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2,337,100	Differences in the characteristics of families with BRCA1 and BRCA2 mutations in Israel.	Three specific mutations in the BRCA1 (185delAG, 5382insC) and BRCA2 (6174delT) genes have been reported to be of high prevalence in the Jewish Ashkenazi population. We studied the differences in phenotype of families carrying these mutations. All consecutive families found by the CHS Familial Cancer Service to carry one of the three 'Jewish' mutations of the BRCA1/BRCA2 genes were evaluated for phenotypic characteristics. Chi-squared and Student's t-test statistics were employed to study differences in a variety of clinical and demographic parameters. A total of 111 families with 1499 family members were included. Among them 454 cases of cancer (297 in breast/ovary) were reported. Ovarian cancer, but not breast cancer, was detected at a significantly younger age among carriers of 185delT compared with other mutation carriers. In families with 185delAG, 5382insC and 6174delT mutations, breast cancer was found in 20.2, 39.4 and 24.1% of all identified women (born between 1900 and 1975), correspondingly. The corresponding figures for ovarian cancer were 13.9, 6.8 and 4.9%. Families carrying the 5382insC mutation had the highest probability of expressing bilateral breast cancer (38.9% of families, 15.4% of women with cancer, 6.1% of all women in family) and metachronous breast and ovary tumours (22.2, 9.8 and 4.5% correspondingly). Other tumours were reported in 7.9, 9.1 and 12.0% of women and 9.5, 12.9 and 15.8% of men in families with 185delAG, 5382insC, 6174delT, correspondingly. Marked phenotypic differences were found between families carrying different BRCA mutations warranting mutation-specific counselling to families seeking risk-reduction advice. 5382insC emerged as a most aggressive mutation.
2,337,101	Exploring whole genome amplification as a DNA recovery tool for molecular genetic studies.	The whole genome amplification (WGA) protocol evaluated during this study, GenomiPhi DNA amplification kit, is a novel method that is not based on polymerase chain reaction but rather relies on the highly processive and high fidelity Phi29 DNA polymerase to replicate linear genomic DNA by multiple strand displacement amplification. As little as 1 ng of genomic DNA template is sufficient to produce microgram quantities of high molecular weight DNA. The question explored during this study is whether such a WGA method is appropriate to reliably replenish and even recover depleted DNA samples that can be used for downstream genetic analysis. A series of human DNA samples was tested in our laboratory and validated using such analytical methods as gene-specific polymerase chain reaction, direct sequencing, microsatellite marker analysis, and single nucleotide polymorphism allelic discrimination using TaqMan and Pyrosequencing chemistries. Although degraded genomic DNA is not a good template for Phi29 WGA, this method is a powerful tool to replenish depleted DNA stocks and to increase the amount of sample for which biological tissue availability is scarce. The testing performed during the validation phase of the study indicates no discernable difference between WGA samples and the original DNA templates. Thus, GenomiPhi WGA can be used to increase precious or depleted DNA stocks, thereby extending the life of a family-based linkage analysis project and increasing statistical power.
2,337,102	Mutations in CYP11B1 and congenital adrenal hyperplasia in Moroccan Jews.	In Jews of Moroccan descent (MJ), the prevalence of steroid 11beta-hydroxylase deficiency (11-OHD) is relatively high, with a carrier rate estimated as approximately one in 40. A single mutation in the CYP11B1 gene (encoding 11beta-hydroxylase), R448H, was suggested to account for the disease alleles in this population.</AbstractText>We screened 236 healthy MJ for R448H.</AbstractText>Only two of the subjects screened were found to be carriers, suggesting that the R448H allele frequency is lower than was assumed previously. An R448H/R448C compound heterozygote patient, diagnosed with 11-OHD, was identified. However, a subsequent screen of MJ subjects for R448C failed to detect any carriers, suggesting that this was a private mutation of this family.</AbstractText>The high incidence of 11-OHD in MJ, therefore, is only partially explained by the presence of R448H as a founder mutation.</AbstractText>
2,337,103	Prevalence of BRCA mutations and founder effect in high-risk Hispanic families.	Approximately 12% of the U.S. population is Hispanic, with the majority residing in urban centers such as Los Angeles. The prevalence of BRCA mutations among high-risk Hispanic families is unknown.</AbstractText>One hundred and ten unrelated probands of Hispanic origin, with a personal or family history of breast and/or ovarian cancer, presented for genetic cancer risk assessment, were enrolled in an Institutional Review Board-approved registry and underwent BRCA testing. Haplotype analyses were done if BRCA mutations were observed in two or more unrelated probands.</AbstractText>Mean age at diagnosis was 37 years (range = 23-59) for the 89 (81%) probands with invasive breast cancer. Overall, 34 (30.9%) had deleterious mutations (25 in BRCA1, 9 in BRCA2), 25 (22.7%) had one or more unclassified variants, and 51 (46.4%) had negative results. The mean pretest mutation probability using the Couch model, Myriad model, and BRCAPro was 19.6% (range = 4-77%). The combined average mutation probability was 32.8% for carriers, 15.5% for noncarriers, and 12.9% for variant carriers (P < 0.0001). The most common deleterious mutation was 185delAG (4 of 34, 11.8%). The Hispanic 185delAG carrier families share the same haplotype from D17s1320 through BRCA1, as do two reference Ashkenazi Jewish families. Haplotype analyses of additional recurrent BRCA1 mutations [IVS5+1G>A (n=2),S955X (n = 3), R1443X (n = 3), and 2552delC (n = 2)] also suggest founder effects, with four of six mutations seen almost exclusively in families with Latin American/Caribbean or Spanish ancestry.</AbstractText>This is the largest study to date of high-risk Hispanic families in the United States. Six recurrent mutations accounted for 47% (16 of 34) of the deleterious mutations in this cohort. The BRCA1185delAG mutation was prevalent (3.6%) in this clinic-based cohort of predominantly Mexican descent, and shared the Ashkenazi Jewish founder haplotype.</AbstractText>
2,337,104	Genetic polymorphisms for 11 Y-STRs haplotypes of Chinese Yi ethnic minority group.	Eleven Y-STRs loci including minimal haplotypes (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, and DYS385a,b) and two additional loci, namely DYS438 and DYS439 have been co-amplified in 100 healthy unrelated males of Chinese Yi minority ethnic group using the Y-PLEX 5 and Y-PLEX 6 kit, in order to investigate allele and haplotype frequencies of Yi population, evaluate their usefulness in forensic paternity testing and human identification, and enrich Chinese population genetic informational resources. Out of a total of 100 individuals 85 showed different haplotypes, while 8 haplotypes occurred more than once. The overall haplotype diversity for 11 Y-STRs loci was 0.9945.
2,337,105	Description and characterization of two new HLA alleles, B4051 and DRB11364, identified by sequence-based typing.	Human leukocyte antigen (HLA)-B and HLA-DRB1 typing in two female individuals revealed reaction patterns that did not correspond to any known HLA-B specificity and appeared to identify a very rare HLA-DRB1 allele, respectively. Sequence-based analysis of these samples revealed two new HLA alleles, one similar to B4023 and the other to DRB11308. The new HLA-B allele, which was assigned the name HLA-B4051, could have been generated by a double crossing over recombination between B4001 and B1401 or 1402, whereas DRB11364, the new DRB1 allele, could have been generated either by a double crossing over recombination between DRB11308 and DRB11201, 1202, or 1203 or by two independent crossing over events between DRB11401, DRB11201, 1202, or 1203 and DRB1*1301.
2,337,106	Identification of an HLA-B07 allele variant (B0740) in the Chinese Han population.	A novel HLA-B07 allele, B0740, has been identified by sequence-based typing (SBT) in the Chinese Han population. This new allele is identical to B0705 and B0706 for exons 2, 3, and 4, except for a single nucleotide at position 605 of codon 202 in exon 3 (AAG-->ATG) leading to an amino acid change from lysine to methionine. SBT was performed following allele separation using the Haploprep method. The serological equivalence of B*0740 to the B7 antigen did not change.
2,337,107	Identification of a novel HLA-A02 allele, A027401*.	A novel HLA-A02 allele was detected in a Caucasian patient from central Italy, requiring a hematopoietic cell transplantation. Direct sequencing identified a variation in one nucleotide position, which was confirmed by cloning. The name A027401 was officially assigned by the WHO Nomenclature Committee in November 2004. A027401 differs from A02010101 by a single G to A substitution at nucleotide position 595 in exon 3. The new variant would lead to a nonsynonymous nucleotide change (GGG to AGG) at codon 175, resulting in a basic Arg in the alpha-helix of the alpha2-domain, in place of a non-polar Gly. The presence of an uncommon variation at a highly conserved nucleotide position could have implications in unrelated hematopoietic cell transplantation.
2,337,108	MHC microsatellite diversity and linkage disequilibrium among common HLA-A, HLA-B, DRB1 haplotypes: implications for unrelated donor hematopoietic transplantation and disease association studies.	Twenty-two human major histocompatibility complex (MHC) region microsatellite (Msat) markers were studied for diversity and linkage disequilibrium (LD) with HLA loci in hematopoietic cell transplant recipients and their HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 allele-matched unrelated donors. These Msats showed highly significant LD over much of the MHC region. The Msat diversity of five common Caucasian haplotypes (HLA-A1-B8-DR3, A3-B7-DR15, A2-B44-DR4, A29-B44-DR7, and A2-B7-DR15) was examined using a new measure called 'haplotype specific heterozygosity' (HSH). Each of the five haplotypes had at least one Msat marker with an HSH value of zero indicating that only one Msat allele was observed for the particular HLA haplotype. In addition, the ability of Msats to predict HLA-A-B-DRB1 haplotypes was studied. Over 90% prediction probability of two common haplotypes (HLA-A1-B8-DR3 and HLA-A3-B7-DR15) was achieved with information from three Msats (D6S265/D6S2787/D6S2894 and D6S510/D6S2810/D6S2876, respectively). We demonstrate how the HSH index can be used in the selection of informative Msats for transplantation and disease association studies. Markers with low HSH values can be used to predict specific HLA haplotypes or multilocus genotypes to supplement the screening of HLA-matched donors for transplantation. Markers with high HSH values will be most informative in studies investigating MHC region disease-susceptibility genes where HLA haplotypic effects are known to exist.
2,337,109	HLA-DQB1 sequencing-based typing using newly identified conserved nucleotide sequences in introns 1 and 2.	Sequencing-based typing (SBT) human leukocyte antigen (HLA) class I and II genes should examine entire exon sequences where polymorphisms lie. Primers for the amplification of complete exons therefore anneal in introns and their design relies on accurate intron sequences being available. We decided to develop a SBT method for HLA-DQB1 using amplification primers which anneal in introns 1 and 2, yet the amount of intron sequence data previously available in databases was sparse. Therefore, we undertook a systematic sequencing of introns 1 and 2 using DNA from cell lines homozygous for DQB1. This study confirmed an earlier report that the non-coding regions of this gene are the most polymorphic seen in the human genome. Intron sequences within an allele group were largely identical, the exceptions being DQB10301 differing from other DQB103 allele groups and DQB10601 differing from all other DQB106 alleles. A retroviral Alu element, related to the AluYa5a2 subfamily, was identified uniquely inserted in intron 2 of DQB1*02 alleles. For the typing approach, six amplification primers were designed based on conserved allele group sequences covering all of the HLA DQB antigens, and two sequencing primers were also designed which anneal in intron 2. This method has proved to be very robust and has been used as part of a referral DNA sequencing service for a number of years.
2,337,110	A study of PSORS1C1 gene polymorphisms in Chinese patients with psoriasis.	Although genetic analyses have identified the HLA-Cw0602 allele as the major risk allele for chronic plaque psoriasis in various ethnic groups, it has been proposed that the association of Cw0602 is due to linkage disequilibrium and that other nearby genes are involved in susceptibility to psoriasis. The psoriasis susceptibility 1 candidate 1 (PSORS1C1, formerly SEEK1) gene, located 127 kb telomeric to the HLA-C locus, is considered to be one of the potential candidate genes of psoriasis. Up to the present, no association study of the PSORS1C1 gene has been conducted on Chinese patients with psoriasis.</AbstractText>We aimed to determine whether the genetic polymorphisms of the PSORS1C1 gene were associated with an increased risk of psoriasis in Chinese patients.</AbstractText>We investigated the PSORS1C1 gene for disease association by direct sequencing of the PSORS1C1 gene in 143 Chinese patients with chronic plaque psoriasis and 188 control subjects. Genotyping for HLA-Cw0602 and the alpha-helix coiled-coil rod homologue (C6orf18, formerly HCR) gene was also carried out using a sequence-based typing method.</AbstractText>We identified 10 single nucleotide polymorphisms (SNPs) on the PSORS1C1 gene in our subjects; four of these SNPs cause amino acid change. We also detected poly(C) repeat variants from nucleotide positions 386-392 (poly(C)6-8). The poly(C) repeat polymorphisms cause a frame shift mutation. Another poly(C) repeat variant was also found at nucleotide positions 748-751. No significantly different allelic distributions of the PSORS1C1 SNPs or poly(C) repeat polymorphisms could be found between the patients with chronic plaque psoriasis and controls after correction for multiple testing. However, a significant increase of the Cw0602 allele and tryptophan-tryptophan allele of the C6orf18 gene (HCRWW) was found in patients with early onset psoriasis (21.9% vs. 4.8%, P < 10(-7)). Haplotype-based association analysis also showed a susceptibility haplotype carrying Cw0602 and HCR*WW alleles in early onset Chinese patients.</AbstractText>Our results indicate that the PSORS1C1 gene might not play an important role in the causation of chronic plaque psoriasis in Chinese people.</AbstractText>
2,337,111	RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors.	Hereditary medullary thyroid carcinoma (MTC) is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene. Associations between specific RET mutations (genotype) and the aggressiveness of MTC and presence or absence of other endocrine neoplasms (phenotype) are well documented. Mutations in six exons (10, 11, 13, 14, 15, and 16) located in either cysteine-rich or tyrosine kinase domains cause one of three distinctive clinical subtypes: familial MTC, multiple endocrine neoplasia (MEN) type 2A (including variants with Hirschsprung's disease and cutaneous lichen amyloidosis), and MEN 2B. Hallmarks of MEN 2A include MTC, pheochromocytoma, and hyperparathyroidism. MEN 2B is associated with an earlier onset of MTC and pheochromocytoma, the absence of hyperparathyroidism, and the presence of striking physical stigmata (e.g., coarse facies, ganglioneuromatosis, and marfanoid habitus). Familial MTC is not associated with other endocrine neoplasms; however, the accurate distinction between familial MTC and MEN 2A may be difficult in kindreds with small size, incomplete histories, or a predominance of young individuals who may not have yet fully manifested the syndrome. Genetic testing detects greater than 95% of mutation carriers and is considered the standard of care for all first-degree relatives of patients with newly diagnosed MTC. Recommendations on the timing of prophylactic thyroidectomy and the extent of surgery are based upon a model that utilizes genotype- phenotype correlations to stratify mutations into three risk levels.
