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PubMedDate not supplied

A rabbit model for evaluation of an extracorporeal LDL removal system.

Elevated levels of plasma low density lipoprotein cholesterol (LDL) are associated with an increased incidence of atherosclerosis and its sequelae. A decrease in LDL levels correlates with a reduction in atherosclerosis. Drug therapy and diet have been moderately successful in lowering cholesterol levels, but require significant periods of treatment. Furthermore, a patient with genetically high LDL levels, as in familial hypercholesterolemia, may need a more rapid and reliable method of decreasing serum LDL. The present study was designed to test a device which can rapidly remove LDL from the circulation. The device consists of a filter cartridge filled with semipermeable hollow fibers which have a proprietary acidic polymer (pap) immobilized on the blood/plasma contacting surfaces; this polymer has been reported to selectively bind LDL cholesterol. The device was evaluated in a hypercholesterolemic rabbit model. Reductions in LDL serum concentration, ranging from 1.4-25.3%, occurred in 6/6 studies. All animals survived the procedure. Autopsy results at 10 days showed normal histology. Binding of other proteins (HDL, albumin) were minimal and no hemolysis was observed. Results of this preliminary study demonstrate the feasibility of reducing serum LDL levels with a hollow fiber device.

Animals↗
PubMed2002

Automating data acquisition into ontologies from pharmacogenetics relational data sources using declarative object definitions and XML.

Ontologies are useful for organizing large numbers of concepts having complex relationships, such as the breadth of genetic and clinical knowledge in pharmacogenomics. But because ontologies change and knowledge evolves, it is time consuming to maintain stable mappings to external data sources that are in relational format. We propose a method for interfacing ontology models with data acquisition from external relational data sources. This method uses a declarative interface between the ontology and the data source, and this interface is modeled in the ontology and implemented using XML schema. Data is imported from the relational source into the ontology using XML, and data integrity is checked by validating the XML submission with an XML schema. We have implemented this approach in PharmGKB (http://www.pharmgkb.org/), a pharmacogenetics knowledge base. Our goals were to (1) import genetic sequence data, collected in relational format, into the pharmacogenetics ontology, and (2) automate the process of updating the links between the ontology and data acquisition when the ontology changes. We tested our approach by linking PharmGKB with data acquisition from a relational model of genetic sequence information. The ontology subsequently evolved, and we were able to rapidly update our interface with the external data and continue acquiring the data. Similar approaches may be helpful for integrating other heterogeneous information sources in order make the diversity of pharmacogenetics data amenable to computational analysis.

Databases, Factual↗
PubMed1992

Polymerase chain reaction (PCR) amplification and human leukocyte antigen (HLA)-DQ alpha oligonucleotide typing on biological evidence samples: casework experience.

The polymerase chain reaction (PCR) method of specific gene amplification was used in casework to synthesize millions of copies of the polymorphic second exon of the human leukocyte antigen (HLA)-DQ alpha (or DQA1) locus from a variety of evidence samples. The HLA-DQ alpha allelic variants in the amplified deoxyribonucleic acid (DNA) were determined in a rapid non-radioactive test by hybridization to sequence-specific oligonucleotide probes in both the dot-blot and reverse dot-blot formats. This genetic typing system has been subjected to blind proficiency testing; the performance of this test in the analysis of experimentally mixed samples was also evaluated. As of August 1990, over 250 cases have been tested and more than 2000 individual evidence (bloodstains, semen stains, individual hairs, bone fragments, and tissue sections) and reference samples have been analyzed. The first 198 of these cases are summarized in this paper; in 65% of the cases with conclusive results a suspect was included, and in 35%, all suspects were excluded. Individual cases as well as some of the general issues relating to forensic science analysis and this genetic typing system are discussed. The high rate of exclusion reported here combined with the ability of PCR to type old evidence samples suggests the relevance of this genetic test for postconviction review; two cases in which the convicted suspect was excluded are discussed.

Adolescent↗
PubMed2004

Rapid accumulation of mutations during seed-to-seed propagation of mismatch-repair-defective Arabidopsis.

