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PubMed1995

Characterization of Hafnia alvei by biochemical tests, random amplified polymorphic DNA PCR, and partial sequencing of 16S rRNA gene.

Hafnia alvei strains which possess the attachment-effacement gene (eaeA) may have clinical importance as new diarrhea-causing pathogens and should therefore be differentiated from other H. alvei strains. We characterized diarrheal H. alvei strains, which were positive in the PCR test for the eaeA gene, using biochemical tests not routinely used for identification of members of the family Enterobacteriaceae, and compared them with eaeA-negative strains isolated from different clinical and nonclinical sources to find characteristics useful for identification. Random amplified polymorphic DNA (RAPD)-PCR and partial sequencing of the 16S rRNA gene were utilized to study the genetic diversity of the isolates. The eaeA-positive strains were found to have many characteristic biochemical properties. Negative reactions in the 2-ketogluconate and histidine assimilation tests and a positive reaction in the 3-hydroxybenzoate assimilation test may be useful in routine diagnostics. Nearly identical RAPD-PCR profiles and identical 353-bp fragments of the 16S rRNA genes indicated little genetic diversity among the eaeA-positive strains. The low level of homology (92%) in the partial 16S rRNA genes of eaeA-positive and -negative H. alvei strains raises questions about the taxonomic positioning of eaeA-positive H. alvei.

Base Sequence↗
PubMed1998

Bacterial complementation as a means to test enzyme-ligand interactions.

A bacterial complementation assay has been developed for the rapid screening of a large number of compounds to identify those that inhibit an enzyme target for structure-based inhibitor design. The target enzyme is the hypoxanthine phosphoribosyltransferase (HPRT). This enzyme has been proposed as a potential target for inhibitors that may be developed into drugs for the treatment of diseases caused by several parasites. The screening assay utilizes genetically deficient bacteria complemented by active, recombinant enzyme grown in selective medium in microtiter plates. By comparing absorbance measurements of bacteria grown in the presence and absence of test compounds, the effect of the compounds on bacterial growth can be rapidly assayed. IC50 values for inhibition of bacterial growth are a reflection of the ability of the compounds to bind and/or inhibit the recombinant enzyme. We have tested this bacterial complementation screening assay using recombinant HPRT from the parasites. Plasmodium falciparum and Trypanosoma cruzi, as well as the human enzyme. The results of these studies demonstrate that a screening assay using bacterial complement selection can be used to identify compounds that target enzymes and can become an important part of structure-based drug design efforts.

Animals↗
PubMed2003

Predictive, pre-natal and diagnostic genetic testing for Huntington's disease: the experience in Canada from 1987 to 2000.

Predictive and pre-natal testing for Huntington's Disease (HD) has been available since 1987. Initially this was offered by linkage analysis, which was surpassed by the advent of the direct mutation test for HD in 1993. Direct mutation analysis provided an accurate test that not only enhanced predictive and pre-natal testing, but also permitted the diagnostic testing of symptomatic individuals. The objective of this study was to investigate the uptake, utilization, and outcome of predictive, pre-natal and diagnostic testing in Canada from 1987 to April 1, 2000. A retrospective design was used; all Canadian medical genetics centres and their affiliated laboratories offering genetic testing for HD were invited to participate. A total of 15 of 22 centres (68.2%), currently offering or ever having offered genetic testing for HD, responded, providing data on test results, demographics, and clinical history. A total of 1061 predictive tests, 15 pre-natal tests, and 626 diagnostic tests were performed. The uptake for predictive testing was approximately 18% of the estimated at-risk Canadian population, ranging from 12.5% in the Maritimes to 20.7% in British Columbia. There appears to have been a decline in the rate of testing in recent years. Of the predictive tests, 45.0% of individuals were found to have an increased risk, and a preponderance of females (60.2%) sought testing. A greater proportion of those at < or = 25% risk sought predictive testing once direct CAG mutation analysis had become available (10.9% after mutation analysis vs 4.7% before mutation analysis, p = 0.0077). Very few pre-natal tests were requested. Of the 15 pre-natal tests, 12 had an increased risk, resulting in termination of pregnancy in all but one. Diagnostic testing identified 68.5% of individuals to be positive by mutation analysis, while 31.5% of those with HD-like symptoms were not found to have the HD mutation. The positive diagnostic tests included 24.5% of individuals with no known prior family history of HD.

Adolescent↗
PubMed2025

In vivo expansion of gene-targeted hepatocytes through transient inhibition of an essential gene.