2,337,112	Review: production, characterization, and testing of banked mammalian cell substrates used to produce biological products.	A critical component in controlling the production of biological products derived from human and animal cell lines is the characterization and testing of banked cell substrates. The objective is to confirm the identity, purity, and suitability of these cells for manufacturing use. Quality concerns for biological products derived from cell lines originate from the presence of cellular and adventitious contaminants. Well-characterized cell banks not only permit a consistent source of production cells throughout the life of a product but also decrease the likelihood of contamination by other cell lines and adventitious agents. An important part of qualifying a cell line is choosing the appropriate testing for the presence of adventitious contaminants. The qualification of cell banks includes tests for cell identity and endogenous and adventitious microbial contaminants (bacteria, fungi, mycoplasmas, and viruses). For cells producing recombinant deoxyribonucleic acid-derived products, analysis of the expression construct at the nucleic acid level (genetic stability) is also a primary concern. The strategy for designing a safety-testing program for banked cells should be based on sound scientific principles and current regulatory guidance.
2,337,113	Development of EST-SSR markers by data mining in three species of shrimp: Litopenaeus vannamei, Litopenaeus stylirostris, and Trachypenaeus birdy.	We report on the data mining of publicly available Litopenaeus vannamei expressed sequence tags (ESTs) to generate simple sequence repeat (SSRs) markers and on their transferability between related Penaeid shrimp species. Repeat motifs were found in 3.8% of the evaluated ESTs at a frequency of one repeat every 7.8 kb of sequence data. A total of 206 primer pairs were designed, and 112 loci were amplified with the highest success in L. vannamei. A high percentage (69%) of EST-SSRs were transferable within the genus Litopenaeus. More than half of the amplified products were polymorphic in a small testing panel of L. vannamei. Evaluation of those primers in a larger testing panel showed that 72% of the markers fit Hardy-Weinberg equilibrium, which shows their utility for population genetic analysis. Additionally, a set of 26 of the EST-SSRs were evaluated for Mendelian segregation. A high percentage of monomorphic markers (46%) proved to be polymorphic by singles-stranded conformational polymorphism analysis. Because of the high number of ESTs available in public databases, a data mining approach similar to the one outlined here might yield high numbers of SSR markers in many animal taxa.
2,337,114	A stop codon polymorphism of Toll-like receptor 5 is associated with resistance to systemic lupus erythematosus.	Systemic lupus erythematosus (SLE) is an autoimmune disease with a complex genetic basis that includes susceptibility gene(s) within the chromosome 1q41-1q42 region. Toll-like receptor 5 (TLR5), the innate immune receptor for bacterial flagellin, maps to chromosome 1q41 and contains a common stop codon polymorphism that abrogates signaling (allele C1174T) and is associated with an increased risk of infection. By using transmission disequilibrium testing in a cohort containing 199 affected patients and their 75 unaffected siblings and 326 parents, we found that allele 1174C, but not 1174T (with the stop codon), was preferentially transmitted to SLE-affected offspring (a 19:6 transmitted/not transmitted ratio, P = 0.009). In contrast, the alleles of the other three TLR5 SNPs did not exhibit preferential transmission. In addition, we found that allele 1174C was not preferentially transmitted to unaffected offspring (3:6 transmitted/not transmitted ratio, P value not significant). The allele frequency of 1174T in the probands was 3.2% compared with 5.8% in unaffected individuals, which was consistent with a protective association (odds ratio, 0.51; 95% confidence interval, 0.26-0.98; P = 0.041). Subjects with the TLR5 stop codon produced significantly lower levels of proinflammatory cytokines in comparison with individuals with the wild-type genotype. Together, these results indicate that the TLR5 stop codon polymorphism is associated with protection from the development of SLE. These data support a role for flagellated bacteria and the innate immune response in the development of SLE with implications for novel immunomodulatory treatment strategies.
2,337,115	Genome-wide screen identifies host genes affecting viral RNA recombination.	Rapid evolution of RNA viruses with mRNA-sense genomes is a major concern to health and economic welfare because of the devastating diseases these viruses inflict on humans, animals, and plants. To test whether host genes can affect the evolution of RNA viruses, we used a Saccharomyces cerevisiae single-gene deletion library, which includes approximately 80% of yeast genes, in RNA recombination studies based on a small viral replicon RNA derived from tomato bushy stunt virus. The genome-wide screen led to the identification of five host genes whose absence resulted in the rapid generation of new viral RNA recombinants. Thus, these genes normally suppress viral RNA recombination, but in their absence, hosts become viral recombination "hotbeds." Four of the five suppressor genes are likely involved in RNA degradation, suggesting that RNA degradation could play a role in viral RNA recombination. In contrast, deletion of four other host genes inhibited virus recombination, indicating that these genes normally accelerate the RNA recombination process. A comparison of deletion strains with the lowest and the highest recombination rate revealed that host genes could affect recombinant accumulation by up to 80-fold. Overall, our results demonstrate that a set of host genes have a major effect on RNA virus recombination and evolution.
2,337,116	Association study between the D10S1423 microsatellite marker and Alzheimer's disease.	Several studies have reported conflicting results concerning the genetic association between Alzheimer's disease (AD) and the microsatellite marker D10S1423 on chromosome 10p12-14. In an ethnically homogeneous German population of 422 patients with AD and 254 cognitively healthy controls, the 238-bp allele of the D10S1423 marker showed a weak, but after correction for multiple testing no longer significant association with AD (p = 0.015, uncorrected; p = 0.11, corrected). These findings do not support the presence of a relevant susceptibility locus for AD on chromosome 10p12-14.
2,337,117	Genome screen for twinning rate QTL in four North American Holstein families.	The objective of this study was to identify twinning rate quantitative trait loci (QTL) by typing pooled samples in a preliminary screening followed by interval mapping to test QTL effects. Four elite North American Holstein half-sib sire families with high twinning rate predicted transmitting abilities (PTA) were used in this study. Chromosomes 5, 7, 19 and 23 were not genotyped as these chromosomes were scanned for QTL in these families in a previous study. DNA was extracted from phenotypically extreme sons in each sire family. Two pools were prepared from sons of sires in each phenotypic tail, two each for high and low PTA levels for twinning rates. Each pool contained DNA from 4 to 15% of all sons of the sire depending on family. A total of 268 fluorescently labelled microsatellite markers were tested for heterozygosity in sires. About 135--170 informative markers per family were genotyped using pooled DNA samples. Based on the preliminary evidence for potential twinning rate QTL from pooled typing, interval mapping was performed subsequently on 12 chromosomal regions by family combinations. Evidence of QTL for twinning rate was found in one family on BTA 21 and 29 at a chromosome-wide P<0.05 and on BTA 8, 10 and 14 with a chromosome-wide P<0.01.
2,337,118	Vaccines in cancer: GVAX, a GM-CSF gene vaccine.	GVAX is a granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transfected tumor cell vaccine. Original work with GM-CSF as a recombinant DNA protein (Leukine) involved proliferative stimulation of macrophages and neutrophils for the purpose of reducing hematopoietic toxicity related to dose-intensive chemotherapy. Following US Food and Drug Administration approval of Leukine several years ago, extensive preclinical results have demonstrated an immunostimulatory effect related to GM-CSF gene when transfected into tumor cells and used as a vaccine (GVAX). Tumor regression and prolonged survival was demonstrated in animal models. Toxicology with GVAX indicated no adverse effects, which enabled further testing in cancer patients. A small number of responses were demonstrated in Phase I trials in immunosensitive cancer patients (renal cell carcinoma and melanoma). However, a series of dramatic complete and durable responses in advanced non-small cell lung cancer patients, demonstrated in recent clinical trials, have generated interest in further development of this vaccine in nontraditional cancer disease types. The rationale of GVAX development and a summary of clinical results are reviewed.
2,337,119	The -1C to T polymorphism in the annexin A5 gene is not associated with the risk of acute myocardial infarction or sudden cardiac death in middle-aged Finnish males.<Pagination><StartPage>133</StartPage><EndPage>140</EndPage><MedlinePgn>133-40</MedlinePgn></Pagination><Abstract><AbstractText Label="OBJECTIVE" NlmCategory="OBJECTIVE">A common polymorphism (-1C to T) in the translation initiation sequence of annexin A5 (ANV) gene has recently been associated with a decreased risk of acute myocardial infarction (AMI). The aim of the present study was to analyze the association between the ANV genepolymorphism and the risk of AMI and ischemic sudden cardiac death (SCD) in middle-aged Finnish males.</AbstractText><AbstractText Label="MATERIAL AND METHODS" NlmCategory="METHODS">A case-control study involving three distinct groups of subjects was carried out: (1) victims of SCD (n=98), (2) survivors of AMI (n=212), and (3) randomly selected control subjects without any history of coronary heart disease (n=243). The ANV polymorphism was genotyped in each study group.</AbstractText><AbstractText Label="RESULTS" NlmCategory="RESULTS">Among the control group of healthy Finnish males the prevalence rates of the CC, CT, and TT genotypes were 83.1%, 15.2%, and 1.6%, respectively. Among the survivors of AMI, the prevalence rates of CC, CT, and TT were 79.7%, 20.3%, and 0%, respectively, and among the victims of SCD 83.7%, 16.3%, and 0%, respectively. No significant differences in the genotype or allele distributions were observed between the study groups.</AbstractText><AbstractText Label="CONCLUSION" NlmCategory="CONCLUSIONS">The -1C to T polymorphism in the ANV gene is not associated with the risk of AMI or SCD in middle-aged Finnish males.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Kaikkonen</LastName><ForeName>K S</ForeName><Initials>KS</Initials><AffiliationInfo><Affiliation>Division of Cardiology, Department of Internal Medicine, University of Oulu, Finland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kakko</LastName><ForeName>S</ForeName><Initials>S</Initials></Author><Author ValidYN="Y"><LastName>Kortelainen</LastName><ForeName>M L</ForeName><Initials>ML</Initials></Author><Author ValidYN="Y"><LastName>Tapanainen</LastName><ForeName>J M</ForeName><Initials>JM</Initials></Author><Author ValidYN="Y"><LastName>Savolainen</LastName><ForeName>M J</ForeName><Initials>MJ</Initials></Author><Author ValidYN="Y"><LastName>Antero Kesäniemi</LastName><ForeName>Y</ForeName><Initials>Y</Initials></Author><Author ValidYN="Y"><LastName>Huikuri</LastName><ForeName>H V</ForeName><Initials>HV</Initials></Author><Author ValidYN="Y"><LastName>Savolainen</LastName><ForeName>E R</ForeName><Initials>ER</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Scand J Clin Lab Invest</MedlineTA><NlmUniqueID>0404375</NlmUniqueID><ISSNLinking>0036-5513</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D020121">5' Untranslated Regions</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D017304">Annexin A5</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D005819">Genetic Markers</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D020121" MajorTopicYN="N">5' Untranslated Regions</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000328" MajorTopicYN="N">Adult</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000368" MajorTopicYN="N">Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017304" MajorTopicYN="N">Annexin A5</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016757" MajorTopicYN="N">Death, Sudden, Cardiac</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName><QualifierName UI="Q000209" MajorTopicYN="Y">etiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005387" MajorTopicYN="N" Type="Geographic">Finland</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005819" MajorTopicYN="N">Genetic Markers</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D020022" MajorTopicYN="Y">Genetic Predisposition to Disease</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005820" MajorTopicYN="N">Genetic Testing</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="D009203" MajorTopicYN="N">Myocardial Infarction</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011110" MajorTopicYN="Y">Polymorphism, Genetic</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012307" MajorTopicYN="N">Risk Factors</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>7</Month><Day>20</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>8</Month><Day>5</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>7</Month><Day>20</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16025836</ArticleId><ArticleId IdType="doi">10.1080/00365510510013550</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="KIE"><PMID Version="1">16025643</PMID><DateCompleted><Year>2005</Year><Month>08</Month><Day>23</Day></DateCompleted><DateRevised><Year>2009</Year><Month>11</Month><Day>19</Day></DateRevised><Article PubModel="Print"><Journal><JournalIssue CitedMedium="Print"><Issue>8</Issue><PubDate><Year>2001</Year><Month>Oct</Month></PubDate></JournalIssue><Title>Second opinion (Chicago, Ill. : 1999)</Title><ISOAbbreviation>Second Opin (Chic)</ISOAbbreviation></Journal>Genetics and the common good.	A common polymorphism (-1C to T) in the translation initiation sequence of annexin A5 (ANV) gene has recently been associated with a decreased risk of acute myocardial infarction (AMI). The aim of the present study was to analyze the association between the ANV genepolymorphism and the risk of AMI and ischemic sudden cardiac death (SCD) in middle-aged Finnish males.</AbstractText>A case-control study involving three distinct groups of subjects was carried out: (1) victims of SCD (n=98), (2) survivors of AMI (n=212), and (3) randomly selected control subjects without any history of coronary heart disease (n=243). The ANV polymorphism was genotyped in each study group.</AbstractText>Among the control group of healthy Finnish males the prevalence rates of the CC, CT, and TT genotypes were 83.1%, 15.2%, and 1.6%, respectively. Among the survivors of AMI, the prevalence rates of CC, CT, and TT were 79.7%, 20.3%, and 0%, respectively, and among the victims of SCD 83.7%, 16.3%, and 0%, respectively. No significant differences in the genotype or allele distributions were observed between the study groups.</AbstractText>The -1C to T polymorphism in the ANV gene is not associated with the risk of AMI or SCD in middle-aged Finnish males.</AbstractText>
2,337,120	A method for identifying genes related to a quantitative trait, incorporating multiple siblings and missing parents.	When studying either qualitative or quantitative traits, tests of association in the presence of linkage are necessary for fine-mapping. In a previous report, we suggested a polytomous logistic approach to testing linkage and association between a di-allelic marker and a quantitative trait locus, using genotyped triads, consisting of an individual whose quantitative trait has been measured and his or her two parents. Here we extend that approach to incorporate marker information from entire nuclear families. By computing a weighted score function instead of a maximum likelihood test, we allow for both an unspecified correlation structure between siblings and "informative" family size. Both this approach and our original approach allow for population admixture by conditioning on parental genotypes. The proposed method allows for missing parental genotype data through a multiple imputation procedure. We use simulations based on a population with admixture to compare our method to a popular non-parametric family-based association test (FBAT), testing the null of no association in the presence of linkage.
2,337,121	Sensorineural hearing loss, early greying, and essential tremor: a new hereditary syndrome?	To present a syndrome composed of sensorineural hearing loss, early greying of scalp hair, and adult-onset essential tremor.</AbstractText>Retrospective chart review.</AbstractText>Tertiary care academic hospital.</AbstractText>Three individuals were seen with this triad, each with family members with similar features. Our patients are a 65-year-old man and two women in their 40s. Two noted hearing loss in adulthood, one as a child. All had complete greying in their 20s. The women developed essential tremor in their 20s, and the man in his 50s. All individuals have blue eyes without heterochromia. Additional evaluation failed to further categorize these patients. Each has two or more immediate family members with a combination of these findings. Molecular genetic testing suggests this is not a variant of Waardenburg syndrome.</AbstractText>We believe this represents a previously unreported hereditary syndrome.</AbstractText>This new syndrome should be considered in the context of other syndromes involving audition, pigmentation, and movement.</AbstractText>
2,337,122	Technical standards and guidelines: venous thromboembolism (Factor V Leiden and prothrombin 20210G >A testing): a disease-specific supplement to the standards and guidelines for clinical genetics laboratories.	These standards and guidelines are designed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to this statement does not necessarily ensure a successful medical outcome. These standards and guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical molecular geneticist should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the laboratory record the rationale for any significant deviation from these standards and guidelines.