During the many cell divisions that precede formation of plant gametes, their apical-meristem and floral antecedents are continually exposed to endogenous and environmental mutagenic threats. Although some deleterious recessive mutations may be eliminated during growth of haploid gametophytes and functionally haploid early embryos ("haplosufficiency quality-checking"), the multiplicity of plant genome-maintenance systems suggests aggressive quality control during prior diploid growth. To test in Arabidopsis a hypothesis that prior mismatch repair (MMR) is paramount in defense of plant genetic fidelity, we propagated in parallel 36 MMR-defective (Atmsh2-1) and 36 wild-type lines. The Atmsh2-1 lines rapidly accumulated a wide variety of mutations: fifth-generation (G5) plants showed abnormalities in morphology and development, fertility, germination efficiency, seed/silique development, and seed set. Only two Atmsh2-1, but all 36 wild-type lines, appeared normal at G5. Analyses of insertion/deletion mutation at six repeat-sequence (microsatellite) loci showed each Atmsh2-1 line to have evolved its own "fingerprint," the results of as many as 10 microsatellite mutations in a single line. Thus, MMR during diploid growth is essential for plant genomic integrity.

Arabidopsis↗
PubMed1992

Research note: effects of beak trimming and genetic stock on rate of mash consumption and feeding-related behavior in egg-strain pullets.

Pullets whose beaks were trimmed once (at 9 days) and twice (at 9 days and 9 wk) were able to ingest feed, in the form of mash, more rapidly under competitive feeding conditions and at least as rapidly in the absence of competition as pullets with intact beaks. Tests of feeding rate, when pullets fed in groups, were carried out after a feed deprivation period of 7 h at ages of 10 through 16 wk. Similar tests were done at 18 wk, when pullets fed without competition. Genetic stock and age had significant effects on frequency of agonistic acts at the feeder and displacements from the feeder during 5-min tests under competitive feeding conditions. Age influenced the number of pullets feeding simultaneously and amount of feed eaten per pullet during the same feeding tests. No interactions were detected among beak treatment, stock, and age for feeding-related behaviors or rate of feed consumption during competitive feeding. In noncompetitive feeding tests, genetic stock affected feeding rate but no stock by beak treatment interaction was present.

Aging↗
PubMed1999

[Penicillin-resistant pneumococcus: practical implications]

OBJECTIVE: To review epidemiological, laboratorial and clinical aspects of the penicillin-resistant pneumococcus, and to consider the impact of the rapidly increasing drug-resistance on the management of the main infections caused by these pathogens. METHODS: Bibliographic review covering the last ten years, using both Medline system and direct research. RESULTS AND CONCLUSIONS: The Streptococcus pneumoniae is an important agent in acute otitis media, pneumonia and meningitis in children. The clinical evaluation of the pneumococcal infections depends on the age and health condition of the patient, site and severity of the infection and the adequacy of the treatment. Penicillin was uniformly effective against pneumococcus until three decades ago, when the first reports of clinical resistance were published. Since then, there has been a rapidly increasing in the level and rates of resistance to penicillin, which parallels to others beta lactams and antimicrobials. This paper includes a suscint review of the genetic and phenotypic mechanisms of the resistance to penicillin, the available bacteriologic tests for determination of in vitro susceptibility to antimicrobials and finally the importance of the pneumococcus in acute otitis media, pneumonia/bacteremia and meningitis. There has been new empirical therapeutic regimens recommended for meningitis, according to the community rates and levels of resistance to beta lactams and to the presence of certain underlying conditions among the patients, such as immunedepressant diseases and frequent antibiotic consumption. The rapidly increasing prevalence of drug-resistant strains emphasizes the importance of judicious antibiotic use and the development of a conjugate vaccine, effective to prevent invasive infections and to reduce the rate of carriage of the pneumococcus, even among infants.

Journal Article↗
PubMed2005

Overview of molecular, cellular, and genetic neurotoxicology.

