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PubMedDate not supplied

Predictions for rapid methods and automation in food microbiology.

A discussion is presented on the present status of rapid methods and automation in microbiology. Predictions are also presented for development in the following areas: viable cell counts; real-time monitoring of hygiene; polymerase chain reaction, ribotyping, and genetic tests in food laboratories; automated enzyme-linked immunosorbent assay and immunotests; rapid dipstick technology; biosensors for Hazard Analysis Critical Control Point programs; instant detection of target pathogens by computer-generated matrix; effective separation and concentration for rapid identification of target cells; microbiological alert systems in food packages; and rapid alert kits for detecting pathogens at home.

Automation↗
PubMed2007

Whole blood RNA offers a rapid, comprehensive approach to genetic diagnosis of cardiovascular diseases.

PURPOSE: Long QT Syndrome, Marfan Syndrome, hypertrophic and dilated cardiomyopathy are caused by mutations in large, multi-exon genes that are principally expressed in cardiovascular tissues. Genetic testing for these disorders is labor-intensive and expensive. We sought to develop a more rapid, comprehensive, and cost-effective approach. METHODS: Paired whole blood samples were collected into tubes with or without an RNA-preserving solution, and harvested for whole blood RNA or leukocyte DNA, respectively. Large overlapping cDNA fragments from KCNQ1 and KCNH2 (Long QT Syndrome), MYBPC3 (hypertrophic and dilated cardiomyopathy), or FBN1 (Marfan Syndrome) were amplified from RNA and directly sequenced. Variants were confirmed in leukocyte DNA. RESULTS: All 4 transcripts were amplified and sequenced from whole blood mRNA. Six known and 2 novel mutations were first identified from RNA of 10 probands, and later confirmed in genomic DNA, at considerable savings in time and cost. In one patient with MFS, RNA sequencing directly identified a splicing mutation. Results from RNA and DNA were concordant for single nucleotide polymorphisms at the same loci. CONCLUSION: Taking advantage of new whole blood RNA stabilization methods, we have designed a cost-effective, comprehensive method for mutation detection that should significantly facilitate clinical genetic testing in four lethal cardiovascular disorders.

Adolescent↗
PubMed1997

Genetic testing, life insurance, and adverse selection.

Life insurance is a key element of the UK social structure in terms of family protection and house purchase; it thus needs to be viewed in this broad context, rather than solely as a commercial activity. Insurers have not so far actively requested genetic tests for life insurance, but have insisted on knowing of and being able to act on existing genetic test information. The main reason given for this has been to avoid serious adverse selection; however, this has never been adequately estimated. Review of the different major categories of Mendelian genetic disorders suggests that the scope for adverse selection is extremely limited and that insurers would lose little, and possibly gain more, by foregoing the disclosure and use of this information in relation to life insurance policies of 'normal' size and nature. The likely future use in service of genetic tests based on susceptibility or population screening makes it especially important that the issue is rapidly resolved for Mendelian disorders; so far there is no sign that insurers are willing to achieve this.

Eligibility Determination↗
PubMed1998

Simultaneous estimation of all the parameters of a stepwise mutation model.