2,337,123	Development and validation of a CGH microarray for clinical cytogenetic diagnosis.	We developed a microarray for clinical diagnosis of chromosomal disorders using large insert genomic DNA clones as targets for comparative genomic hybridization (CGH).</AbstractText>The array contains 362 FISH-verified clones that span genomic regions implicated in over 40 known human genomic disorders and representative subtelomeric clones for each of the 41 clinically relevant human chromosome telomeres. Three or four clones from almost all deletion or duplication genomic regions and three or more clones for each subtelomeric region were included. We tested chromosome microarray analysis (CMA) in a masked fashion by examining genomic DNA from 25 patients who were previously ascertained in a genetic clinic and studied by conventional cytogenetics. A novel software package implemented in the R statistical programming language was developed for normalization, visualization, and inference.</AbstractText>The CMA results were entirely consistent with previous cytogenetic and FISH findings. For clone by clone analysis, the sensitivity was estimated to be 96.7% and the specificity was 99.1%. Major advantages of this selected human genome array include the following: interrogation of clinically relevant genomic regions, the ability to test for a wide range of duplication and deletion syndromes in a single analysis, the ability to detect duplications that would likely be undetected by metaphase FISH, and ease of confirmation of suspected genomic changes by conventional FISH testing currently available in the cytogenetics laboratory.</AbstractText>The array is an attractive alternative to telomere FISH and locus-specific FISH, but it does not include uniform coverage across the arms of each chromosome and is not intended to substitute for a standard karyotype. Limitations of CMA include the inability to detect both balanced chromosome changes and low levels of mosaicism.</AbstractText>
2,337,124	Genomewide linkage scan in a multigeneration Caucasian pedigree identifies a novel locus for keratoconus on chromosome 5q14.3-q21.1.	Keratoconus is a corneal dystrophy with an incidence of 1 in 2000 and a leading cause for cornea transplantation in Western developed countries. Both clinical observations and segregation analyses suggest a major role for genes in its pathogenesis. It is genetically heterogeneous, most commonly sporadic, but inherited patterns with recessive or dominant modes have also been reported. We studied a four-generation autosomal-dominant pedigree to identify disease loci for keratoconus.</AbstractText>A two-stage genome-wide scan was applied to 27 family members. First linkage analysis was performed with 343 microsatellite markers along the 22 autosomal chromosomes at approximately 10 cM density. This was followed by fine mapping at approximately 2 cM density, in regions suggestive of linkage. Multipoint linkage analysis was performed using GeneHunter2.</AbstractText>Evidence of suggestive linkage from the initial scan was observed at the 82 to 112 cM region of chromosome 5q14.1-q21.3 with a maximum lod score (LOD) of 3.48 (penetrance = 0.5). Fine mapping by testing an additional 11 microsatellite markers at 1 to 3 cM intervals revealed a narrower and higher peak (99-119 cM) with LOD 3.53. By analysis of the recombination of haplotypes, the putative locus of keratoconus was further narrowed to a 6 cM region (8.2 Mbp physical distance) between markers D5S2499 and D5S495.</AbstractText>These results indicate a promising new locus for keratoconus in this pedigree. Because of the heterogeneous nature of keratoconus, this locus may be specific to familial autosomal-dominant keratoconus. Nevertheless, the identification of this locus may provide new insights into the pathogenesis of keratoconus.</AbstractText>
2,337,125	An international survey of predictive genetic testing in children for adult onset conditions.	Predictive genetic testing is offered to asymptomatic adults even when there is no effective prophylaxis or treatment. Testing of young people in similar circumstances is controversial, and guidelines recommend against it. We sought to document descriptive examples of the occurrence of genetic testing in young people for nonmedical reasons, in the countries where guidelines exist.</AbstractText>Clinical geneticists in the USA, Canada, UK, Australia, and New Zealand were surveyed about the occurrence and outcomes of testing in asymptomatic young people for conditions where no prophylaxis or treatment exists and onset is usually in adulthood.</AbstractText>Of 301 responses, details were provided of 49 cases where such testing had occurred. The most common condition tested for was Huntington Disease. In 22 cases (45%), the young person tested was immature, defined as under the age of 14 years. Results were disclosed to only two immature minors and in three cases parents experienced clinically significant anxiety related to how they would pass on information to their gene positive child. In 27 cases (55%), the young person tested was mature. Results were disclosed to 26 mature minors and it was reported that two individuals experienced an adverse event. Consistent follow-up did not take place and findings represent the minimum frequency of adverse events. The majority of respondents agree with existing guidelines but many believe each case must be considered individually.</AbstractText>Clinicians agree with existing guidelines regarding predictive testing in young people, but choose to provide tests for nonmedical reasons in specific cases.</AbstractText>
2,337,126	Introducing genetic testing for adult-type hypolactasia.	To evaluate genotyping for two DNA variants (c.1993+327C>T and c.1438+117G>A), recently found to be associated with adult-type hypolactasia, in the diagnosis of lactose intolerance.</AbstractText>In total, 166 consecutive patients with gastrointestinal symptoms mimicking hypolactasia admitted to the clinic between March 2002 and December 2002 were included. Genotyping for the two DNA variants (c.1993+327C>T and c.1438+117G>A) and standard H2 breath test was performed.</AbstractText>Among 116 patients with positive H2 breath test, the c.1993+327C variant was detectable in 106 (91.4%) patients. Among 50 patients with negative H2 breath test, the c.1993+327C variant was seen in 2 patients. Sensitivity, specificity, positive and negative predictive values for the c.1993+327C variant were 91.4, 96.0, 98.1 and 82.8%, respectively. Genotyping for the c.1438+117G variant did not bring any additional information. Among 4 of the 10 patients with positive H2 breath test but negative for the c.1993+327C and the c.1438+117G variant,further evaluation revealed other diseases known to cause secondary hypolactasia such as celiac disease and short bowel syndrome.</AbstractText>In symptomatic patients, genotyping for the DNA variant c.1993+327C is a reliable test for adult-type hypolactasia with high sensitivity and specificity and thus provides a new tool in the diagnostic workup of hypolactasia.</AbstractText>Copyright (c) 2005 S. Karger AG, Basel.</CopyrightInformation>
2,337,127	Isogenic autosomes to be applied in optimal screening for novel mutants with viable phenotypes in Drosophila melanogaster.	Most insertional mutagenesis screens of Drosophila performed to date have not used target chromosomes that have been checked for their suitability for phenotypic screens for viable phenotypes. To address this, we have generated a selection of stocks carrying either isogenized second chromosomes or isogenized third chromosomes, in a genetic background derived from a Canton-S wild-type strain. We have tested these stocks for a range of behavioral and other viable phenotypes. As expected, most lines are statistically indistinguishable from Canton-S in most phenotypes tested. The lines generated are now being used as target chromosomes in mutagenesis screens, and the characterization reported here will facilitate their use in screens of these lines for behavioral and other viable phenotypes.
2,337,128	Selection strength and hitchhiking around two anti-malarial resistance genes.	Neutral mutations may hitchhike to high frequency when they are situated close to sites under positive selection, generating local reductions in genetic diversity. This process is thought to be an important determinant of levels of genomic variation in natural populations. The size of genome regions affected by genetic hitchhiking is expected to be dependent on the strength of selection, but there is little empirical data supporting this prediction. Here, we compare microsatellite variation around two drug resistance genes (chloroquine resistance transporter (pfcrt), chromosome 7, and dihydrofolate reductase (dhfr), chromosome 4) in malaria parasite populations exposed to strong (Thailand) or weak selection (Laos) by anti-malarial drugs. In each population, we examined the point mutations underlying resistance and length variation at 22 (chromosome 4) or 25 (chromosome 7) microsatellite markers across these chromosomes. All parasites from Thailand carried the K76T mutation in pfcrt conferring resistance to chloroquine (CQ) and 2-4 mutations in dhfr conferring resistance to pyrimethamine. By contrast, we found both wild-type and resistant alleles at both genes in Laos. There were dramatic differences in the extent of hitchhiking in the two countries. The size of genome regions affected was smaller in Laos than in Thailand. We observed significant reduction in variation relative to sensitive parasites for 34-64 kb (2-4 cM) in Laos on chromosome 4, compared with 98-137 kb (6-8 cM) in Thailand. Similarly, on chromosome 7, we observed reduced variation for 34-69 kb (2-4 cM) around pfcrt in Laos, but for 195-268 kb (11-16 cM) in Thailand. Reduction in genetic variation was also less extreme in Laos than in Thailand. Most loci were monomorphic in a 12 kb region surrounding both genes on resistant chromosomes from Thailand, whereas in Laos, even loci immediately proximal to selective sites showed some variation on resistant chromosomes. Finally, linkage disequilibrium (LD) decayed more rapidly around resistant pfcrt and dhfr alleles from Laos than from Thailand. These results demonstrate that different realizations of the same selective sweeps may vary considerably in size and shape, in a manner broadly consistent with selection history. From a practical perspective, genomic regions containing resistance genes may be most effectively located by genome-wide association in populations exposed to strong drug selection. However, the lower levels of LD surrounding resistance alleles in populations under weak selection may simplify identification of functional mutations.
2,337,129	Construction of a bispecific antisense oligonucleotide containing multiple binding sites for the treatment of hormone insensitive prostate tumors.	Antisense oligonucleotides (oligos) have demonstrated efficacy for the treatment of various cancers, infectious diseases and metabolic disorders. While most studies have utilized single oligos either administered alone, or more recently in combination therapy with other drugs, some investigators have administered more than one oligo in a combined administration or have designed oligos which target multiple proteins (those which share mRNA sequence homology). Antisense oligos inhibit mRNA translation through complementary base pair binding, often about the AUG initiation codon. This inhibition is further enhanced through destruction of the mRNA:oligo hybrid by RNAse H. Construction of an oligo with multiple binding sites located about the respective mRNA initiation codons could simultaneously block translation of more than one protein, even those unrelated in sequence. Such binding could produce a complex mRNA:oligo hybrid more prone to degradation and clearance. Furthermore, such a formulation would increase oligo specific activity and cellular uptake, reduce toxicity, and stabilize at 1:1 the ratio between multiple oligo active sites which otherwise must be comparably delivered (in amount) and individually targeted. The activity of these newly constructed oligos could be tested in both in vitro and in vivo prostate tumor models, utilizing the hormone sensitive LNCaP and the hormone insensitive PC-3 lines. In vitro testing would evaluate oligos administered either alone or in combination with other chemotherapeutics. In vivo testing would administer the oligos to tumors carried in athymic nude mice by either intratumoral inoculation or by using a diffusion pump. Antisense oligos which target proteins associated with growth factors or their receptors, could have a role in the treatment of human prostate cancers when administered with hormone deprivation therapy, or against tumors which have already become hormone insensitive. In the later case, such treatment could form the basis of a second tier of therapy based upon growth factor deprivation.
2,337,130	An optimized experimental protocol based on neuro-evolutionary algorithms application to the classification of dyspeptic patients and to the prediction of the effectiveness of their treatment.	This paper aims to present a specific optimized experimental protocol (EP) for classification and/or prediction problems. The neuro-evolutionary algorithms on which it is based and its application with two selected real cases are described in detail. The first application addresses the problem of classifying the functional (FD) or organic (OD) forms of dyspepsia; the second relates to the problem of predicting the 6-month follow-up outcome of dyspeptic patients treated by helicobacter pylori (HP) eradication therapy.</AbstractText>The database built by the multicentre observational study, performed in Italy by the NUD-look Study Group, provided the material studied: a collection of data from 861 patients with previously uninvestigated dyspepsia, being referred for upper gastrointestinal endoscopy to 42 Italian Endoscopic Services. The proposed EP makes use of techniques based on advanced neuro-evolutionary systems (NESs) and is structured in phases and steps. The use of specific input selection (IS) and training and testing (T and T) techniques together with genetic doping (GenD) algorithm is described in detail, as well as the steps taken in the two benchmark and optimization protocol phases.</AbstractText>In terms of accuracy results, a value of 79.64% was achieved during optimization, with mean benchmark values of 64.90% for the linear discriminant analysis (LDA) and 68.15% for the multi layer perceptron (MLP), for the classification task. A value of 88.61% was achieved during optimization for the prediction task, with mean benchmark values of 49.32% for the LDA and 70.05% for the MLP.</AbstractText>The proposed EP has led to the construction of inductors that are viable and usable on medical data which is representative but highly not linear. In particular, for the classification problem, these new inductors may be effectively used on the basal examination data to support doctors in deciding whether to avoid endoscopic examinations; whereas, in the prediction problem, they may support doctors' decisions about the advisability of eradication therapy. In both cases the variables selected indicate the possibility of reducing the data collection effort and also of providing information that can be used for general investigations on symptom relevance.</AbstractText>
2,337,131	Uniparental disomy and imprinting defects in Japanese patients with Angelman syndrome.	We examined 54 patients with deletion-negative Angelman syndrome (AS) using DNA methylation testing and microsatellite polymorphism analysis, and identified three patients with paternal uniparental disomy (UPD) and seven patients with imprinting defects (ID). The three patients with UPD were shown to have paternal isodisomy 15, which we hypothesized to have arisen from duplication of chromosome 15. Two of the patients with ID were siblings and carried microdeletions of the imprinting center (IC), while the remaining five patients had no evidence of deletions and represented sporadic cases. Two of the three patients with UPD and two of the seven patients with ID had not developed seizures. The only patients displaying microcephaly were those with ID who had microdeletions at the IC. These data support the previous findings that indicate that patients with UPD and ID may have a milder phenotype of AS.
2,337,132	Fulminant neurological deterioration in a neonate with Leigh syndrome due to a maternally transmitted missense mutation in the mitochondrial ND3 gene.	Leigh syndrome can result from both nuclear and mitochondrial DNA defects. Mutations in complex V genes of the respiratory chain were considered until recently as the most frequent cause for mitochondrial inherited Leigh syndrome, while gene defects in complex I were related to recessive Leigh syndrome. Recently few reports of mutations in the mitochondrial-encoded complex I subunit genes causing Leigh syndrome have been reported. We describe a 1-month-old baby who acutely deteriorated, with abrupt onset of brainstem dysfunction, due to basal ganglia lesions extending to the brainstem. A muscle biopsy demonstrated complex I deficiency. Subsequent analysis of the mitochondrial genome revealed a homoplastic T10191C mutation in the ND3 gene (in blood and muscle), resulting in a substitution of serine to proline. Hair root analysis revealed a 50% mutant load, reflecting heteroplasmy in early embryonic stages. The mutation was also detected in his mother (5%). Western blot analysis revealed a decrease of the 20 kDa subunit (likely ND6) and of the 30 kDa subunit (NDUFA9), which is probably due to instability attributed to the inability to form subcomplexes with ND3. This is the first description of infantile Leigh syndrome due to a maternally transmitted T10191C substitution in ND3 and not due to a de novo mutation. This mutation is age and tissue dependent and therefore may not be amenable to prenatal testing.
