Unnamed: 0
int64 0
2.34M
| title
stringlengths 5
21.5M
| abst
stringlengths 1
21.5M
|
|---|---|---|
2,338,600 |
Screening for mutations in the WNT-4 gene in patients with 46,XX true hermaphroditism.
|
We investigated if eight SRY-negative 46,XX true hermaphrodites presented mutations in WNT-4, in blood leukocytes and/or gonadal tissue, as the cause of their disorder. We designed the sequences of the reverse primer of exon 1 and the primers of exons 2-5. Direct sequencing of all five exons demonstrated no mutant alleles in any of the patients. The possibility of the existence of causative mutations in the untranslated regions of WNT-4, or within introns cannot be ruled out.
|
2,338,601 |
A rapid method for promoter exchange in Aspergillus nidulans using recombinant PCR.
|
Recombinant PCR has been used to generate linear fragments for promoter replacement by transformation in Aspergillus nidulans. A cassette vector carrying the pyr-4 non-homologous selectable marker and conditional promoter Pr-alcA was constructed for use as a template for PCR, and is suitable for testing the function of essential genes. Two genes involved in polar growth, cotA and bemA, were used to assess the system. Efficient targeting was possible with both genes using approximately 500bp of flanking homologous sequence. Depending on yield, the linear PCR product could be used directly for transformation, or after first cloning into a suitable vector. bemA, a putative homologue of the Saccharomyces cerevisiae BEM1 gene was identified through sequence comparison. In A. nidulans, this protein appears to have a similar role to the yeast Bem1p, which acts as a scaffold protein involved in the establishment of cell polarity.
|
2,338,602 |
Genetic association studies: web-based resources for effective screening and assessment of candidate genes and pathways.
|
The increased availability of polymorphism resources for humans and high-throughput genotyping technologies account for the large number of genetic associations published every month. Resources that allow one to synthesise published data quickly and effectively are needed to keep up to date with such information. In addition, the full exploitation of data from the HapMap project will depend on the availability of tools for the analysis of clinical and phenotypic information at the genome-wide level. Here, web resources created to aid access to such data, starting from a gene, disease or pathway of interest, are reviewed.
|
2,338,603 |
Clinical aspects of preimplantation genetic diagnosis for single gene disorders combined with HLA typing.
|
Preimplantation genetic diagnosis (PGD) for single gene disorders combined with human leukocyte antigen (HLA) matching has recently emerged as a therapeutic tool for stem cell transplantation in couples bearing an affected offspring. There may exist, however, several patient- or cycle-specific limitations for certain couples. This article documents data regarding experience of single gene disorders combined with HLA matching obtained at Istanbul Memorial Hospital, Turkey. The data were obtained from 20 couples undergoing 26 PGD-HLA cycles for thalassaemia (n = 23), Wiscott-Aldrich syndrome (n = 1) and acute lymphoblastic leukaemia (n = 2). A total of 206 embryos was biopsied on day 3 of embryo development and subsequently analysed. After the analysis, 26 (12.6%) of them were found to be both healthy and HLA compatible. In 16 embryo transfers performed, seven (43.7%) clinical pregnancies were obtained, one of which resulted in miscarriage. Ten of the 26 cycles started (38.4%) were cancelled due to a lack of suitable (mutation-free and/or HLA-compatible) embryos. The data suggest that application of PGD in combination with HLA typing is a promising therapeutic tool for an affected sibling.
|
2,338,604 |
Men's values-based factors on prostate cancer risk genetic testing: a telephone survey.
|
While a definitive genetic test for Hereditary Prostate Cancer (HPC) is not yet available, future HPC risk testing may become available. Past survey data have shown high interest in HPC testing, but without an in-depth analysis of its underlying rationale to those considering it.</AbstractText>Telephone computer-assisted interviews of 400 men were conducted in a large metropolitan East-coast city, with subsequent development of psychometric scales and their correlation with intention to receive testing.</AbstractText>Approximately 82% of men interviewed expressed that they "probably" or "definitely" would get genetic testing for prostate cancer risk if offered now. Factor analysis revealed four distinct, meaningful factors for intention to receive genetic testing for prostate cancer risk. These factors reflected attitudes toward testing and were labeled "motivation to get testing," "consequences and actions after knowing the test result," "psychological distress," and "beliefs of favorable outcomes if tested" (alpha = 0.89, 0.73, 0.73, and 0.60, respectively). These factors accounted for 70% of the total variability. The domains of motivation (directly), consequences (inversely), distress (inversely), and positive expectations (directly) all correlated with intention to receive genetic testing (p < 0.001).</AbstractText>Men have strong attitudes favoring genetic testing for prostate cancer risk. The factors most associated with testing intention include those noted in past cancer genetics studies, and also highlights the relevance in considering one's motivation and perception of positive outcomes in genetic decision-making.</AbstractText>
|
2,338,605 |
The Depression Network (DeNT) Study: methodology and sociodemographic characteristics of the first 470 affected sibling pairs from a large multi-site linkage genetic study.
|
The Depression Network Study (DeNt) is a multicentre study designed to identify genes and/or loci linked to and/or associated with susceptibility to unipolar depression in Caucasian families. This study presents the method and socio-demographic details of the first 470 affected sibling pairs recruited from 8 different sites in Europe and the United States of America.</AbstractText>Probands fulfilling either the Diagnostic and Statistical Manual 4th edition (DSM-IV) or the International Classification of Diseases 10th edition (ICD-10) criteria for recurrent unipolar depression of moderate or severe degree and who had at least one similarly affected sibling were eligible for the study. Detailed clinical and psychological assessments were undertaken on all subjects including an interview using the Schedules for Clinical Assessment in Neuropsychiatry. Blood samples were collected from all participants to extract DNA for linkage analysis.</AbstractText>The different sites used different recruitment strategies depending on local health care organisation but despite this there was remarkable similarity across sites for the subjects recruited. Although the Bonn site had significantly older subjects both for age of onset and age at interview, for the sample as a whole, subjects were interviewed in their mid-40s and had experienced the onset of their recurrent depression in their 20s. Preliminary genome screening was able to include 929 out of the 944 subjects (98.4%) typed at 932 autosomal and 544 X chromosome markers.</AbstractText>This paper describes the methodology and the characteristics of the subjects from the 414 families included in the first wave of genotyping from the multi-site DeNT study. Ultimately the study aims to collect affected sibling pairs from approximately 1200 families.</AbstractText>
|
2,338,606 |
Genetic determinants of folate status in Central Bohemia.
|
Although several genetic factors have been implicated as determinants of blood folate concentration in various populations, their effect on folate status in the Czech population has not yet been examined. We explored whether blood folate concentrations in healthy Czech population are associated with polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR), folate hydrolase 1 (FOLH1), reduced folate carrier (RFC), and folate receptor (FOLR1) genes. In a cross-sectional study of 591 control subjects we determined genotypes by PCR-RFLP or ARMS-PCR methods, and plasma and erythrocyte folates by MEIA. The effect of different genotypes on folate status was examined by non-parametric tests and by regression analysis. The prevalence of the MTHFR 677C>T, MTHFR 1298A>C, FOLH1 1561C>T, RFC 80G>A and FOLR1 480G>C variant alleles was 0.34, 0.33, 0.05, 0.44 and 0.00, respectively. Only the MTHFR 677C>T variant was significantly associated with plasma folate concentrations (median 14.7, 14.0 and 12.2 nmol/l for the CC, CT and TT genotypes, respectively). Our study showed that among the five studied allelic variants, only the 677C>T polymorphism in the MTHFR gene is a significant genetic determinant of plasma folate concentrations in Czech population.
|
2,338,607 |
Molecular analysis of delta-aminolevulinic acid dehydratase (ALAD) gene polymorphism in a Turkish population.
|
delta-Aminolevulinic acid dehydratase (ALAD) is a cytosolic enzyme in the heme biosynthetic pathway. ALAD is a polymorphic enzyme showing marked ethnic group differences. In this study, ALAD polymorphism is studied in a Turkish population. Genomic DNA extracted from 230 individuals and polymerase chain reaction (PCR) coupled with the restriction fragment length polymorphism (RFLP) technique were used to identify variants. The frequencies of the alleles ALAD1 and ALAD2 in Turkey were 0.887 and 0.113, respectively. This study provides the first analysis of the allele frequency distribution of the ALAD gene in a Turkish population. The results are compared with other world populations.
|
2,338,608 |
A functional truncated form of c-kit tyrosine kinase is produced specifically in the testis of the mouse but not the rat, pig, or human.
|
The complete nucleotide sequence of mouse-truncated mRNA of c-kit, tr-kit, has been determined using the CD1 strain. In this study, the nucleotide sequences of tr-kit from AKR/N, C57BL/6, and ICR strains of mice were determined and found to be identical, although many silent variations were found compared with the sequence in a database for CD1. Tr-kit protein consists of 12 amino acids encoded by the 16th intron and the following 190 amino acids of c-kit. In the sequences of tr-kit encoding 12 specific amino acids, no substitution was detected among the three strains and CD1. Furthermore, RT-PCR analysis clearly showed that tr-kit mRNA expression was present only in testis. No nucleotide mutation in two important regions of the presumptive promoter for tr-kit mRNA was detected within the 16th intron of the mouse strains examined. However, no functional form of tr-kit was found in the rat, pig, or human by sequence analysis and homology testing.
|
2,338,609 |
Genetic susceptibility to psychiatric disorders.
|
Genetics contributes susceptibility to most psychiatric conditions and the understanding of these genetic factors is increasing rapidly. Because of such breakthroughs and their implications for patient care, professional nursing organizations support the incorporation of genetics into nursing curricula and the attainment of a working knowledge of genetics by all nurses. In this article, the basics of psychiatric genetics are presented to provide a foundation for the understanding of current and future findings in the field as well as information about family history assessment and appropriate references that the practitioner may find helpful.
|
2,338,610 |
Novel biodegradable polymers as gene carriers.
|
This study investigated two new biodegradable polymers as gene controlled-released coatings for gene transfer. Poly(ethylene glycol)-co-poly(D,L-lactic acid) (PELA) and poly(ethylene glycol)-co-poly(lactic acid)-co-poly(glycolic acid) random copolymer (PELGA) were synthesized and used as microspheres matrices with encapsulated plasmid pCH110. The plasmid loading efficiency, cytotoxicity, transfection efficiency and in vitro degradation and release profiles of microsphere complexes were evaluated in details. The biodegradable polymers showed high DNA loading efficiency and low cytotoxicity as gene controlled-released coatings, and the poly(ethylene glycol) (PEG) contents of polymer matrices influenced the diameter, loading efficiency and transfection efficiency of plasmid DNA within the microspheres. The average diameters of PELA and PELGA microspheres were between 0.5 and 1.5 microm, and the plasmid loading efficiency was 62 and 73% for PELA and PELGA microspheres with 10% PEG content, respectively. In vitro testing showed a gradual release profile of DNA from polymeric matrices. The polymers/DNA microspheres had high transfection efficiency and early gene expression and maintenance of gene expression level for up to 96 h, although transfection efficiency were slightly lower than that of liposome in the initial 24 h. The biodegradable polymeric materials possess potential superiority as gene carriers.
|
2,338,611 |
Somatic mosaicism for a heterozygous deletion of the survival motor neuron (SMN1) gene.
|
Infantile spinal muscular atrophy (SMA) is a common autosomal recessive disease with a high demand for carrier testing. The disease is caused by homozygous deletions of the survival motor neuron (SMN)1 gene on chromosome 5q13 in more than 90% of cases. Meanwhile, several reliable quantitative methods for carrier detection in the general population have been implemented with a risk of at least 5% for false negative results. Linkage analyses with chromosome 5 markers can be used for complementary information, but they are restricted to risk estimation of close relatives in affected families. Here, we present the first observation of a somatic mosaicism in an SMA carrier. Molecular genetic studies gave evidence that the SMN1 deletion of an SMA type I patient most probably arose from somatic mosaicism in the paternal grandmother. The patient's father and his two brothers were shown to be carriers of three different maternal haplotypes in 5q13. Final conclusions for genetic counselling were only possible after both linkage analysis and quantitative real-time PCR analysis of SMN1 copy numbers.
|
2,338,612 |
Mutation screening of EXT1 and EXT2 by direct sequence analysis and MLPA in patients with multiple osteochondromas: splice site mutations and exonic deletions account for more than half of the mutations.
|
Multiple osteochondromas (MO) is an autosomal dominant condition, caused by mutations in either the EXT1 or the EXT2 gene. The DNA of a cohort of 35 patients, clinically suspected to be affected with MO, was screened for mutations by a combination of direct sequence analysis and multiplex ligation-dependent probe amplification (MLPA). In this cohort, 26 pathogenic gene alterations were found (74%). With sequence analysis mutations were detected in 22 patients (63%). In total, 10 mutations were detected in the EXT1 and 12 in the EXT2 gene. The number of the splice site mutations detected was larger than expected from the literature. In addition, with the MLPA four deletions of one or more exons were found in this cohort. Two patients, of whom one had a negative family history, showed deletions of exon 1 of the EXT1 gene, which is possibly a deletion hot spot. In patients suspected to be affected by MO, we recommend a quantitative analysis such as MLPA, followed by direct sequence analysis for the screening of the EXT1 and EXT2 genes.
|
2,338,613 |
Papillon-Lefèvre syndrome: correlating the molecular, cellular, and clinical consequences of cathepsin C/dipeptidyl peptidase I deficiency in humans.
|
A variety of neutral serine proteases are important for the effector functions of immune cells. The neutrophil-derived serine proteases cathepsin G and neutrophil elastase are implicated in the host defense against invading bacterial and fungal pathogens. Likewise, the cytotoxic lymphocyte and NK cell granule-associated granzymes A and B are important for the elimination of virus-infected cells. The activation of many of these serine proteases depends on the N-terminal processing activity of the lysosomal cysteine protease cathepsin C/dipeptidyl peptidase I (DPPI). Although mice deficient in DPPI have defects in serine protease activation in multiple cellular compartments, the role of DPPI for human serine protease activation is largely undefined. Papillon-Lefevre syndrome (PLS) is a rare autosomal recessive disease associated with loss-of-function mutations in the DPPI gene locus. In this study, we established that the loss of DPPI activity is associated with severe reduction in the activity and stability of neutrophil-derived serine proteases. Surprisingly, patients with PLS retain significant granzyme activities in a cytotoxic lymphocyte compartment (lymphokine-activated killer) and have normal lymphokine-activated killer-mediated cytotoxicity against K562 cells. Neutrophils from patients with PLS do not uniformly have a defect in their ability to kill Staphylococcus aureus and Escherichia coli, suggesting that serine proteases do not represent the major mechanism used by human neutrophils for killing common bacteria. Therefore, this study defines the consequences of DPPI deficiency for the activation of several immune cell serine proteases in humans, and provides a molecular explanation for the lack of a generalized T cell immunodeficiency phenotype in patients with PLS.
|
2,338,614 |
Refining hormonal diagnosis of type II 3beta-hydroxysteroid dehydrogenase deficiency in patients with premature pubarche and hirsutism based on HSD3B2 genotyping.
|
Congenital adrenal hyperplasia due to 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4)-isomerase (3betaHSD), a rare autosomal recessive disorder that affects both sexes, has a heterogeneous clinical presentation ranging from the severe salt-wasting to the non-salt-wasting forms and results from mutations in the HSD3B2 gene. The hormonal criteria for diagnosing the mild variant of 3betaHSD deficiency have been controversial because the initial studies were not based on genetic evidence. We investigated the relationship between the hormonal phenotype and HSD3B2 genotype in 22 patients with clinical and/or biochemical features suggestive of 3betaHSD2 deficiency, including nine female children with premature pubarche, 12 hirsute females, and one boy with salt-wasting and ambiguous genitalia. Serum 17-hydroxypregnenolone (Delta5-17P), cortisol (F), 17-hydroxyprogesterone, dehydroepiandrosterone, and androstenedione levels were determined by RIA and were compared with Tanner pubic hair stage-matched control groups. The genomic DNA was extracted, and the entire HSD3B2 gene was amplified by PCR followed by automatic sequencing. Besides two different mutations previously observed in three patients (T259M and G129R/P222Q mutations), we observed the P222Q mutation in the male patient with salt-wasting form of 3betaHSD2 deficiency. Basal and ACTH-stimulated Delta5-17P levels (nanomoles per liter) ranged from 4-41 (-0.2 to 14 sd) and 36-97 (3.5-15.5 sd), respectively, in patients without mutation in HSD3B2 and from 69-153 (25-57 sd) and 201-351 (36-65 sd), respectively, in patients with mutation in HSD3B2. Basal and ACTH-stimulated Delta5-17P to F ratios ranged from 11-159 (0.5-25 sd) and 42-122 (2.4-11.3 sd), respectively, in patients without mutation in HSD3B2 and from 181-1700 (29-282 sd) and 487-1523 (52-167 sd), respectively, in patients with mutation in HSD3B2. The hormone findings in the genotype-proven patients suggest that the following hormonal criteria are compatible with 3betaHSD2 deficiency in children with premature pubarche: ACTH-stimulated Delta5-17P and Delta5-17P to F ratios at or greater than 201 and 487 nmol/liter, respectively, equivalent to or greater than 36 and 52 sd above matched control mean. Basal and ACTH-stimulated Delta5-17P and Delta5-17P to F ratios in all genotype-proven patients in childhood were unequivocally higher than the levels of either genotype-normal patients. All the other parameters overlapped between the patients with and without mutations in the HSD3B2 gene. In conclusion, genotyping more patients in the present study, we confirm that patients with mutations in the HSD3B2 gene have extremely elevated basal and ACTH-stimulated Delta5-17P levels and Delta5-17P to F ratios. Therefore, these data refine the hormonal criteria proposed to predict more accurately 3betaHSD2 deficiency.
|
2,338,615 |
OLIN: optimized normalization, visualization and quality testing of two-channel microarray data.
|
Microarray data are generated in complex experiments and frequently compromised by a variety of systematic errors. Subsequent data normalization aims to correct these errors. Although several normalization methods have recently been proposed, they frequently fail to account for the variability of systematic errors within and between microarray experiments. However, optimal adjustment of normalization procedures to the underlying data structure is crucial for the efficiency of normalization. To overcome this restriction of current methods, we have developed two normalization schemes based on iterative local regression combined with model selection. The schemes have been demonstrated to improve considerably the quality of normalization. They are implemented in a freely available R package. Additionally, functions for visualization and detection of systematic errors in microarray data have been incorporated in the software package. A graphical user interface is also available.</AbstractText>The R package can be downloaded from http://itb.biologie.hu-berlin.de/~futschik/software/R/OLIN. It underlies the GPL version 2.</AbstractText>[email protected]</AbstractText>Further information about the methods used in the OLIN software package can be found at http://itb.biologie.hu-berlin.de/~futschik/software/R/OLIN.</AbstractText>
|
2,338,616 |
A novel method of cocaine delivery to fruit flies using a graphic arts airbrush.