It has become increasingly evident that the field of neurotoxicology is not only rapidly growing but also rapidly evolving, especially over the last 20 years. As the number of drugs and environmental and bacterial/viral agents with potential neurotoxic properties has grown, the need for additional testing has increased. Only recently has the technology advanced to a level that neurotoxicologic studies can be performed without operating in a "black box." Examination of the effects of agents that are suspected of being toxic can occur on the molecular (protein-protein), cellular (biomarkers, neuronal function), and genetic (polymorphisms) level. Together, these areas help to elucidate the potential toxic profiles of unknown (and in some cases, known) agents. The area of proteomics is one of the fastest growing areas in science and particularly applicable to neurotoxicology. Lubec et al, provide a review of the potential and limitations of proteomics. Proteomics focuses on a more comprehensive view of cellular proteins and provides considerably more information about the effects of toxins on the CNS. Proteomics can be classified into three different focuses: post-translational modification, protein-expression profiling, and protein-network mapping. Together, these methods represent a more complete and powerful image of protein modifications following potential toxin exposure. Cellular neurotoxicology involves many cellular processes including alterations in cellular energy homeostasis, ion homeostasis, intracellular signaling function, and neurotransmitter release, uptake, and storage. The greatest hurdle in cellular neurotoxicology has been the discovery of appropriate biomarkers that are reliable, reproducible, and easy to obtain. There are biomarkers of exposure effect, and susceptibility. Finding the appropriate biomarker for a particular toxin is a daunting task. The appropriate biomarker for a particular toxin is a daunting task. The advantage to biomarker/toxin combinations is they can be detected and measured shortly following exposure and before overt neuroanatomic damage or lesions. Intervention at this point, shortly following exposure, may prevent or at least attenuate further damage to the individual. The use of peripheral biomarkers to assess toxin damage in the CNS has numerous advantages: time-course analysis may be performed, ethical concerns with the use of human subjects can partially be avoided, procedures to acquire samples are less invasive, and in general, peripheral studies are easier to perform. Genetic neurotoxicology comprises two focuses--toxin-induced alterations in genetic expression and genetic alterations that affect toxin metabolism, distribution, and clearance. These differences can be beneficial or toxic. Polymorphisms have been shown to result in altered metabolism of certain toxins (paraoxonase and paraoxon). Conversely, it is possible that some polymorphisms may be beneficial and help prevent the formation of a toxic by-product of an exogenous agent (resistance to ozone-induced lung inflammation). It has also become clear that interactions of potential toxins are not straightforward as interactions with DNA, causing mutations. There are numerous agents that cause epigenetic responses (cellular alterations that are not mutagenic or cytotoxic). This finding suggests that many agents that may originally have been thought of as nontoxic should be re-examined for potential "indirect" toxicity. With the advancement of the human genome project and the development of a human genome map, the effects of potential toxins on single or multiple genes can be identified. Although collectively, the field of neurotoxicology has recently come a long way, it still has a long way to go reach its full potential. As technology and methodology advances continue and cooperation with other disciplines such as neuroscience, biochemistry, neurophysiology, and molecular biology is improved, the mechanisms of toxin action will be further elucidated. With this increased understanding will come improved clinical interventions to prevent neuronal damage following exposure to a toxin.

Animals↗
PubMedDate not supplied

Molecular genetic methods in the diagnosis of lower respiratory tract infections.

Molecular diagnostic techniques, such as PCR, have become useful tools for the rapid etiological diagnosis of lower respiratory tract infections. Nucleic acid amplification tests (NAATs) have been evaluated for detecting most respiratory pathogens, and commercial assays are available for some pathogens. However, standardized protocols are needed before these assays are introduced into routine diagnostic use. For pneumonia, NAATs offer advantages over conventional tests for the detection of Mycoplasma pneumoniae, Legionella spp. and Chlamydia pneumoniae. For pneumococcal pneumonia in adults, PCR adds little to existing diagnostic tests, and is unable to distinguish pneumococcal colonization from infection when testing respiratory samples. Although less sensitive than culture-based methods, several commercial molecular diagnostic assays have been developed for tuberculosis and are useful rapid tests for selected patients. PCR can now be considered the rapid diagnostic test of choice for pertussis and some respiratory virus infections. Further work is required to better characterize the role of molecular diagnostic tests for diagnosing lower respiratory tract infections, and to develop standard assays that can be readily adopted by routine diagnostic laboratories.

Bacterial Infections↗
PubMed1998

Genetic analysis of a mammalian wound-healing trait.