2,337,133	Large-scale genomic approaches to brain development and circuitry.	Over the past two decades, molecular genetic studies have enabled a common conceptual framework for the development and basic function of the nervous system. These studies, and the pioneering efforts of mouse geneticists and neuroscientists to identify and clone genes for spontaneous mouse mutants, have provided a paradigm for understanding complex processes of the vertebrate brain. Gene cloning for human brain malformations and degenerative disorders identified other important central nervous system (CNS) genes. However, because many debilitating human disorders are genetically complex, phenotypic screens are difficult to design. This difficulty has led to large-scale, genomic approaches to discover genes that are uniquely expressed in brain circuits and regions that control complex behaviors. In this review, we summarize current phenotype- and genotype-driven approaches to discover novel CNS-expressed genes, as well as current approaches to carry out large-scale, gene-expression screens in the CNS.
2,337,134	[A late-onset case of oculopharyngeal muscular dystrophy carrying a (GCG)8 repeat expansion in the PAPBN1 gene].	We report a sporadic case of a female patient with oculopharyngeal muscular dystrophy (OPMD). Her father died at age 86 and mother at age 74. There was no familial occurrence of the disease. The patient initially developed a nasal voice at age 66. Neurological examinations on admission at age 72 revealed bilateral ptosis, a limitation of ocular movement without diplopia, dysphagia, and proximal muscle weakness. Serum creatine kinase level was slightly increased. Biopsied muscle specimens showed variation in fiber size as well as the occasional presence of rimmed vacuoles. On the basis of these clinical and laboratory findings, we suspected a diagnosis of OPMD, although a family history was absent. To confirm the diagnosis of OPMD, we performed a gene analysis for poly A binding protein, nuclear 1 (PABPN1; PABP2), which revealed a mild expansion of GCG repeat (8 repeats) as a heterozygous state. Clinical features of the patient were consistent with those in a previous literature reporting that patients carrying (GCG)8 repeat as a heterozygous state show a relatively late onset and a mild phenotype. The case of this patient emphasizes the importance of the PABPN1 gene analysis for patients showing muscular weakness involving oculopharyngeal and proximal limb muscles even when a familial occurrence of the disease is not apparent.
2,337,135	Report of the roundtable discussion organised by the Swiss Proteomics Society (SPS), Bern, 8th December 2004.	How close are we to using proteomics tools in the every day practice of physicians? What are the socio-economical issues our health care system may face with the advent of biomarkers for early diagnosis? How to get the specialists from the various disciplines integrated in proteomics to establish a common understanding of the clinical issues and develop the necessary standards (methods, biochemicals and IT)? These were the kind of questions a panel of specialists tried to answer during the roundtable discussion that took place in Bern during the Swiss Proteomics Society 2004 congress.
2,337,136	Mutations in the NHLRC1 gene are the common cause for Lafora disease in the Japanese population.	Lafora disease (LD) is a rare autosomal recessive genetic disorder characterized by epilepsy, myoclonus, and progressive neurological deterioration. LD is caused by mutations in the EMP2A gene encoding a protein phosphatase. A second gene for LD, termed NHLRC1 and encoding a putative E3 ubiquitin ligase, was recently identified on chromosome 6p22. The LD is relatively common in southern Europe, the Middle East, and Southeast Asia. A few sporadic cases with typical LD phenotype have been reported from Japan; however, our earlier study failed to find EPM2A mutations in four Japanese families with LD. We recruited four new families from Japan and searched for mutations in EPM2A . All eight families were also screened for NHLRC1 mutations. We found five independent families having novel mutations in NHLRC1. Identified mutations include five missense mutations (p.I153M, p.C160R, p.W219R, p.D245N, and p.R253K) and a deletion mutation (c.897insA; p.S299fs13). We also found a family with a ten base pair deletion (c.822-832del10) in the coding region of EPM2A. In two families, no EPM2A or NHLRC1 mutation was found. Our study, in addition to documenting the genetic and molecular heterogeneity observed for LD, suggests that mutations in the NHLRC1 gene may be a common cause of LD in the Japanese population.
2,337,137	Follow-up of children and adolescents with short stature: the importance of the growth rate.	Short stature is defined as a height of more than two standard deviations below the average for a given age and sex in a reference population. The objective was to describe follow-up conducted among short-stature children and adolescents.</AbstractText>Descriptive study, at the Growth outpatient clinic, Department of Pediatrics, Universidade Federal de São Paulo.</AbstractText>The study included 152 patients aged 2 to 15 years who had height for age of less than P5, on the National Center for Health Statistics curve. The children underwent nutritional evaluation, and several variables relating to height and growth rate were calculated to establish etiological diagnosis. Bone age was evaluated by X-ray.</AbstractText>The majority (63.2%) were male. In 77.8%, the stature observed was within the family pattern. Among the 99 patients followed up for more than 6 months, 17.2% presented inadequate growth rates. The preponderant etiological diagnosis for short stature was familial/constitutional in 58.6% of the cases; 27 patients (34.2%) with adequate growth rate presented bone age alterations. Even with inadequate growth rates, 75% of such patients had a normal result from growth hormone stimulation testing. Close to 90% of patients with a diagnosis of short stature of familial/constitutional origin and intrauterine growth retardation presented adequate growth rate. The genetic etiology was significantly characteristic of patients with inadequate growth rate.</AbstractText>Growth rate assessment must form part of the investigation and follow-up of short-stature cases. However, its utilization and validity should form part of an overall view of each patient.</AbstractText>
2,337,138	Ranks of genuine associations in whole-genome scans.	With the recent advances in high-throughput genotyping techniques, it is now possible to perform whole-genome association studies to fine map causal polymorphisms underlying important traits that influence susceptibility to human diseases and efficacy of drugs. Once a genome scan is completed the results can be sorted by the association statistic value. What is the probability that true positives will be encountered among the first most associated markers? When a particular polymorphism is found associated with the trait, there is a chance that it represents either a "true" or a "false" association (TA vs. FA). Setting appropriate significance thresholds has been considered to provide assurance of sufficient odds that the associations found to be significant are genuine. However, the problem with genome scans involving thousands of markers is that the statistic values of FAs can reach quite extreme magnitudes. In such situations, the distributions corresponding to TAs and the most extreme FAs become comparable and significance thresholds tend to penalize TAs and FAs in a similar fashion. When sorting between true and false associations, the "typical" place (i.e., rank) of TAs among the most significant outcomes becomes important, ordered by the association statistic value. The distribution of ranks that we study here allows calculation of several useful quantities. In particular, it gives the number of most significant markers needed for a follow-up study to guarantee that a true association is included with certain probability. This can be calculated conditionally on having applied a multiple-testing correction. Effects of multilocus (e.g., haplotype association) tests and impact of linkage disequilibrium on the distribution of ranks associated with TAs are evaluated and can be taken into account.
2,337,139	goCluster integrates statistical analysis and functional interpretation of microarray expression data.	Several tools that facilitate the interpretation of transcriptional profiles using gene annotation data are available but most of them combine a particular statistical analysis strategy with functional information. goCluster extends this concept by providing a modular framework that facilitates integration of statistical and functional microarray data analysis with data interpretation.</AbstractText>goCluster enables scientists to employ annotation information, clustering algorithms and visualization tools in their array data analysis and interpretation strategy. The package provides four clustering algorithms and GeneOntology terms as prototype annotation data. The functional analysis is based on the hypergeometric distribution whereby the Bonferroni correction or the false discovery rate can be used to correct for multiple testing. The approach implemented in goCluster was successfully applied to interpret the results of complex mammalian and yeast expression data obtained with high density oligonucleotide microarrays (GeneChips).</AbstractText>goCluster is available via the BioConductor portal at www.bioconductor.org. The software package, detailed documentation, user- and developer guides as well as other background information are also accessible via a web portal at http://www.bioz.unibas.ch/gocluster</AbstractText>[email protected]</AbstractText>
2,337,140	A discordant sib-pair linkage analysis of age-related macular degeneration.	Age-related macular degeneration (AMD) is the leading cause of visual impairment and blindness among older adults in the United States and throughout the developed world. Etiological research implicates both genetic and environmental components. Our prior genome scan in 511 affected sib-pairs and other relative pairs identified significant or suggestive linkage signals on chromosomes 1, 2, 3, 6, 8, 10, 12, 16, and 22.</AbstractText>To search for genetic loci for AMD using the extremely discordant sib-pair (EDSP) method of linkage analysis, which until now has never been applied to the study of AMD.</AbstractText>The EDSP method is a more powerful approach than standard methods which rely on relative pairs selected at random or pairs concordant for the phenotype. The EDSP approach has also been characterized as the only design that is uniformly powerful in nearly all genetic situations. Thus, substantial reductions in sample size can be achieved.</AbstractText>The study sample for analysis included 110 EDSPs from 40 families that comprise a subset of the 158 families studied in a prior genome-wide scan using affected relative pairs.</AbstractText>Evidence for linkage was found on chromosomes 1q, 2q, 6q, 19p, and 20q. The regions identified on chromosomes 1q and 2q were the same regions identified in our prior analysis, whereas the identified region on 6q was approximately 80 cM distal to our previous signal.</AbstractText>Within this study population, we have narrowed the focus to chromosomes 1q, 2q, 6q, 19p, and 20q in our search for AMD loci. However, given the fact that a gene was recently identified on chromosome 1q, future family- and population-based analyses should concentrate on testing for associations with candidate gene variants in the other identified chromosomal regions in searches for additional AMD loci.</AbstractText>
2,337,141	Molecular genetics of adult-type hypolactasia.	Adult-type hypolactasia (lactase non-persistence; primary lactose malabsorption) is characterized by the down-regulation of the lactase enzyme activity in the intestinal wall after weaning. The down-regulation is genetically determined and a mutation has occurred that has made part of mankind tolerate milk (lactase persistence). A DNA-variant, single nucleotide polymorphism C/T-13910 located 13 910 base pairs (bp) upstream of the lactase gene (LCT) at chromosome 2q21-22 has been shown to associate with the lactase persistence/non-persistence trait both in family and case-control studies. The C/T-13910 variant is located in a non-coding region in the genome in intron 13 of the minichromosome maintenance type 6 gene (MCM6). Significant correlation between the C/T-13910-variant and lactase activity in the intestinal biopsy specimens has been demonstrated. Molecular epidemiological studies on the prevalence of the C/C-13910 genotype associated with low lactase activity are in agreement with the prevalence figures for adult type hypolactasia in>70 diverse ethnic groups studied. Recent functional studies have suggested that this variant has an enhancer effect over the lactase gene. Based on the biochemical, functional, genetic and molecular epidemiological studies of the C/T-13910 variant, genetic testing for adult type hypolactasia has been introduced into clinical practice in Finland. Identification of the genetic change has highlighted the role of non-coding variants in the regulation of common genes and created new tools to study the mechanism of lactase enzyme activation.
2,337,142	Autoimmune retinopathy with RPE hypersensitivity and 'negative ERG' in X-linked hyper-IgM syndrome.	To report the clinical, electrophysiological, and immunological features of a patient with X-linked hyper-IgM immunodeficiency syndrome type 1 (HIGM1) accompanied by a novel type of autoimmune retinopathy, including retinal pigment epithelium (RPE) hypersensitivity.</AbstractText>Comprehensive ophthalmological examinations, electrophysiological function testing, and inquiries into the immunological status of a 13-year-old presenting with subacute loss of vision in association with a molecularly confirmed diagnosis of HIGM1 were performed. The patient was genotyped by a PCR-based sequence tag content mapping strategy to define the genetic defect within the causative X-HIM gene TNFSF5. Since conventional allogenic bone marrow transplantation has been reported to cure HIGM1, a peripheral blood stem-cell transplantation was performed.</AbstractText>(1) The patient's reduced visual acuity included prolonged dark adaptation and visual field constriction. Electrophysiology revealed a 'negative ERG' indicating post-receptoral dysfunction. (2) Initial immunological examination of the patient's serum identified abnormal antibody activity with components of the photoreceptors and the inner nuclear layer. The patient later developed indications of RPE hypersensitivity. A massively reduced light-peak to dark-trough ratio of the EOG slow oscillations (L/D ratio) corresponded to impaired RPE-photoreceptor complex function. (3) Molecular genetic analyses revealed the patient to be nullizygous for the tumor necrosis factor ligand member 5 gene (TNFSF5; CD40LG). A large chromosomal deletion of approximately 27.6-32.3 kb in size was identified in Xq26. (4) The transplant with its associated immunomodulation appeared to worsen rather than improve the patient's condition.</AbstractText>The fundus appearance and electrophysiological function testing revealed indications of atypical retinal degeneration. However, the clinical course and the serological findings were consistent with those of ocular autoimmunity involving both antiretinal activity and RPE hypersensitivity. In this case, peripheral stem-cell transfusion with its associated chemotherapy failed to benefit the patient's vision; indications of autoimmunity appeared to increase following this treatment.</AbstractText>
2,337,143	Analysis of HLA class I and class II gene polymorphisms in Japanese patients with human T-cell lymphotropic virus type 1-associated uveitis.	To investigate the immunogenetic background of human T-cell lymphotropic virus type 1 (HTLV-1)-associated uveitis (HAU) that presents immune-mediated reactive changes in the uvea.</AbstractText>HLA class I and class II genes were studied in 51 patients with HAU, 192 asymptomatic HTLV-1 carriers, and 266 HTLV-1-seronegative controls using a high-resolution method of HLA DNA typing. The HLA alleles of HAU were compared with those of HTLV-1 carriers and healthy controls.</AbstractText>We identified 62 distinct alleles of HLA-A, HLA-Cw, and HLA-B and 49 distinct alleles of HLA-DRB1 and HLA-DQB1 in patients with HAU, asymptomatic HTLV-1 carriers, and healthy controls. The relative frequencies of these HLA alleles did not differ among the three groups.</AbstractText>The results suggest that HLA class I and class II genes do not contribute to susceptibility to HAU.</AbstractText>
2,337,144	Mitochondrial inheritance in depression, dysmotility and migraine?	Several studies have reported a high degree of association of the common conditions of depression, bowel dysmotility and migraine. Mitochondrial dysfunction and mitochondrial DNA (mtDNA) sequence variants have been linked individually to each of these three conditions, providing a plausible hypothesis for the reported association. If this hypothesis is correct, the matrilineal relatives (who all share essentially the same mtDNA sequence) of patients with mitochondrial disease secondary to inherited mtDNA mutations would be expected to have an elevated prevalence of each of these three conditions.</AbstractText>Families were recruited by an advertisement posted on the United Mitochondrial Disease Foundation website and invited to participate in an on-line questionnaire if at least one member was diagnosed with mitochondrial disease by a physician. Based upon the reported family histories, families were assigned by the investigators to either the probable maternal inheritance (PMI) group (55 families) or the probable non-maternal inheritance (PnMI) group (111 families).</AbstractText>Bowel disorders, migraine and depression were reported at very high prevalence in the PMI mothers (60%, 54% and 51%, respectively), but were present at significantly lower prevalence rates among the PnMI mothers (16%, 26% and 12%; P<0.0001 for each) and the fathers of both groups (range 9-16%; P < 2 x 10(-6) for each). Similar data was obtained comparing the prevalence rates among maternal and paternal grandmothers, aunts and uncles.</AbstractText>Our data was obtained from families ascertained by the presence of a severely affected individual, and may not be applicable to families lacking this proband.</AbstractText>Depression, bowel dysmotility and migraine are common manifestations in individuals with mtDNA sequence-related mitochondrial dysfunction, which supports our hypothesis that mitochondrial dysfunction is a major common factor underlying the association of these three conditions.</AbstractText>
2,337,145	Cone-rod dystrophy, intrafamilial variability, and incomplete penetrance associated with the R172W mutation in the peripherin/RDS gene.	To determine the underlying molecular genetic basis of a retinal dystrophy identified in a 5-generation family, and to examine the phenotype and degree of intrafamilial variability.</AbstractText>Family genetic study.</AbstractText>Nine affected individuals from a nonconsanguineous British family.</AbstractText>Ophthalmologic examination, color vision testing, fundus photography, autofluorescence imaging, and electrophysiological assessment were performed. The clinical notes of 2 additional deceased affected family members were also reviewed. Blood samples were taken for DNA extraction, with linkage analysis being performed, and subsequent mutation screening of the peripherin/RDS gene.</AbstractText>Linkage analysis established a disease interval on chromosome 6p, which harbored the retinal candidate gene, peripherin/RDS. The 3 coding exons of the peripherin/RDS gene were subsequently screened for mutations in affected and unaffected family members. A nonconservative missense substitution, Arg172Trp (R172W), segregated uniquely in all affected subjects. The majority of subjects carrying the R172W peripherin/RDS mutation complained of reduced central vision starting in the second or third decade, with subsequent gradual deterioration of visual acuity and color vision. Three affected individuals complained of nyctalopia. A range of macular appearances were seen, varying from a typical granular appearance to extensive macular atrophy. Autofluorescence imaging in the majority of individuals identified a highly characteristic speckled macular appearance. All affected subjects had abnormal pattern electroretinograms (ERGs) consistent with macular dysfunction and 4 subjects showed additional full-field ERG abnormalities, providing evidence of generalized retinal dysfunction. There was marked variation in the clinical phenotype in those individuals who carried the R172W peripherin/RDS mutation, ranging from severe cone-rod dystrophy to asymptomatic individuals with normal retinal function.</AbstractText>The Arg172Trp (R172W) peripherin/RDS mutation has been previously reported to cause a fully penetrant progressive macular dystrophy with high intrafamilial and interfamilial consistency of phenotype. This is the first report describing marked intrafamilial variation associated with this mutation, including nonpenetrance. These findings are clinically important in relation to advice on prognosis and accurate genetic counseling.</AbstractText>
2,337,146	Dissecting systems-wide data using mixture models: application to identify affected cellular processes.	Functional analysis of data from genome-scale experiments, such as microarrays, requires an extensive selection of differentially expressed genes. Under many conditions, the proportion of differentially expressed genes is considerable, making the selection criteria a balance between the inclusion of false positives and the exclusion of false negatives.</AbstractText>We developed an analytical method to determine a p-value threshold from a microarray experiment that is dependent on the quality and design of the data set. To this aim, populations of p-values are modeled as mathematical functions in which the parameters to describe these functions are estimated in an unsupervised manner. The strength of the method is exemplified by its application to a published gene expression data set of sporadic and familial breast tumors with BRCA1 or BRCA2 mutations.</AbstractText>We present an objective and unsupervised way to set thresholds adapted to the quality and design of the experiment. The resulting mathematical description of the data sets of genome-scale experiments enables a probabilistic approach in systems biology.</AbstractText>
2,337,147	[The characteristics of combined genetic screening of the first trimester of pregnancy after use of assisted reproductive technology programs].	Results of comparison of nuchal translucency measurments (NT) and parameters of the biochemical analysis of blood serum of pregnant women in the first trimester and after use of assisted reproductive technologies (in vitro fertilization and cytoplasmic sperm injection (ICSI)) are submitted. It was shown that NT does not differ from those of women with spontaneous pregnancy, and parameters of biochemical markers tend only to change. After ICSI use concentration of free beta-HCG authentically increases.