|
The fruit fly Drosophila melanogaster is a model system for studying pathways regulating responses to cocaine. We describe a new method for delivering cocaine to Drosophila. Freebase cocaine dissolved in ethanol is sprayed onto cold-anaesthetized flies using a graphic arts airbrush modified to reproducibly control the drug dosage. Cocaine dose response curves were generated to characterize the behavioral responses of flies using the airbrush method or the established cocaine smoke method of drug delivery. The stereotypic responses observed with the airbrush showed a dose-dependent increase and were qualitatively similar to those elicited by cocaine smoke. The variation in behaviors of flies dosed with the airbrush was smaller than that of the smoke-dosed flies, indicating that the airbrush method gives better reproducibility. Since flies are exposed to alcohol as well as cocaine in the airbrush behavioral paradigm, it was important to control for possible effects of ethanol. Control experiments indicated that none of the stereotypies elicited with cocaine were caused by vehicle alone and very little ethanol remains in the flies following this protocol. The utility of the airbrush method was demonstrated by its use in a pilot genetic screen that identified a cocaine resistant mutant.
|
2,338,617 |
Simulated annealing of microarray data reduces noise and enables cross-experimental comparisons.
|
Microarrays are a powerful tool for assessing the genome-wide induction of a transcriptional response to internal or external stimuli, but are not considered quantitatively rigorous (i.e., the signal intensity of hybridized probe is normally used to quantify relative transcript abundance). Thus, it is difficult, if not impossible, to accurately compare separate microarray experiments without a reference standard. However, even among replicated microarray experiments, each gene varies significantly in the amount of signal detected, suggesting no single gene would be appropriate as a standard. We propose and test a method to "align" experimental transcription profiles to a set of reference experiments using simulated annealing (SA), essentially using the relative positions of all genes as a reference standard. SA attempts to find a globally optimal adjustment factor for the relative expression level of each experimental gene expression signal, given a previously observed range of gene expression measurements. By defining a relative dynamic range of gene expression under control conditions for all genes, we can more accurately compare transcription profiles between separate experiments and, potentially, between species--enabling comparative transcriptomics. Testing SA on a published dataset, we find that it significantly reduces interexperimental variation, suggesting it holds promise to accomplish this goal.
|
2,338,618 |
Apolipoprotein E and cognitive performance: a meta-analysis.<Pagination><StartPage>592</StartPage><EndPage>600</EndPage><MedlinePgn>592-600</MedlinePgn></Pagination><Abstract><AbstractText>The epsilon4 allele of the apolipoprotein E (APOE) gene is a known risk factor for Alzheimer's disease and may also affect cognitive performance in normal aging. Evidence of the presence and magnitude of epsilon4-related cognitive deficits was examined with a meta-analysis of the available literature. Thirty-eight studies were included, and cognitive performance was collapsed into 8 domains. Results indicated significant APOE-epsilon4 group differences for global cognitive functioning, episodic memory, and executive functioning, in favor of non-epsilon4 carriers. In addition, older age and APOE-epsilon4 heterozygosity was associated with smaller epsilon4-related impairments. The meta-analysis results suggest that APOE-epsilon4 genotype does affect cognitive performance in healthy aging, although the influence is relatively small and specific to certain domains of cognitive performance.</AbstractText><CopyrightInformation>copyright (c) 2004 APA, all rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Small</LastName><ForeName>Brent J</ForeName><Initials>BJ</Initials><AffiliationInfo><Affiliation>School of Aging Studies, University of South Florida, Tampa, FL 33620, USA. [email protected]</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rosnick</LastName><ForeName>Christopher B</ForeName><Initials>CB</Initials></Author><Author ValidYN="Y"><LastName>Fratiglioni</LastName><ForeName>Laura</ForeName><Initials>L</Initials></Author><Author ValidYN="Y"><LastName>Bäckman</LastName><ForeName>Lars</ForeName><Initials>L</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D017418">Meta-Analysis</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Psychol Aging</MedlineTA><NlmUniqueID>8904079</NlmUniqueID><ISSNLinking>0882-7974</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D053327">Apolipoprotein E4</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D001057">Apolipoproteins E</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000328" MajorTopicYN="N">Adult</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000368" MajorTopicYN="N">Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000369" MajorTopicYN="N">Aged, 80 and over</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000375" MajorTopicYN="N">Aging</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000483" MajorTopicYN="N">Alleles</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000544" MajorTopicYN="N">Alzheimer Disease</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D053327" MajorTopicYN="N">Apolipoprotein E4</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D001057" MajorTopicYN="N">Apolipoproteins E</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D003071" MajorTopicYN="N">Cognition</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006580" MajorTopicYN="N">Genetic Carrier Screening</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005838" MajorTopicYN="N">Genotype</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008875" MajorTopicYN="N">Middle Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009483" MajorTopicYN="Y">Neuropsychological Tests</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011930" MajorTopicYN="N">Reaction Time</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2004</Year><Month>12</Month><Day>9</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>4</Month><Day>9</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2004</Year><Month>12</Month><Day>9</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">15584785</ArticleId><ArticleId IdType="doi">10.1037/0882-7974.19.4.592</ArticleId><ArticleId IdType="pii">2004-21181-005</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="KIE"><PMID Version="1">15584198</PMID><DateCompleted><Year>2004</Year><Month>12</Month><Day>20</Day></DateCompleted><DateRevised><Year>2021</Year><Month>12</Month><Day>03</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">1543-1215</ISSN><JournalIssue CitedMedium="Print"><Issue>2</Issue><PubDate><Year>2003</Year><Season>Summer</Season></PubDate></JournalIssue><Title>New Atlantis (Washington, D.C.)</Title><ISOAbbreviation>New Atlantis</ISOAbbreviation></Journal>Eugenics--sacred and profane.<Pagination><StartPage>79</StartPage><EndPage>89</EndPage><MedlinePgn>79-89</MedlinePgn></Pagination><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Rosen</LastName><ForeName>Christine</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Ethics and Public Policy Center, 1015 Fifteenth Street N.W., Suite 900, Washington, DC 20005, USA.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>New Atlantis</MedlineTA><NlmUniqueID>101218011</NlmUniqueID><ISSNLinking>1543-1215</ISSNLinking></MedlineJournalInfo><MeshHeadingList><MeshHeading><DescriptorName UI="D017668" MajorTopicYN="N">Age of Onset</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D001709" MajorTopicYN="N">Biotechnology</DescriptorName><QualifierName UI="Q000941" MajorTopicYN="N">ethics</QualifierName><QualifierName UI="Q000639" MajorTopicYN="N">trends</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D033002" MajorTopicYN="N">Duty to Recontact</DescriptorName><QualifierName UI="Q000941" MajorTopicYN="N">ethics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005006" MajorTopicYN="N">Ethnicity</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005053" MajorTopicYN="N">Eugenics</DescriptorName><QualifierName UI="Q000639" MajorTopicYN="Y">trends</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006580" MajorTopicYN="N">Genetic Carrier Screening</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005817" MajorTopicYN="N">Genetic Counseling</DescriptorName><QualifierName UI="Q000941" MajorTopicYN="N">ethics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D030342" MajorTopicYN="N">Genetic Diseases, Inborn</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005820" MajorTopicYN="N">Genetic Testing</DescriptorName><QualifierName UI="Q000941" MajorTopicYN="Y">ethics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007585" MajorTopicYN="N">Jews</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D007599" MajorTopicYN="N">Judaism</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D019836" MajorTopicYN="N">Preimplantation Diagnosis</DescriptorName><QualifierName UI="Q000941" MajorTopicYN="Y">ethics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011291" MajorTopicYN="N">Premarital Examinations</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011296" MajorTopicYN="N">Prenatal Diagnosis</DescriptorName><QualifierName UI="Q000941" MajorTopicYN="N">ethics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013240" MajorTopicYN="N">Stereotyping</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013661" MajorTopicYN="N">Tay-Sachs Disease</DescriptorName><QualifierName UI="Q000208" MajorTopicYN="N">ethnology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading></MeshHeadingList><OtherID Source="KIE">117564</OtherID><KeywordList Owner="KIE"><Keyword MajorTopicYN="N">Genetics and Reproduction</Keyword></KeywordList><GeneralNote Owner="KIE">KIE Bib: eugenics; genetic screening; prenatal diagnosis</GeneralNote></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2004</Year><Month>12</Month><Day>9</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2004</Year><Month>12</Month><Day>21</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2004</Year><Month>12</Month><Day>9</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">15584198</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="KIE"><PMID Version="1">15584193</PMID><DateCompleted><Year>2004</Year><Month>12</Month><Day>28</Day></DateCompleted><DateRevised><Year>2009</Year><Month>11</Month><Day>19</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">1543-1215</ISSN><JournalIssue CitedMedium="Print"><Issue>1</Issue><PubDate><Year>2003</Year><Season>Spring</Season></PubDate></JournalIssue><Title>New Atlantis (Washington, D.C.)</Title><ISOAbbreviation>New Atlantis</ISOAbbreviation></Journal>Liberty, privacy, and DNA databases.
|
The epsilon4 allele of the apolipoprotein E (APOE) gene is a known risk factor for Alzheimer's disease and may also affect cognitive performance in normal aging. Evidence of the presence and magnitude of epsilon4-related cognitive deficits was examined with a meta-analysis of the available literature. Thirty-eight studies were included, and cognitive performance was collapsed into 8 domains. Results indicated significant APOE-epsilon4 group differences for global cognitive functioning, episodic memory, and executive functioning, in favor of non-epsilon4 carriers. In addition, older age and APOE-epsilon4 heterozygosity was associated with smaller epsilon4-related impairments. The meta-analysis results suggest that APOE-epsilon4 genotype does affect cognitive performance in healthy aging, although the influence is relatively small and specific to certain domains of cognitive performance.
|
2,338,619 |
Novel parkin mutations detected in patients with early-onset Parkinson's disease.
|
A multiethnic series of patients with early-onset Parkinson's disease (EOP) was studied to assess the frequency and nature of parkin/PARK2 gene mutations and to investigate phenotype-genotype relationships. Forty-six EOP probands with an onset age of < 45 years, and 14 affected relatives were ascertained from Italy, Brazil, Cuba, and Turkey. The genetic screening included direct sequencing and exon dosage using a new, cost-effective, real-time polymerase chain reaction method. Mutations were found in 33% of the indexes overall, and in 53% of those with family history compatible with autosomal recessive inheritance. Fifteen parkin alterations (10 exon deletions and five point mutations) were identified, including four novel mutations: Arg402Cys, Cys418Arg, IVS11-3C > G, and exon 8-9-10 deletion. Homozygous mutations, two heterozygous mutations, and a single heterozygous mutation were found in 8, 6, and 1 patient, respectively. Heterozygous exon deletions represented 28% of the mutant alleles. The patients with parkin mutations showed significantly earlier onset, longer disease duration, more frequently symmetric onset, and slower disease progression than the patients without mutations, in agreement with previous studies. This study confirms the frequent involvement of parkin and the importance of genetic testing in the diagnostic work-up of EOP.
|
2,338,620 |
[Allele frequencies and species specificity of six short tandem repeat loci in Chinese population].
|
To develop a set of new markers for forensic application, the authors have chosen 6 short tandem repeat(STR) loci to study the allele frequencies and species specificity in Chinese Han population in Chengdu.</AbstractText>One hundred and ten EDTA-blood samples were collected from the unrelated individuals in Chengdu city, Sichuan province. DNA was extracted by Chelex-100 and amplified by the polymerase chain reaction(PCR). Polyacrylamide gel electrophoresis (PAGE) and silver staining were used to analyze the PCR products.</AbstractText>The polymorphisms of all 6 STR loci have been obtained in Chinese Han population in Chengdu, the alleles of D4S2366, D4S2367, D6S474, D6S1281, D2S1396 and D20S601 being 7, 7, 6, 7, 5, 7, the observed heterozygosity of them being 0.802, 0.708, 0.770, 0.627, 0.542, 0.672, the discrimination power of them being 0.887, 0.828, 0.849, 0.848, 0.794, 0.865; and the power of exclusion of them being 0.602, 0.441, 0.544, 0.325, 0.227, 0.386. Evaluated by comparison with the data from 14 different animals as controls, the 6 STR loci contain good specificity of human beings.</AbstractText>The 6 STR loci are highly polymorphic and can play a key role in species identification. They are new candidate markers for forensic personal identification and paternity testing.</AbstractText>
|
2,338,621 |
Negative association between catechol-O-methyltransferase (COMT) gene Val158Met polymorphism and persistent tardive dyskinesia in schizophrenia.
|
Chronic administration of typical antipsychotic agents, which mainly act on the dopamine receptors, implicates a role of dopamine system on the susceptibility of tardive dyskinesia (TD). In the present study, the association between a functional Val158Met polymorphism of Catechol-O-methyltransferase (COMT) gene and TD occurrence and TD severity was investigated in 299 Chinese schizophrenic patients with long-term antipsychotic treatment (TD: 166, non-TD: 133). After adjusting the effects of confounding factors, there was no significant association between COMT genotype and TD occurrence (p=0.367). Among TD patients, we found no significant correlation between COMT genotypes and the total scores of abnormal involuntary movement scale (AIMS) (p=0.629). We concluded that this COMT polymorphism might not play a major role in the susceptibility of TD nor on the severity of TD.
|
2,338,622 |
A micro costing of NHS cancer genetic services.
|
This paper presents the first full micro costing of a commonly used cancer genetic counselling and testing protocol used in the UK. Costs were estimated for the Cardiff clinic of the Cancer Genetics Service in Wales by issuing a questionnaire to all staff, conducting an audit of clinic rooms and equipment and obtaining gross unit costs from the finance department. A total of 22 distinct event pathways were identified for patients at risk of developing breast, ovarian, breast and ovarian or colorectal cancer. The mean cost per patient were pound sterling 97- pound sterling 151 for patients at moderate risk, pound sterling 975- pound sterling 3072 for patients at high risk of developing colorectal cancer and pound sterling 675- pound sterling 2909 for patients at high risk of developing breast or ovarian cancer. The most expensive element of cancer genetic services was labour. Labour costs were dependent upon the amount of labour, staff grade, number of counsellors used and the proportion of staff time devoted to indirect patient contact. With the growing demand for cancer genetic services and the growing number of national and regional cancer genetic centers, there is a need for the different protocols being used to be thoroughly evaluated in terms of costs and outcomes.
|
2,338,623 |
DNA-based prenatal exclusion of bullous congenital ichthyosiform erythroderma at the early stage, 10 to 11 weeks' of pregnancy, in two consequent siblings.
|
The proband was a Japanese woman with bullous congenital ichthyosiform erythroderma harboring a keratin 10 gene mutation M150T. DNA-based prenatal exclusion of bullous congenital ichthyosiform erythroderma was successfully performed in her two consequent pregnancies using chorionic villus samples at 10 to 11 weeks' gestation, several weeks earlier than the previously reported cases.
|
2,338,624 |
Ethical issues in psychiatric genetics.
|
As knowledge grows regarding the genetic bases of psychiatric disorders, a variety of ethical issues will need to be confronted. Current evidence suggests that the etiology of most psychiatric disorders rests on a combination of multiple genes and environmental factors. As tests for the genes involved become more easily available, pressures will arise to use them for prenatal testing, screening of children and adults, selection of potential adoptees, and pre-marital screening. Common problems that will need to be addressed include popular misunderstanding of the consequences of possessing an affected allele, impact of knowledge of one's genetic make-up on one's sense of self, and the discriminatory use of genetic information to deny persons access to insurance and employment. Although most states have some legislation aimed at preventing discrimination, the laws' coverage is spotty and federal rules are lacking. Physicians may find that newly available genetic information creates new duties for them, including warning third parties who may share the patient's genetic endowment. And genetics research itself has raised questions about when to disclose information to subjects and their family members about the genes that are being studied, and how to define the subjects of the research when information is collected about family members other than the proband. Knowledge of these dilemmas is a first step to resolving them, something that the medical profession will need to attend to in the near-term. Neglect will lead others to set the rules that will control medical practice, including the practice of psychiatry, in the new world of genetic medicine.
|
2,338,625 |
Approaches to familial aggregation: hypothesis testing and estimation when families are selected through parent probands under a variant of single ascertainment.
|
Epidemiologic approaches to testing and estimating familial aggregation of a disease consist of comparing rates of disease in relatives of individuals with the disease (known as case probands) with rates of disease in relatives of individuals without the disease (known as control probands). Gold et al. (J Am Stat Ass 1967;62: 409-420) derived an explicit mathematical model and sampling methods, under which this approach is equivalent to testing the null hypotheses that the disease risk in families is homogenous. A basic assumption of this model is that every family member has the same risk of disease and that disease status is independent among family members, although the disease risk may vary between families. When the disease is suspected of having a genetic component, rather than being purely environmental, this model has been shown to be appropriate for detecting disease aggregation in siblings, when relatives are siblings of probands. This model however is unrealistic for use in nuclear families when the affected status of offspring is not independent of the affected status of parents, and these families are selected through an affected or an unaffected parent, so that a parent is the proband and relatives are offspring of probands. We extend the Gold et al. model to allow for the disease risk in offspring to vary with the affected status of the parent. We assume that families are selected through affected and unaffected parents, under a variation of single ascertainment. Under this study design, we show that the usual test of association between affected status of probands and relatives, performed by comparing sample proportions of affected relatives of affected and unaffected probands, respectively, is no longer equivalent to a test of homogeneity of disease risk in offspring. Instead, it is equivalent to testing that the disease risk in offspring is independent of the number of affected parents. This test reduces to a test of homogeneity if and only if one assumes that the variation in disease risk in offspring, between families, is solely due to the variation in the number of affected parents. As a result, we show that under this study design, the standard chi2 test must be modified in order to obtain a valid test of familial aggregation. In addition the sample proportions of affected relatives of case and control probands, respectively, are shown to provide unbiased estimates of the expected risk of disease in an offspring given an affected/unaffected parent. We apply these results to methods of sample selection and discuss the practical implications of these findings.
|
2,338,626 |
Effects of genotype x environment interaction on genetic gain in breeding programs.