Wound healing of mammalian tissue is an essential process in the maintenance of body integrity. The general mechanism of wound healing usually studied in adult mammals is repair, in contrast to the regeneration seen in more primitive vertebrates. We recently have discovered that MRL/MpJ mice, unlike all other strains of mice tested, undergo rapid and complete wound closure that resembles regeneration. Specifically, through-and-through surgical ear hole wounds close without scarring in <4 weeks with normal gross and microanatomic architecture, including chondrogenesis. We also demonstrated that this healing is a heritable trait in inbred mice. In this study, we present results pertaining to its genetic control in progeny segregating for this phenotype. To identify the genetic loci that control the wound closure process, a genome-wide scan was performed on (MRL/MpJ-Faslpr x C57BL/6)F2 and backcross populations. In the primary screens of these populations, quantitative trait loci that control the extent of wound closure were detected on chromosomes 8, 12, and 15 and at two separate locations on chromosome 13. Evidence of further genetic control of healing was found on chromosome 7. All alleles that contribute to full wound closure are derived from the MRL/MpJ-Faslpr parent except for the quantitative trait locus on chromosome 8, which is derived from C57BL/6.

Alleles↗
PubMed2006

Evidence for overdominant selection maintaining X-linked fitness variation in Drosophila melanogaster.

The role of balancing selection in maintaining genetic variation for fitness is largely unresolved. This reflects the inherent difficulty in distinguishing between models of recurrent mutation versus selection, which produce similar patterns of inbreeding depression, as well as the limitations of testing such hypotheses when fitness variation is averaged across the genome. Signatures of X-linked overdominant selection are less likely to be obscured by mutational variation because X-linked mutations are rapidly eliminated by purifying selection in males. Although models maintaining genetic variation for fitness are not necessarily mutually exclusive, a series of predictions for identifying X-linked overdominant selection can be used to separate its contribution from other underlying processes. We consider the role of overdominant selection in maintaining fitness variation in a sample of 12 X chromosomes from a population of Drosophila melanogaster. Substantial variation was observed for male reproductive success and female fecundity, with heterozygous-X genotypes exhibiting the greatest degree of variance, a finding that agrees well with predictions of the overdominance model. The importance of X-linked overdominant selection is discussed along with models of recurrent mutation and sexually antagonistic selection.

Alleles↗
PubMed2000

Tests of the mouse visual system.

To apply the approach of forward genetics (e.g., gene identification with mutagenesis and screening, followed by positional cloning) to the mouse, it is necessary to have available screening tests that can be applied rapidly to individual mice and that give a reliable assessment of visual function. This paper reviews the strengths and limitations of two anatomical tests related to visual function, fundus examination and retinal histological examination. Two tests that do not depend on behavior of a conscious animal are reviewed: the electroretinogram and the visual evoked potentials of the cortex. Eight behavioral tests are also summarized: maze-based tests, cued fear conditioning, tests based on conditioned suppression, visual placing, optokinetic nystagmus, pupillary reflex, and light-induced shifts in circadian phase. It is recommended that retinal histology, the electroretinogram, and visual-evoked potentials be used at the present time for screening because they assess the function and structure of the visual system rapidly and reliably. In fact, the electroretinogram (or visually evoked potentials) can be recorded from several animals simultaneously in response to the same stimulus. It is also recommended that efforts be made to develop more appropriate, automated, behavioral tests of visual perception than are now available, particularly tests that rely solely on rewarding visually evoked behavior. Two other promising behavioral tests are cued fear conditioning and variants of maze tests.

Animals↗
PubMed1985

T-dependent production and activation of mononuclear phagocytes during murine BCG infection.

Mice infected with a high dose of viable Bacillus Calmette Guerin (BCG) intravenously offer an interesting model to study regulatory functions of T cells on hemopoiesis. The proposition that T lymphocytes may play such a regulatory role was tested in nu/nu and two genetically different strains of mice: while the hemopoiesis of C3H/He mice remained unchanged during BCG injection, that of infected C57BL/6 mice was rapidly and transiently modified towards increased production of phagocytes at the expense of the erythroid lineage. The number of BCG-specific T cells present in C57BL/6 bone marrow was 50-100 higher than that determined in C3H/He mice. Moreover, between day 0 and 5 of infection the majority of BCG-specific T cells in C57BL/6 animals were of the L3T4+ Lyt2- surface phenotype. An attempt was made to identify the nature of the T cell product(s) able to activate young bone marrow-derived macrophages to render them non-permissive to growth of BCG.