2,337,148	Adrenomyeloneuropathy: report of a new mutation in a French Canadian female.	X-linked adrenoleukodystrophy is a peroxisomial disorder caused by mutations in the ABCD1 gene. Adrenomyeloneuropathy is the second most frequent phenotype (25-46%) of this disease and classically presents in adulthood with spastic paraparesis. Female heterozygotes can be symptomatic, but they are frequently misdiagnosed as having multiple sclerosis.</AbstractText>We report a novel missense mutation in the ABCD1 gene in a 47-year-old French-Canadian female with spastic paraparesis and no confirmed family history of X-linked adrenoleukodystrophy. The mutation is located on exon 1 and causes the amino acid substitution of a valine for an alanine in a region of the protein highly conserved between mouse and man.</AbstractText>Adrenomyeloneuropathy must be considered in the differential diagnosis of spastic paraparesis in men or women. This is an initial report of an ABCD1 gene mutation in the French-Canadian population, which should lead to the recognition of other cases in the future.</AbstractText>
2,337,149	Cancer gene discovery in solid tumours using transposon-based somatic mutagenesis in the mouse.	Retroviruses, acting as somatic cell insertional mutagens, have been widely used to identify cancer genes in the haematopoietic system and mammary gland. An insertional mutagen for use in other mouse somatic cells would facilitate the identification of genes involved in tumour formation in a wider variety of tissues. Here we report the ability of the Sleeping Beauty transposon to act as a somatic insertional mutagen to identify genes involved in solid tumour formation. A Sleeping Beauty transposon, engineered to elicit loss-of-function or gain-of-function mutations, transposed in all somatic tissues tested and accelerated tumour formation in mice predisposed to cancer. Cloning transposon insertion sites from these tumours revealed the presence of common integration sites, at known and candidate cancer genes, similar to those observed in retroviral mutagenesis screens. Sleeping Beauty is a new tool for unbiased, forward genetic screens for cancer genes in vivo.
2,337,150	Auditory neuropathy or endocochlear hearing loss?	The purpose of the study was to define boundaries between endocochlear hearing loss and auditory neuropathy in children with congenital profound hearing loss and positive otoacoustic emissions.</AbstractText>A child presented with bilateral profound hearing loss, which was confirmed by the absence of evoked auditory potentials at 110 dB and with conserved otoacoustic emissions. The lack of any relevant medical history, a normal neurologic pediatric examination, and the improvement obtained with powerful hearing aids suggested an endocochlear cause. Genetic testing identified mutations in OTOF, responsible for the DFNB9 recessive form of hearing loss.</AbstractText>In recent years, cases of children with hearing loss associated with positive otoacoustic emissions have been labeled as "auditory neuropathy." Classically, this form of hearing loss is refractory to the use of hearing aids and cochlear implants. Mutations in OTOF lead to inner hair cells dysfunction, whereas the outer hair cells are initially functionally preserved. As this form of endocochlear hearing loss can be detected at a molecular level, genetic testing can be proposed for cases of nonsyndromic auditory neuropathy, as those children could benefit from cochlear implantation.</AbstractText>It is advisable to reserve the term "auditory neuropathy" for patients who present hearing loss and conserved otoacoustic emissions in the context of a neurologic syndrome or for children with suggestive perinatal history. In other cases, genetic testing for mutations in OTOF should be carried out.</AbstractText>
2,337,151	Genomic epidemiology of complex disease: the need for an electronic evidence-based approach to research synthesis.	Modern microarray genotyping now permits simultaneous analysis of tens of thousands of polymorphisms, and this technology is being widely used to associate the role of genes with the etiology of complex disease. Genome-wide hypothesis-free mapping will also increasingly generate candidate genes that require further testing in association studies. At the same time, genetic effects are increasingly observed to be buffered by a wide array of biologic mechanisms that evolved to protect the genome from environmental insult and that serve to obscure observation of direct effects of polymorphisms on a disease phenotype. These two forces combine to make replication of genomic epidemiology extraordinarily difficult. Traditional research synthesis of emerging bodies of genomic epidemiology is problematic and often quickly outdated. The author proposes that electronic evidence-based methodology, perhaps modeled after that used by the Cochrane Collaboration in clinical medicine, would facilitate the systematic preparation and frequent updating of systematic reviews, which is essential for identifying valid and replicable gene-disease associations.
2,337,152	Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral.	Genetic testing for hereditary cancer syndromes contributes to the medical management of patients who may be at increased risk of one or more cancers. BRCA1 and BRCA2 testing for hereditary breast and ovarian cancer is one such widely used test. However, clinical testing methods with high sensitivity for deleterious mutations in these genes also detect many unclassified variants, primarily missense substitutions.</AbstractText>We developed an extension of the Grantham difference, called A-GVGD, to score missense substitutions against the range of variation present at their position in a multiple sequence alignment. Combining two methods, co-occurrence of unclassified variants with clearly deleterious mutations and A-GVGD, we analysed most of the missense substitutions observed in BRCA1.</AbstractText>A-GVGD was able to resolve known neutral and deleterious missense substitutions into distinct sets. Additionally, eight previously unclassified BRCA1 missense substitutions observed in trans with one or more deleterious mutations, and within the cross-species range of variation observed at their position in the protein, are now classified as neutral.</AbstractText>The methods combined here can classify as neutral about 50% of missense substitutions that have been observed with two or more clearly deleterious mutations. Furthermore, odds ratios estimated for sets of substitutions grouped by A-GVGD scores are consistent with the hypothesis that most unclassified substitutions that are within the cross-species range of variation at their position in BRCA1 are also neutral. For most of these, clinical reclassification will require integrated application of other methods such as pooled family histories, segregation analysis, or validated functional assay.</AbstractText>
2,337,153	Predictive genetic test decisions for Huntington's disease: elucidating the test/no-test dichotomy.	Predictive genetic testing for serious, mature-onset genetic illness represents a unique context in health decision making. This article presents findings from an exploratory qualitative Australian-based study into the decision making of individuals at risk for Huntington's disease (HD) with regard to predictive genetic testing. Sixteen in-depth interviews were conducted with a range of at-risk individuals. Data analysis revealed four discrete decision-making positions rather than a 'to test' or 'not to test' dichotomy. A conceptual dimension of (non-)openness and (non-)engagement characterized the various decisions. Processes of decision making and a concept of 'test readiness' were identified. Findings from this research, while not generalizable, are discussed in relation to theoretical frameworks and stage models of health decision making, as well as possible clinical implications.
2,337,154	Scope for improving congenital cataract blindness prevention by screening of infants (red reflex screening) in a New Zealand setting.	To assess the coverage and quality of routine red reflex screening in a single region and to consider the results in the context of the current New Zealand guidelines.</AbstractText>All the health practitioners partaking in routine Well Child - Tamariki Ora checks in the Nelson-Tasman region were asked to complete a simple one-page questionnaire on red reflex screening.</AbstractText>Out of 127 providers potentially involved in routine infant examinations, the response rate was 92%. Red reflex screening was not being performed at the appropriate routine infant check with an ophthalmoscope by 16% (10/61) of the general practitioners and 29% (10/35) of the midwives. Eighteen per cent of the doctors and 47% of the midwives did not understand why red reflex screening was important or what was being looked for.</AbstractText>There is substantial scope for improving the coverage and quality of red reflex screening in this region to meet national guidelines. The importance and technique of examining the red reflex should be stressed in the training of both doctors and midwives who are lead maternity carers in New Zealand.</AbstractText>
2,337,155	Pharmacogenomics of tumor necrosis factor antagonists in rheumatoid arthritis.	Tumor necrosis factor (TNF)-alpha plays a central role in the pathogenesis of rheumatoid arthritis (RA) and is instrumental in causing joint destruction, the clinical hallmark of the disease. Recognizing this, in recent years biological therapies have been developed that work by blocking the damaging effects of TNF-alpha on synovium and cartilage. Three such agents are currently approved for treatment in RA - etanercept, infliximab and adalimumab. Although these agents are very effective in slowing the clinical and structural progression in RA, they are expensive, totaling several thousand dollars in yearly costs. Furthermore, only about 60% of patients respond effectively to these agents. As RA is a chronic disease, with most patients expected to remain on these therapies for life, ways to prospectively identify patients most likely to benefit from these agents are being explored. Pharmacogenomic approaches form the basis of most such screening methods. Polymorphisms in genes encoding TNF-alpha, TNF-alpha receptors, other cytokines, and the major histocompatibility complex region, and their ability to predict response to anti-TNF therapies, have been the focus of many recent studies. The results from such studies are mixed, with some suggesting that single nucleotide polymorphisms (SNPs) in these genes are significant, while others conclude that such SNPs are irrelevant in predicting response. Such conflicting results are likely to be due to a variety of factors, as discussed in this article. Whether pharmacogenomics will allow prediction of anti-TNF therapy efficacy in RA remains a question with no clear answers to date. Large, prospective, multicenter studies with the examination of not just individual SNPs, but also multi-SNP haplotypes, are needed to address this question in the future.
2,337,156	Molecular testing for microsatellite instability and its value in tumor characterization.	Molecular analysis of tumor tissue has become a rapidly expanding field in medical research, exploiting the advantages of new technologies adapted to high-throughput examination of genetic alterations, gene and protein expression patterns. Only exceptionally, these approaches have found their way into routine clinical diagnosis and therapy. Microsatellite instability testing has been established as a very powerful tool to identify patients with hereditary nonpolyposis colorectal cancer, one of the most common familial cancer syndromes. In addition, there is emerging evidence that microsatellite instability analysis may become increasingly important for the clinician, having considerable impact on patients' prognosis as well as therapeutic decisions, at least in colorectal cancer patients. A better understanding of the microsatellite instability phenotype, its pathogenesis and implications for the course of the disease will pave the way for novel diagnostic and therapeutic strategies specifically tailored to microsatellite-unstable tumors. This review summarizes the current significance of molecular testing for microsatellite instability in several tumor entities and provides prospects of future developments.
2,337,157	Miniaturized detection technology in molecular diagnostics.	Miniaturization of genetic tests represents the convergence of molecular biology and engineering and is leading to a new class of small analyzers and test systems for genetic testing with improved analytical characteristics. Miniaturization initially focused on devices that contained micrometer-sized features designed for a particular analytical purpose (e.g., filters for cell isolation and chips for capillary electrophoresis). Now, the focus is shifting to analytical applications based on nano-sized objects such as nanotubes, nanochannels, nanoparticles, nanopores and nanocapacitors. These nanofabricated objects provide new tools for sequencing of nucleic acids and rapid, multiplexed, nucleic acid detection.