Minisatellite and microsatellite are short tandemly repetitive sequences dispersed in eukaryotic genomes, many of which are highly polymorphic due to copy number variation of the repeats. Because mutation changes copy numbers of the repeat sequences in a generalized stepwise fashion, stepwise mutation models are widely used for studying the dynamics of these loci. We propose a minimum chi-square (MCS) method for simultaneous estimation of all the parameters in a stepwise mutation model and the ancestral allelic type of a sample. The MCS estimator requires knowing the mean number of alleles of a certain size in a sample, which can be estimated using Monte Carlo samples generated by a coalescent algorithm. The method is applied to samples of seven (CA)n repeat loci from eight human populations and one chimpanzee population. The estimated values of parameters suggest that there is a general tendency for microsatellite alleles to expand in size, because (1) each mutation has a slight tendency to cause size increase and (2) the mean size increase is larger than the mean size decrease for a mutation. Our estimates also suggest that most of these CA-repeat loci evolve according to multistep mutation models rather than single-step mutation models. We also introduced several quantities for measuring the quality of the estimation of ancestral allelic type, and it appears that the majority of the estimated ancestral allelic types are reasonably accurate. Implications of our analysis and potential extensions of the method are discussed. SINCE the discovery that a large number of loci with tandemly repeated sequences in human and many eukaryote species are highly polymorphic because of copy number variation of the repeats in different individuals (Jeffreys 1985; Litt and Luty 1989; Weber and May 1989), allele size data from such loci are rapidly becoming the dominant source of genetic markers for genome mapping, forensic testing, and population studies. Loci with repeat sequences longer than 5 bp are generally referred to as minisatellite or variable number tandem repeat loci, and those with repeat sequences between 2 to 5 bp are referred to as microsatellite or short tandem repeat loci (Tautz 1993). Because mutations change the copy number of such loci in a stepwise fashion, rapid accumulation of population samples from minisatellite and microsatellite loci has resurrected the interest of the stepwise mutation model (SMM), which was popular in the 1970s.

Chi-Square Distribution↗
PubMed1993

Protein truncation test (PTT) for rapid detection of translation-terminating mutations.

Currently available techniques used to recognize point mutations in genetic disease are time consuming and are capable of screening only small pieces of DNA. Moreover, they detect all sequence differences including phenotypically silent changes. Consequently, they are not convenient to analyse mutations in large, multi-exonic genes, where a large fraction of pathological point mutations arises from early termination, as is the case for the one third non-deletion/duplication cases of Duchenne Muscular Dystrophy. We have developed a rapid and sensitive method, the Protein Truncation Test (PTT). PTT is based on a combination of RT-PCR, transcription and translation and selectively detects translation-terminating mutations. We demonstrate its effectiveness to detect point mutations in DMD-patients and carrier females. PTT should be widely applicable diagnostically in any disease where early terminations contribute substantially to the disease cause.

Base Sequence↗
PubMed1998

Neurogenetics in developmental and behavioral pediatrics: advances in molecular diagnosis.

The discovery and characterization of thousands of genes involved in human disorders has the potential for great benefit in patient diagnosis and treatment. A combined approach using molecular genetic testing for some disorders as an adjunct to the clinical evaluation of children with developmental or behavioral features is rapidly occupying a more prominent role in the diagnostic evaluation. In some instances, molecular testing might confirm a genetic etiology in a child initially referred with a DSM-IV diagnosis, but molecular testing might be of limited use in other instances. This review presents advances in the diagnosis of inherited disorders affecting the pediatric population, with an emphasis on those with a developmental/behavioral component. We examine several relatively common disorders in detail (and less common disorders in a more cursory fashion) to elucidate the strengths and weaknesses of molecular diagnosis in clinical practice.

Child↗
PubMed2007

Multiple system atrophy in a patient with the spinocerebellar ataxia 3 gene mutation.

The cerebellar variant of multiple system atrophy (MSA-C) has overlapping clinical features with the hereditary spinocerebellar ataxias (SCAs), but can usually be distinguished on a clinical basis. We describe a patient who developed a sporadic, late-onset, rapidly progressive neurodegenerative disorder consistent with MSA-C. Genetic testing, however, showed an abnormal expansion of one allele of the spinocerebellar ataxia 3 (SCA3) gene. The clinical impression of MSA-C was confirmed by identification of numerous alpha-synuclein-containing glial cytoplasmic inclusions on autopsy. These findings suggest that abnormal expansion of the SCA3 gene may be a risk factor for the development of MSA-C.

Alleles↗
PubMed2005

Thymidine phosphorylase gene mutations in patients with mitochondrial neurogastrointestinal encephalomyopathy syndrome.

The mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome is characterized by the association of gastrointestinal and neurological symptoms. It is a rare autosomal recessive mitochondrial disorder with multiple mitochondrial DNA deletions and/or depletion. It is caused by thymidine phosphorylase (TP) gene mutations resulting in a complete abolition of TP activity. We tested 31 unrelated patients presenting either with a complete MNGIE syndrome (8 patients), a severe intestinal pseudo-obstruction (10 patients), and multiple deletions and/or depletion of mitochondrial DNA (13 patients). All the tested patients presenting with a complete MNGIE had increased thymidine levels in plasma and urine, and no TP activity. The group with pseudo-obstruction syndrome had normal or partial reduction of TP activity. We found pathogenic mutations on TP gene only in the MNGIE syndrome group: all the MNGIE patients were compound heterozygous or homozygous for mutations in the TP gene. Eight of these mutations are yet unreported, confirming the lack of genotype/phenotype correlation in this syndrome. Enzymatic activity and thymidine level are thus rapid diagnosis tests to detect MNGIE affected patients prior to genetic testing for patients with gastrointestinal symptoms.

Adult↗
PubMed2002

DNA probes on beads arrayed in a capillary, 'Bead-array', exhibited high hybridization performance.

A DNA analysis platform called 'Bead-array' is presented and its features when used in hybridization detection are shown. In 'Bead-array', beads of 100- micro m diameter are lined in a determined order in a capillary. Each bead is conjugated with DNA probes, and can be identified by its order in the capillary. This probe array is easily produced by just arraying beads conjugated with probes into the capillary in a fixed order. The hybridization is also easily completed by introducing samples (1-300 micro l) into the capillary with reciprocal flow. For hybridization detection, as little as 1 amol of fluorescent-labeled oligo DNA was detected. The hybridization reaction was completed in 1 min irrespective of the amount of target DNA. When the number of target molecules was smaller than that of probe molecules on the bead, 10 fmol, almost all targets were captured on the bead. 'Bead-array' enables reliable and reproducible measurement of the target quantity. This rapid and sensitive platform seems very promising for various genetic testing tasks.

Base Sequence↗
PubMed2005

A combined approach exploring gene function based on worm-human orthology.

BACKGROUND: Many aspects of the nematode Caenorhabditis elegans biology are conserved between invertebrates and vertebrates establishing this particular organism as an excellent genetic model. Because of its small size, large populations and self-fertilization of the hermaphrodite, functional predictions carried out by genetic modifications as well as RNAi screens, can be rapidly tested. RESULTS: In order to explore the function of a set of C. elegans genes of unknown function, as well as their potential functional roles in the human genome, we performed a phylogenetic analysis to select the most probable worm orthologs. A total of 13 C. elegans genes were subjected to down-regulation via RNAi and characterization of expression profiles using GFP strains. Previously unknown distinct expression patterns were observed for four of the analyzed genes, as well as four visible RNAi phenotypes. In addition, subcellular protein over-expression profiles of the human orthologs for seven out of the thirteen genes using human cells were also analyzed. CONCLUSION: By combining a whole-organism approach using C. elegans with complementary experimental work done on human cell lines, this analysis extends currently available information on the selected set of genes.

Animals↗
PubMedDate not supplied

New interest in an old disease: familial Mediterranean fever.

Familial Mediterranean fever (FMF) is characterized by recurrent attacks of fever and serositis. Identifying the mutated gene has shed light on the pathogenesis of the disease. Typical attacks of FMF last 3 to 5 days. Arthritis is present in almost half of all patients and is localized to the ankle, knee or hip. Recently vasculitic features have been increasingly reported in FMF patients, and it may be speculated that vasculitis constitutes a feature of this disease. Genetic analysis is very important to confirm the diagnosis in patients with a European ancestry. However, at present the yield of genetic testing is not satisfactory; new sequencing techniques permitting more rapid screening and definition of all mutations are necessary. Colchicine is the drug of choice. A trial of colchicine may also help in the differential diagnosis with other periodic fever syndromes.

Colchicine↗
PubMed1990

A LDL receptor gene homozygous mutation: PCR amplification, direct genomic sequencing, associated haplotype, rapid screening for frequency.