|
Genotype x environment interaction (G x E) is increasingly important, because breeding programs tend to be more internationally oriented. The aim of this theoretical study was to investigate the effects of G x E on genetic gain in sib-testing and progeny-testing schemes. Loss of genetic gain due to G x E was predicted for different values of heritability, number of progeny per dam, number of progeny per sire, proportion of selected sires, and population size in the selection environment. Two environments were considered: a selection environment (SLE) and a production environment (PDE). The breeding goal was only for performance in PDE. A pseudo-BLUP selection index was used to predict genetic gain. Recording of half-sibs or progeny in PDE limited the loss in genetic gain in PDE due to G x E between SLE and PDE. Progeny-testing schemes had less loss in genetic gain than sib-testing schemes. Higher heritability increased the loss in genetic gain, whereas increasing the number of progeny per sire in PDE decreased the loss in genetic gain. The number of progeny per sire required to minimize loss in genetic gain due to G x E was greater for sib-testing schemes than for progeny-testing schemes. More progeny per dam slightly increased the loss in genetic gain. Genetic gains for sex-limited and carcass traits were less affected by G x E than traits measured on both sexes. Loss in genetic gain was due to decreased accuracy of selection in most situations, but it was due to decreased selection intensity in situations with small population size and a low proportion of selected sires. It was concluded that recording performance of relatives in PDE minimizes loss in genetic gain due to G x E, and that progeny-testing schemes rather than sib-testing schemes are preferable in situations with low to moderate heritability (h(2) <or= 0.3), relatively short generation interval of progeny-tested sires (L(prog)/L(sib) <or= 1.7), and moderate to severe G x E interaction (r(g) <or= 0.8).
|
2,338,627 |
Ethanol preexposure increases ethanol self-administration in C57BL/6J and DBA/2J mice.
|
Genetic variables are thought to interact with environmental factors, such as alcohol exposure history, to produce individual differences in alcohol abuse and alcoholism. The objective of this study was to test the potential interaction between genetic predisposition to consume alcohol and alcohol pretreatment on subsequent self-administration. To accomplish this goal, four groups of mice from the ethanol-avoiding DBA/2J (D2) and ethanol-preferring C57BL/6J (B6) inbred strains were exposed to saline, acute ethanol (2 g/kg), or chronic intermittent ethanol (1 or 2 g/kg) intraperitoneal (i.p.) injections. Locomotor activity was monitored after each injection. After preexposure, animals were given a two-bottle choice test with various concentrations of ethanol/sucrose vs. sucrose or ethanol vs. water for 4 days at each concentration. Then, all animals were challenged with a 2.0 g/kg ethanol i.p. injection and locomotor activity was assessed. Acute and chronic ethanol pretreatment increased locomotor activity in response to a challenge dose of ethanol (2 g/kg) in D2 mice but had no effect on B6 mice. Prior exposure to ethanol altered the amount of ethanol consumed in a mouse strain-dependent manner. D2 mice showed a positive relationship between ethanol intake and dose or duration of ethanol preexposure. B6 mice preexposed to ethanol consumed more ethanol than naive animals, independent of dose or duration of exposure. During the last phase of self-administration testing, D2 mice exposed to chronic ethanol (2 g/kg) consumed as much ethanol as B6 from the same pretreatment condition. After a history of ethanol self-administration, saline control mice from the D2 strain showed equal locomotor activation as compared to D2 mice that were pretreated with ethanol injections. B6 mice showed no change in locomotor activity after ethanol self-administration or injection. These results demonstrate that genetic predisposition to avoid alcohol (D2 mice) can be modified by a history of preexposure and that a predisposition to prefer alcohol (B6 mice) may be also amenable to influence by drug history. In general, the results of this study suggest that genetic factors may interact with previous exposure to ethanol to modify ethanol self-administration.
|
2,338,628 |
Specificity of modified Drosophila mariner transposons in the identification of Leishmania genes.
|
Genetic manipulation of the protozoan Leishmania has led to a better understanding of the survival and development of these pathogens within their hosts. The association of the Leishmania genome sequencing information with the ability of transposons to introduce or destroy phenotypes allows a global perspective on the role and importance of genes in cellular pathways. Herein we report the construction and testing of mariner transposable elements carrying the neomycin phosphotransferase, green fluorescent protein, or beta-glucuronidase genes as reporters for translational fusion events. We demonstrate that the expression of the reporter genes will occur only when the genes are inserted in-frame within predicted genes. Our results not only add to the mariner toolkit for gene manipulation but also strengthen the evidence that the mariner system is a reliable means for the study of gene expression in Leishmania.
|
2,338,629 |
Transcriptional mechanisms of hippocampal aging.
|
Aging related cognitive decline is an increasing health problem but affects only a subset of elderly humans. This research uses outbred young (Y) and aged rats. Behavioral characterization distinguishes aged rats with impaired spatial learning (AI) and aged rats with unimpaired learning ability (AU), mimicking the varied susceptibility of the human population to age-associated learning impairment. Studies are testing a hypothesis that hippocampal transcriptional mechanisms and gene expression profiles linked to activator protein-1 (AP-1) and glucocorticoid receptor (GR), mineralocorticoid receptor (MR) or cyclic AMP response element binding protein (CREB) families of transcription factors distinguish successful or unsuccessful aging and cognition. Results from mRNA assays, in situ hybridization, electromobility shift assays and western immunoblot indicate changes in GR and CREB in AI rats. State of the art future approaches to define downstream transcription targets are described.
|
2,338,630 |
Retinal degeneration in Aipl1-deficient mice: a new genetic model of Leber congenital amaurosis.
|
Leber congenital amaurosis (LCA) is the most severe inherited retinopathy, with the earliest age of onset. Because this currently incurable disease is present from birth and is a relatively rare disorder, the development of animal models that closely resemble the phenotype in patients is especially important. Our previous genetic analyses of LCA patients identified mutations in the aryl-hydrocarbon interacting protein-like 1 (AIPL1) gene. Here we present development of an animal model of AIPL1-associated LCA, the Aipl1-deficient mouse. Aipl1 is expressed at low levels throughout human and mouse retinal development and is rapidly upregulated as photoreceptors differentiate. The mouse displays rapid retinal degeneration and massive Müler cell gliosis, resembling the phenotype of the rd mouse, which is caused by a mutation in the gene for the beta-subunit of the rod-specific phosphodiesterase. We confirm that this phenotype is consistent with the human disease using electroretinograms, and document the disease pathogenesis by analyzing the development of all retinal cell types and synaptogenesis during retinal histogenesis. Ectopic expression of AIPL1 led to deregulated retinal progenitor cell proliferation and alterations in cell fate specification; however, no gross abnormalities of proliferation during retinal development were detected. Data from analysis of proliferation and cell fate specification during retinal development of Aipl1-deficient mice suggests that there may be redundancy or compensation for Aipl1 loss by other related proteins. Because this mouse model closely mimics the human retinopathy caused by homozygous mutations in this gene, it provides a preclinical model for testing therapies to rescue the vision of children whose blindness is caused by AIPL1 mutations.
|
2,338,631 |
Congenital spherocytosis with hereditary hemochromatosis without pathogenic mutations in the HFE gene.
|
We report a case of an 80-year-old woman with congenital spherocytosis who presented with massive iron overload. Iatrogenic iron overload could be ruled out. Familial history was suggestive of hereditary hemochromatosis; however, molecular genetic testing for the most common HFE mutations remained negative. The patient was treated successfully with phlebotomies. The hypothesis that this patient suffered from hereditary hemochromatosis is discussed on the basis of a brief review of the literature.
|
2,338,632 |
Population genetic structure of Anopheles gambiae mosquitoes on Lake Victoria islands, west Kenya.
|
Understanding the genetic structure of island Anopheles gambiae populations is important for the current tactics in mosquito control and for the proposed strategy using genetically-modified mosquitoes (GMM). Genetically-isolated mosquito populations on islands are a potential site for testing GMM. The objective of this study was to determine the genetic structure of A. gambiae populations on the islands in Lake Victoria, western Kenya.</AbstractText>The genetic diversity and the population genetic structures of 13 A. gambiae populations from five islands on Lake Victoria and six villages from the surrounding mainland area in the Suba District were examined using six microsatellite markers. The distance range of sampling sites varied between 2.5 and 35.1 km.</AbstractText>A similar level of genetic diversity between island mosquito populations and adjacent mainland populations was found. The average number of alleles per locus was 7.3 for the island populations and 6.8 for the mainland populations. The average observed heterozygosity was 0.32 and 0.28 for the island and mainland populations, respectively. A low but statistically significant genetic structure was detected among the island populations (FST = 0.019) and between the island and mainland populations (FST = 0.003). A total of 12 private alleles were found, and nine of them were from the island populations.</AbstractText>A level of genetic differentiation between the island and mainland populations was found. Large extent of gene flow between the island and mainland mosquito populations may result from wind- or human-assisted dispersal. Should the islands on Lake Victoria be used as a trial site for the release program of GMM, mosquito dispersal between the islands and between the island and the mainland should be vigorously monitored.</AbstractText>
|
2,338,633 |
[Genetic counseling in the Mental Health Research Center of the Russian Academy of Medical Sciences].<Pagination><StartPage>49</StartPage><EndPage>53</EndPage><MedlinePgn>49-53</MedlinePgn></Pagination><Abstract><AbstractText>Current concepts on the role of genetic factors in the development of schizophrenia and on the relative risk for this disease and spectrum disorders are reviewed. An analysis of the results of genetic counseling of 120 subjects revealed that, comparing to other mental disorders, patients with schizophrenia or relatives, mostly those having a schizophrenic parent (40%) or spouse (25%), referred more frequently for a consultation. Most of the referrals (70%) had a high educational level. As it was found out during the counseling, up to 20% of the relatives met a diagnosis of psychiatric disorders, mostly personality disorder (9%) and depressive state (7%). Psychological testing with personality inventories revealed a high level of personality abnormalities (schizoid--22%, hyperthymic--16% and obsessive-anxiety--4%) in 43% close relatives of patients seeking medicogenetic advice. The genetic counseling featured by the use of the comprehensive approach, basing on all obtained data (psychiatric, psychological, neurophysiologic etc.), that increases its accuracy and may assist families in taking a reasonable decision in birth planning.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Golimbet</LastName><ForeName>V E</ForeName><Initials>VE</Initials></Author><Author ValidYN="Y"><LastName>Demikova</LastName><ForeName>N S</ForeName><Initials>NS</Initials></Author><Author ValidYN="Y"><LastName>Alfimova</LastName><ForeName>M V</ForeName><Initials>MV</Initials></Author><Author ValidYN="Y"><LastName>Urarova</LastName><ForeName>L G</ForeName><Initials>LG</Initials></Author><Author ValidYN="Y"><LastName>Lezheĭko</LastName><ForeName>T V</ForeName><Initials>TV</Initials></Author><Author ValidYN="Y"><LastName>Asanov</LastName><ForeName>A Iu</ForeName><Initials>AIu</Initials></Author></AuthorList><Language>rus</Language><PublicationTypeList><PublicationType UI="D004740">English Abstract</PublicationType><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D016454">Review</PublicationType></PublicationTypeList><VernacularTitle>Opyt mediko-geneticheskogo konsul'tirovaniia v Nauchnom tsentre psikhicheskogo zdorov'ia RAMN.</VernacularTitle></Article><MedlineJournalInfo><Country>Russia (Federation)</Country><MedlineTA>Zh Nevrol Psikhiatr Im S S Korsakova</MedlineTA><NlmUniqueID>9712194</NlmUniqueID><ISSNLinking>1997-7298</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000046" MajorTopicYN="Y">Academic Medical Centers</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005817" MajorTopicYN="N">Genetic Counseling</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="Y">methods</QualifierName><QualifierName UI="Q000706" MajorTopicYN="Y">statistics & numerical data</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D001523" MajorTopicYN="N">Mental Disorders</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008605" MajorTopicYN="Y">Mental Health Services</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012106" MajorTopicYN="Y">Research</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012426" MajorTopicYN="N" Type="Geographic">Russia</DescriptorName></MeshHeading></MeshHeadingList><NumberOfReferences>27</NumberOfReferences></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2004</Year><Month>12</Month><Day>8</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>8</Month><Day>3</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2004</Year><Month>12</Month><Day>8</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">15581037</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="KIE"><PMID Version="1">15580696</PMID><DateCompleted><Year>2005</Year><Month>03</Month><Day>02</Day></DateCompleted><DateRevised><Year>2009</Year><Month>11</Month><Day>19</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0099-9660</ISSN><JournalIssue CitedMedium="Print"><PubDate><Year>2004</Year><Month>Feb</Month><Day>06</Day></PubDate></JournalIssue><Title>Wall Street journal (Eastern ed.)</Title><ISOAbbreviation>Wall St J (East Ed)</ISOAbbreviation></Journal>Bill seeking to ban DNA discrimination isn't really necessary.
|
Current concepts on the role of genetic factors in the development of schizophrenia and on the relative risk for this disease and spectrum disorders are reviewed. An analysis of the results of genetic counseling of 120 subjects revealed that, comparing to other mental disorders, patients with schizophrenia or relatives, mostly those having a schizophrenic parent (40%) or spouse (25%), referred more frequently for a consultation. Most of the referrals (70%) had a high educational level. As it was found out during the counseling, up to 20% of the relatives met a diagnosis of psychiatric disorders, mostly personality disorder (9%) and depressive state (7%). Psychological testing with personality inventories revealed a high level of personality abnormalities (schizoid--22%, hyperthymic--16% and obsessive-anxiety--4%) in 43% close relatives of patients seeking medicogenetic advice. The genetic counseling featured by the use of the comprehensive approach, basing on all obtained data (psychiatric, psychological, neurophysiologic etc.), that increases its accuracy and may assist families in taking a reasonable decision in birth planning.
|
2,338,634 |
HAEdb: a novel interactive, locus-specific mutation database for the C1 inhibitor gene.
|
Hereditary angioneurotic edema (HAE) is an autosomal dominant disorder characterized by episodic local subcutaneous and submucosal edema and is caused by the deficiency of the activated C1 esterase inhibitor protein (C1-INH or C1INH; approved gene symbol SERPING1). Published C1-INH mutations are represented in large universal databases (e.g., OMIM, HGMD), but these databases update their data rather infrequently, they are not interactive, and they do not allow searches according to different criteria. The HAEdb, a C1-INH gene mutation database (http://hae.biomembrane.hu) was created to contribute to the following expectations: 1) help the comprehensive collection of information on genetic alterations of the C1-INH gene; 2) create a database in which data can be searched and compared according to several flexible criteria; and 3) provide additional help in new mutation identification. The website uses MySQL, an open-source, multithreaded, relational database management system. The user-friendly graphical interface was written in the PHP web programming language. The website consists of two main parts, the freely browsable search function, and the password-protected data deposition function. Mutations of the C1-INH gene are divided in two parts: gross mutations involving DNA fragments >1 kb, and micro mutations encompassing all non-gross mutations. Several attributes (e.g., affected exon, molecular consequence, family history) are collected for each mutation in a standardized form. This database may facilitate future comprehensive analyses of C1-INH mutations and also provide regular help for molecular diagnostic testing of HAE patients in different centers.
|
2,338,635 |
Testing predictions of the double-strand break repair model relating to crossing over in Mammalian cells.
|
In yeast, four-stranded, biparental "joint molecules" containing a pair of Holliday junctions are demonstrated intermediates in the repair of meiotic double-strand breaks (DSBs). Genetic and physical evidence suggests that when joint molecules are resolved by the cutting of each of the two Holliday junctions, crossover products result at least most of the time. The double-strand break repair (DSBR) model is currently accepted as a paradigm for acts of DSB repair that lead to crossing over. In this study, a well-defined mammalian gene-targeting assay was used to test predictions that the DSBR model makes about the frequency and position of hDNA in recombinants generated by crossing over. The DSBR model predicts that hDNA will frequently form on opposite sides of the DSB in the two homologous sequences undergoing recombination [half conversion (HC); 5:3, 5:3 segregation]. By examining the segregation patterns of poorly repairable small palindrome genetic markers, we show that this configuration of hDNA is rare. Instead, in a large number of recombinants, full conversion (FC) events in the direction of the unbroken chromosomal sequence (6:2 segregation) were observed on one side of the DSB. A conspicuous fraction of the unidirectional FC events was associated with normal 4:4 marker segregation on the other side of the DSB. In addition, a large number of recombinants displayed evidence of hDNA formation. In several, hDNA was symmetrical on one side of the DSB, suggesting that the two homologous regions undergoing recombination swapped single strands of the same polarity. These data are considered within the context of modified versions of the DSBR model.
|
2,338,636 |
High throughput screening of genetic polymorphisms by matrix-assisted laser desorption ionization time-of-flight mass spectrometry.
|
In the post genomic era, the screening of many different genetic polymorphisms in large populations represents a major goal that will facilitate the understanding of individual genetic variability in the development of multi factor diseases and in drug response and toxicities. The increasing interest in these pathogenetic and pharmacogenomic studies by both academic and pharmaceutical industry researchers has increased the demand for broad genome association studies. This demand has produced a boom in the development of new and robust high throughput screening methods for genotype analysis. Matrix-assisted laser-desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) represents an emerging and powerful technique for DNA analysis because of its high speed, accuracy, no label requirement, and cost-effectiveness. So far, many MALDI-TOF MS approaches have been developed for rapid screening of single nucleotide polymorphisms (SNPs), variable sequences repeat, epigenotype analysis, quantitative allele studies, and for the discovery of new genetic polymorphisms. The more established methods are based on single base primer extension and minisequencing implemented with new chemical features to overcome the limitations associated with DNA analysis using MALDI-TOF MS. These new promising methods of genotyping include both photochemical and other different chemical and enzyme cleavage strategies that facilitate sample automation and MS analysis for both real-time genotyping and resequencing screening. In this review, we analyze and discuss in depth the advantages and the limitations of the more recent developments in MALDI-TOF MS analysis for large-scale genomic studies applications.
|
2,338,637 |
Microdissection techniques for molecular testing in surgical pathology.
|
To describe the techniques for microdissection of paraffin-embedded and frozen tissue sections for the use in molecular applications.</AbstractText>Original research papers and review papers and the authors' personal experiences.</AbstractText>Manual and laser-capture microdissection are described in detail, with specific protocols for sample preparation and instructions for performing the microdissection. A section addressing frequently asked questions is also included.</AbstractText>Microdissection is a technique that is very useful both in the research setting and for clinical molecular testing in paraffin-embedded tissue samples. The available techniques range from simple and inexpensive (manual microdissection) to complex and expensive (laser-capture microdissection). All of the techniques, however, require the user to be familiar with microscopy and histology.</AbstractText>
|
2,338,638 |
The -omics era and its impact.