2,337,158	A cluster of cholesterol-related genes confers susceptibility for Alzheimer's disease.	Polygenic diseases are related to the complex interplay of genetic variations. We evaluated whether clusters of cholesterol- and lipid-related genetic variations are associated with Alzheimer's disease.</AbstractText>We analyzed 12 cholesterol-related single nucleotide polymorphisms and 48 control polymorphisms in 545 study participants (Alzheimer's disease group N = 284; control group N = 261). Diagnoses of Alzheimer's disease were made according to the NINCDS-ADRDA criteria. Multi-locus genetic association analysis was done with the set-association method. Dates of data collection were from January 2000 to December 2003.</AbstractText>We identified a cluster of polymorphisms in APOE, SOAT1, APOE 5'-untranslated region, OLR1, CYP46A1, LPL, LIPA, and APOA4 conferring significant (p = .0002) susceptibility for Alzheimer's disease. This gene cluster reached a diagnostic accuracy of 74% and correlated significantly (p = .018) with the levels of the brain cholesterol catabolite 24S-hydroxycholesterol in the cerebrospinal fluid.</AbstractText>Our results establish a novel approach for the identification of disease-related genetic clusters and demonstrate the need for multi-locus methods in the genetics of complex diseases.</AbstractText>
2,337,159	Psychiatric genetics: a survey of psychiatrists' knowledge, opinions, and practice patterns.	Knowledge about the genetic basis of psychiatric illness is growing rapidly, and psychiatrists may be called upon to incorporate this information into clinical practice. The goal of this study was to assess psychiatrists' familiarity with and attitudes toward genetic information.</AbstractText>We surveyed 844 participants, the majority of whom were psychiatrists, attending a continuing medical education course in the fall of 2002 and measured knowledge, opinions, and current practice patterns in regard to psychiatric genetics.</AbstractText>Responses were received from 352 psychiatrists (54% of those surveyed). Most psychiatrists correctly answered fewer than half of survey items assessing general and psychiatric genetic knowledge. While 83% considered it their role to discuss genetic information with patients and families, fewer than 25% felt prepared or competent to do so. In response to hypothetical questions regarding genetic testing, a substantial proportion of psychiatrists indicated willingness to use such tests for diagnostic clarification, as well as presymptomatic and even prenatal risk prediction. The majority of respondents expressed interest in further genetics education.</AbstractText>Our results suggest that psychiatrists view genetic information as clinically relevant, but have limitations in knowledge that may impact the incorporation of psychiatric genetics into clinical practice.</AbstractText>
2,337,160	Is HBV genotyping of clinical relevance?	The hepatitis B virus, as is the case of the hepatitis C virus, can be categorized in several genotypes. The genotyping of HBV is based on the nucleotide sequence divergence encoding the amino acids constituting the HBV surface proteins. Since the genotype of the hepatitis C virus is shown to be related to epidemiology and response to interferon therapy, one wonders whether this also holds for the hepatitis B virus. HBV genotypes clearly are found to be different in various geographical areas of infection. In Europe, genotypes A and D are predominant, whereas in Asian patients genotypes B and C are more frequent, and in the Middle-East the genotype D. Data concerning the clinical relevance are less clear but it seems that in Europe, the genotype A has a higher HBeAg clearance rate and a better outcome. In Asia, genotype B (and especially the genotype Bj) is associated with a higher HBeAg clearance and with less development of cirrhosis and HCC. The impact on spontaneous or therapy induced viral resolution is not yet clearly identified. Further evaluation in different countries is needed to delineate the impact of the genotype relative to other factors such as age at infection, level of serum transaminases and viral load, on the course of infection, complication, outcome of treatment and prognosis.
2,337,161	Bioinformatics and approaches to identifying polygenic susceptibility traits.	The role of genetic factors in periodontal disease is now well recognized, although details for the genetic mechanisms of the disease and implications for therapy can be as obscure as they are for other human traits. This paper addresses the role that the analysis of genome-wide data might play in helping to understand the molecular determinants of periodontal risk. Very few human diseases are not polygenic, in that an individual's susceptibility depends on his or her constitution at many genetic loci, each of which may have a small effect. Not only do these loci interact, but also their actions and interactions depend on nongenetic factors. Much of the statistical machinery to handle this complexity was developed in the plant and animal breeding context, where crosses between inbred lines selected for trait differences could be conducted. Human polygenic studies began with studies on large pedigrees, but have expanded to include case-control analyses of random samples of individuals who differ in disease status, and studies of marker transmissions within nuclear families. In the area of characterizing the genetic architecture of complex traits, the relatively new field of bioinformatics is distinguished from the more mature fields of statistical genetics or genetic epidemiology by its focus on genome-wide data. The very dense sets of genetic markers now available, particularly those at single nucleotide positions (SNPs), have meant that it is possible to seek linkages or associations between chromosomal position and disease from the whole genome in a single study. Apart from the obvious problems of scale, there are real issues involved with multiple testing and recognizing interactions. Current thinking tends to focus on relatively conserved "haplotype blocks" instead of single genetic markers, although there is no consensus on the utility of this emphasis.
2,337,162	Bacterial vaginosis: many questions--any answers?	Bacterial vaginosis, a common disorder among young women, is associated with adverse reproductive health outcomes. This review summarizes our current understanding of bacterial vaginosis and where future research should be focused. Recommendations for prevention, diagnosis, and treatment in both nonpregnant and pregnant populations are discussed.</AbstractText>Little progress has been made in understanding the causal factors. The results of several large prospective studies have shown that racial differences persist for rates of bacterial vaginosis even when other known risk factors are controlled for. Studies of the gene-environment interaction that examine the genetic aspects of immune response may explain racial differences and why some but not all women with bacterial vaginosis experience complications. Trials to prevent preterm birth by the treatment of bacterial vaginosis in pregnancy are disappointing. Resistance to clindamycin by bacterial vaginosis-associated anaerobic organisms has also been documented. New technology to provide rapid point-of-care diagnostic testing for bacterial vaginosis has emerged.</AbstractText>To understand the vaginal ecosystem and its role in reproductive health and disease, we will need to study not only the microflora but also the host-immune response. Currently recommended treatment options for bacterial vaginosis are associated with high rates of recurrence. A new concern is the development of macrolide resistance to vaginal anaerobic flora when clindamycin is used as treatment. Further studies are still needed to determine whether prevention or control of bacterial vaginosis, particularly approaches that rely not on antibiotic treatment but on the maintenance of a healthy vaginal ecosystem, can reduce adverse health outcomes.</AbstractText>
2,337,163	Branch-length prior influences Bayesian posterior probability of phylogeny.	The Bayesian method for estimating species phylogenies from molecular sequence data provides an attractive alternative to maximum likelihood with nonparametric bootstrap due to the easy interpretation of posterior probabilities for trees and to availability of efficient computational algorithms. However, for many data sets it produces extremely high posterior probabilities, sometimes for apparently incorrect clades. Here we use both computer simulation and empirical data analysis to examine the effect of the prior model for internal branch lengths. We found that posterior probabilities for trees and clades are sensitive to the prior for internal branch lengths, and priors assuming long internal branches cause high posterior probabilities for trees. In particular, uniform priors with high upper bounds bias Bayesian clade probabilities in favor of extreme values. We discuss possible remedies to the problem, including empirical and full Bayesian methods and subjective procedures suggested in Bayesian hypothesis testing. Our results also suggest that the bootstrap proportion and Bayesian posterior probability are different measures of accuracy, and that the bootstrap proportion, if interpreted as the probability that the clade is true, can be either too liberal or too conservative.
2,337,164	Weighted least-squares likelihood ratio test for branch testing in phylogenies reconstructed from distance measures.	A variety of analytical methods is available for branch testing in distance-based phylogenies. However, these methods are rarely used, possibly because the estimation of some of their statistics, especially the covariances, is not always feasible. We show that these difficulties can be overcome if some simplifying assumptions are made, namely distance independence. The weighted least-squares likelihood ratio test (WLS-LRT) we propose is easy to perform, using only the distances and some of their associated variances. If no variances are known, the use of the Felsenstein F-test, also based on weighted least squares, is discussed. Using simulated data and a data set of 43 mammalian mitochondrial sequences we demonstrate that the WLS-LRT performs as well as the generalized least-squares test, and indeed better for a large number of taxa data set. We thus show that the assumption of independence does not negatively affect the reliability or the accuracy of the least-squares approach. The results of the WLS-LRT are no worse than the results of the bootstrap methods, such as the Felsenstein bootstrap selection probability test and the Dopazo test. We also show that WLS-LRT can be applied in instances where other analytical methods are inappropriate. This point is illustrated by analyzing the relationships between human immunodeficiency virus type 1 (HIV-1) sequences isolated from various organs of different individuals.
2,337,165	Associations between malaria and MHC genes in a migratory songbird.	Malaria parasites are a widespread and species-rich group infecting many wild populations of mammals, birds and reptiles. Studies on humans have demonstrated that genetic factors play a key role in the susceptibility and outcome of malaria infections. Until the present study, it has not been examined whether genetic variation in hosts is important for the outcome of malaria infections in natural avian populations. We investigated associations between major histocompatibility complex (MHC) genes and prevalence of three different avian malaria parasites (Haemoproteus payevskyi (GRW1), Plasmodium sp. (GRW2) and Plasmodium sp. (GRW4)) in a long-term study of great reed warblers Acrocephalus arundinaceus. We hypothesized that the MHC genes could either give full protection against a malaria infection, or confer protection against lethal malaria and direct the infection towards being milder. We found a positive association between numbers of MHC class I alleles (a measure of level of heterozygosity) and prevalence of the GRW2 parasite, suggesting the latter scenario. There was also a positive association between a specific MHC allele (B4b), previously shown to be under frequency-dependent selection in the study population, and prevalence of GRW2. These associations suggest that individuals carrying either a large number of MHC alleles or a specific MHC allele are protected against lethal malaria infections.
2,337,166	Normal uniform mixture differential gene expression detection for cDNA microarrays.	One of the primary tasks in analysing gene expression data is finding genes that are differentially expressed in different samples. Multiple testing issues due to the thousands of tests run make some of the more popular methods for doing this problematic.</AbstractText>We propose a simple method, Normal Uniform Differential Gene Expression (NUDGE) detection for finding differentially expressed genes in cDNA microarrays. The method uses a simple univariate normal-uniform mixture model, in combination with new normalization methods for spread as well as mean that extend the lowess normalization of Dudoit, Yang, Callow and Speed (2002) 1. It takes account of multiple testing, and gives probabilities of differential expression as part of its output. It can be applied to either single-slide or replicated experiments, and it is very fast. Three datasets are analyzed using NUDGE, and the results are compared to those given by other popular methods: unadjusted and Bonferroni-adjusted t tests, Significance Analysis of Microarrays (SAM), and Empirical Bayes for microarrays (EBarrays) with both Gamma-Gamma and Lognormal-Normal models.</AbstractText>The method gives a high probability of differential expression to genes known/suspected a priori to be differentially expressed and a low probability to the others. In terms of known false positives and false negatives, the method outperforms all multiple-replicate methods except for the Gamma-Gamma EBarrays method to which it offers comparable results with the added advantages of greater simplicity, speed, fewer assumptions and applicability to the single replicate case. An R package called nudge to implement the methods in this paper will be made available soon at http://www.bioconductor.org.</AbstractText>
2,337,167	Exploratory Bayesian model selection for serial genetics data.	Characterizing the process by which molecular and cellular level changes occur over time will have broad implications for clinical decision making and help further our knowledge of disease etiology across many complex diseases. However, this presents an analytic challenge due to the large number of potentially relevant biomarkers and the complex, uncharacterized relationships among them. We propose an exploratory Bayesian model selection procedure that searches for model simplicity through independence testing of multiple discrete biomarkers measured over time. Bayes factor calculations are used to identify and compare models that are best supported by the data. For large model spaces, i.e., a large number of multi-leveled biomarkers, we propose a Markov chain Monte Carlo (MCMC) stochastic search algorithm for finding promising models. We apply our procedure to explore the extent to which HIV-1 genetic changes occur independently over time.
2,337,168	Genetic variation in heroin-induced changes in behaviour: effects of B6 strain dose on conditioned reward and locomotor sensitization in 129-B6 hybrid mice.	Substantial interindividual variability exists in the propensity to develop opiate addiction. Genetic variation in opiate reward may contribute to this variability. A large body of evidence indicates genetic variation in mice for several effects of opiate drugs. The present study examined heroin-induced place conditioning and locomotor sensitization in the two strains of mice employed most frequently in the generation of transgenic animals, C57BL/6J (B6) and 129X1/sVJ (129), as well as in groups of B6-129 hybrid mice, differing in their amount of B6 genetic background. Four pairings of 100 microg/kg of heroin elicited robust place conditioning and locomotor sensitization in B6 controls and in N(10) congenic B6-129 hybrid mice. In comparison, the identical treatment produced no locomotor sensitization and induced place aversion in 129 controls. No heroin-induced changes in the behaviour of N(3) congenic B6-129 hybrid mice or F5-8 non-congenic B6-129 hybrid mice were observed. The expression of place conditioning was not facilitated in any group by the administration of a heroin-priming injection prior to testing. These data indicate that genetic variation exists in mice for the rewarding and locomotor-sensitizing effects of heroin and that the capacity of heroin to induce conditioned reward and locomotor sensitization can be modulated in a B6 strain dose-dependent manner in B6-129 hybrid mice. Thus, strain differences in heroin responsiveness should be considered when examining transgenic lines on B6-129 backgrounds for opiate-induced changes in behaviour that may be relevant for addiction.
2,337,169	Impact of the introduction of a guideline on the targeted detection of hereditary haemochromatosis.	In 1998 a clinical guideline for the targeted, accurate and early detection and treatment of HFE-related hereditary haemochromatosis (HH), which comprises a test for the causative HFE-gene mutations, was introduced in our outpatient department.</AbstractText>The impact of this guideline was evaluated retrospectively. Data were acquired from medical records of patients with discharge diagnosis codes suggestive of HH (n=878 patients), obtained from a period before (n=422) and after guideline introduction (n=456).</AbstractText>Combined measurements of serum transferrin saturation and serum ferritin rose from 12.2% (n=53) to 29.5% (n=138, p<0.001), leaving 70% of the patients eligible for HH not tested for iron parameters. The HFE-gene mutation detection test was correctly used in II (40.7%) of 27 tested patients and improperly interpreted in six (22.2%) of these 27 patients. Five new HH patients were diagnosed before and 13 after introduction. Seven of these 13 patients appeared to be incorrectly diagnosed, due to misinterpretation of laboratory results. Diagnostic costs of case detection for each accurately diagnosed patient were euro 2380 before and euro 2600 after introduction of the guideline.</AbstractText>Evaluation of the introduction of a practical guideline for targeted HH detection reveals a low compliance with the guideline, resulting in both a small percentage of patients tested for HH and overdiagnosis of HH. Therefore, the introduction of the guideline should be combined with a more appropriate implementation strategy which includes education on its most critical points, i.e. the indication and interpretation of the iron parameters and the HFE genotype.</AbstractText>
2,337,170	Testing population genetic structure using parametric bootstrapping and MIGRATE-N.	We present a method for investigating genetic population structure using sequence data. Our hypothesis states that the parameters most responsible for the formation of genetic structure among different populations are the relative rates of mutation (micro) and migration (M). The evolution of genetic structure among different populations requires rates of M << p because this allows population-specific mutation to accumulate. Rates of micro << M will result in populations that are effectively panmictic because genetic differentiation will not develop among demes. Our test is implemented by using a parametric bootstrap to create the null distribution of the likelihood of the data having been produced under an appropriate model of sequence evolution and a migration rate sufficient to approximate panmixia. We describe this test, then apply it to mtDNA data from 243 plethodontid salamanders. We are able to reject the null hypothesis of no population structure on all but smallest geographic scales, a result consistent with the apparent lack of migration in Plethodon idahoensis. This approach represents a new method of investigating population structure with haploid DNA, and as such may be particularly useful for preliminary investigation of non-model organisms in which multi-locus nuclear data are not available.
