results indicate that NASBA can be used in the rapid detection of V. cholerae from various environmental water samples. This method has a strong potential for detecting toxigenic strains by using the tcpA and ctxA markers. The entire assay including RNA extraction and NASBA was completed within 3 h.

Animals↗

PubMed2006

Genomic imprinting and the social brain.

Genomic imprinting refers to the parent-of-origin-specific epigenetic marking of a number of genes. This epigenetic mark leads to a bias in expression between maternally and paternally inherited imprinted genes, that in some cases results in monoallelic expression from one parental allele. Genomic imprinting is often thought to have evolved as a consequence of the intragenomic conflict between the parental alleles that occurs whenever there is an asymmetry of relatedness. The two main examples of asymmetry of relatedness are when there is partiality of parental investment in offspring (as is the case for placental mammals, where there is also the possibility of extended postnatal care by one parent), and in social groups where there is a sex-biased dispersal. From this evolutionary starting point, it is predicted that, at the behavioural level, imprinted genes will influence what can broadly be termed bonding and social behaviour. We examine the animal and human literature for examples of imprinted genes mediating these behaviours, and divide them into two general classes. Firstly, mother-offspring interactions (suckling, attachment and maternal behaviours) that are predicted to occur when partiality in parental investment in early postnatal offspring occurs; and secondly, adult social interactions, when there is an asymmetry of relatedness in social groups. Finally, we return to the evolutionary theory and examine whether there is a pattern of behavioural functions mediated by imprinted genes emerging from the limited data, and also whether any tangible predictions can be made with regards to the direction of action of genes of maternal or paternal origin.

Animals↗

PubMed2006

X-monosomy effects on visuospatial attention in mice: a candidate gene and implications for Turner syndrome and attention deficit hyperactivity disorder.

BACKGROUND: The loss of all, or part of an X chromosome, in Turner syndrome (TS, 45,XO) results in deficits in attentional functioning. METHODS: Using a 39,XO mouse model, we tested the hypothesis that X-monosomy and/or parental origin of the single X chromosome may influence visuospatial attentional functioning in a 5-choice serial reaction time task (5-CSRTT). RESULTS: Under attentionally demanding conditions 39,XO mice displayed impaired discriminative response accuracy and slowed correct reaction times relative to 40,XX mice; these deficits were alleviated in a version of the task with reduced attentional demands. Parental origin of the X did not affect performance of the 5-CSRTT. In contrast, the attentional phenotype was rescued in 40,XY*X mice possessing a single maternally inherited X chromosome and a small Y*X chromosome that comprises a complete pseudoautosomal region (PAR), and a small X-specific segment. CONCLUSIONS: Our findings are consistent with an X-monosomy effect on attention and suggest the existence of X-linked gene(s) that escape X-inactivation, are present on the small Y*X chromosome and impact on attentional functioning; the strongest candidate gene is Sts, encoding steroid sulfatase. The data inform the TS literature and indicate novel genetic mechanisms that may be of general significance to the neurobiology of attention.

Animals↗

PubMed2006

It is not all hormones: alternative explanations for sexual differentiation of the brain.

Males and females of many species differ with regard to neurodevelopment, ongoing brain function and behavior. For many years, it was assumed that these differences primarily arose due to hormonal masculinization of the male brain (and to a lesser extent hormonal feminization of the female brain). Recent elegant experiments in model systems have revealed that, while gonadal hormones undoubtedly play an important role in sexual differentiation of the brain, they are not the only possible mechanism for this phenomenon. In the present review, we discuss the concept that genes residing upon the sex chromosomes (which are asymmetrically inherited between males and females) may influence sexually dimorphic neurobiology directly, and suggest possible mechanisms. Future work will be directed towards understanding the extent and specificity with which sex-linked genes and hormones define brain structure and function, and towards elucidating potential interactions between the two mechanisms. Ultimately, it is hoped that such studies will provide insights into why men and women are differentially vulnerable to certain mental disorders, and will enable the development of effective sex-tailored therapeutics.