Many mutations in the LDL receptor (LDLR) gene have now been identified mostly as gross gene rearrangements, however they only represent a weak percentage of all deleterious gene mutations causing Familial Hypercholesterolemia (FH). This discrepancy may be related to the difficulties in characterizing point or small defective mutations. In a three-generation family with Familial Hypercholesterolemia, one specific haplotype constructed with 12 intragenic restriction fragment length polymorphisms (RFLP) cosegregated with the disease, while in the consanguineous propositus there was homozygosity for this haplotype. By polymerase chain reaction (PCR) amplification followed by direct sequencing there was unequivocal evidence for a double dose of a unique mutation, (namely a duplication of 4 bases in exon 17), while there was a single dose in heterozygote relatives. We consequently screened a population selected under clinical and geographical criteria for this mutation by PCR and allele specific oligonucleotides (ASO) hybridization. None of the 158 type IIa individuals tested carried the same mutation. Herein, is a rapid combined genetic and molecular approach to characterize and evaluate the frequency of LDL Receptor gene mutations causing Familial Hypercholesterolemia, towards targeted prevention and therapy.

Alleles↗
PubMed1998

Pilot study on patients' and spouses' attitudes toward potential genetic testing for bipolar disorder.

OBJECTIVE: The purpose of this pilot study was to gain information about attitudes of individuals with bipolar disorder and their spouses toward some of the ethical and social issues arising from rapidly advancing genetic research on bipolar disorder. METHOD: Patients with bipolar disorder and their unaffected spouses were asked to answer questionnaires assessing their knowledge and attitudes about treatment response rates for bipolar disorder, probability of inheritance, genetic testing, disclosure of genetic information, abortion, marriage, and child-bearing. RESULTS: The overwhelming majority of the patients and spouses said that they would take advantage of genetic tests for bipolar disorder if such tests were to become available. Most patients and spouses agreed that the benefits of knowing whether one carries a gene for bipolar disorder would outweigh the risks. The decisive majority of respondents also felt that they would not abort a fetus that carried a gene for bipolar disorder. Furthermore, most patients and spouses agreed that the knowledge that one of them carried a gene for bipolar disorder would not have deterred them from marriage or childbearing. CONCLUSIONS: The results of this study suggest that most individuals believe that they would benefit from the use of genetic testing for bipolar disorder if it were to become available. Follow-up studies using a broader patient sample and nonclinical control groups would be useful in further evaluating the issues addressed in this pilot study.

Abortion, Eugenic↗
PubMed2002

[External quality assessment of the genetic testings for hematopoietic tumor, CML].

Genetic testings are commonly employed in various fields of clinical medicine and the test items performed at clinical laboratories are increasing rapidly in number. They are utilized to make early and/or definite diagnoses of infectious diseases, leukemia, cancers and molecular inherited diseases and also to monitor the progress of the diseases. However, these genetic testings except for infectious diseases have been developed independently at each clinical laboratory and the test results obtained at each laboratory are not always compatible each other. Under these situations it is widely expected to construct advanced genetic testing systems that can supply standardized data at any of domestic and international clinical laboratories. For the period from April, 1999 to March, 2002 three major clinical laboratories, SRL, Inc., BML, Inc. and MBC, Inc., were consigned by JBA (Japan Bioindustry Association) to collaborate in standardizing the evaluation methods for genetic testing systems among the clinical laboratories. The aim of the study is to develop the standardized genetic testing systems and to propose them as international standard operational procedures to the ISO/TC212 working group. Although one of the most important issues for standardization is the external quality assessment, they have not been carried out in reality. In this study we evaluated the difference of the genetic testing results obtained during the year of 2000 and 2001 among the clinical laboratories. The genetic testings for hematopoietic tumor, CML were selected to be evaluated since they are widely accepted as clinically useful tests.

Blotting, Southern↗
PubMed1986

Palatal width growth rates as the genetic determinant of cleft palate induced by vitamin A.