|
To review the advances in clinically useful molecular biologic techniques and to identify their applications, as presented at the 12th Annual William Beaumont Hospital DNA Symposium.</AbstractText>The 7 manuscripts submitted were reviewed and their major findings were compared with literature on the same or related topics.</AbstractText>Manuscripts address the use of molecular techniques in the detection of severe acute respiratory syndrome (SARS) and bacterial ribosome mutations, which may lead to ribosome-targeted drug resistance; pharmacogenomics as a clinical laboratory service and example of warfarin dosing using CYP2C9 mutation analysis; definition of the potential of cytosine arabinoside incorporation into DNA to disrupt transcription using an in vitro model of oligonucleotides; use of laser capture microdissection to isolate solid tumor cells free of nontumor cells; and molecular methods used to classify lymphomas.</AbstractText>Two current issues related to the use of molecular tests in the clinical laboratories are (1) decentralization of molecular-based testing to a variety of nonmolecular laboratories and (2) need for wider acceptance of molecular-based testing through its incorporation in clinical practice guidelines. Molecular methods have had a major impact on infectious disease through the rapid identification of new infectious agents, SARS, and the characterization of drug resistance. Pharmacogenomics identifies the genetic basis for heritable and interindividual variation in response to drugs. The incorporation of the nucleoside analog, cytosine arabinoside, into DNA leads to local perturbation of DNA structure and reduces the ability of transcription factors to bind to their specific DNA binding elements as measured by electrophoretic mobility shift assays. Laser capture microdissection of tumor cells can provide an adequate number of cells for whole genome amplification. Gene expression microassay profiles of various lymphomas have modified classification systems and predict prognosis and response to therapy.</AbstractText>The current -omics era will continue to emphasize the use of microarrays and database software for genomic, transcriptomic, and proteomic screening to search for a useful clinical assay. The number of molecular pathologic techniques will expand as additional disease-associated mutations are defined.</AbstractText>
|
2,338,639 |
Animal models for studying respiratory syncytial virus infection and its long term effects on lung function.
|
Human respiratory syncytial virus (hRSV) infection causes a spectrum of illnesses ranging from mild infection to life-threatening bronchiolitis and respiratory failure. Human studies on the pathogenesis of RSV infection are invaluable, but animal models permit advances with the use of experimental strategies that would be inappropriate in human studies.</AbstractText>We review the advantages and disadvantages of various animal models for the study of hRSV infection.</AbstractText>No animal model of hRSV infection replicates the complete spectrum of disease severity seen in humans. Available models differ in their ability to incorporate genetic technology and to allow the study of immunity, vaccine efficacy and treatment interventions. Although hRSV establishes disease in primates, this advantage is outweighed by the impracticalities and cost of using such models. The study of bovine RSV infection in calves is appealing because of parallels with human disease. Among rodent models, BALB/c mice have helped delineate the mechanisms underlying vaccine-enhanced RSV disease, and cotton rats have been used for preclinical testing. The single major disadvantage of studying hRSV in rodent models is the limited extent to which this host-restricted human pneumovirus replicates in mouse lung tissue. The rodent-specific Pneumovirus pathogen, pneumonia virus of mice, causes an infection that mirrors severe bronchiolitis and pneumonia in infants infected with RSV, including robust virus replication with profound inflammation.</AbstractText>The recent development of the pneumonia virus of mice model has permitted exploration of the mechanisms of severe Pneumovirus disease in vivo with the use of sophisticated genetic tools and genetically manipulated mouse strains.</AbstractText>
|
2,338,640 |
Early onset may predict G101W CDKN2A founder mutation carrier status in Ligurian melanoma patients.
|
Although the presence of multiple cases of melanoma on the same side of a family is the best predictor of germline CDKN2A mutation, other features (i.e. early age at onset) may be useful to identify carriers. We analysed the records of 682 hospital-based Ligurian melanoma patients. Of these, 238 cases (34 familial, 14 non-familial multiple primary and 190 non-familial single primary melanomas) were consecutively enrolled for screening of the CDKN2A and CDK4 genes. Screening of the 34 familial patients revealed that nine were carriers of the CDKN2A G101W founder mutation. Of the 14 non-familial multiple primary melanoma patients, three carried the G101W founder mutation and one the P48T mutation. For the non-familial patients with a single melanoma, 17 of 190 carried germline CDKN2A mutations, with most (16/17) carrying the G101W Ligurian founder mutation and one a novel single base pair substitution, D74Y. The effect of mutation on age at diagnosis was significant (P=0.012) after correcting for melanoma type (familial or non-familial), number of primaries (single or multiple), gender and disease occurrence (incident or prevalent). Early age at onset may be a good predictor of CDKN2A mutation in Liguria, where the G101W founder mutation is prevalent among melanoma patients, independent of family history.
|
2,338,641 |
High expression of cyclin B1 predicts a favorable outcome in patients with follicular lymphoma.
|
Substantial research has been dedicated to the study of the relationship between genetic mechanisms regulating cell functions in tumors and how those tumors respond to various treatment regimens. Because these mechanisms are still not well understood, we have chosen to study the genetic makeup of 57 tumor samples from patients with follicular lymphoma (FL). Our goal was to develop a prognostic tool, which can be used as an aid in determining FL patients with tumors genetically predisposed to a successful treatment with the CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone) regimen. To select relevant genes, high-density oligonucleotide arrays were used. There were 14 genes highly expressed in FL patients that responded well to CHOP chemotherapy, and 11 of these were involved in G2/M transition of the cell cycle, in mitosis, or in DNA modulation. A high expression of CCNB1 (cyclin B1), CDC2, CDKN3A, CKS1B, ANP32E, and KIAA0101, but not of the proliferation-related antigen Ki-67, was associated with better survival rate in a univariate analysis. CCNB1 expression had an independent prognostic value when included in a multivariate analysis together with the 5 parameters of the follicular lymphoma international prognostic index.
|
2,338,642 |
Chemotherapeutic deletion of CTG repeats in lymphoblast cells from DM1 patients.
|
Myotonic dystrophy type 1 (DM1) is caused by the expansion of a (CTG).(CAG) repeat in the DMPK gene on chromosome 19q13.3. At least 17 neurological diseases have similar genetic mutations, the expansion of DNA repeats. In most of these disorders, the disease severity is related to the length of the repeat expansion, and in DM1 the expanded repeat undergoes further elongation in somatic and germline tissues. At present, in this class of diseases, no therapeutic approach exists to prevent or slow the repeat expansion and thereby reduce disease severity or delay disease onset. We present initial results testing the hypothesis that repeat deletion may be mediated by various chemotherapeutic agents. Three lymphoblast cell lines derived from two DM1 patients treated with either ethylmethanesulfonate (EMS), mitomycin C, mitoxantrone or doxorubicin, at therapeutic concentrations, accumulated deletions following treatment. Treatment with EMS frequently prevented the repeat expansion observed during growth in culture. A significant reduction of CTG repeat length by 100-350 (CTG).(CAG) repeats often occurred in the cell population following treatment with these drugs. Potential mechanisms of drug-induced deletion are presented.
|
2,338,643 |
Computational method for discovery of estrogen responsive genes.
|
Estrogen has a profound impact on human physiology and affects numerous genes. The classical estrogen reaction is mediated by its receptors (ERs), which bind to the estrogen response elements (EREs) in target gene's promoter region. Due to tedious and expensive experiments, a limited number of human genes are functionally well characterized. It is still unclear how many and which human genes respond to estrogen treatment. We propose a simple, economic, yet effective computational method to predict a subclass of estrogen responsive genes. Our method relies on the similarity of ERE frames across different promoters in the human genome. Matching ERE frames of a test set of 60 known estrogen responsive genes to the collection of over 18,000 human promoters, we obtained 604 candidate genes. Evaluating our result by comparison with the published microarray data and literature, we found that more than half (53.6%, 324/604) of predicted candidate genes are responsive to estrogen. We believe this method can significantly reduce the number of testing potential estrogen target genes and provide functional clues for annotating part of genes that lack functional information.
|
2,338,644 |
Pharmacogenomic genotyping methodologies.
|
"Personalized medicine" based on an individual's genetic makeup is slowly becoming a reality as pharmacogenomics moves from the research setting to the clinical laboratory. Concordance studies between genotype and phenotype have shown that inherited mutations in several key drug-metabolizing enzymes, such as cytochrome P450 ( CYP ) 2D6 , 2C9 , and 2C19 , result in several distinct phenotypes that lead to different individual responses following drug administration. One of the major driving forces behind pharmacogenomics and its ability to be used effectively are the technologies that are available. A beneficial genotyping test must identify most or all of the mutations that have a significant impact on the expression or function of drug-metabolizing enzymes, transporter proteins, and/or drug receptors. Selection of the appropriate technology will be based on several issues, including prior knowledge of the mutation/polymorphism, sensitivity/specificity, sample requirements, and cost. Since the future volume of pharmacogenomic testing is anticipated to be large, automation of pharmacogenomics will also become increasingly important. This paper provides an overview of current technologies available for assessing polymorphisms on a small- to large-scale basis.
|
2,338,645 |
Associations between relationship support and psychological reactions of participants and partners to BRCA1 and BRCA2 testing in a clinic-based sample.
|
Despite the potential importance of communication about genetic testing between test participants and their significant others, little is known about social support and communication between women undergoing BRCA1 and BRCA2 testing and their partners.</AbstractText>The aims of this longitudinal study were to examine communication about genetic testing during and following testing and to evaluate whether communication is associated with psychological distress reported by test participants and their partners.</AbstractText>Participants were 153 women who were undergoing genetic testing and 118 partners of women undergoing testing. Relationship communication and distress were evaluated at the time of pretest education and 6 months postdisclosure.</AbstractText>Overall, the decision to undergo testing was discussed by the majority of test participants and partners, and most couples felt their partners were supportive. Most women disclosed their results to their partners. Longitudinal analyses suggested that less support and protective buffering were associated with greater distress 6 months postdisclosure among test participants, whereas lower comfort in sharing concerns and partner support were associated with lower distress 6 months postdisclosure among partners.</AbstractText>The results of this study suggest that the majority of couples respond supportively during the test experience, but for a small subset of couples the process can strain the relationship. Partner support during this process is important, particularly for test participants dealing with an uninformative test result.</AbstractText>
|
2,338,646 |
DNA encapsulated magnesium and manganous phosphate nanoparticles: potential non-viral vectors for gene delivery.
|
Nanoparticles of Mg and Mn (II) phosphates encapsulating pDNA were prepared. The sizes of these DNA loaded particles in aqueous dispersion were about 100-130 nm diameter, and they aggregated with the progression of time. Although magnesium phosphate nanoparticles were crystalline, the manganous phosphate nanoparticles were found to be amorphous in nature. Nanoparticle dissolution and pDNA release were studied using atomic absorption spectroscopy and gel electrophoresis experiments. These inorganic phosphate nanoparticles dissolved in mild acidic pH ( approximately 5) releasing pDNA indicating that DNA release in the endosomal compartment is possible. In vitro transfection in HeLa cells demonstrated that while magnesium phosphate nanoparticles showed 100% efficiency, manganous phosphate nanoparticles exhibited about 85% transfection efficiency compared to that of 'polyfect', as control.
|
2,338,647 |
Detecting changes in the relative expression of KRAS2 splice variants using polymerase colonies.
|
Because splice variants of a gene with multiple isoforms give rise to proteins with different functions, it seems plausible that changes in the expression levels of the splice variants could be a contributing factor to disease. In fact, recent examples in the literature clearly illustrate that altered expression levels of splice variants may play an important role in disease. Furthermore, these works demonstrate that changes in expression levels could potentially be used to (1) monitor disease progression, (2) diagnose disease, and/or (3) determine disease state. In this work an immobilized form of PCR, known as polony technology, was adapted to quantify the relative expression levels of splice variants. Specifically, the relative expression levels of the two splice variants of the oncogene K-ras, namely, K-RAS2A and K-RAS2B, were determined using polony technology.
|
2,338,648 |
Microsatellite analysis in FVB/N mice.
|
The purpose of the study reported here was to identify, by size, a set of microsatellite markers for use in diagnostic genetic monitoring of FVB/N mouse colonies. A large panel of microsatellite markers were chosen on the basis oftheir high degree of allelic variability. These markers were then tested for their ability to amplify well under a standard set of polymerase chain reaction analysis conditions and to present an easily identifiable band on an agarose gel. From this panel, we chose at least one marker on each chromosome that amplified well under our standard high-throughput conditions. Using this approach, we identified the allele sizes for 27 microsatellite markers in the FVB/N strain of mice. Each autosomal chromosome and the X chromosome were analyzed using at least one locus marker. We have determined a precise size for FVB/N microsatellite alleles, as opposed to a description of size in relation to that of a known allele.
|
2,338,649 |
Duty to warn of genetic harm in breach of patient confidentiality.
|
Harm caused by the failure of health professionals to warn an at-risk genetic relative of her or his risk is genetic harm. Genetic harm should be approached using the usual principles of negligence. When these principles are applied, it is shown that (a) genetic harm is foreseeable; (b) the salient features of vulnerability, the health professional's knowledge of the risk to the genetic relative and the determinancy of the affected class and individual result in a duty of care being owed to the genetic relative; (c) the standard of care required to fulfil the duty to warn should be the expectations of a reasonable person in the position of the relative; and (d) causation is satisfied as the harm is caused by the failure of intervention of the health professional. Legislation enacted subsequent to the Report of the Commonwealth of Australia, Panel of Eminent Persons (Chair D Ipp), Review of the Law of Negligence Report (2002) and relevant to a duty to warn of genetic harm is considered. The modes of regulation and penalties for breach of any future duty to warn of genetic harm are considered.
|
2,338,650 |
Genogroup I and II noroviruses detected in stool samples by real-time reverse transcription-PCR using highly degenerate universal primers.
|
Genogroup I noroviruses from five genetic clusters and genogroup II noroviruses from eight genetic clusters were detected in stool extracts using degenerate primers and single-tube, real-time reverse transcription-PCR (RT-PCR) with SYBR Green detection. Two degenerate primer sets, designated MON 431-433 and MON 432-434, were designed from consensus sequences from the major clusters of norovirus based on the RNA-dependent RNA polymerase region of the norovirus genome. Viruses were extracted from stool samples within 20 min using a viral RNA extraction kit. Real-time RT-PCR for noroviruses generated semiquantitative results by means of the cycle threshold data and dilution endpoint standard curves. Presumptive product verification was achieved by evaluation of first-derivative melt graphs. Multiple clusters of noroviruses were identified simultaneously in a multiplex fashion by virtue of slight differences in melting temperature. The detection of 13 different genetic clusters suggests that the MON primers may serve as universal primers for most, if not all, of the noroviruses in a multiplex assay. Our technique provides a framework for broad application of real-time RT-PCR in clinical, environmental, and food testing laboratories for a wide range of noroviruses.
|
2,338,651 |
The person, the soul, and genetic engineering.
|
Argument about the ethical possibility of the therapeutic use of embryonic stem cells depends critically on the evaluation of the moral status of the very early embryo. Some assert that at the blastocyst stage it is only potentially human, not yet possessing the full ethical status of personhood, while others assert that from its formation the embryo possesses all the moral rights of a human person. It is shown that a decision on this issue is closely related to how human nature is to be understood. The idea of a person as a dual combination of body and spirit correlates naturally with the assertion of absolute personhood from conception, while an idea of human psychosomatic unity encourages a development picture in which the embryo only grows gradually into personhood. The latter view is seen to be encouraged by new advances in science which emphasise the importance of the concept of information in the discussion of complex systems. Other ethical issues related to human genetics are also briefly reviewed.
|
2,338,652 |
Attitudes of healthcare professionals and parents regarding genetic testing for violent traits in childhood.
|
Although no genetic tests for violent behaviour are currently available, research is ongoing to isolate genes related to a propensity for violence. We explored the attitudes of parents and healthcare professionals toward behavioural genetic testing for violence.</AbstractText>The attitudes of healthcare professionals and the lay public about genetic testing of children were elicited for a range of conditions through interviews with healthcare professionals and focus groups with parents. All participants were informed that behavioural genetic testing was the only hypothetical genetic test in our script and it was presented as the last condition.</AbstractText>The healthcare professionals included both genetic professionals and paediatricians. Focus group participants were recruited through various community institutions in the southside of Chicago and nearby suburbs.</AbstractText>The healthcare professionals tended to medicalise behavioural genetics, and were opposed to testing unless treatment was available. They were also uniformly concerned about the potential harms of this information, including unintentional adverse effects from environmental changes. In contrast, parents wanted genetic testing for behavioural traits to be available even in the absence of proved medical treatments. Not all parents wanted to test their own children, and some parents were concerned about self-fulfilling prophecies. Some parents, however, felt the information was important for their understanding, and could be used to support environmental changes.</AbstractText>While healthcare professionals medicalised behavioural genetics, parents focused on environmental causes and influences. Consequently, healthcare professionals do not want to offer testing if there is no clear treatment, while parents may want this information to shape environmental influences.</AbstractText>
|
2,338,653 |
Multiple spinal cavernous malformations with atypical phenotype after prior irradiation: case report.
|
This is the first reported case of histologically proven multiple spinal cavernous malformations (CMs) associated with previous irradiation. There are only two cases reported in the literature of solitary spinal CM after irradiation. In addition, the lesions in our patient had an atypical magnetic resonance imaging appearance mimicking intraspinal drop metastasis.</AbstractText>A 33-year-old man had an incidental finding of multiple enhancing intraspinal lesions as revealed by magnetic resonance imaging during staging tests for hepatocellular carcinoma. He had a history of Wilms' tumor at a young age with irradiation to the abdomen and pelvis. His family history included a paternal cousin with multiple cerebral CMs. The diagnosis of spinal drop metastasis was made, and further intervention was undertaken for confirmation.</AbstractText>The patient underwent a lumbar laminectomy with durotomy and excision of two of the lesions. Macroscopic analysis revealed mulberry-like appearance with nerve root involvement, and pathological analysis confirmed the diagnosis of CM. Genetic testing of the patient and his affected cousin was negative for the CCM1 gene.</AbstractText>The occurrence of multiple spinal lesions in the context of known neoplasia indicates a diagnosis of metastasis. Spinal CMs were not suspected preoperatively because of the atypical appearance revealed by magnetic resonance imaging scans, with uniform contrast enhancement and absence of hemosiderin rim. This case report is discussed relative to previous literature regarding radiation-induced CMs and other known causes of the disease.</AbstractText>
|
2,338,654 |
Cytogenetics and etiology of ambiguous genitalia in 120 pediatric patients.