Animals↗

PubMed2006

X-linked imprinting: effects on brain and behaviour.

Imprinted genes are monoallelically expressed in a parent-of-origin-dependent manner and can affect brain and behavioural phenotypes. The X chromosome is enriched for genes affecting neurodevelopment and is donated asymmetrically to male and female progeny. Hence, X-linked imprinted genes could potentially influence sexually dimorphic neurobiology. Consequently, investigations into such loci may provide new insights into the biological basis of behavioural differences between the sexes and into why men and women show different vulnerabilities to certain mental disorders. In this review, we summarise recent advances in our knowledge of X-linked imprinted genes and the brain substrates that they may act upon. In addition, we suggest strategies for identifying novel X-linked imprinted genes and their downstream effects and discuss evolutionary theories regarding the origin and maintenance of X-linked imprinting.

Animals↗

PubMed2006

A systematic review of randomized trials comparing revascularization rate and graft patency of off-pump and conventional coronary surgery.

OBJECTIVE: Although many trials have been conducted to evaluate the benefits of off-pump coronary surgery, few have concentrated on graft patency. We sought to evaluate the impact of off-pump surgery on completeness of revascularization and graft patency compared with conventional surgery. METHODS: A systematic literature search was undertaken of all randomized trials of off-pump coronary surgery in MEDLINE, EMBASE, the Cochrane Library Controlled Trials Register, the National Research Register, and abstracts from major conferences. RESULTS: In total, 132 publications were identified. From this number, we excluded 43 without a conventional surgery arm and 80 that did not evaluate graft patency. One trial was excluded for selective angiography and one abstract was excluded because of insufficient information. A total of 7 trials were eligible for overview. On initial analysis, the relative risk of graft patency in off-pump coronary surgery compared with conventional surgery was 0.959 (95% confidence interval 0.936-0.983; P = .001). The analysis was repeated after excluding one specific trial because of clinical and statistical heterogeneity (chi2(6) = 27.78; P < .001), and a relative risk of 0.953 (95% confidence interval 0.927-0.980; P = .001) was obtained with no further evidence of heterogeneity (chi2(5) = 5.35; P = .374). In 5 trials that included the mean number of grafts performed per arm, the standardized mean difference in revascularization comparing off-pump with conventional surgery was -0.164 (-0.286 to -0.043; P = .008). CONCLUSION: In a meta-analysis of randomized trials, patients undergoing off-pump coronary surgery had a lower rate of revascularization and lower graft patency than did patients undergoing conventional coronary surgery.

Coronary Artery Bypass, Off-Pump↗

PubMed2005

Xlr3b is a new imprinted candidate for X-linked parent-of-origin effects on cognitive function in mice.

Imprinted genes show differential expression between maternal and paternal alleles as a consequence of epigenetic modification that can result in 'parent-of-origin' effects on phenotypic traits. There is increasing evidence from mouse and human studies that imprinted genes may influence behavior and cognitive functioning. Previous work in girls with Turner syndrome (45,XO) has suggested that there are X-linked parent-of-origin effects on brain development and cognitive functioning, although the interpretation of these data in terms of imprinted gene effects has been questioned. We used a 39,XO mouse model to examine the influence of the parental origin of the X chromosome on cognitive behaviors and expression of X-linked genes in brain. Our findings confirm the existence of X-linked imprinted effects on cognitive processes and identify a new maternally expressed imprinted gene candidate on the X chromosome, Xlr3b, which may be of importance in mediating the behavioral effects.

Animals↗

PubMed2005

Imprinted gene expression in the brain.