2,337,171	Autopsy diagnosis of 21-hydroxylase deficiency CAH in a case of apparent SIDS.	A 5-month-old boy with no history of vomiting, early sexual development, or noticeable significant illness was found dead in bed. Autopsy demonstrated bilateral adrenal hyperplasia unequivocally shown on biochemical testing of blood and urine to be due to 21-hydroxylase deficiency. Genetic analysis of the CYP21 gene showed compound heterozygosity; 1 allele contained a pseudogene sequence (gene conversion) and the other contained a previously described I172N point mutation. On theoretical grounds, the genotype would have been expected to cause simple virilizing congenital adrenal hyperplasia but, because no other cause of death could be found, it is possible that it caused a fatally severe loss of enzyme activity in this child. If this assumption is valid, newborn screening would have prevented this death, had it been available.
2,337,172	A genome-wide screen and linkage mapping for a large pedigree with episodic ataxia.	Episodic ataxias are ion channel disorders characterized by attacks of incoordination. The authors performed a genome-wide screen in a large pedigree segregating a novel episodic ataxia and found significant linkage on 1q42 with a multipoint lod score of 3.65. Haplotype analysis and fine mapping yielded a peak 2-point lod score of 4.14 and indicated a 4-cM region on 1q42 that is likely to harbor an episodic ataxia gene.
2,337,173	Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes.	To assess the prevalence, nature, and associated phenotypes of PINK1 gene mutations in a large series of patients with early-onset (<50 years) parkinsonism.</AbstractText>The authors studied 134 patients (116 sporadic and 18 familial; 77% Italian) and 90 Italian controls. The whole PINK1 coding region was sequenced from genomic DNA; cDNA was analyzed in selected cases.</AbstractText>Homozygous pathogenic mutations were identified in 4 of 90 Italian sporadic cases, including the novel Gln456Stop mutation; single heterozygous truncating or missense mutations were found in another 4 Italian sporadic cases, including two novel mutations, Pro196Leu and Gln456Stop. Pathogenic mutations were not identified in the familial cases. Novel (Gln115Leu) and known polymorphisms were identified with similar frequency in cases and controls. In cases carrying single heterozygous mutation, cDNA analysis detected no additional mutations, and revealed a major pathogenic effect at mRNA level for the mutant C1366T/Gln456Stop allele. All patients with homozygous mutations had very early disease onset, slow progression, and excellent response to l-dopa, including, in some, symmetric onset, dystonia at onset, and sleep benefit, resembling parkin-related disease. Phenotype in patients with single heterozygous mutation was similar, but onset was later.</AbstractText>PINK1 homozygous mutations are a relevant cause of disease among Italian sporadic patients with early-onset parkinsonism. The role of mutations found in single heterozygous state is difficult to interpret. Our study suggests that, at least in some patients, these mutations are disease causing, in combination with additional, still unknown factors.</AbstractText>
2,337,174	Mutation analysis of SPG4 and SPG3A genes and its implication in molecular diagnosis of Korean patients with hereditary spastic paraplegia.	Hereditary spastic paraplegia (HSP), a genetically and clinically heterogeneous group of neurodegenerative disorders, is characterized by progressive lower limb weakness and spasticity. Among the 8 loci associated with the autosomal dominant uncomplicated HSP (AD-HSP), the spastin (SPG4) and atlastin (SPG3A) genes have been known to account for approximately 40% and 10% of all cases, respectively.</AbstractText>To investigate the contribution of these 2 genes in the occurrence of HSP in Korean patients.</AbstractText>Clinical and genetic study.</AbstractText>Tertiary care center.</AbstractText>Eighteen patients with uncomplicated HSP (11 AD and 7 sporadic) underwent screening for gene mutation.</AbstractText>Mutations in the SPG4 and SPG3A genes as detected by direct sequencing of all coding exons and flanking intronic sequences.</AbstractText>We identified 8 different SPG4 mutations, 7 of which have not been reported elsewhere. Among the detected mutations were 3 missense mutations, 2 in-frame deletions, 2 frameshift mutations, and 1 splice-site mutation. No mutation was found in the SPG3A gene.</AbstractText>Compared with previous studies, a higher frequency of SPG4 gene mutations in AD-HSP (7/11; 64%) was observed, suggesting that a mutation analysis for the SPG4 gene might be helpful for molecular diagnosis of AD-HSP in Korean patients.</AbstractText>
2,337,175	Transthyretin-related familial amyloidotic polyneuropathy.	Transthyretin-related familial amyloidotic polyneuropathy (FAP) is a fatal hereditary amyloidosis. Until 20 years ago, FAP was thought to be restricted to endemic occurrence in certain areas. However, owing to progress in biochemical and molecular genetic analyses, FAP is now believed to occur worldwide. As of today, reports of about 100 different points of single or double mutations, or a deletion in the transthyretin gene, have been published, and several different phenotypes of FAP have been documented, even for the same mutation in the transthyretin gene. We present herein the current clinicopathological, biochemical, molecular genetic, and epidemiological aspects of transthyretin-related FAP, and we introduce a new diagnostic procedure for the disease.
2,337,176	Moving primate genomics beyond the chimpanzee genome.	The comparative DNA sequence data that already exist on individual genomic loci depict the phylogenetic relationships of nearly all extant primate genera. Such a phylogenetic representation of the primates, validated by many sequenced primate genomes, and encompassing the full adaptive diversity of the order, is a prerequisite for identifying the genetic basis of humankind, and for testing the proposed human uniqueness of these traits. Some of these traits have been discovered recently, particularly in genes encoding proteins that are important for brain function.
2,337,177	G-308A TNF-alpha polymorphism is associated with an increased risk of invasive cervical cancer.	Cervical cancer is initiated by high-risk human papillomaviruses (HPV-16 and HPV-18), but an effective immune response may control the progression of this disease. Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine, that has been implicated in several cancers. In a case-control study, we evaluated the association between the G-308A TNF-alpha promoter polymorphism and the risk for invasive cervical cancer (ICC). TNF-alpha polymorphism was analyzed by PCR-RFLP and confirmed by sequencing. DNA was obtained from blood samples of 439 individuals, including 195 patients with ICC and 244 normal healthy controls. According to our results, women carrying the A allele present a twofold increased risk of developing ICC (p=0.006; OR=1.88; 95% CI [1.20-2.94]). In conclusion, our study suggests that the presence of the high producer allele -308A in the TNF-alpha gene appears to be associated with an increased risk for the development of ICC.
2,337,178	Molecular diagnosis in lymphoma.	The evolution of our ability to diagnose and classify lymphomas in an increasingly refined manner has paralleled the development of novel technologic approaches, with contemporary practice dependent upon the harnessing of a plethora of data that include microscopic, immunophenotypic, and genetic information. Although each of these components is currently indispensable, there is a purported progressive improvement in biologic objectivity as one maneuvers through these respective technologies. Accordingly, and in particular given the rapid pace at which key insights into lymphoma biology are emerging with microarray and other cutting-edge technologies, the role of molecular genetic testing is assuming even greater relevance. The ability to diagnose and classify lymphomas more accurately, precisely, and rationally by incorporating molecular data ought to lead to the development of more appropriate directed therapies.
2,337,179	Papillon-Lefèvre syndrome treated with acitretin.	A 7-year-old boy born to consanguineous parents had suffered from palmoplantar keratoderma and chronic gingivitis since the age of 3 months. He was diagnosed with Papillon-Lefèvre syndrome. Genetic testing confirmed that he was homozygous with a point mutation in exon 6 of the cathepsin C gene. One year after initiating treatment with acitretin 10 mg oral daily and trimethoprim-sulfamethoxazole, the patient's skin remains almost lesion-free, and he has new teeth that erupted during treatment and are free of periodontal disease.
2,337,180	Fine mapping of autosomal dominant nonsyndromic hearing impairment DFNA21 to chromosome 6p24.1-22.3.	Previously, the DFNA21 locus was positioned telomeric to the DFNA13 locus based on testing of candidate loci. One family member in this region did not carry the at risk haplotype, although he had the same nonspecific midfrequency hearing impairment as other affected family members. Hence, we performed a whole genome linkage scan excluding other regions of the genome and confirming the localization of DFNA21 to 6p22.3-24.1. The DFNA21 interval was determined to span 12.4 Mb (approximately 22 cM) and is delimited on the telomeric side by BV097155 and on the centromeric side by D6S1691. A maximum lod score of 3.51 (theta = 0.066), was calculated for marker D6S1721. The DFNA21 region does not overlap the adjacent DFNA31 and DFNA13 loci and contains 31 known genes. The coding regions and exon-intron boundaries of four candidate genes, SOX4, MYLIP, CAP2, and RPEL1, were sequenced, but no mutations were identified.
2,337,181	A genetically engineered strain of Pseudomonas putida as a useful tool for identifying new therapeutic herbicides.	A genetically engineered strain of Pseudomonas putida U designed for the identification of new therapeutic herbicides has been obtained. In this bacterium, deletion of the homogentisate gene cluster (hmgRABC) confers upon this mutant huge biotechnological possibilities since it can be used: (i) as a target for testing new specific herbicides (p-hydroxy-phenylpyruvate dioxygenase inhibitors); (ii) to identify new therapeutic drugs-effective in the treatment of alkaptonuria and other related tyrosinemia - and (iii) as a source of homogentisic acid in a plant-bacterium association.
2,337,182	[Prognosis work-up in prenatal medicine: the example of Down's syndrome].	Establishing a prognosis in prenatal medicine is often a complex and uncertain task. Predictive tools such as imagery techniques and biological markers may lack accuracy since they are used while the fetus is still pursuing its development. In France, antenatal euthanasia and fetal abandon are legal issues and socially accepted. Several non-medical factors may interfere with the final outcome such as the manner a condition is announced by the staff, the way it is experienced by the parents and the acceptance of the handicap within the society. We analysed the different medical and non medical factors intervening in the prognosis work up for Down's syndrome. Currently, the outcome of fetus with Down's syndrome is influenced by the orientation of our society that promotes screening tests and pregnancy interruptions instead of emphasizing on therapeutic research and improving their social integration.
2,337,183	Surgical decisions made by 158 women with hereditary breast cancer aged <50 years.	To establish the uptake of contralateral risk reducing mastectomy in women informed of their risks and options at time of diagnosis of their primary unilateral breast cancer.</AbstractText>We have assessed the surgical choices of 70 women diagnosed with breast cancer <50 years as part of a family history surveillance program and fully informed about their contralateral risks and surgical options. We have compared this to women from other surgical clinics who were subsequently found to harbour a pathogenic BRCA1/2 mutation.</AbstractText>Sixty-five percent (13/20) of BRCA1/2 mutation carriers and 59% (n=20/34) of those at the highest level of risk pre-diagnosis (33+% lifetime risk) opted for contra-lateral mastectomy in the study sample. In contrast only 10% (n=9/88) women identified as mutation carriers from other clinics opted for such surgery.</AbstractText>We would suggest that women with a significant family history and therefore a high contra-lateral breast cancer risk, should have these risks and management options discussed at the time of diagnosis of breast cancer.</AbstractText>
2,337,184	Screening for RAD51 and BRCA2 BRC repeat mutations in breast and ovarian cancer families.	Together, germline mutations in the two major susceptibility genes BRCA1 and BRCA2 account for approximately 20-30% and 70-80% of the familial breast and ovarian cancer cases, respectively. This indicates involvement of additional susceptibility genes, perhaps in combination with a polygenic effect. However, it is also possible that part of the mutations disrupting BRCA1 and BRCA2 function still remains to be discovered. In response to double-strand DNA damage the co-operation between RAD51 and BRCA2 is of great importance, and the conserved BRC repeat motifs in BRCA2 are crucial for this interaction. In the current study, patients belonging to 126 breast and/or ovarian cancer families were screened for RAD51 and BRCA2 BRC repeat mutations in order to uncover aberrations that may contribute to hereditary cancer susceptibility. The performed study revealed several novel alterations, however, none of them appeared to be disease-related. Thus, it seems likely that germline mutations in the highly conserved RAD51 gene are extremely rare and generally poorly tolerated.
2,337,185	High local genetic diversity and low outcrossing rate in Caenorhabditis elegans natural populations.	Caenorhabditis elegans is a major model system in biology, yet very little is known about its biology outside the laboratory. In particular, its unusual mode of reproduction with self-fertile hermaphrodites and facultative males raises the question of its frequency of outcrossing in natural populations.</AbstractText>We describe the first analysis of C. elegans individuals sampled directly from natural populations. C. elegans is found predominantly in the dauer stage and with a very low frequency of males versus hermaphrodites. Whereas C. elegans was previously shown to display a low worldwide genetic diversity, we find by comparison a surprisingly high local genetic diversity of C. elegans populations; this local diversity is contributed in great part by immigration of new alleles rather than by mutation. Our results on heterozygote frequency, male frequency, and linkage disequilibrium furthermore show that selfing is the predominant mode of reproduction in C. elegans natural populations but that infrequent outcrossing events occur, at a rate of approximately 1%.</AbstractText>Our results give a first insight in the biology of C. elegans in the natural populations. They demonstrate that local populations of C. elegans are genetically diverse and that a low frequency of outcrossing allows for the recombination of these locally diverse genotypes.</AbstractText>
2,337,186	Pharmacogenomics: questions and concerns.	The progressively aging population in the western world, rising socioeconomic expenditure and increasing costs for the treatment of adverse drug reactions, lead to increasing pressure on public spending. The public acceptance of pharmacogenomics is high, therefore, because it promises individualized safe and effective treatment at lower cost. Pharmacogenomics studies the genetic polymorphisms that underlie the variability in drug response between individuals. Despite the great benefits being awaited from this new field, a number of ethical, social and legal concerns arise, which demand rapid strict international regulations in order to prevent discrimination or harm of any kind from society, industry, groups or individuals.
2,337,187	Gene expression profile analysis: an emerging approach to investigate mechanisms of genotoxicity.	The response to stress triggers transcriptional activation of genes involved in cell survival and/or cell death. Thus, the monitoring of gene expression levels in large gene sets or whole genomes in response to various agents (toxicogenomics) has been proposed as a tool for investigating mechanisms of toxicity. Although standard in vitro genetic toxicity testing provides relatively simple and accurate hazard detection, interpretation of positive findings, i.e., in vitro chromosome aberrations, in terms of relevant risk to humans is difficult, due to the limited insight into the underlying mechanisms. Therefore, the development of experimental approaches capable of differentiating a wide range of genotoxic mechanisms is expected to significantly improve risk assessment. The goal of this review is to summarize current developments in toxicogenomic analysis of genotoxic stress, and to provide a perspective on the application of gene expression profile analysis in genetic toxicology.