Animals↗
PubMed2004

Single-cell variability in growing Saccharomyces cerevisiae cell populations measured with automated flow cytometry.

Cell cultures normally are heterogeneous due to factors such as the cell cycle, inhomogeneous cell microenvironments, and genetic differences. However, distributions of cell properties usually are not taken into account in the characterization of a culture when only population averaged values are measured. In this study, the cell size, green fluorescence protein (Gfp) content, and viability after automated staining with propidium iodide (PI) are monitored at the single-cell level in Saccharomyces cerevisiae cultures growing in a batch bioreactor using an automated flow injection flow cytometer system. To demonstrate the wealth of information that can be obtained with this system, three cultures containing three different plasmids are compared. The first plasmid is a centromeric plasmid expressing under the control of a TEF2 promoter the S65T mutant form of Gfp. The other two plasmids are 2 microm plasmids and express the FM2 mutant of Gfp under the control of either the TEF1 or the TEF2 promoter. The automated sampling, cell preparation, and analysis permitted frequent quantification of the culture characteristics. The time course of the data representing not only population average values but also their variability, provides a detailed and reproducible "fingerprint" of the culture dynamics. The data demonstrate that small changes in the genetic make up of the recombinant system can result in large changes in the culture Gfp production and viability. Thus, the developed instrumentation is valuable for rapidly testing promoter strength, plasmid stability, cell viability, and culture variability.

Bioreactors↗
PubMed2000

T-maze behaviour in broiler chicks is not sensitive to right-left preferences, test order or time-of-day.

There is substantial individual variation in the time taken by broiler chicks to traverse a T-maze and thereby reinstate visual contact with their companions. Chicks completing this task quickly (high performance, HP) subsequently grew faster in the laboratory and on farm, exhibited greater sociality, and showed less pronounced adrenocortical responses to a partial water immersion stressor than did their slower (low performance, LP) counterparts [Marin, R.H., Jones, R.B., 1999. Latency to traverse a T-maze at 2 days of age and later adrenocortical responses to an acute stressor in domestic chicks. Physiol. Behav. 66, 809-813.; Marin, R.H., Arce, A., Martijena, I.D., 1997. T-maze performance and body weight relationship in broiler chicks. Appl. Anim. Behav. Sci. 54, 197-205.; Jones, R.B., Marín, R.H., García, D.A., Arce, A., 1999. T-maze behaviour in domestic chicks: a search for underlying variables. Anim. Behav. 58, 211-217.]. Given its simplicity, rapidity and non-invasiveness, the T-maze test might represent a commercially attractive selection criterion for future breeding programmes if this behavioural trait exhibits sufficient genetic variability. However, it is first necessary to ensure that performance in the T-maze is not sensitive to potentially confounding variables, such as existing preferences to turn right or left at the junction of the maze, the order of testing, or the time of day. In the present study, 240 newly hatched, mixed-sex broiler chicks (Cobb) were randomly allocated to 12 groups of 20 upon receipt. When they were 2 days of age a group of 20 chicks was placed in the brood area of each of two T-mazes at 0830 h; the brood areas were positioned on either the right or the left sides of the mazes. After acclimatisation, one chick from each group was placed in the isolation chamber of the T-maze and we recorded the time it took to traverse the maze. This procedure was repeated until all 20 chicks and all 12 groups had been tested. The locations of the brood areas were rotated after each block of 20 tests. Testing was completed in the same day and two groups were tested at each of the following times: 0900, 1030, 1200, 1330. 1500, and 1630 h. Analyses of variance (ANOVA) revealed no detectable effects of: positioning the brood area on the right or the left side of the T-maze (F(1,200)=0.06, P<0.80), test order (F(19,200)=0.48; P<0.96), or time-of-day (F(5,234)=0.44; P<0.81). These findings strongly suggest that the future classification and possible selection of broiler chicks according to their T-maze responses are unlikely to be confounded by right-left preferences, test order, or the time of day.