Homology-directed repair (HDR)-based genome editing is an approach that could permanently correct a broad range of genetic diseases. However, its utility is limited by inefficient and imprecise DNA repair mechanisms in terminally differentiated tissues. Here, we tested Repair Drive, a platform technology for selectively expanding HDR-corrected hepatocytes in adult mice in vivo. Repair Drive involves transient conditioning of the liver by knocking down an essential gene, fumarylacetoacetate hydrolase (Fah), and delivering an untargetable version of the essential gene in cis with a therapeutic transgene. We show that Repair Drive increased the percentage of correctly targeted hepatocytes in healthy wild-type mice up to 25%, which resulted in a fivefold increased expression of a therapeutic transgene, human factor IX (FIX). Repair Drive was well tolerated and did not induce toxicity or tumorigenesis during a 1-year follow-up. This approach may broaden the range of liver diseases that can be treated with somatic genome editing.

Animals↗
PubMed2006

Hypersomnias of central origin.

Hypersomnia related to CNS disorders can be due to a variety of conditions. In this review, we discuss the diagnosis and treatment of narcolepsy with and without cataplexy, idiopathic hypersomnia, recurrent hypersomnia, and related illnesses. Research has provided insight into the underlying etiologies of these disorders, such as the genetic influences on disease development and the fundamental role of hypocretins in narcolepsy. We define the current utility of diagnostic testing, including sleep studies, neuroimaging techniques, and laboratory investigations. New treatment options for hypersomnia are discussed.

Central Nervous System↗
PubMed1999

[Genetic examination in clinical laboratory].

Genetic technology is finding active application today in the field of clinical laboratory medicine. Genetic examinations are divided into following three main classes: 1) examination for infectious disease according to the detection of the gene derived from bacteria or viruses, 2) examination for inherited disease according to molecular analysis of the genetic variation, 3) examination for oncogene according to molecular analysis of genetic abnormalities. At present, the main genetic examination in a large number of laboratories is for infectious disease because of its relatively simplified technique and high demand. The division of genetics is not a new independent section of clinical laboratory, but rather an ultramodern and powerful tool for existing divisions, such as biochemistry, serology, hematology, microbiology, and pathology. Genetic technology quickly provides results with high sensitivity and reliability, and plays a role at the core of the clinical laboratory. We should remember that the genetic technology is a great present given to clinical laboratories, however, it will eventually change into only one of the routine examinations according to the method of used. Examinations utilized in the clinical laboratory must be well established and standardized. Genetic examinations are no exception to that rule. These tests require a remarkably high precision since the results have an extraordinarily important meaning. There are more than 8,000 inherited diseases for instance. It is difficult to cover all examinations for those 8,000 in one laboratory. We need a network of laboratories that possess a genetic division, so that the examinations for as many inherited disease as possible can be comprehensively offered.

Clinical Laboratory Techniques↗
PubMed1996

Protein phylogenetic inference using maximum likelihood with a genetic algorithm.

This paper presents a method to construct phylogenetic trees from amino acid sequences. Our method uses a maximum likelihood approach which gives a confidence score for each possible alternative tree. Based on this approach, we developed a genetic algorithm for exploring the best score tree: randomly generated alternative trees are rearranged so that their scores are improved by utilizing crossover and mutation operators. In a test of our algorithm on a data set of EF-1 alpha sequences, we found that the performance of our algorithm is comparable to that of other tree-construction methods.

Algorithms↗
PubMed2026

Pharmacogenomic and drug interactions risk in cardio-oncology: A precision medicine perspective for India.

Cardio-oncology patients may face complex treatment regimens due to the concurrent existence of cancer and cardiovascular disease, leading to a considerable polypharmacy burden. This significantly increases the prospect of drug-drug interactions (DDIs) and gene-drug interactions. The majority of these interactions arise from comparable pharmacokinetic and pharmacological pathways associated with drug transporters and cytochrome P450 enzymes. The significance of pharmacogenomics in tailored treatment strategies are emphasised by the fact that genetic variability enhances individual differences in drug response, safety, and efficacy. This narrative review focus on the effects of key genetic polymorphisms (e.g., DPYD, CYP2C19, and CYP2C9) on the metabolism and efficacy of commonly prescribed anticancer and cardiovascular medications such as fluoropyrimidines, clopidogrel, and warfarin. In addition it explore the role of pharmacogenomic variants on drug-drug interactions within the field of cardio-oncology. The study ultimately emphasizes the necessity of precision medicine in India to address the genetic diversity and underrepresentation in global genomic databases. The absence of pharmacogenomic testing, infrastructural deficiencies, financial constraints, and insufficient clinical integration hinder the widespread use of this technology in India. The Genome India Project and other national initiatives establish the foundation for pharmacogenomic-guided therapy. Utilizing genetic data, together with artificial intelligence-based predictive tools, for clinical decision-making may enhance medication safety and yield optimal outcomes in Indian cardio-oncology patients.