|
A newborn with ambiguous genitalia needs prompt evaluation to detect life-threatening conditions (e.g., salt-losing crisis in congenital adrenal hyperplasia [CAH]) and gender assignment. Sex assignment in these children continues to be a challenging diagnostic and therapeutic problem. We studied the causes and characteristics of ambiguous genitalia in children who were referred to a cytogenetic laboratory.</AbstractText>We retrospectively reviewed a total of 120 medical records of patients with a primary indication of ambiguous genitalia that were referred to the cytogenetic lab for karyotyping during the period of 1989 to 1999. Diagnosis was based on a clinical impression from the primary physician, who was primarily a staff pediatrician, endocrinologist and/or pediatric urologist.</AbstractText>CAH was the underlying cause of ambiguous genitalia in 41 of 63 patients with ambiguity due to endocrine causes; 39 of these patients showed a 46,XX karyotype and 2 cases were 46,XY (both the 46,XY patients had 3 beta-hydroxylase deficiency). In 57 patients, ambiguous genitalia were due to congenital developmental defects. The most common endocrine case of ambiguous genitalia was 21-OH deficiency. Seven patients were classified as idiopathic with six showing the 46,XY and one the 46,XX karyotype. Gender was reassigned at birth or at diagnosis in 15 patients.</AbstractText>The etiology of ambiguous genitalia is variable. The physician managing these families could minimize the trauma of having a child with unidentified sex by providing appropriate genetic counseling so that the parents can make an early decision. Prenatal DNA testing in at-risk families should be considered and appropriate therapy offered to minimize or prevent genital ambiguity.</AbstractText>
|
2,338,655 |
[Polymorphisms and species specificity of D2S2944 and D1S2134 loci in Chinese Han population in Chengdu].
|
To obtain the data of polymorphism distribution of the two STR loci D2S2944, D1S2134 in Chinese Han population in Chengdu and evaluate their usefulness in the field of forensic science.</AbstractText>PCR, polyacrylamide gel electrophoresis (PAGE) and silver staining were used to analyze 120 unrelated individuals of Chinese Han ethnic group in Chengdu. Fourteen different animals: monkey, pig, dog, bull, goat, chicken, duck, fish, cat, rabbit, Guinea pig, mouse, eel and frog were selected as controls in this study for evaluating the species specificity of the two STR loci.</AbstractText>Eight alleles and twenty-two genotypes were found in D2S2944. The observed heterozygosity (h), discrimination power (DP), polymorphism information content (PIC), chance of paternity exclusion power (EP) were 0.824, 0.925, 0.78, 0.644 respectively. Ten alleles and twenty-six genotypes were observed in D1S2134. The h, DP, PIC and EP were 0.769, 0.920, 0.79, 0.543 respectively. The genotype distributions of the two loci were analyzed by some related software and no deviation from the Hardy-Weinberg equilibrium was observed. Evaluated by way of using different animals as controls, the two STR loci of human beings were found to have good specificity.</AbstractText>These data indicate that D1S2134 and D2S2944 are of good polymorphism, high EP and DP, and can be applied as the candidate genetic marks to forensic parentage testing and identification. The methods to analyze them are simple, dependable and repeatable.</AbstractText>
|
2,338,656 |
Ensuring the appropriate use of genetic tests.
|
Ensuring the correct use of genetic tests is an important challenge for health-policy makers. Many new genetic tests will identify susceptibility to common diseases or adverse drug responses. Some will lead to new prevention opportunities, but others will have minimal clinical value. Statutory regulation alone cannot guarantee appropriate use. Other strategies, including resource allocation and matters related to clinical governance - such as practice-guideline development and health-provider education - are also important.
|
2,338,657 |
Carrier frequency of congenital adrenal hyperplasia (21-hydroxylase deficiency) in a middle European population.
|
Based on newborn screening data, the carrier frequency of congenital adrenal hyperplasia (CAH) in the general population has been estimated to be 1:55. The higher CAH frequency (particularly of milder forms of the disease) reported for certain populations including Yugoslavs (1.6%) relates to population genetic and hormonal data. However, so far, true carrier frequency for CAH due to 21-OH deficiency has not been determined by comprehensive mutation analysis of the 21-OH gene (CYP21A2) in an unselected European population. This study used CYP21A2 genotyping (sequence/Southern blot analysis) to determine CAH carrier frequency in a middle European (Austrian) population. The study included 100 migrants from the former Yugoslavia and 100 individuals of non-Yugoslavian origin. None of these individuals showed clinical hyperandrogenism or had a family history of CAH. Genotyping 400 unrelated alleles from 200 clinically unaffected individuals, this study revealed a carrier frequency of 9.5%, including so-called "classic" (5.5%) and "nonclassic" (4%) CYP21A2-gene aberrations. The observed heterozygosity for CAH in Yugoslavs was not different (P = 0.8095) from that in non-Yugoslavs. In conclusion, the observed CAH carrier frequency of 9.5% suggests a higher prevalence of CAH heterozygosity in a middle European population than hitherto estimated independently of the individuals' Yugoslav or non-Yugoslav origin.
|
2,338,658 |
Genetic testing has no place as a routine diagnostic test in sporadic and familial cases of Alzheimer's disease.
|
The challenges inherent in diagnosing and treating patients with Alzheimer's disease are increasing. Early diagnosis and modification of risk factors have received growing attention from the media in recent years. As a result, the general public, and patients and family members, are increasingly better informed about the disease, its genetic background, and the possibilities for treatment. The physician is often faced with questions about hereditary patterns within the family and with requests to perform genetic testing. Children, with increasing frequency, ask for a separate appointment with the treating physician, during the patient's life or after the patient has died, to discuss whether they are likely to get the disease and whether genetic tests should be performed. In this paper, some of the clinical and ethical questions that physicians face are explored. Arguments as to why we think routine genetic assessment should not be part of the diagnostic examination of the patient suspected of Alzheimer's disease are given.
|
2,338,659 |
Role of human-tissue transglutaminase IgG and anti-gliadin IgG antibodies in the diagnosis of coeliac disease in patients with selective immunoglobulin A deficiency.
|
Selective IgA deficiency is associated with coeliac disease, and studies have shown an increased prevalence of coeliac disease in these patients ranging from 0.71 to 30.7%, depending on the test used for screening.</AbstractText>To determine the sensitivity of IgG anti-gliadin-antibodies and of IgG human-tissue-transglutaminase for diagnosing coeliac disease and assessing its prevalence in subjects with IgA deficiency.</AbstractText>We tested serum samples from 126 IgA-deficient children (66 female, median age: 10.8 years).</AbstractText>All samples were analysed to measure IgG anti-gliadin-antibodies and IgG anti-human-tissue-transglutaminase. Patients testing positive to either test underwent intestinal biopsy. Subjects testing positive for IgG anti-human-tissue-transglutaminase underwent genetic testing for the human leucocyte antigen heterodimer.</AbstractText>Twenty-seven of 126 subjects tested positive for IgG anti-gliadin-antibodies (five of whom tested positive also for IgG anti-human-tissue-transglutaminase) and 18 (including the aforementioned five) for IgG anti-human-tissue-transglutaminase. Intestinal biopsy was performed in 37 of the 40 patients who tested positive (three subjects refused). Eleven had positive intestinal biopsies all of whom tested positive for IgG anti-human-tissue-transglutaminase, but only five of these tested positive also for IgG anti-gliadin-antibodies. All 22 patients testing positive for anti-gliadin-antibody alone had normal intestinal mucosa. All the patients who tested positive for IgG anti-human-tissue-transglutaminase and underwent genetic screening (15/18) had the coeliac-related human leucocyte antigen. Overall, coeliac disease was diagnosed in 11 of the 126 subjects with IgA deficiency (8.7%).</AbstractText>The prevalence of coeliac disease in subjects with total IgA deficiency was 8.7%. Assay of IgG anti-human-tissue-transglutaminase can be recommended for screening coeliac disease in IgA-deficient subjects.</AbstractText>
|
2,338,660 |
[Prostate cancer: Diagnosis and staging].
|
The discovery and the use of serum prostate specific antigen (PSA) has considerably improved the diagnosis of prostate cancer during the past 20 years. Before PSA era, early diagnosis was only based on the digital rectal examination (DRE) of which the Limitations have been evidenced; over half of the tumours diagnosed by such means had already spread out of the prostate and were incurable. Assessment of serum PSA has allowed the diagnosis to be made at an earlier stage of the disease, curable by current treatments. Whichever the diagnostic tools, transrectal ultrasound (TRUS) prostatic biopsies remain necessary for diagnosis ascertainment, taking into account the low specificity of PSA assessment. The feasibility of a diagnosis at an early and curable stage of the disease has logically resulted in screening procedures aimed at reducing the high mortality related to prostate cancer. The numerous publications on prostate cancer screening provide precise information on the accuracy of available diagnostic means (PSA, DRE, TRUS, combined PSA and DRE), on the characteristics of screened tumours (stage and differentiation), and also on the population of men likely to benefit from the screening (age at beginning and end of the screening, frequency of PSA testing, identification of the men with ethnic and/or genetic predisposition). In those early diagnosed prostate cancers, the assessment of loco-regional cancer extension (extracapsular and/or, microscopic nodal involvement), remains unsatisfactory because no imaging technique (ultrasonography, CT scan, MRI,...) allows visualising the tumour itself or microscopic metastases. Nevertheless, the combination of multiple parameters such as DRE data, PSA level, biopsy data and tumour differentiation helps approaching with an increasing precision (nomograms) the true pathologic stage of the disease. Such advances allow distinguishing, among the very heterogeneous group of prostate cancers, tumours that differ from one to another in terms of disease stage, progression and prognosis, which is helpful for the determination of an adapted therapeutic strategy.
|
2,338,661 |
Mannose-binding lectin: laying the stepping stones from clinical research to personalized medicine.
|
As a key component of the complement system, mannose-binding lectin (MBL) is one of the linchpins of innate immunity. It is, therefore, not surprising that MBL2 genetic variants affecting the quantity and activity of the MBL protein in serum have been associated with increased susceptibility to infection and autoimmune diseases, and with poorer prognostic outcomes. This enhanced risk is particularly the case for children and immunosuppressed patients, especially when immunity is further compromised by coexistent primary or secondary immune deficiencies. In several disease areas, such as sepsis, cystic fibrosis, and recurrent childhood infections, the association between low MBL-producing allelic variants and disease risk and/or severity is particularly strong. It is here that the use of MBL testing and replacement therapy has reached the threshold of personalized medicine. The role of MBL in health and disease, advances in MBL testing methodologies and key areas for possible applications of MBL replacement therapy are reviewed.
|
2,338,662 |
[The case of a 86-years old woman first diagnosed with Huntington's disease].
|
This is the rare case of a woman first diagnosed with Huntington's disease at the age of 86. She was first seen at our hospital in 1999 for evaluation of dementia. Prior to her hospitalization, she had been treated with Melperone for restlessness. There was no essential psychopathology other than mild dementia (MMSE 21). A neurological work-up identified generalized involuntary movements and genetic testing revealed 40 CAG repeats. Over the course of the next several years, the patient began to exhibit the full range of symptoms associated with Huntington's disease, such as severe involuntary movements and progressive dementia. In the end, she was bed-ridden and only able to utter a few unintelligible words and she succumbed to an infection in 2003 at the age of 89, almost 4 years after her initial diagnosis of Huntington's disease. This case points to the need to consider Huntington's disease as a differential diagnosis even when evaluating the geropsychiatric population. It is particularly important to isolate involuntary movements which cannot be attributed to tardive dyskinesia in those who have been treated with neuroleptics in the past.
|
2,338,663 |
[Genetic tau-variants in patients with frontotemporal dementia].
|
[corrected] To evaluate tau-associated genetic polymorphisms in patients with sporadic frontotemporal dementia (FTD) and healthy control subjects.</AbstractText>Tau-gene sequence of 30 patients with FTD and 30 healthy controls was analysed by polymerase-chain-reaction (PCR). Subsequent sequencing was performed to identify exonic and intronic differences between both groups.</AbstractText>The following polypmorphisms, which are localized closely to each exon-intron-border, have been identified: In 37 % (n = 11) of the control subjects three different intronic polymorphisms occur simultaneously (Intron 2, 263, C --> Y; Intron 3, 590, A --> R; Intron 11, 150, G --> A). In the FTD group, this coexistance has been observed only in 17 % (n = 5).</AbstractText>In how far there exists a significant correlation between the newly identified triple polymorphism in the Tau gene and an alternated risk for FTD must be evaluated in a lager population. The proximity of these polymorphisms to the exon-intron border would facilitate functional influences on gene expression patterns. These preliminary results described, above potentially point to further pathogenetic factors in the genesis of FTD.</AbstractText>
|
2,338,664 |
[Neurobiology of violence: results of empirical and experimental studies of reactive violence].
|
An overview on neurobiological findings of violence is given: We present 1. neurochemical findings, 2. genetical aspects, 3. neuroanatomical correlates and 4. a functional network of violence. Even if specific neurobiological findings have not been found, impulsive violence is closely linked to serotonergic function and to several brain regions: orbitofrontal cortex, temporale lobe, amygdala. Knowing that violence has multifactorial determinants, a model on the neurobiological findings on violence is given. Thus, neurobiology is just an important part of conditions correlated with violence.
|
2,338,665 |
Genetic testing in New Zealand: the role of the general practitioner.
|
The aim of the study commissioned by the National Health Committee (NHC) was to explore the current practice and training needs of general practitioners (GPs) in relation to genetic testing in New Zealand, and to gauge GPs' perceptions of access to genetic services for their patients.</AbstractText>A postal survey was sent to a national, random sample of 600 GPs. Responses were received from 328 (56%) of the 586 eligible GPs.</AbstractText>Most GPs felt they lacked experience and knowledge of genetic testing, had received little formal training, and many were unsure of how to contact genetic services locally. GPs recognised the importance of their role in genetic testing and requested further information.</AbstractText>GPs in New Zealand have an increasingly important role to play in genetic testing. The nature of this role in the new genetics era needs to be carefully considered as will the best way to implement any future educational strategies.</AbstractText>
|
2,338,666 |
Methylenetetrahydrofolate reductase genotype affects risk of relapse after hematopoietic cell transplantation for chronic myelogenous leukemia.
|
Methylenetetrahydrofolate reductase (MTHFR) directs intracellular folate toward homocysteine metabolism and away from nucleotide synthesis. Two common MTHFR polymorphisms, C677T and A1298C, are associated with reduced enzyme activity. We evaluated the association of these polymorphisms with risk of relapse and bcr-abl mRNA transcript detection among 336 Caucasian patients who underwent allogeneic hematopoietic cell transplantation for chronic myelogenous leukemia.</AbstractText>Data on the transplant course and folate-related exposures were abstracted from medical records. MTHFR C677T and A1298C genotypes were determined using polymerase chain reaction/restriction fragment length polymorphism and TaqMan assays. Qualitative bcr-abl mRNA testing was conducted using a two-step reverse transcription-polymerase chain reaction assay. Cox regression analysis was used to assess the association between MTHFR genotypes and time to relapse and bcr-abl mRNA detection.</AbstractText>A statistically significant decreased risk of relapse was observed in patients with the variant A1298C genotype [1298AC, hazard ratio (HR)=0.48 and 95% confidence interval (CI)=0.26-0.88; 1298CC, HR=0.28 and 95% CI=0.09-0.84; P-trend <0.01). For the joint C677T/A1298C genotype, variant genotypes were associated with a decreased risk of relapse when compared with the wild-type 677CC/1298AA genotype. This risk was lowest for the 677CC/1298CC genotype (HR, 0.23; 95% CI, 0.08-0.72). MTHFR genotypes were not associated with bcr-abl transcript detection.</AbstractText>These findings suggest that individuals with the 677CC/1298AA genotype are at higher risk of relapse after hematopoietic cell transplantation and that the balance of intracellular folate metabolites available for nucleotide synthesis (regulated by the relative activity of the MTHFR enzyme) may affect the progression from bcr-abl positivity to clinical relapse.</AbstractText>
|
2,338,667 |
Initial experience with surgical treatment planning in the newly diagnosed breast cancer patient at high risk for BRCA-1 or BRCA-2 mutation.
|
Despite an abundance of information available for dealing with patients with BRCA-1 and BRCA-2 mutations, little guidance is available to assist the surgeon in dealing with the genetically high-risk patient recently diagnosed with breast cancer. A retrospective review was undertaken of 170 patients who underwent genetic counseling and testing over a 3-year period from March 2000 to March 2003. Forty-three of the 170 patients tested were diagnosed with breast cancer prior to genetic testing. Nine patients (20.9%) tested positive for a deleterious mutation. Fifty-eight percent underwent genetic counseling prior to definitive cancer surgery. Five of the 25 patients who underwent lumpectomy tested positive for a deleterious mutation. Testing results became available during systemic therapy or radiation was delayed until results were known. After counseling, all five patients testing positive went on to bilateral prophylactic mastectomy and reconstruction. None had radiation therapy. Because of a strong family history, eight patients elected to undergo prophylactic mastectomy and reconstruction prior to obtaining genetic test results; and despite compelling histories, all eight tested negative for a mutation. Treatment algorithms are developed to manage patients that are first discovered to be at high risk for a BRCA-1 or BRCA-2 mutation at the time they are diagnosed with breast cancer. Patients diagnosed with breast cancer who are discovered to be at high risk for a genetic mutation should undergo counseling prior to definitive surgery. This maximizes the time that patients have to consider options for prophylaxis and monitoring should their test be positive. It also prevents women who would otherwise be candidates for breast preservation from undergoing unnecessary radiation therapy should they chose prophylactic mastectomy in the face of a positive test.
|
2,338,668 |
Mutation analysis in F9 gene of 17 families with haemophilia B from Iran.
|
Seventeen haemophilia B families from Iran were investigated to determine the causative mutation. All the essential regions of the F9 gene were initially screened by conformational sensitive gel electrophoresis and exons with band shift were sequenced. Seven of the 15 mutations identified in these families were novel mutations. The mutations were authenticated in nine families as other affected members or heterozygous female carriers were available for verification.
|
2,338,669 |
Developmental validation of a single-tube amplification of the 13 CODIS STR loci, D2S1338, D19S433, and amelogenin: the AmpFlSTR Identifiler PCR Amplification Kit.