In normal mammals, autosomal genes are present in duplicate (i.e. two alleles), one inherited from the father, and one from the mother. For the majority of genes both alleles are transcribed (or expressed) equally. However, for a small subset of genes, known as imprinted genes, only one allele is expressed in a parent-of-origin dependent manner (note that the 'imprint' here refers to the epigenetic mechanism through which one allele is silenced, and is completely unrelated to classical 'filial imprinting' manifest at the behavioural level). Thus, for some imprinted genes expression is only (or predominantly) seen from the paternally inherited allele, whilst for the remainder, expression is only observed from the maternally inherited allele. Early work on this class of genes highlighted their importance in gross developmental and growth phenotypes. Recent studies in mouse models and humans have emphasised their contribution to brain function and behaviour. In this article, we review the literature concerning the expression of imprinted genes in the brain. In particular, we attempt to define emerging organisation themes, especially in terms of the direction of imprinting (i.e. maternal or paternal expression). We also emphasise the likely role of imprinted genes in neurodevelopment. We end by pointing out that, so far as discerning the precise functions of imprinted genes in the brain is concerned, there are currently more questions than answers; ranging from the extent to which imprinted genes might contribute to common mental disorders, to wider issues related to how easily the new data on brain may be accommodated within the dominant theory regarding the origins and maintenance of imprinting, which pits the maternal and paternal genomes against each other in an evolutionary battle of the sexes.

Animals↗

PubMed2004

Effects on fear reactivity in XO mice are due to haploinsufficiency of a non-PAR X gene: implications for emotional function in Turner's syndrome.

Recent work has indicated altered emotional functioning in Turner's syndrome (TS) subjects (45,XO). We examined the role of X-chromosome deficiency on fear reactivity in X-monosomic mice (39,XO), and found that they exhibited anxiogenic behaviour relative to normal females (40,XX). A molecular candidate for this effect is Steroid sulfatase (Sts) as this is located in the pseudoautosomal region (PAR) of the X-chromosome and consequently is normally biallelically expressed. In addition, the steroid sulfatase enzyme (STS) is putatively linked to fear reactivity by an effect on GABAA receptors via the action of neurosteroids. Real-time PCR demonstrated that levels of Sts mRNA were reduced by half in the brains of 39,XO mice compared with 40,XX, and that expression levels of a number of GABAA subunits previously shown to be important components of fear processing (Gabra3, Gabra1 and Gabrg2) were also altered. However, 40,XY*X mice, in which the Y*X is a small chromosome comprising of a complete PAR and a small non-PAR segment of the X-chromosome, exhibited the same pattern of fear reactivity behaviour as 39,XO animals, but equivalent expression levels of Sts, Gabra1, Gabra3 and Gabrg2 to 40,XX females. This showed that although Sts may cause alterations in GABAA subunit expression, these changes do not result in increased fear reactivity. This suggests an alternative X-chromosome gene, that escapes inactivation, is responsible for the differences in fear reactivity between 39,XO and 40,XX mice. These findings inform the TS data, and point to novel genetic mechanisms that may be of general significance to the neurobiology of fear.

Affective Symptoms↗

PubMed2004

Climate change and evolving human diversity in Europe during the last glacial.

A link between climate change and human evolution during the Pleistocene has often been assumed but rarely tested. At the macro-evolutionary level Foley showed for hominids that extinction, rather than speciation, correlates with environmental change as recorded in the deep sea record. Our aim is to examine this finding at a smaller scale and with high-resolution environmental and archaeological archives. Our interest is in changing patterns of human dispersal under shifting Pleistocene climates during the last glacial period in Europe. Selecting this time frame and region allows us to observe how two hominid taxa, Neanderthals and Crô-Magnons, adapted to climatic conditions during oxygen isotope stage 3. These taxa are representative of two hominid adaptive radiations, termed terrestrial and aquatic, which exhibited different habitat preferences but similar tolerances to climatic factors. Their response to changing ecological conditions was predicated upon their ability to extend their societies in space and time. We examine this difference further using a database of all available radiocarbon determinations from western Europe in the late glacial. These data act as proxies for population history, and in particular the expansion and contraction of regional populations as climate changed rapidly. Independent assessment of these processes is obtained from the genetic history of Europeans. The results indicate that climate affects population contraction rather than expansion. We discuss the consequences for genetic and cultural diversity which led to the legacy of the Ice Age: a single hominid species, globally distributed.

Adaptation, Biological↗

PubMed2004

Expression patterns of the novel imprinted genes Nap1l5 and Peg13 and their non-imprinted host genes in the adult mouse brain.