Humans↗
PubMed2002

A critical assessment of interleukin-1 (IL-1) genotyping when used in a genetic susceptibility test for severe chronic periodontitis.

BACKGROUND: This review addresses the ability of a commercially available genetic susceptibility test to determine the risk of developing severe chronic periodontitis. The test is used to detect the simultaneous occurrence of allele 2 at the IL-1A+4845 and IL-1B+3954 loci. If both of these polymorphisms are present, patients are referred to as being genotype-positive and considered predisposed to becoming afflicted with severe chronic periodontitis. A basic premise of this test is the assumption that individuals who are genotype-positive produce increased amounts of IL-beta in response to microbial lipopolysaccharides, which allegedly predisposes them to an exaggerated inflammatory response and an increased incidence of chronic periodontitis. METHODS: Controlled clinical trials were selected that evaluated the ability of the genetic test to predict which patients were susceptible to bleeding upon probing, periodontitis, peri-implantitis, and tooth loss. RESULTS: Comparison of results from test (genotype-positive) and control groups (genotype-negative) revealed that there is ambiguity with regard to predicting which patients will manifest elevated sub-gingival levels of IL-beta. Similarly, it is questionable if the test is able to forecast which individuals will demonstrate an increased occurrence of bleeding upon probing, diminished clinical attachment, decreased osseous support, or loss of teeth. CONCLUSIONS: There are many unanswered questions concerning the utility of detecting allele 2 at the IL-1A+4845 and IL-IB+3954 loci to foretell which patients will develop severe chronic periodontitis. Therefore, clinicians must cautiously interpret results obtained with the commercially available genetic susceptibility test before they alter maintenance schedules or treatment regimens of symptomatic or asymptomatic patients.

Alleles↗
PubMed1993

Molecular screening. Prospects for a new approach.

Tumors arise through a series of genetic steps that involve alterations of various cellular genes. The recent revolution in molecular genetic techniques has allowed direct identification of genetic changes within tumors. Because these changes are intimately involved in tumor progression, they are specific markers for cancer. A novel assay based on the polymerase chain reaction allows detection of a rare cancer cell containing a specific point mutation among an excess background of normal cells. This technique has allowed identification of p53 gene mutations in pathologic tissue samples from primary head and neck cancer. A small population of cancer cells has been detected in a variety of histologically negative clinical specimens, including saliva, surgical margins, lymph nodes, and chyle. The precise detection of these rare cancer cells in various clinical samples has significant implications for otolaryngology-head and neck surgery. This approach holds promise for screening of head and neck cancer and may call for the reassessment of current histopathologic staging through utilization of new molecular genetic techniques.

Genes, p53↗
PubMed2002

Age-age and trait-trait correlations for Eucalyptus grandis Hill ex Maiden and their implications for optimal selection age and design of clonal trials.

Previous results from seven locations of Eucalyptus grandis clonal trials in Colombia supported the a priori contention of sub-dividing them into three different environmental zones for testing and deployment. Within these zones, the determination of age-age genetic correlations for both height and mean annual increment (MAI) showed that strong age-age correlations are present for a rotation age of 6 years starting at 3 years age and, thereafter, suggesting this age as appropriate for selection. This biological selection age coincides with an "economical" age for selection based on discounted selection efficiency in perpetuity, considering a range of interest rates between 10% and 20%. High genetic correlations between wood density at 3 years and 6 years as well as the lack of genetic correlation between this trait and growth traits, also favors selection at age 3 and facilitates breeding strategies that consider the utilization of both traits for improvement. A simulation of optimal clonal test designs indicated that by using six locations and six blocks per location in a single-tree plot design, between 80% and 90% of the maximum selection efficiency could be obtained. This type of design allows testing of a large number of genotypes across a reasonable number of locations in a cost-effective manner.

Chromosome Mapping↗
PubMed2004

In search of a depressed mouse: utility of models for studying depression-related behavior in genetically modified mice.