|
Analysis of length polymorphism at short tandem repeat (STR) loci utilizing the polymerase chain reaction (PCR) process has proven to be an ideal assay for human identification purposes. The short length of STR loci coupled with the amplification of target sequence through PCR allows for a robust, sensitive, and specific assay for highly polymorphic markers. A multiplex containing fifteen STR loci plus the gender-determining locus Amelogenin was developed to provide a single amplification/detection of all CODIS (Combined DNA Index System) STR loci (CSF1PO, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D21S11, FGA, TH01, TPOX, and vWA) as well as two internationally-accepted STRs (D2S1338 and D19S433). By incorporating five-dye fragment analysis technology and non-nucleotide linkers, previously optimized AmpFlSTR kit primer sequences have been maintained. This kit has been developed in accordance with the standards of the forensic community as defined by the DNA Advisory Board. Validation studies were performed to include developmental validation, and the results support the use of the AmpFlSTR Identifiler PCR Amplification Kit for human identity and parentage testing.
|
2,338,670 |
Molecular, clinical and political approaches to the problem of cleft lip and palate.
|
The oral facial complex in man appears to be exquisitively sensitive to genetic and environmental influences which is why clefts of the palate are the most common congenital birth anomaly. The development of the palate starts at about the 6th week of inter-uterine life and requires development of the palatal shelves from the maxillary processes of the first arch, shelf elevation, medial edge epithelial breakdown and mesenchyme flow with subsequent establishment of osteogenic and myogenic blastemata. This significant level of matrix turnover is partly regulated by the matrix metalloproteinases and potentially this could be affected by abnormalities in gene function. This may represent a common mechanism for a variety of different genes associated with clefting of the palate. The measurement of outcomes for children born with a cleft requires a wide input from a variety of specialities. The development of these outcome measures requires rigorous testing and validation, but it is now possible to use a variety of outcome measures to establish clinical standards and this has been done nationally. The impact of identifying a need for a change in organisation of service delivery was probably underestimated. It is clear that the current organisations in the National Health Service struggle to implement change, even with a detailed study and hard evidence. Reasons for this are outlined and a potential harder hitting strategy for effecting this change is outlined. The move towards primary care trusts within the latest reorganisation of the Health Service is potentially extremely damaging for specialised services for low incidence anomalies.
|
2,338,671 |
Effect of environment on resistance to the European corn borer (Lepidoptera: Crambidae) in maize.
|
The European corn borer, Ostrinia nubilalis (Hübner) (Lepidoptera: Crambidae), is a major pest of maize, Zea mays L., in many temperate parts of the world. Genotype-by-environment interaction effects can make relative performance unpredictable and may hamper selection for resistance to European corn borer. The objective of this study was to determine the effect of environment on genotypic reaction to European corn borer resistance in maize. A set of 12 maize inbred lines was chosen to represent a range of European corn borer responses. Eleven testing environments ranged from Delaware, Ohio, Illinois, Iowa, Nebraska, Missouri, to Mississippi. For length of stalk tunneling, environmental and genotypic main effects (estimated by restricted maximum likelihood) were >20- and 10-fold larger than their interaction effect, respectively. Length of tunneling means for genotypes (across environments) ranged from 10.1 to 35.4 cm. Several putatively resistant genotypes grouped with the susceptible checks, B73 and Mol7. By breaking factors and the interaction into single degree of freedom components, we observed that GEMS-0001 had significant crossover interactions toward less susceptibility in both Mississippi and the Nebraska environments. Environments displaying several crossover interactions indicated that European corn borer screening at these sites would not necessarily apply to other locations, whether due to small differences in experimental conduct and/or environmental effects. The five most resistant genotypes were fairly consistent across environments. Because all environments except Illinois used larvae from the same insectary, and these environments differed in damage intensity and rankings, it is unlikely that insect biotype was a factor contributing to genotype-by-environment effects.
|
2,338,672 |
The impact of diagnostic error on testing genetic association in case-control studies.
|
In case-control studies, subjects in the case group may be recruited from suspected patients who are diagnosed positively with disease. While many statistical methods have been developed for measurement error or misclassification of exposure variables in epidemiological studies, no studies have been reported on the effect of errors in diagnosing disease on testing genetic association in case-control studies. We study the impact of using the original Cochran-Armitage trend test assuming no diagnostic error when, in fact, cases and controls may be clinically diagnosed by an imperfect gold standard or a reference test. The type I error, sample size and asymptotic power of trend tests are examined under a family of genetic models in the presence of diagnostic error. The empirical powers of the trend tests are also compared by simulation studies under various genetic models.
|
2,338,673 |
A method for meta-analysis of molecular association studies.
|
Although population-based molecular association studies are becoming increasingly popular, methodology for the meta-analysis of these studies has been neglected, particularly with regard to two issues: testing Hardy-Weinberg equilibrium (HWE), and pooling results in a manner that reflects a biological model of gene effect. We propose a process for pooling results from population-based molecular association studies which consists of the following steps: (1) checking HWE using chi-square goodness of fit; we suggest performing sensitivity analysis with and without studies that are in HWE. (2) Heterogeneity is then checked, and if present, possible causes are explored. (3) If no heterogeneity is present, regression analysis is used to pool data and to determine the gene effect. (4) If there is a significant gene effect, pairwise group differences are analysed and these data are allowed to 'dictate' the best genetic model. (5) Data may then be pooled using this model. This method is easily performed using standard software, and has the advantage of not assuming an a priori genetic model.
|
2,338,674 |
[Predicting human tumor-specific promoter using transcription factor binding sites].
|
To predict human tumor-specific promoters using computer technology, three data sets of tumor-specific promoter sequences, transcription factor binding site sequences and non-tumor promoter sequences were collected, and the tumor-specific promoter sequences and non-tumor promoter sequences were analyzed for the comparative density of each unique transcription factor binding site. The density of each transcription factor binding site in the corresponding data set was used to derive the density ratio, from which the eigenvector was constructed to identify human tumor-specific promoters. This method proved to be highly accurate in predicting the tumor-specific promoters, with recognition rates of over 90% of the training sequences and over 80% of the testing sequences.
|
2,338,675 |
Association analysis between a functional polymorphism in the monoamine oxidase A gene promoter and severe mood disorders.
|
Monoamine oxidase A (MAOA) has been suggested to be involved in human behaviour and physiology due to its key role in the metabolism of several different biological amines including the neurotransmitters serotonin, norepinephrin and dopamine.Recently, a 30 bp repeat in the MAOA gene promoter (uMAOA) has been demonstrated to be polymorphic and to affect transcriptional activity. In the context of an association case-control study design, we analysed the uMAOA polymorphism in 389 unrelated patients affected by severe mood disorders (88 bipolar subjects and 301 major depressive individuals) and in 156 controls. No association was found between the uMAOA locus and bipolar disorder or major depression. However, an increase of high-activity uMAOA alleles was found in major depression female patients presenting a seasonal pattern (chi2=3.013, P=0.05) or psychotic symptoms in their episodes (chi2=2.679, P=0.07). In female bipolar disorder patients, long alleles were associated with longest times of admission (F=4.604, P=0.037). A trend for association with seasonal pattern was also defined in this group (data not corrected for multiple testing). Our results suggest that MAOA gene variation may modulate the expression of some clinical aspects of severe mood disorders, especially in females, and support the existence of a genetic and aetiologic heterogeneity underlying the diagnoses of bipolar disorder and major depression.
|
2,338,676 |
Psychiatric findings in four female carriers of Fabry disease.
|
Anderson-Fabry disease (AFD) is an X-linked recessive disorder of glycosphingolipid metabolism. Most female carriers are clinically symptomatic; however, psychiatric diagnoses have not been reported in this population. We describe four female carriers of AFD disease who met DSM-IV criteria for major depression. All cases had a score above 26 on the Hamilton Rating Scale for Depression, indicating severe depression. This was independent of the severity or number of symptoms of AFD disease. Excessive guilt, fatigue, occupational difficulty, suicidal ideation and depressed mood were findings in all cases. In conclusion, the common presence of depression in carriers of AFD implies the need for a multidisciplinary approach, including psychiatry, in management of these patients. Further studies are recommended to establish the etiology of psychiatric complications, as well as the incidence and the response to pharmacotherapy and psychotherapy.
|
2,338,677 |
Replicon system for Lassa virus.
|
Lassa virus is endemic to West Africa and causes hemorrhagic fever in humans. To facilitate the functional analysis of this virus, a replicon system was developed based on Lassa virus strain AV. Genomic and antigenomic minigenomes (MG) were constructed consisting of the intergenic region of S RNA and a reporter gene (Renilla luciferase) in antisense orientation, flanked by the 5' and 3' untranslated regions of S RNA. MGs were expressed under the control of the T7 promoter. Nucleoprotein (NP), L protein, and Z protein were expressed from plasmids containing the T7 promoter and internal ribosomal entry site. Transfection of cells stably expressing T7 RNA polymerase (BSR T7/5) with MG in the form of DNA or RNA and plasmids for the expression of NP and L protein resulted in high levels of Renilla luciferase expression. The replicon system was optimized with respect to the ratio of the transfected constructs and by modifying the 5' end of the MG. Maximum activity was observed 24 to 36 h after transfection with a signal-to-noise ratio of 2 to 3 log units. Northern blot analysis provided evidence for replication and transcription of the MG. Z protein downregulated replicon activity close to background levels. Treatment with ribavirin and alpha interferon inhibited replicon activity, suggesting that both act on the level of RNA replication, transcription, or ribonucleoprotein assembly. In conclusion, this study describes the first replicon system for a highly pathogenic arenavirus. It is a tool for investigating the mechanisms of replication and transcription of Lassa virus and may facilitate the testing of antivirals outside a biosafety level 4 laboratory.
|
2,338,678 |
Serial SimCoal: a population genetics model for data from multiple populations and points in time.
|
We present Serial SimCoal, a program that models population genetic data from multiple time points, as with ancient DNA data. An extension of SIMCOAL, it also allows simultaneous modeling of complex demographic histories, and migration between multiple populations. Further, we incorporate a statistical package to calculate relevant summary statistics, which, for the first time allows users to investigate the statistical power provided by, conduct hypothesis-testing with, and explore sample size limitations of ancient DNA data.</AbstractText>Source code and Windows/Mac executables at http://www.stanford.edu/group/hadlylab/ssc.html</AbstractText>[email protected].</AbstractText>
|
2,338,679 |
Two novel CAV3 gene mutations in Japanese families.
|
Caveolin-3 deficiency is a rare, autosomal dominant, muscle disorder caused by caveolin-3 gene (CAV3) mutations and consists of four clinical phenotypes: limb-girdle muscular dystrophy type 1C (LGMD-1C), rippling muscle disease, distal myopathy, and familial hyperCKemia. So far, only 13 mutations have been reported. We here report two novel heterozygous mutations, 96C>G (N32K) and 128T>A (V43E), in the CAV3 gene in two unrelated Japanese families with LGMD-1C. Both probands presented with elevated serum CK level with calf muscle hypertrophy in their childhood but without apparent muscle weakness. However, their mothers showed mild limb-girdle weakness in addition to high CK level. Caveolin-3 was deficient and caveolae were lacking in muscles from both patients. Our data confirm that caveolin-3 deficiency causes LGMD-1C and expand the variability in CAV3 gene mutations.
|
2,338,680 |
Application of multiplex ligation-dependent probe analysis to define a small deletion encompassing PMP22 exons 4 and 5 in hereditary neuropathy with liability to pressure palsies.
|
Hereditary neuropathy with liability to pressure palsies arises as a result of defects at the chromosome 17p11.2-12 locus and in 84% of cases a 1.5 Mb deletion containing the PMP22 gene is detected by analysis that utilises polymorphic (CA)n repeat markers which flank this gene. We report the clinical and electrophysiological findings observed in a kindred with three members affected by HNPP due to a deletion containing exons 4 and 5 of the PMP22 gene. This small deletion cannot be detected using standard analysis with polymorphic (CA)n repeat markers and a definitive diagnosis was made by multiplex ligation-dependent probe analysis of PMP22 exons 1A-5. MLPA can be readily utilised as a routine diagnostic laboratory test to detect the common HNPP 1.5 Mb deletion, as well as the reciprocal 1.5 Mb insertion observed in CMT1A, but has the advantage over other diagnostic techniques of being able to define single exon deletions.
|
2,338,681 |
Magnetic resonance imaging of muscle in congenital myopathies associated with RYR1 mutations.
|
Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are associated with a wide range of phenotypes, comprising central core disease and distinct subgroups of multi-minicore disease. We report muscle MRI findings of 11 patients from eight families with RYR1 mutations (n=9) or confirmed linkage to the RYR1 locus (n=2). Patients had clinical features of a congenital myopathy with a wide variety of associated histopathological changes. Muscle MR images showed a consistent pattern characterized by (a) within the thigh: selective involvement of vasti, sartorius, adductor magnus and relative sparing of rectus, gracilis and adductor longus; (b) within the lower leg: selective involvement of soleus, gastrocnemii and peroneal group and relative sparing of the tibialis anterior. Our findings indicate that patients with RYR1-related congenital myopathies have a recognizable pattern of muscle involvement irrespective of the variability of associated histopathological findings. Muscle MRI may supplement clinical assessment and aid selection of genetic tests particularly in patients with non-diagnostic or equivocal histopathological features.
|
2,338,682 |
Magnetic resonance imaging of muscle in nemaline myopathy.
|
We report muscle MRI findings of 10 patients from 8 families with nemaline myopathy. Patients with involvement of the nebulin (NEB) gene showed a consistent pattern of selective muscle involvement corresponding to clinical severity. In mild cases, there was complete sparing of thigh muscles and selective involvement of tibialis anterior and soleus. In moderate cases, there was predominant involvement of rectus femoris, vastus lateralis and hamstring muscles and diffuse involvement of anterior compartment and soleus. Patients with nemaline myopathy secondary to mutations in the skeletal muscle alpha-actin (ACTA1) gene showed diffuse involvement of thigh and leg muscles with relative sparing of the gastrocnemii. Selective muscle involvement in both genetic categories was distinct from what has been reported in other congenital myopathies. We conclude that muscle MRI may be applied to distinguish nemaline myopathy from other conditions with similar clinical and histopathological features, to supplement clinical assessment in individual patients and to help direct genetic testing.
|
2,338,683 |
Novel mutations in the BCHE gene in patients with no butyrylcholinesterase activity.
|
Butyrylcholinesterase (BCHE) deficiency is characterized by prolonged apnea after the use of certain muscle relaxants with the genetic defect lying in the BCHE gene.</AbstractText>Two Chinese patients with no serum BCHE activity were studied. The BCHE genes were screened for mutations by polymerase chain reaction and direct DNA sequencing.</AbstractText>Of the four mutations detected, two novel mutations were identified in the two patients, i.e., F474L, and an insertion of an adenine between nucleotide positions 395 and 396. This information was used to screen the immediate families of the patients for carrier status.</AbstractText>We established the molecular basis of butyrylcholinesterase deficiency in two Chinese patients. The developed mutation detection assay provides a reliable method for identifying mutant BCHE carriers.</AbstractText>
|
2,338,684 |
Gene mutations in retinitis pigmentosa and their clinical implications.
|
Retinitis pigmentosa (RP) is a group of inherited progressive retinal diseases affecting about 1 in 3500 people worldwide. So far, there is no prevention or cure, with permanent visual loss or even blindness the ultimate consequence usually after midlife. The genetics of RP are complex. It can be sporadic, autosomal dominant, autosomal recessive, or X-linked. Thirty-two genes are known to be associated with RP, sometimes the same gene gets involved in different inheritance traits. Some RP cases have a digenic cause. About 60% RP cases still have no known genetic cause. A large number of mutations cause RP, and they can be deletions, insertions, or substitutions that cause missense mutations or truncations. The RHO, RP1, and RPGR genes contribute the greatest number of known mutations causative of RP. But there is no single mutation that alone accounts for more than 10% of unrelated patients. Genetic testing for RP therefore requires screening for a group of genes. High-throughput and automated sequence detection technologies are essential. Due to the complexity in phenotype and genetics, and the fact that RP is untreatable, genetic testing for presymptomatic diagnosis of RP is controversial. Meanwhile, new genes are still to be identified, mostly by family linkage and sib-pair analysis. Research on gene therapy for RP requires information on gene mutations causative of RP.
|
2,338,685 |
Single-track sequencing for genotyping of multiple SNPs in the N-acetyltransferase 1 (NAT1) gene.
|
Fast, cheap and reliable methods are needed to identify large populations, which may be at risk in relation to environmental exposure. Polymorphisms in NAT1 (N-acetyl transferase) may be suitable markers to identify individuals at risk.</AbstractText>A strategy allowing to address simultaneously 24 various genetic variants in the NAT1 gene using the single sequencing reaction method on the same PCR product is described. A modified automated DNA sequencing using only one of the sequence terminators was used to genotype PCR products in single-track sequencing reactions of NAT1 and was shown to be universal for both DNA sequencing using labeled primers and labeled nucleotides. By this method we detected known SNPs at site T640G, which confers the NAT1*11 allele with frequency of 0.036, further T1088A and C1095A with frequency of 0.172 and 0.188, respectively and a deletion of TAATAATAA in the poly A signal area with a frequency 0.031. All observed frequencies were in Hardy Weinberg equilibrium and comparable to those in Caucasian population. The single-track signatures of the variant genotypes were verified on samples previously genotyped by RLFP.</AbstractText>The method could be of great help to scientists in the field of molecular epidemiology of screening of large populations for known informative biomarkers of susceptibility, such as NAT1.</AbstractText>
|
2,338,686 |
Mouse models of diabetic nephropathy.
|
Mice provide an experimental model of unparalleled flexibility for studying mammalian diseases. Inbred strains of mice exhibit substantial differences in their susceptibility to the renal complications of diabetes. Much remains to be established regarding the course of diabetic nephropathy (DN) in mice as well as defining those strains and/or mutants that are most susceptible to renal injury from diabetes. Through the use of the unique genetic reagents available in mice (including knockouts and transgenics), the validation of a mouse model reproducing human DN should significantly facilitate the understanding of the underlying genetic mechanisms that contribute to the development of DN. Establishment of an authentic mouse model of DN will undoubtedly facilitate testing of translational diagnostic and therapeutic interventions in mice before testing in humans.
|
2,338,687 |
A new mixture model approach to analyzing allelic-loss data using Bayes factors.