Recent work has implicated imprinted gene functioning in neurodevelopment and behaviour and defining the expression patterns of these genes in brain tissue has become a key prerequisite to establishing function. In this work we report on the expression patterns of two novel imprinted loci, Nap1l5 and Peg13, in adult mouse brain using in situ hybridisation methods. Nap1l5 and Peg13 are located, respectively, within the introns of the non-imprinted genes Herc3 and the Tularik1 (T1)/KIAA1882 homologue in two separate microimprinted domains on mouse chromosomes 6 and 15. These 'host' genes are highly expressed in brain and consequently we were interested in assessing their expression patterns in parallel to the imprinted genes. The brain expression of all four genes appeared to be mainly neuronal. The detailed expression profiles of Nap1l5 and Peg13 were generally similar with widespread expression that was relatively high in the septal and hypothalamic regions, the hippocampus and the cerebral cortex. In contrast, there was some degree of dissociation between the imprinted genes and their non-imprinted hosts, in that, whilst there was again widespread expression of Herc3 and the T1/KIAA1882 homologue, these genes were also particularly highly expressed in Purkinje neurons and piriform cortex. We also examined expression of the novel imprinted genes in the adrenal glands. Nap1l5 expression was localised mainly to the adrenal medulla, whilst Peg13 expression was observed more generally throughout the adrenal medulla and the outer cortical layers.

Animals↗

PubMed2004

Provider perceptions of pharmacy management: lessons from the military health system.

OBJECTIVE: The objective of this study was to contrast experiences and opinion of providers in military treatment facilities, where a single formulary is used, with those of community providers where multiple formularies and preferred lists are commonly encountered. STUDY DESIGN: We conducted cross-sectional surveys. SETTING: The study was conducted at military and community practices that serve military beneficiaries. PARTICIPANTS: We studied randomly selected clinicians, stratified by military treatment facility (MTF) size or number of military beneficiaries served. The final samples included 566 eligible MTF and 557 private clinicians, with 69% and 38% response rates, respectively. OUTCOME MEASURES: We wanted to determine experiences with and opinions of formularies and/or preferred lists and related policies. RESULTS: Sixty-three percent of military providers were very familiar with formulary content and 60% with nonformulary request procedures; 67% thought their formulary was up-to-date and 84% felt Pharmacy & Therapeutics (P&T) committees were responsive to providers. In contrast, 23% of community providers felt very familiar with (multiple) formulary content and 10% with nonformulary request procedures. Only 15% perceived that formularies were current and 34% thought P&T committees were responsive to providers. Statistically significant differences remained after analysis of potential bias. CONCLUSIONS: Community providers were less aware and less satisfied with pharmacy benefits management policies than military providers, likely as a result of their daily interactions with multiple, unrelated pharmacy management systems. Addressing the problems expressed by community providers is imperative for pharmacy benefits managers.

Adult↗

PubMed2003

Natural variation in the microcystin synthetase operon mcyABC and impact on microcystin production in Microcystis strains.

Toxic Microcystis strains often produce several isoforms of the cyclic hepatotoxin microcystin, and more than 65 isoforms are known. This has been attributed to relaxed substrate specificity of the adenylation domain. Our results show that in addition to this, variability is also caused by genetic variation in the microcystin synthetase genes. Genetic characterization of a region of the adenylation domain in module mcyB1 resulted in identification of two groups of genetic variants in closely related Microcystis strains. Sequence analyses suggested that the genetic variation is due to recombination events between mcyB1 and the corresponding domains in mcyC. Each variant could be correlated to a particular microcystin isoform profile, as identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Among the Microcystis species studied, we found 11 strains containing different variants of the mcyABC gene cluster and 7 strains lacking the genes. Furthermore, there is no concordance between the phylogenies generated with mcyB1, 16S ribosomal DNA, and DNA fingerprinting. Collectively, these results suggest that recombination between imperfect repeats, gene loss, and horizontal gene transfer can explain the distribution and variation within the mcyABC operon.

Amino Acid Sequence↗