While many studies have demonstrated sexual dimorphism and racial variation (Mongoloid greater than Caucasian greater than Black) in the incidence of palatal clefting, only generalized statements have been made concerning the causal mechanism (eg, "genetic propensity"). The present study tests the hypothesis that the more rapid the growth rate of the width of the facial skeleton, the higher the incidence of palatal clefting, given a uniform environmental insult. Two strains of pregnant rats with differing rates of craniofacial development (Wistar-fast and Sprague-Dawley-slow) were injected prenatally with high doses of vitamin A (300,000 IU/kg) on days 10-13 gestation. Fetuses were examined at 20 d prenatally and the incidence of palatal clefting was recorded. A significantly higher (P less than .05) incidence of palatal clefting was noted in the more rapidly developing strain (66% vs 81%). These results support statements by Fraser and others who suggest that head width and palatal clefting are causally related. The "genetic propensity" in this case, then, is the rate of palatal width development.

Aging↗
PubMed2006

Correlations between heterozygosity and measures of genetic similarity: implications for understanding mate choice.

There is currently considerable interest in testing the effects of genetic compatibility and heterozygosity on animal mate preferences. Evidence for either effect is rapidly accumulating, although results are not always clear-cut. However, correlations between mating preferences and either genetic similarity or heterozygosity are usually tested independently, and the possibility that similarity and heterozygosity may be confounded has rarely been taken into account. Here we show that measures of genetic similarity (allele sharing, relatedness) may be correlated with heterozygosity, using data from 441 human individuals genotyped at major loci in the major histocompatibility complex, and 281 peafowl (Pavo cristatus) individuals genotyped at 13 microsatellite loci. We show that average levels of allele sharing and relatedness are each significantly associated with heterozygosity in both humans and peafowl, that these relationships are influenced by the level of polymorphism, and that these similarity measures may correlate with heterozygosity in qualitatively different ways. We discuss the implications of these inter-relationships for interpretation of mate choice studies. It has recently become apparent that mating preferences for 'good genes' and 'compatible genes' may introduce discordant choice amongst individuals, since the optimal mate for one trait may not be optimal for the other, and our results are consistent with this idea. The inter-relationship between these measures of genetic quality also carries implications for the way in which mate choice studies are designed and interpreted, and generates predictions that can be tested in future research.

Animals↗
PubMed1993

Research samples from families with genetic diseases: a proposed code of conduct.

Research on samples from families with genetic disease underlies many of the major advances that are occurring in medical genetics. But ethical and practical problems may arise when samples from relatives who are healthy but at risk are included in such studies. In particular, new molecular tests for specific gene mutations may result in the detection of a genetic defect in relatives who had neither expected this possibility nor given specific consent to such testing. Family members at risk should not be included in such studies unless strictly necessary, and in such cases specific consent should be obtained and information should be given about the implications of an abnormal result of a test. This is particularly important when stored samples from previous studies without such implications are being reused and is also relevant to the genetic testing of samples taken primarily for epidemiological studies of disorders when only a small proportion of cases is thought to be genetic in origin. There is a need for guidelines to protect both subjects and investigators in a field which is spreading rapidly and involving many clinical and laboratory research workers previously unfamiliar with genetic testing.

Anonymous Testing↗
PubMed1999

Genetic predictive testing for bowel cancer predisposition: the impact on the individual.

When considering the impact of a genetic diagnosis of hereditary predisposition to colon cancer, there are many similarities to other predictive genetic tests, but also many differences. The development and availability of such genetic diagnoses, and the concept of testing being linked to effective prevention, have advanced rapidly, opening up not only unique opportunities but also unique psychosocial situations for the affected families-and unusual ethical issues for the professional. Compared to a diagnosis of sporadic colorectal cancer for a patient, hereditary colorectal cancer requires an understanding of genetics, heredity, and the attendant mathematics of risk calculation, but, most importantly, there must be a belief that it is possible to remain healthy whilst having an increased risk. This paper outlines the possible impact of a genetic diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) or familial adenomatous polyposis (FAP) on both the individual and the family and concludes that genetic testing should be accompanied by genetic counseling. Relevant ethical issues are also introduced, with the opinion presented suggesting that if primary considerations are always for the individual rather than the family or society, then unethical or eugenic decisions are likely to be avoided.

Adenomatous Polyposis Coli↗