|
Allelic-loss studies record data on the loss of genetic material in tumor tissue relative to normal tissue at various loci along the genome. As the deletion of a tumor suppressor gene can lead to tumor development, one objective of these studies is to determine which, if any, chromosome arms harbor tumor suppressor genes.</AbstractText>We propose a large class of mixture models for describing the data, and we suggest using Bayes factors to select a reasonable model from the class in order to classify the chromosome arms. Bayes factors are especially useful in the case of testing that the number of components in a mixture model is n0 versus n1. In these cases, frequentist test statistics based on the likelihood ratio statistic have unknown distributions and are therefore not applicable. Our simulation study shows that Bayes factors favor the right model most of the time when tumor suppressor genes are present. When no tumor suppressor genes are present and background allelic-loss varies, the Bayes factors are often inconclusive, although this results in a markedly reduced false-positive rate compared to that of standard frequentist approaches. Application of our methods to three data sets of esophageal adenocarcinomas yields interesting differences from those results previously published.</AbstractText>Our results indicate that Bayes factors are useful for analyzing allelic-loss data.</AbstractText>
|
2,338,688 |
The use of pharmacokinetic and pharmacodynamic data in the assessment of drug safety in early drug development.
|
The pharmaceutical industry continues to look for ways to reduce drug candidate attrition throughout the drug discovery and development process. A significant cause of attrition is due to safety issues arising either as a result of animal toxicity testing or in the clinical programme itself. A factor in the assessment of safety during early drug development is the pharmacokinetic profile of the compound. This allows safety data to be considered in the light of systemic drug exposure and therefore permits a quantitative assessment. This is particularly applicable when assessing the risk of a new chemical entity (NCE) in relation to safety parameters such as QT interval prolongation, where free plasma concentrations have been shown to be predictive of this property in relation to potency in preclinical testing. Prior to actual human exposure it is therefore important to be able to predict reliably the pharmacokinetic behaviour of an NCE in order to place such safety findings into a quantitative risk context. The emerging science of pharmacogenetics is likely to further our ability to assess the risk of NCEs to populations and individuals due to genetic variance. The drug metabolizing enzyme CYP2D6 has been recognized as providing the potential to result in widely differing systemic drug exposure in the patient population due to polymorphic expression. Further knowledge is likely to add to our understanding of population differences in exposure and response and aid in the identification of risk factors. One potential strategy for improving the effectiveness of the drug discovery process is to obtain clinical pharmacokinetic data more rapidly in order to assess more accurately the potential for both efficacy and safety of an NCE. Whilst procedures and technologies are available that allow this on the microdose scale, it is important that we recognize potential limitations of these approaches in order that they can be applied beneficially.
|
2,338,689 |
Frequency of haemoglobinopathies and glucose-6-phosphate dehydrogenase deficiency in Basra.
|
Basra, southern Iraq, was mapped for haemoglobinopathies and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Of 1064 couples aged 14-60 years recruited from the Public Health Laboratory, 49 had beta-thalassaemia trait, 69 had sickle-cell trait, 2 had haemoglobin D trait, 2 had haemoglobin C trait and 1 had high persistent fetal haemoglobin. Carriers of major beta-globin disorders comprised 11.48%. G6PD deficiency was detected in 133 individuals (12.5%). Only 10 couples (0.94%) were at risk of having children affected with either sickle-cell disease or beta-thalassaemia major. These defects constitute a real health problem and necessitate a management plan and public health education for early diagnosis and therapy.
|
2,338,690 |
Testing the out-of-Florida hypothesis on the origin of cheating in the yucca-yucca moth mutualism.
|
Mutualistic interactions can be exploited by cheaters that take the rewards offered by mutualists without providing services in return. The evolution of cheater species from mutualist ancestors is thought to be possible under particular ecological conditions. Here we provide a test of the first explicit model of the transition from mutualism to antagonism. We used the obligate pollination mutualism between yuccas and yucca moths to examine the origins of a nonpollinating cheater moth, Tegeticula intermedia, and its pollinating sister species, T. cassandra. Based on geographic distribution and ecological factors affecting the pollinators, previous research had indicated that the cheaters evolved in Florida as a result of sympatry of T. cassandra and another pollinator species. We used mitochondrial DNA (mtDNA) sequences and amplified fragment length polymorphism (AFLP) data to investigate the phylogeographic history of the pollinator-cheater sister pair and to test whether the cheaters arose in Florida. Contrary to predictions, phylogenetic and population genetic analyses suggested that the cheaters evolved in the western United States and subsequently spread eastward. Western populations of cheaters had the most ancestral haplotypes and the highest genetic diversity, and there was also significant genetic structure associated with a geographic split between eastern and western populations. In comparison, there was evidence for weak genetic structure between northern and southern pollinator populations, suggesting a long history in Florida. The western origin of the cheaters indicated that the pollinators have more recently become restricted to the southeastern United States. This was supported by AFLP analyses that indicated that the pollinators were more closely related to the western cheaters than they were to geographically proximate cheaters in the east. Shared mtDNA between pollinators and eastern cheaters suggested hybridization, possibly in a secondary contact zone. The results negate the out-of-Florida hypothesis and reveal instead a long, complex, and disparate history for the pollinator-cheater sister pair.
|
2,338,691 |
Friedreich ataxia in carriers of unstable borderline GAA triplet-repeat alleles.
|
Friedreich ataxia patients are homozygous for expanded GAA triplet-repeats containing 66 to 1,700 triplets. We report two patients with delayed-onset, hyperreflexia and gradually progressive disease. Both were heterozygous for large expansions and also carried alleles with 44 and 66 triplet-repeats, respectively. Due to somatic instability, 15% (GAA-44) and 75% (GAA-66) of cells contained alleles with >/=66 triplet-repeats, constituting a plausible mechanism for their mild phenotype. A sibling with a stable GAA-37 allele and a large expansion was clinically normal. Instability of borderline alleles confers a risk for Friedreich ataxia, and the range of pathogenic alleles is broader than previously recognized.
|
2,338,692 |
Molecular screening and association analyses of the interleukin 6 receptor gene variants with type 2 diabetes, diabetic nephropathy, and insulin sensitivity.
|
IL-6 levels and polymorphisms have been implicated in type 2 diabetes mellitus (T2DM) and insulin resistance. The IL-6 receptor (IL-6R) comprises two subunits, IL-6R and gp130, of which IL-6R confers specificity to IL-6 action and is located in a region of replicated linkage to T2DM on chromosome 1q21. We screened this gene for variation in Northern European Caucasian and African-American ethnic groups. We identified 11 variants with a minor allele frequency over 5%, including two amino acid changes (D358A and V385I) and four variants in the 3' untranslated region. No variant was associated with obesity or measures of insulin sensitivity, but two single nucleotide polymorphisms in the 3' untranslated region showed a trend to an association with T2DM in all Caucasians, and three single nucleotide polymorphisms, including D358A, showed a trend (P < 0.06) to an association with T2DM among the subset of Northern European Caucasians. Variant V385I was unique to African-Americans and was significantly associated with diabetes and diabetic nephropathy (P < 0.05). Among individuals heterozygous for the four variants in the transcribed sequence, one allele was significantly overrepresented, thus suggesting the existence of a regulatory variant controlling mRNA stability or expression. IL-6R is not likely to explain the linkage to diabetes in this region, but our work supports a minor role of variants in T2DM risk and suggests that sequence variants may alter IL-6R mRNA levels and possibly levels of soluble IL-6R.
|
2,338,693 |
Variation in the interleukin-6 receptor gene associates with type 2 diabetes in Danish whites.
|
Interleukin-6 (IL-6) is a pleiotropic cytokine involved in the pathophysiology of various human diseases such as type 2 diabetes and obesity. IL-6 signals via a heterodimeric receptor complex consisting of a soluble IL-6 alpha-subunit (IL-6 receptor [IL6R]) and a signal transducing subunit (gp130). The IL6R gene maps to an important candidate locus for type 2 diabetes on chromosome 1q21. An Asp358Ala polymorphism of the IL6R has been reported to associate with obesity in Pima Indians. We investigated the Asp358Ala polymorphism in relation to type 2 diabetes, obesity, and other pre-diabetic quantitative traits among Danish whites. By applying a recessive genetic model in a case-control study of 1,349 type 2 diabetic patients and 4,596 glucose-tolerant control subjects, we found a significant difference in genotype distribution (P = 0.008) and in allele frequency (Ala-allele 38.3% [95% CI 36.5-40.1] in diabetic subjects vs. 41.2% [40.2-42.2] in control subjects; P = 0.007). The odds ratio for the Asp/Asp carriers versus Ala/Ala carriers was 1.38 (1.09-1.71). Among 4,251 middle-aged glucose-tolerant subjects, the Asp358Ala polymorphism was not associated with estimates of obesity, post-oral glucose tolerance test serum insulin release, or the homeostasis model assessment of insulin resistance index. In conclusion, the Asp358Ala polymorphism of the IL6R associates with type 2 diabetes in Danish whites.
|
2,338,694 |
Heterogeneity in the magnitude of the insulin gene effect on HLA risk in type 1 diabetes.<Pagination><StartPage>3286</StartPage><EndPage>3291</EndPage><MedlinePgn>3286-91</MedlinePgn></Pagination><Abstract><AbstractText>There is still uncertainty concerning the joint action of the two established type 1 diabetes susceptibility loci, the HLA class II DQB1 and DRB1 genes (IDDM1) and the insulin gene (INS) promoter (IDDM2). Some previous studies reported independence, whereas others suggested heterogeneity in the relative effects of the genotypes at these disease loci. In this study, we have assessed the combined effects of the HLA-DQB1/DRB1 and INS genotypes in 944 type 1 diabetic patients and 1,023 control subjects, all from Sardinia. Genotype variation at INS significantly influenced disease susceptibility in all HLA genotype risk categories. However, there was a significant heterogeneity (P = 2.4 x 10(-4)) in the distribution of the INS genotypes in patients with different HLA genotypes. The INS predisposing genotype was less frequent (74.9%) in high-risk HLA genotype-positive patients than in those with HLA intermediate-risk (86.1%) and low-risk (84.8%) categories. Gene-gene interaction modeling led to rejection of the additive model, whereas a multiplicative model showed a better, albeit still partial, fit to the observed data. These genetic results are consistent with an interaction between the protein products of the HLA and INS alleles, in which both the affinity of the various HLA class II molecules for a preproinsulin-derived peptide and the levels of this peptide in the thymus act jointly as key regulators of type 1 diabetes autoimmunity.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Motzo</LastName><ForeName>Costantino</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Dipartimento di Scienze Biomediche e Biotecnologie, Universita' di Cagliari, Sardinia, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Contu</LastName><ForeName>Daniela</ForeName><Initials>D</Initials></Author><Author ValidYN="Y"><LastName>Cordell</LastName><ForeName>Heather J</ForeName><Initials>HJ</Initials></Author><Author ValidYN="Y"><LastName>Lampis</LastName><ForeName>Rosanna</ForeName><Initials>R</Initials></Author><Author ValidYN="Y"><LastName>Congia</LastName><ForeName>Mauro</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Marrosu</LastName><ForeName>Maria Giovanna</ForeName><Initials>MG</Initials></Author><Author ValidYN="Y"><LastName>Todd</LastName><ForeName>John A</ForeName><Initials>JA</Initials></Author><Author ValidYN="Y"><LastName>Devoto</LastName><ForeName>Marcella</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Cucca</LastName><ForeName>Francesco</ForeName><Initials>F</Initials></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>E.1109</GrantID><Acronym>TI_</Acronym><Agency>Telethon</Agency><Country>Italy</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D003160">Comparative Study</PublicationType><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Diabetes</MedlineTA><NlmUniqueID>0372763</NlmUniqueID><ISSNLinking>0012-1797</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D006680">HLA Antigens</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D006683">HLA-DQ Antigens</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D059866">HLA-DQ beta-Chains</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C069051">HLA-DQB1 antigen</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D006684">HLA-DR Antigens</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D059811">HLA-DRB1 Chains</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D003922" MajorTopicYN="N">Diabetes Mellitus, Type 1</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="Y">epidemiology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005190" MajorTopicYN="N">Family</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006680" MajorTopicYN="N">HLA Antigens</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006683" MajorTopicYN="N">HLA-DQ Antigens</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D059866" MajorTopicYN="N">HLA-DQ beta-Chains</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006684" MajorTopicYN="N">HLA-DR Antigens</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D059811" MajorTopicYN="N">HLA-DRB1 Chains</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006650" MajorTopicYN="N">Histocompatibility Testing</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012016" MajorTopicYN="N">Reference Values</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018570" MajorTopicYN="N">Risk Assessment</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012307" MajorTopicYN="N">Risk Factors</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2004</Year><Month>11</Month><Day>25</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>4</Month><Day>15</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2004</Year><Month>11</Month><Day>25</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">15561961</ArticleId><ArticleId IdType="doi">10.2337/diabetes.53.12.3286</ArticleId><ArticleId IdType="pii">53/12/3286</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">15561692</PMID><DateCompleted><Year>2005</Year><Month>04</Month><Day>21</Day></DateCompleted><DateRevised><Year>2021</Year><Month>12</Month><Day>03</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">1520-4391</ISSN><JournalIssue CitedMedium="Print"><PubDate><Year>2004</Year></PubDate></JournalIssue><Title>Hematology. American Society of Hematology. Education Program</Title><ISOAbbreviation>Hematology Am Soc Hematol Educ Program</ISOAbbreviation></Journal>Stem cell transplantation (cord blood transplants).<Pagination><StartPage>354</StartPage><EndPage>371</EndPage><MedlinePgn>354-71</MedlinePgn></Pagination><Abstract><AbstractText>Allogeneic stem cell transplantation is an accepted treatment modality for selected malignant and non-malignant diseases. However, the ability to identify suitably matched related or unrelated donors can be difficult in some patients. Alternative sources of stem cells such as cord blood provide a readily available graft for such patients. Data accumulated over the past several years have demonstrated that the use of cord blood is an accepted source of stem cells for pediatric patients. Since the cell numbers of hematopoietic progenitors in cord blood is limited and the collection can occur only in a single occasion, its use in adult patients can be more problematic. Here, new developments in the use of cord blood for adults and studies aimed at expansion of cord blood cells and immune reconstitution are described. In Section I, Dr. Nelson Chao describes the early data in cord blood transplantation in adult patients. The patient outcomes are reviewed and analyzed for various factors such as cell dose, HLA typing, and patient selection that could have contributed to the final outcome of these adult patients. Myeloablative as well as nonmyeloablative approaches are presented. Discussion of the various benefits and risks are presented. More recent data from multiple single institutions as well as larger registry data comparisons are also provided. Analyses of these studies suggest methods to improve on the outcome. These newer data should lead to a logical progression in the use of cord blood cells in adult patients. In Section II, Dr. Stephen Emerson describes the historical efforts associated with expansion of hematopoietic stem cells, specifically with cord blood cells. These efforts to expand cord blood cells continue with novel methods. Moreover, a better understanding of stem cell biology and signaling is critical if we are to be able to effectively expand these cells for clinical use. An alternative, more direct, approach to expanding stem cells could be achieved by specific genetic pathways known or believed to support primitive HSC proliferation such as Notch-1 receptor activation, Wnt/LEF-1 pathway induction, telomerase or the Homeobox (Hox) gene products. The clinical experience with the use of expanded cord blood cells is also discussed. In Section III, Dr. Kenneth Weinberg describes immune reconstitution or lack thereof following cord blood transplantation. One of the hallmarks of successful hematopoietic stem cell transplantation is the ability to fully reconstitute the immune system of the recipient. Thus, the relationship between stem cell source and the development of T lymphocyte functions required for protection of the recipient from infection will be described, and cord blood recipients will be compared with those receiving other sources of stem cells. T cell development is described in detail, tracking from prethymic to postthymic lymphocytes with specific attention to umbilical cord blood as the source of stem cells. Moreover, a discussion of the placenta as a special microenvironment for umbilical cord blood is presented. Strategies to overcome the immunological defects are presented to improve the outcome of these recipients.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Chao</LastName><ForeName>Nelson J</ForeName><Initials>NJ</Initials><AffiliationInfo><Affiliation>Duke University, Durham, NC 27705-3976, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Emerson</LastName><ForeName>Stephen G</ForeName><Initials>SG</Initials></Author><Author ValidYN="Y"><LastName>Weinberg</LastName><ForeName>Kenneth I</ForeName><Initials>KI</Initials></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>AI50765</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>HL70005</GrantID><Acronym>HL</Acronym><Agency>NHLBI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>M01 RR00043</GrantID><Acronym>RR</Acronym><Agency>NCRR NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P50 HL54850</GrantID><Acronym>HL</Acronym><Agency>NHLBI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 HL54729</GrantID><Acronym>HL</Acronym><Agency>NHLBI NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013487">Research Support, U.S. Gov't, P.H.S.</PublicationType><PublicationType UI="D016454">Review</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Hematology Am Soc Hematol Educ Program</MedlineTA><NlmUniqueID>100890099</NlmUniqueID><ISSNLinking>1520-4383</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000328" MajorTopicYN="N">Adult</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018929" MajorTopicYN="N">Cell Culture Techniques</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002454" MajorTopicYN="N">Cell Differentiation</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002469" MajorTopicYN="N">Cell Separation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D036101" MajorTopicYN="Y">Cord Blood Stem Cell Transplantation</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="N">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005312" MajorTopicYN="N">Fetal Blood</DescriptorName><QualifierName UI="Q000166" MajorTopicYN="Y">cytology</QualifierName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006410" MajorTopicYN="Y">Hematopoiesis</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006412" MajorTopicYN="Y">Hematopoietic Stem Cells</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006650" MajorTopicYN="N">Histocompatibility Testing</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007165" MajorTopicYN="Y">Immunosuppression Therapy</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="N">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010920" MajorTopicYN="N">Placenta</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011247" MajorTopicYN="N">Pregnancy</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012307" MajorTopicYN="N">Risk Factors</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015398" MajorTopicYN="N">Signal Transduction</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013601" MajorTopicYN="N">T-Lymphocytes</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016896" MajorTopicYN="N">Treatment Outcome</DescriptorName></MeshHeading></MeshHeadingList><NumberOfReferences>62</NumberOfReferences></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2004</Year><Month>11</Month><Day>25</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>4</Month><Day>22</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2004</Year><Month>11</Month><Day>25</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">15561692</ArticleId><ArticleId IdType="doi">10.1182/asheducation-2004.1.354</ArticleId><ArticleId IdType="pii">2004/1/354</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">15561683</PMID><DateCompleted><Year>2005</Year><Month>04</Month><Day>21</Day></DateCompleted><DateRevised><Year>2016</Year><Month>11</Month><Day>24</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">1520-4391</ISSN><JournalIssue CitedMedium="Print"><PubDate><Year>2004</Year></PubDate></JournalIssue><Title>Hematology. American Society of Hematology. Education Program</Title><ISOAbbreviation>Hematology Am Soc Hematol Educ Program</ISOAbbreviation></Journal>Hodgkin's lymphoma: evolving concepts with implications for practice.