The ability to modify mice genetically has been one of the major breakthroughs in modern medical science affecting every discipline including psychiatry. It is hoped that the application of such technologies will result in the identification of novel targets for the treatment of diseases such as depression and to gain a better understanding of the molecular pathophysiological mechanisms that are regulated by current clinically effective antidepressant medications. The advent of these tools has resulted in the need to adopt, refine and develop mouse-specific models for analyses of depression-like behavior or behavioral patterns modulated by antidepressants. In this review, we will focus on the utility of current models (eg forced swim test, tail suspension test, olfactory bulbectomy, learned helplessness, chronic mild stress, drug-withdrawal-induced anhedonia) and research strategies aimed at investigating novel targets relevant to depression in the mouse. We will focus on key questions that are considered relevant for examining the utility of such models. Further, we describe other avenues of research that may give clues as to whether indeed a genetically modified animal has alterations relevant to clinical depression. We suggest that it is prudent and most appropriate to use convergent tests that draw on different antidepressant-related endophenotypes, and complimentary physiological analyses in order to provide a program of information concerning whether a given phenotype is functionally relevant to depression-related pathology.

Animals↗
PubMed2004

Preimplantation genetic diagnosis of human congenital heart malformation and Holt-Oram syndrome.

Holt-Oram syndrome (HOS) is a multiple malformation syndrome associated with congenital heart malformation (CHM) and caused by mutations in the TBX5 transcription factor. Effective prenatal genetic diagnosis of HOS is limited by factors that modify clinical manifestations and confound prediction of an individual's phenotype. Although preimplantation genetic diagnosis (PGD) has been applied to complex disorders with some cardiovascular manifestations, its utility in Mendelian CHM has not been previously demonstrated. We tested whether PGD and in vitro fertilization (IVF) technology, including oocyte donation, can identify fertilized eggs affected by HOS for potential embryo selection. Five donor oocytes were fertilized in vitro with sperm from a HOS patient heterozygous for a Glu69ter-TBX5 mutation and then underwent embryo biopsy and genotyping. One carried the Glu69ter-TBX5 mutation; all others had wildtype genotypes. Two wildtype blastocysts were transferred to the mother, and the resulting singleton pregnancy was successfully delivered. Mutational analysis of fetal amniocytes and postpartum umbilical cord blood confirmed PGD. Fetal ultrasonography as well as postpartum electrocardiography and echocardiography also validated accurate prediction of normal skeletal and cardiac phenotypes. We conclude that PGD is an effective reproductive strategy for HOS patients. As more genetic etiologies for CHM are identified, application of PGD as adjunctive therapy to IVF will be increasingly available to prevent transmission of such diseases from affected parents to their children. Clinical application of PGD must balance the benefits of avoiding disease transmission with the medical risks and financial burdens of IVF.

Adult↗
PubMed1996

Multilocus genetic determinants of LDL particle size in coronary artery disease families.

Recent interest in atherosclerosis has focused on the genetic determinants of low-density lipoprotein (LDL) particle size, because of (i) the association of small dense LDL particles with a three-fold increased risk for coronary artery disease (CAD) and (ii) the recent report of linkage of the trait to the LDL receptor (chromosome 19). By utilizing nonparametric quantitative sib-pair and relative-pair analysis methods in CAD families, we tested for linkage of a gene or genes controlling LDL particle sizes with the genetic loci for the major apolipoproteins and enzymes participating in lipoprotein metabolism. We confirmed evidence for linkage to the LDL receptor locus (P=.008). For six candidate gene loci, including apolipoprotein(apo)B, apoAII, apo(a), apoE-CI-CII, lipoprotein lipase, and high-density lipoprotein-binding protein, no evidence for linkage was observed by sib-pair linkage analyses (P values ranged from .24 to .81). However, in addition, we did find tentative evidence for linkage with the apoAI-CIII-AIV locus (chromosome 11) (P=.06) and significant evidence for linkage of the cholesteryl ester transfer protein locus (chromosome 16) (P=.01) and the manganese superoxide dismutase locus (chromosome 6) (P=.001), thus indicating multilocus determination of this atherogenic trait.

Adolescent↗
PubMed1989

Meaning of biodistance statistics: a test case using adult monozygotic twins.

Anthropometry, historically one of the primary research techniques in physical anthropology, has been widely utilized in biodistance studies. The complex genetic and environmental interaction that governs the expression of anthropometric dimensions, together with concerns over measurement error, have sometimes clouded the interpretation of biodistances based upon anthropometry. In this study, 51 pairs of adult monozygotic twins were analysed using discriminant analysis and Mahalanobis' generalized distance. Both male and female twins, grouped by first- versus second-born, displayed very small, statistically insignificant distances between groups. When literature estimates of intra-observer measurement errors were used as a frame of reference, the average absolute differences between the twin pairs were approximately twice the size of the measurement error estimates. The results of this study suggest that, first, the environmental effect upon the genetically influenced traits measured by anthropometry is not large enough to bring about significant multivariate differences between identical twin pairs; and, second, biodistance studies based upon anthropometry can be reliable so long as measurement error is minimized.

Adult↗