Journal Article↗
PubMed2003

Rheb promotes cell growth as a component of the insulin/TOR signalling network.

Insulin signalling is a potent stimulator of cell growth and has been proposed to function, at least in part, through the conserved protein kinase TOR (target of rapamycin) [corrected]. Recent studies suggest that the tuberous sclerosis complex Tsc1-Tsc2 may couple insulin signalling to Tor activity [corrected]. However, the regulatory mechanism involved remains unclear, and additional components are most probably involved. In a screen for novel regulators of growth, we identified Rheb (Ras homologue enriched in brain), a member of the Ras superfamily of GTP-binding proteins. Increased levels of Rheb in Drosophila melanogaster promote cell growth and alter cell cycle kinetics in multiple tissues. In mitotic tissues, overexpression of Rheb accelerates passage through G1-S phase without affecting rates of cell division, whereas in endoreplicating tissues, Rheb increases DNA ploidy. Mutation of Rheb suspends larval growth and prevents progression from first to second instar. Genetic and biochemical tests indicate that Rheb functions in the insulin signalling pathway downstream of Tsc1-Tsc2 and upstream of TOR. Levels of rheb mRNA are rapidly induced in response to protein starvation, and overexpressed Rheb can drive cell growth in starved animals, suggesting a role for Rheb in the nutritional control of cell growth.

Animals↗
PubMed1996

Genetic diversity of Neisseria gonorrhoeae IB-2 and IB-6 isolates revealed by whole-cell repetitive element sequence-based PCR.

Phenotypic characterization of 19 Neisseria gonorrhoeae serovar IB-2 and 8 serovar IB-6 isolates by the combined use of auxotypes, serological characterization, and penicillin susceptibility testing indicated intraserovar genetic diversity. In the present study, we applied whole-cell repetitive element sequence-based PCR (rep-PCR) analysis which allows a rapid assessment of the clonal relationships of IB-2 and IB-6 isolates. DNA templates were prepared by boiling cells harvested directly from plate cultures, eliminating the need for time-consuming phenol extraction. Six different rep-PCR profiles were established among the 19 IB-2 isolates. Rep-PCR typing results had a good correlation with pulsed-field gel electrophoresis patterns. It is slightly less discriminatory than BglII-generated macrorestriction pattern analysis by pulsed-field gel electrophoresis. It is capable of discriminating epidemiologically related from epidemiologically unrelated IB-2 isolates. It should serve as a rapid and useful subtyping tool for epidemiologic investigations in which there is a predominance of major serovar groups.

Bacterial Typing Techniques↗
PubMed1995

Geographical structuring in the mtDNA of Italians.

Geographical patterns of mtDNA variation were studied in 12 Italian samples (1072 individuals) by two different spatial autocorrelation methods. Separate analyses of the frequencies of 12 restriction morphs show North-South clines, differences between Sardinia and the mainland populations, and the effects of isolation by distance. A recently developed autocorrelation statistic summarizing molecular similarity at all sites (AIDA; autocorrelation index for DNA analysis) confirms the presence of a clinical pattern; differences between random pairs of haplotypes tend to increase with their geographical distance. The partition of gene diversity, however, reveals that most variability occurs within populations, whereas differences between populations are minor (GST = 0.057). When the data from the 12 samples are pooled, two descriptors of genetic variability (number of polymorphic sites and average sequence difference between pairs of individuals) do not behave as expected under neutrality. The presence of clinal patterns, Tajima's tests, and a simulation experiment agree in suggesting that population sizes increased rapidly in Italy and Sicily but not necessarily so in Sardinia. The distribution of pairwise sequence differences in the Italian peninsula (excluding Sardinia) permits a tentative location of the demographic increase between 8000 and 20,500 years ago. These dates are consistent with archaeological estimates of two distinct expansion processes, occurring, respectively, in the Neolithic and after the last glacial maximum in the Paleolithic. Conversely, there is no genetic evidence that such processes have had a major impact on the Sardinian population.

Biological Evolution↗