|
There is still uncertainty concerning the joint action of the two established type 1 diabetes susceptibility loci, the HLA class II DQB1 and DRB1 genes (IDDM1) and the insulin gene (INS) promoter (IDDM2). Some previous studies reported independence, whereas others suggested heterogeneity in the relative effects of the genotypes at these disease loci. In this study, we have assessed the combined effects of the HLA-DQB1/DRB1 and INS genotypes in 944 type 1 diabetic patients and 1,023 control subjects, all from Sardinia. Genotype variation at INS significantly influenced disease susceptibility in all HLA genotype risk categories. However, there was a significant heterogeneity (P = 2.4 x 10(-4)) in the distribution of the INS genotypes in patients with different HLA genotypes. The INS predisposing genotype was less frequent (74.9%) in high-risk HLA genotype-positive patients than in those with HLA intermediate-risk (86.1%) and low-risk (84.8%) categories. Gene-gene interaction modeling led to rejection of the additive model, whereas a multiplicative model showed a better, albeit still partial, fit to the observed data. These genetic results are consistent with an interaction between the protein products of the HLA and INS alleles, in which both the affinity of the various HLA class II molecules for a preproinsulin-derived peptide and the levels of this peptide in the thymus act jointly as key regulators of type 1 diabetes autoimmunity.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Motzo</LastName><ForeName>Costantino</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Dipartimento di Scienze Biomediche e Biotecnologie, Universita' di Cagliari, Sardinia, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Contu</LastName><ForeName>Daniela</ForeName><Initials>D</Initials></Author><Author ValidYN="Y"><LastName>Cordell</LastName><ForeName>Heather J</ForeName><Initials>HJ</Initials></Author><Author ValidYN="Y"><LastName>Lampis</LastName><ForeName>Rosanna</ForeName><Initials>R</Initials></Author><Author ValidYN="Y"><LastName>Congia</LastName><ForeName>Mauro</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Marrosu</LastName><ForeName>Maria Giovanna</ForeName><Initials>MG</Initials></Author><Author ValidYN="Y"><LastName>Todd</LastName><ForeName>John A</ForeName><Initials>JA</Initials></Author><Author ValidYN="Y"><LastName>Devoto</LastName><ForeName>Marcella</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Cucca</LastName><ForeName>Francesco</ForeName><Initials>F</Initials></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>E.1109</GrantID><Acronym>TI_</Acronym><Agency>Telethon</Agency><Country>Italy</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D003160">Comparative Study</PublicationType><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Diabetes</MedlineTA><NlmUniqueID>0372763</NlmUniqueID><ISSNLinking>0012-1797</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D006680">HLA Antigens</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D006683">HLA-DQ Antigens</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D059866">HLA-DQ beta-Chains</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C069051">HLA-DQB1 antigen</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D006684">HLA-DR Antigens</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D059811">HLA-DRB1 Chains</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D003922" MajorTopicYN="N">Diabetes Mellitus, Type 1</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="Y">epidemiology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005190" MajorTopicYN="N">Family</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006680" MajorTopicYN="N">HLA Antigens</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006683" MajorTopicYN="N">HLA-DQ Antigens</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D059866" MajorTopicYN="N">HLA-DQ beta-Chains</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006684" MajorTopicYN="N">HLA-DR Antigens</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D059811" MajorTopicYN="N">HLA-DRB1 Chains</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006650" MajorTopicYN="N">Histocompatibility Testing</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012016" MajorTopicYN="N">Reference Values</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018570" MajorTopicYN="N">Risk Assessment</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012307" MajorTopicYN="N">Risk Factors</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2004</Year><Month>11</Month><Day>25</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>4</Month><Day>15</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2004</Year><Month>11</Month><Day>25</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">15561961</ArticleId><ArticleId IdType="doi">10.2337/diabetes.53.12.3286</ArticleId><ArticleId IdType="pii">53/12/3286</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">15561692</PMID><DateCompleted><Year>2005</Year><Month>04</Month><Day>21</Day></DateCompleted><DateRevised><Year>2021</Year><Month>12</Month><Day>03</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">1520-4391</ISSN><JournalIssue CitedMedium="Print"><PubDate><Year>2004</Year></PubDate></JournalIssue><Title>Hematology. American Society of Hematology. Education Program</Title><ISOAbbreviation>Hematology Am Soc Hematol Educ Program</ISOAbbreviation></Journal><ArticleTitle>Stem cell transplantation (cord blood transplants).</ArticleTitle><Pagination><StartPage>354</StartPage><EndPage>371</EndPage><MedlinePgn>354-71</MedlinePgn></Pagination><Abstract>Allogeneic stem cell transplantation is an accepted treatment modality for selected malignant and non-malignant diseases. However, the ability to identify suitably matched related or unrelated donors can be difficult in some patients. Alternative sources of stem cells such as cord blood provide a readily available graft for such patients. Data accumulated over the past several years have demonstrated that the use of cord blood is an accepted source of stem cells for pediatric patients. Since the cell numbers of hematopoietic progenitors in cord blood is limited and the collection can occur only in a single occasion, its use in adult patients can be more problematic. Here, new developments in the use of cord blood for adults and studies aimed at expansion of cord blood cells and immune reconstitution are described. In Section I, Dr. Nelson Chao describes the early data in cord blood transplantation in adult patients. The patient outcomes are reviewed and analyzed for various factors such as cell dose, HLA typing, and patient selection that could have contributed to the final outcome of these adult patients. Myeloablative as well as nonmyeloablative approaches are presented. Discussion of the various benefits and risks are presented. More recent data from multiple single institutions as well as larger registry data comparisons are also provided. Analyses of these studies suggest methods to improve on the outcome. These newer data should lead to a logical progression in the use of cord blood cells in adult patients. In Section II, Dr. Stephen Emerson describes the historical efforts associated with expansion of hematopoietic stem cells, specifically with cord blood cells. These efforts to expand cord blood cells continue with novel methods. Moreover, a better understanding of stem cell biology and signaling is critical if we are to be able to effectively expand these cells for clinical use. An alternative, more direct, approach to expanding stem cells could be achieved by specific genetic pathways known or believed to support primitive HSC proliferation such as Notch-1 receptor activation, Wnt/LEF-1 pathway induction, telomerase or the Homeobox (Hox) gene products. The clinical experience with the use of expanded cord blood cells is also discussed. In Section III, Dr. Kenneth Weinberg describes immune reconstitution or lack thereof following cord blood transplantation. One of the hallmarks of successful hematopoietic stem cell transplantation is the ability to fully reconstitute the immune system of the recipient. Thus, the relationship between stem cell source and the development of T lymphocyte functions required for protection of the recipient from infection will be described, and cord blood recipients will be compared with those receiving other sources of stem cells. T cell development is described in detail, tracking from prethymic to postthymic lymphocytes with specific attention to umbilical cord blood as the source of stem cells. Moreover, a discussion of the placenta as a special microenvironment for umbilical cord blood is presented. Strategies to overcome the immunological defects are presented to improve the outcome of these recipients.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Chao</LastName><ForeName>Nelson J</ForeName><Initials>NJ</Initials><AffiliationInfo><Affiliation>Duke University, Durham, NC 27705-3976, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Emerson</LastName><ForeName>Stephen G</ForeName><Initials>SG</Initials></Author><Author ValidYN="Y"><LastName>Weinberg</LastName><ForeName>Kenneth I</ForeName><Initials>KI</Initials></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>AI50765</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>HL70005</GrantID><Acronym>HL</Acronym><Agency>NHLBI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>M01 RR00043</GrantID><Acronym>RR</Acronym><Agency>NCRR NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P50 HL54850</GrantID><Acronym>HL</Acronym><Agency>NHLBI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 HL54729</GrantID><Acronym>HL</Acronym><Agency>NHLBI NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013487">Research Support, U.S. Gov't, P.H.S.</PublicationType><PublicationType UI="D016454">Review</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Hematology Am Soc Hematol Educ Program</MedlineTA><NlmUniqueID>100890099</NlmUniqueID><ISSNLinking>1520-4383</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000328" MajorTopicYN="N">Adult</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018929" MajorTopicYN="N">Cell Culture Techniques</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002454" MajorTopicYN="N">Cell Differentiation</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002469" MajorTopicYN="N">Cell Separation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D036101" MajorTopicYN="Y">Cord Blood Stem Cell Transplantation</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="N">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005312" MajorTopicYN="N">Fetal Blood</DescriptorName><QualifierName UI="Q000166" MajorTopicYN="Y">cytology</QualifierName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006410" MajorTopicYN="Y">Hematopoiesis</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006412" MajorTopicYN="Y">Hematopoietic Stem Cells</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006650" MajorTopicYN="N">Histocompatibility Testing</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007165" MajorTopicYN="Y">Immunosuppression Therapy</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="N">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010920" MajorTopicYN="N">Placenta</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011247" MajorTopicYN="N">Pregnancy</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012307" MajorTopicYN="N">Risk Factors</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015398" MajorTopicYN="N">Signal Transduction</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013601" MajorTopicYN="N">T-Lymphocytes</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016896" MajorTopicYN="N">Treatment Outcome</DescriptorName></MeshHeading></MeshHeadingList><NumberOfReferences>62</NumberOfReferences></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2004</Year><Month>11</Month><Day>25</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>4</Month><Day>22</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2004</Year><Month>11</Month><Day>25</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">15561692</ArticleId><ArticleId IdType="doi">10.1182/asheducation-2004.1.354</ArticleId><ArticleId IdType="pii">2004/1/354</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">15561683</PMID><DateCompleted><Year>2005</Year><Month>04</Month><Day>21</Day></DateCompleted><DateRevised><Year>2016</Year><Month>11</Month><Day>24</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">1520-4391</ISSN><JournalIssue CitedMedium="Print"><PubDate><Year>2004</Year></PubDate></JournalIssue><Title>Hematology. American Society of Hematology. Education Program</Title><ISOAbbreviation>Hematology Am Soc Hematol Educ Program</ISOAbbreviation></Journal><ArticleTitle>Hodgkin's lymphoma: evolving concepts with implications for practice.</ArticleTitle><Pagination><StartPage>184</StartPage><EndPage>202</EndPage><MedlinePgn>184-202</MedlinePgn></Pagination><Abstract>Hodgkin's lymphoma is a unique neoplasm of B lymphocytes. Recent data provide new understandings of the pathogenesis and options for staging and therapy of the disease. Three specific topics are addressed in this chapter. In Section I, Dr. Richard Ambinder reviews implications of the relationship of Epstein-Barr virus (EBV) and Hodgkin's lymphoma. This relation includes varying geographic epidemiologic associations, including varying associations with the clinical syndrome of infectious mononucleosis. There are plausible mechanisms, including processes initiated by viral proteins, by which EBV might lead to tumorigenesis. These mechanisms include promotion of genetic instability and alteration of normal processes of apoptosis. In addition to an epidemiologic association and potential role in pathogenesis, viral antigens may pose theoretical targets for anti-cancer therapies, including vaccination. In Section II, Dr. Sigrid Stroobants describes the potential role of positron emission tomographic (PET) scanning. By assessing differences in the metabolic activities of cancer cells, PET scanning may be superior to computerized tomographic scanning, which is limited to showing structural anatomical abnormalities. In patients with Hodgkin's and non-Hodgkin's lymphoma, PET scanning has been tested as an initial staging tool, to assess the rate of therapeutic response from a prognostic perspective, and to differentiate residual tumor from fibrotic masses in patients who have completed therapy. Particularly in assessing the nature of a residual mass seen with other post-therapeutic imaging modalities, PET scanning may provide unique information; very high negative predictive values have been reported. However, before this technology can be recommended for incorporation into standard management, properly conducted prospective trials are required to better evaluate the clinical utility of PET with respect to eventual patient outcomes. In Section III, Dr. Ralph Meyer reviews current data regarding the management of patients with limited-stage Hodgkin's lymphoma. Over the past decade, standard treatment has evolved to consist of combined-modality therapy that includes an abbreviated course of chemotherapy and involved-field radiation. As this therapy continues to include radiation therapy, patients will remain at risk of long-term toxicities that include the development of second cancers and cardiovascular events. These "late-effects" now account for more deaths than those attributed to progressive Hodgkin's lymphoma. Comparative data testing the role of chemotherapy alone are now available and demonstrate that omission of radiation therapy results in small but statistically significant reduction in disease control, but no detectable differences in overall survival. Further follow-up will clarify whether chemotherapy alone is the preferred treatment option; at present patients should be informed of the trade-offs involved in choosing between this option and combined modality therapy.
|
2,338,695 |
Nurses' views on their role in genetics.
|
To determine the views of nurses about their roles in genetics.</AbstractText>A descriptive study.</AbstractText>Two university hospitals in Ankara, Turkey.</AbstractText>From a population of 1,717 nurses, 313 were selected by using the stratified random sampling method. Two hundred seventy nurses agreed to participate.</AbstractText>Nurses' viewpoints on their role in genetics.</AbstractText>Nurses defined their roles in genetics as gathering family history, providing information about a genetic test including its duration and risks, and providing counseling and psychological support. More graduates of baccalaureate degree nursing programs were in favor of nurses' roles in genetics than were graduates of lower educational level. Nurses reported that their knowledge of basic genetics is insufficient and that they need additional training. The majority of nurses were not aware of the possible risks and harms of genetic information for the individual, suggesting a very important point of ethical lack.</AbstractText>The results of this study demonstrate a need for educational preparation for nurses in both genetics and ethics. Nurses could assume their potential roles if their educational needs were met.</AbstractText>
|
2,338,696 |
Modified vaccinia virus Ankara as antigen delivery system: how can we best use its potential?
|
Safety-tested modified vaccinia virus Ankara (MVA) has been established as a potent vector system for the development of candidate recombinant vaccines. The versatility of the vector system was recently demonstrated by the rapid production of experimental MVA vaccines for immunization against severe acute respiratory syndrome associated coronavirus. Promising results were also obtained in the delivery of Epstein-Barr virus or human cytomegalovirus antigens and from the clinical testing of MVA vectors for vaccination against immunodeficiency virus, papilloma virus, Plasmodium falciparum or melanoma. Moreover, MVA is considered to be a prime candidate vaccine for safer protection against orthopoxvirus infections. Thus, vector development to challenge dilemmas in vaccinology or immunization against poxvirus bio-threat seems possible, yet the right choice should be made for a most beneficial use.
|
2,338,697 |
Laser Scanning Cytometry for selection of green fluorescent protein transgenic mice using small number of blood cells.
|
A Laser Scanning Cytometry-based method was developed for identification of transgenic mice expressing green fluorescent protein (GFP) using minute amounts of peripheral blood. The difference between the autofluorescence of cells not expressing GFP and the fluorescence of GFP expressing cells after excitation with Ar-ion laser (wavelength 488 nm) and detection of emitted fluorescent light in the green channel was high enough for unambiguous identification of the GFP expressing mice. The sensitivity of this method was estimated 1:10(4) for detection of rare GFP expressing cells under the conditions used. This sensitivity should be sufficient for many studies on microchimerism. Because of the possibility for relocation of the cells, this method will be particularly useful for characterizing the cells with high GFP expression using other markers of cell phenotype or conventional morphological analysis.
|
2,338,698 |
Nanoparticle based systemic gene therapy for lung cancer: molecular mechanisms and strategies to suppress nanoparticle-mediated inflammatory response.
|
Cancer gene therapy for the treatment of lung cancer has shown promise in the laboratory and in Phase I/II clinical trials. However, it is currently limited to treating localized tumors due to host-immunity against the gene delivery vector and the transgene. Therefore, there is a tremendous effort to develop and test alternate gene delivery vectors that are efficient, non-immunogenic, and applicable for systemic therapy. One such gene delivery vehicle is the non-viral vector, DOTAP:cholesterol (DOTAP:Chol) nanoparticle. Preclinical studies from our laboratory has shown that DOTAP:Chol. nanoparticles are effective systemic gene delivery vectors that efficiently deliver tumor-suppressor genes to disseminated lung tumors. Based on our findings we have recently initiated a Phase-I trial for systemic treatment of lung cancer using a novel tumor suppressor gene, FUS1. Although DOTAP:Chol. nanoparticles complexed to DNA (DNA-nanoparticles) are efficient vectors for systemic therapy, induction of an inflammatory response in a dose-dependent fashion has also been observed thereby limiting its use. A better understanding of the underlying mechanism for DNA-nanoparticles-mediated inflammatory response will allow us to develop strategies to suppress inflammation and expand the therapeutic window in treating human cancer. In the present study we conducted experiments examining the mechanism of nanoparticle-mediated inflammatory response in vitro and in vivo. We demonstrate that systemic administration of DNA-nanoparticles induced multiple signaling molecules both in vitro and in vivo that are associated with inflammation. Use of small molecule inhibitors against the signaling molecules resulted in their suppression and thereby reduced inflammation without affecting transgene expression. Our results provide a rationale to use small molecule inhibitors to suppress nanoparticle-mediated inflammation when administered systemically. Further development and testing will allow us to incorporate this strategy into future clinical trials that is based on systemic non-viral vector gene therapy.
|
2,338,699 |
Predictors of cognitive appraisals following genetic testing for BRCA1 and BRCA2 mutations.
|
The objectives of this study were (1) to describe perceptions of stress and confidence following genetic testing for BRCA1 and BRCA2 (BRCA1/2) mutations and (2) to identify predictors of these processes. Participants were 130 high-risk women affected with cancer who received BRCA1/2 test results. Individual difference characteristics and interpersonal factors were measured by self-report before genetic counseling and perceptions of stress and confidence were evaluated by self-report 1 month following disclosure of test results. BRCA1/2 test results had a significant effect only on perceptions of stress (beta = 0.38, p = 0.0001), while trait anxiety had a significant effect on both perceptions of stress (beta = 0.44, p = 0.0001) and confidence (beta = -0.41, p = 0.001). These results suggest that interventions designed to address perceptions of stress related to medical decision-making and familial concerns may need to be targeted to BRCA1/2 mutation carriers and individuals who are highly anxious.
|
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.