2,337,188	[Curriculum reform in dental medicine at the University of Ghent].	The need for dental and oral treatment in the society is constantly changing. Epidemiological studies show that in the rapidly aging population in Western Europe, caries (except for root caries) is declining but more complex periodontal treatment is needed. The number of completely edentulous patients is decreasing. Patients have a longer life expectancy but are medically and psychologically more compromised. Many more patients are at high risk for medical complications. Therefore, a more medical orientation of the dental education is needed. The basic cellular and molecular knowledge in medicine is rapidly expanding. The practical application of this expanded knowledge has been introduced in dentistry such as use of DNA probes, genetic testing, vaccines etc. The graduating dentist should be aware of the scientific progress and be able to apply this technology in his future practice. Therefore, the urgent need was felt to reform the dental education fundamentally and to give it a more medical orientation. Teaching is organised in coherent blocks of lectures covering specific parts of' a discipline and discussing the content from different angles by different lecturers. Basic information (eg. physiology, microscopy, microbiology) is provided in the same block as the clinical and therapeutic information. Preclinical laboratories prepare the student for the clinical phase of a discipline and are not any longer devoted to dental technical laboratory work. More time is given to prosthetic planning, communication with the dental technician and to analyse the biological effects of prosthetic appliances. In the final year a large number of teaching hours is devoted to general medical pathology including physiopathology, dermatology, general head and neck pathology and surgery (ENT, oncology, orthognathic surgery) as well as gerodontology including general medical, psychological and nutritional themes. Finally, clinically the student has a multidisciplinary approach in his diagnosis and treatment of patients. The final aim is train and educated oral physicians.
2,337,189	[Denys-Drash syndrome. Experience gathered in Erlangen illustrated by two case reports].	Denys-Drash syndrome is a rare symptom complex associated with obligatory childhood nephrotic syndrome, male pseudohermaphroditism, and Wilms' tumor. The etiology of Denys-Drash syndrome is attributed to a mutation of the WT1 gene. We report on two cases of Deny-Drash syndrome confirmed by genetic testing. Rapidly evolving terminal renal insufficiency was detected in both patients necessitating bilateral nephrectomies with prophylactic intent. In one of the patients, a Wilms' tumor had already been verified in one kidney so that chemotherapy had to be initiated.The risk of Wilms' tumor is very high in patients with a WT1 mutation, which leads to the need for removal of both kidneys during or before transplantation. It would be important to perform a diagnostic work-up for WT1 gene mutation in children who develop renal failure in the 1st year of life.
2,337,190	Fragile X-associated tremor/ataxia syndrome and movements disorders.	Fragile X-associated tremor/ataxia syndrome (FXTAS) is a multiple-system neurologic disorder caused by expansion of 55-200 CGG repeats in the FMR1 (fragile site mental retardation 1) gene. The presence of both hyperkinetic and hypokinetic movement disorders such as ataxia, tremor, and parkinsonism are clinical features of FXTAS. The purpose of this review is to summarize the description of movement disorders associated with FXTAS and to discuss recent observations regarding the relationship between abnormal expansion in the FMR1 gene and development of neurodegenerative disorders.</AbstractText>The clinical expression of FXTAS occasionally resembles the phenotypes of other idiopathic neurodegenerative disorders. However, the unique pathological feature - appearance of the intranuclear inclusions in the neurons and astrocytes, is discriminatory from those in other neurodegenerative disorders. Several studies found no association between the FMR1 gene premutation and development of other neurodegenerative disorders with similar movement disorders to FXTAS. However, a premutation expansion in the FMR1 gene may be a frequent genetic cause of late-onset sporadic ataxia with magnetic-resonance-image abnormality.</AbstractText>FXTAS exhibits various movement-disorder phenotypes. However, the FMR1 gene premutation is unlikely to be a common genetic cause of neurodegenerative disorders with tremor or ataxia. Patients with sporadic late-onset ataxia associated with magnetic-resonance-image abnormality should be considered for testing for a CGG-repeat expansion in the FMR1 gene.</AbstractText>
2,337,191	Neuroacanthocytosis.	The term neuroacanthocytosis describes a group of phenotypically and genetically heterogeneous disorders, and thus has long been a source of confusion and diagnostic imprecision. It is vital to distinguish between the lipoprotein deficiency disorders which affect gait, but do not cause movement disorders or neuropsychiatric problems, and the diseases described here, of which these are characteristic features. This review summarizes the current state of knowledge regarding this group of diseases in order to facilitate clinical recognition, accurate diagnosis and appropriate management.</AbstractText>Advances in molecular medicine have enabled us to distinguish precisely among the disorders described under the label of neuroacanthocytosis, most notably between autosomal recessive chorea-acanthocytosis and the X-linked McLeod syndrome. This has facilitated appreciation of the range of phenotypes in each of the various conditions. Acanthocytosis is also found in a smaller percentage of cases with pantothenate kinase-associated neurodegeneration (PKAN) and Huntington's disease-like 2 (HDL2). An improved method of determination of acanthocytosis has been described, which if adopted as standard practice may facilitate detection of these conditions.</AbstractText>Genetic testing has led to increased diagnostic accuracy of the neuroacanthocytosis syndromes, which is essential to extend recognition of these disorders, as well as to improve understanding of the disease process. Most importantly, given the absence of a cure, it is vital for appropriate genetic counselling. Treatments, as in other neurodegenerative conditions, are at present limited to symptomatic therapies.</AbstractText>
2,337,192	Determination of functional interactions among signalling pathways in Escherichia coli K-12.	Interaction among different signalling pathways has been noted repeatedly. However, no systematic method has been developed to identify and quantify such interactions. Here we reported that network component analysis (NCA) was able to determine interactions among various signalling pathways in Escherichia coli K-12 based on known transcription factor (TF)-promoter connectivity information and microarray data from genetic knockout strains. The TF activities determined from NCA allow the quantitation of functional interactions, barring gross errors in the connectivity and microarray data. By using a robust statistical test, 37 pairs of functional interactions were identified. Eighteen interaction pairs confirmed previous implications, while 19 others represent new predictions. These results demonstrate that the functional interactions among various signalling pathways may be rather significant. With reasonable TF-promoter connectivity, NCA coupled with genetic knockouts and microarray experiments provides a systematic way to elucidate interaction networks. As this approach cannot distinguish between cross-talks and unidentified direct regulation, the results should provide incentives for further experimental testing.
2,337,193	Genetic association of alpha2-Heremans-Schmid glycoprotein polymorphism with late-onset Alzheimer's disease in Italians.	Alpha2-Heremans-Schmid glycoprotein (AHSG), also known as fetuin-A, is a highly glycosylated protein which has been recently reported to be decreased in the cerebrospinal fluid of patients with Alzheimer's disease. AHSG is genetically polymorphic and two common alleles, AHSG1 and AHSG2, have been described. The purpose of this study was to investigate the distribution of AHSG gene polymorphism in 235 Caucasian Italian patients with late-onset Alzheimer's disease (LOAD) and 235 age- and gender-matched healthy controls. In patients with LOAD, the genotype distribution was 184 AHSG 11, 44 AHSG 12, 7 AHSG 22, and was significantly different from that observed in the 235 control subjects (117 AHSG 11, 103 AHSG 12, 15 AHSG 22) (chi(2)=41.50, P<0.0001). After allowance for age, gender and APOE epsilon4 status, multivariate logistic regression analysis revealed that the adjusted odds ratio for the development of LOAD in AHSG 1*1 homozygotes was 3.90 (95% CI: 2.58-5.90, P<0.0001). These results suggest that the AHSG gene polymorphism may be associated with LOAD in Italians. Additional studies are warranted to examine the biological relevance of AHSG in the pathophysiology of neurodegenerative disorders.
2,337,194	Real-time polymerase chain reaction detection of cauliflower mosaic virus to complement the 35S screening assay for genetically modified organisms.	Labeling of genetically modified organisms (GMOs) is now in place in many countries, including the European Union, in order to guarantee the consumer's choice between GM and non-GM products. Screening of samples is performed by polymerase chain reaction (PCR) amplification of regulatory sequences frequently introduced into genetically modified plants. Primers for the 35S promoter from Cauliflower mosaic virus (CaMV) are those most frequently used. In virus-infected plants or in samples contaminated with plant material carrying the virus, false-positive results can consequently occur. A system for real-time PCR using a TaqMan minor groove binder probe was designed that allows recognition of virus coat protein in the sample, thus allowing differentiation between transgenic and virus-infected samples. We measured the efficiency of PCR amplification, limits of detection and quantification, range of linearity, and repeatability of the assay in order to assess the applicability of the assay for routine analysis. The specificity of the detection system was tested on various virus isolates and plant species. All 8 CaMV isolates were successfully amplified using the designed system. No cross-reactivity was detected with DNA from 3 isolates of the closely related Carnation etched ring virus. Primers do not amplify plant DNA from available genetically modified maize and soybean lines or from different species of Brassicaceae or Solanaceae that are natural hosts for CaMV. We evaluated the assay for different food matrixes by spiking CaMV DNA into DNA from food samples and have successfully amplified CaMV from all samples. The assay was tested on rapeseed samples from routine GMO testing that were positive in the 35S screening assay, and the presence of the virus was confirmed.
2,337,195	[Evaluation of outpatient management in HNPCC].	The differential diagnostic assignment of patients with hereditary non-polyposis colorectal cancer among patients with non-familial colorectal carcinoma is difficult but essential to provide early sufficient cancer screening. In order to analyze the actual situation of outpatients, 36 gastroenterologists in private practice have been interviewed with respect to their experience concerning outpatients. The interview data revealed that care for patients with colorectal cancer is a fundamental component of their work. A third of the gastroenterologists deal with patients suffering from colorectal cancer before 45 years of age. Yet these gastroenterologists did not report a single HNPCC patient. Especially gastroenterologists with long lasting experience in private practice did not mention HNPCC patients at all. These results may indicate that identifying the cases at risk for HNPCC is difficult in daily routine work. The possibility of genetic diagnostics (and counselling) should be taken into consideration in individual cases. In consequence comprehensive screening programs can be initiated for patients and their families.
2,337,196	New insights in the genetics of adrenocortical tumors, pheochromocytomas and paragangliomas.	Recent advances in the molecular genetic of adrenal tumors give new insights in the pathophysiology of these neoplasms in both hereditary and sporadic cases. The practice of genetic counselling in patients with adrenal tumors have been recently changed by the identification and the understanding of new specific hereditary cancer susceptibility syndromes. In the case of sporadic adrenocortical tumors these progress also offer new prognosis predictors. The genetic predisposition to adrenocortical cancer in children has been well established in the Li-Fraumeni and Beckewith-Wiedeman syndromes due to germline p53 mutation located at 17p13 and dysregulation of the imprinted IGF-2 locus at 11p15, respectively. Adrenocortical tumors are also observed in Multiple Endocrine Neoplasia type I syndrome. Cushing's syndrome due to primary pigmented nodular adrenocortical disease have been observed in patients with germline PRKAR1A inactivating mutations. Interestingly allelic loss at 17p13 and 11p15 have been observed in sporadic adrenocortical cancer and somatic PRKAR1A mutations in secreting adrenocortical adenomas. The potential interest of these finding for the diagnosis of these tumors will be discussed. In the case of pheochromocytoma and paraganglioma, the demonstration that three genes encoding three succinate dehydrogenase subunits (SDHD, SDHB, SDHC), belonging to the complex II of the respiratory chain in the mitochondria, are involved in the genetics of familial and especially in apparently sporadic phaeochromocytomas have dramatically modified our practice. Up to date, four diagnosis of familal disease (multiple endocrine neoplasia type II, von Hippel Lindau disease, neurofibromatosis type 1 and hereditary paraganglioma) should be discussed and causative mutations in six different phaechomocytoma susceptibility genes (RET, VHL, NF1, SDHB, SDHD, SDHC) could be identified. In this review, we will perform an update compiling these new clinical, genetic and functional data recently published. We will suggest guidelines for the practice of the phaeochomocytoma genetic testing in the patients and their families, and for an early detection of tumors in the patients or in individuals determined to be at-risk of disease by the presymptomatic genetic testing.
2,337,197	Development of a recA gene-based identification approach for the entire Burkholderia genus.	Burkholderia is an important bacterial genus containing species of ecological, biotechnological, and pathogenic interest. With their taxonomy undergoing constant revision and the phenotypic similarity of several species, correct identification of Burkholderia is difficult. A genetic scheme based on the recA gene has greatly enhanced the identification of Burkholderia cepacia complex species. However, the PCR developed for the latter approach was limited by its specificity for the complex. By alignment of existing and novel Burkholderia recA sequences, we designed new PCR primers and evaluated their specificity by testing a representative panel of Burkholderia strains. PCR followed by restriction fragment length polymorphism analysis of an 869-bp portion of the Burkholderia recA gene was not sufficiently discriminatory. Nucleotide sequencing followed by phylogenetic analysis of this recA fragment differentiated both putative and known Burkholderia species and all members of the B. cepacia complex. In addition, it enabled the design of a Burkholderia genus-specific recA PCR that produced a 385-bp amplicon, the sequence of which was also able to discriminate all species examined. Phylogenetic analysis of 188 novel recA genes enabled clarification of the taxonomic position of several important Burkholderia strains and revealed the presence of four novel B. cepacia complex recA lineages. Although the recA phylogeny could not be used as a means to differentiate B. cepacia complex strains recovered from clinical infection versus the natural environment, it did facilitate the identification of clonal strain types of B. cepacia, B. stabilis, and B. ambifaria capable of residing in both niches.
2,337,198	In one's own image: ethics and the reproduction of deafness.	The ethics of the use of genetic screening and reproductive technologies to select against and for deafness is presented. It is argued that insofar as deafness is a disability it is ethical to act in such a way as to avoid the conception or birth of children with genetic or congenital deafness. The discovery and recognition of signing deaf communities as cultural and linguistic communities (minorities) does not alter this basic ethical position, although the consequences of widespread application of this technology appears destined to lead to the eventual disappearance of these communities. The argument that acting to avoid deafness is unethical because it will lead to the elimination of a linguistic or cultural group (genocide or ethnocide) or conversely that acting to ensure deafness is ethical, if not praiseworthy, can only be sustained if deafness is not regarded as a disability at all. I argue that the premise that deafness is not a disability of some sort is false and thus the claim that genetic selection against deafness is unethical is untenable.
2,337,199	Applicability of oral fluid collected onto filter paper for detection and genetic characterization of measles virus strains.	Expansion of measles molecular surveillance to developing countries where measles is endemic will help facilitate measles control. Limited infrastructure in these areas is a barrier to referral of specimens suitable for measles virus (MV) genotyping. In this study, we demonstrate that oral fluid dried onto filter paper can be used for the detection and characterization of MV strains. Using this approach, an MV-positive sample by reverse transcriptase PCR could be obtained from 67% of serologically confirmed acute measles cases. Mimicking certain environmental conditions and duration of transportation established that MV RNA remained detectable and suitable for nucleic acid sequencing in oral fluid spots for at least 1 week. In the context of a measles outbreak in a remote region of the world where infrastructure is poor, oral fluid samples dried onto filter paper and sent to a specialized laboratory for testing will aid in the identification and characterization of the causative MV strain.

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