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Sample records for low-risk variants fgfr2

  1. A gain-of-function mutation of Fgfr2c demonstrates the roles of this receptor variant in osteogenesis

    PubMed Central

    Eswarakumar, Veraragavan P.; Horowitz, Mark C.; Locklin, Rachel; Morriss-Kay, Gillian M.; Lonai, Peter

    2004-01-01

    The b and c variants of fibroblast growth factor receptor 2 (FGFR2) differ in sequence, binding specificity, and localization. Fgfr2b, expressed in epithelia, is required for limb outgrowth and branching morphogenesis, whereas the mesenchymal Fgfr2c variant is required by the osteocyte lineage for normal skeletogenesis. Gain-of-function mutations in human FGFR2c are associated with craniosynostosis syndromes. To confirm and extend this evidence, we introduced a Cys342Tyr replacement into Fgfr2c to create a gain-of-function mutation equivalent to a mutation in human Crouzon and Pfeiffer syndromes. Fgfr2cC342Y/+ heterozygote mice are viable and fertile with shortened face, protruding eyes, premature fusion of cranial sutures, and enhanced Spp1 expression in the calvaria. Homozygous mutants display multiple joint fusions, cleft palate, and trachea and lung defects, and die shortly after birth. They show enhanced Cbfa1/Runx2 expression without significant change in chondrocyte-specific Ihh, PTHrP, Sox9, Col2a, or Col10a gene expression. Histomorphometric analysis and bone marrow stromal cell culture showed a significant increase of osteoblast progenitors with no change in osteoclastogenic cells. Chondrocyte proliferation was decreased in the skull base at embryonic day 14.5 but not later. These results suggest that long-term aspects of the mutant phenotype, including craniosynostosis, are related to the Fgfr2c regulation of the osteoblast lineage. The effect on early chondrocyte proliferation but not gene expression suggests cooperation of Fgfr2c with Fgfr3 in the formation of the cartilage model for endochondral bone. PMID:15316116

  2. Fine-Scale Mapping of the FGFR2 Breast Cancer Risk Locus: Putative Functional Variants Differentially Bind FOXA1 and E2F1

    PubMed Central

    Meyer, Kerstin B.; O’Reilly, Martin; Michailidou, Kyriaki; Carlebur, Saskia; Edwards, Stacey L.; French, Juliet D.; Prathalingham, Radhika; Dennis, Joe; Bolla, Manjeet K.; Wang, Qin; de Santiago, Ines; Hopper, John L.; Tsimiklis, Helen; Apicella, Carmel; Southey, Melissa C.; Schmidt, Marjanka K.; Broeks, Annegien; Van ’t Veer, Laura J.; Hogervorst, Frans B.; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Fasching, Peter A.; Lux, Michael P.; Ekici, Arif B.; Beckmann, Matthias W.; Peto, Julian; dos Santos Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Marme, Federick; Schneeweiss, Andreas; Sohn, Christof; Burwinkel, Barbara; Guénel, Pascal; Truong, Thérèse; Laurent-Puig, Pierre; Menegaux, Florence; Bojesen, Stig E.; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Milne, Roger L.; Zamora, M. Pilar; Arias, Jose I.; Benitez, Javier; Neuhausen, Susan; Anton-Culver, Hoda; Ziogas, Argyrios; Dur, Christina C.; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Meindl, Alfons; Schmutzler, Rita K.; Engel, Christoph; Ditsch, Nina; Brauch, Hiltrud; Brüning, Thomas; Ko, Yon-Dschun; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Yatabe, Yasushi; Dörk, Thilo; Helbig, Sonja; Bogdanova, Natalia V.; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Chenevix-Trench, Georgia; Wu, Anna H.; Tseng, Chiu-chen; Van Den Berg, David; Stram, Daniel O.; Lambrechts, Diether; Thienpont, Bernard; Christiaens, Marie-Rose; Smeets, Ann; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Radice, Paolo; Peterlongo, Paolo; Bonanni, Bernardo; Bernard, Loris; Couch, Fergus J.; Olson, Janet E.; Wang, Xianshu; Purrington, Kristen; Giles, Graham G.; Severi, Gianluca; Baglietto, Laura; McLean, Catriona; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S.; Labrèche, France; Dumont, Martine; Teo, Soo-Hwang; Yip, Cheng-Har; Phuah, Sze-Yee; Kristensen, Vessela; Grenaker Alnæs, Grethe; Børresen-Dale, Anne-Lise; Zheng, Wei; Deming-Halverson, Sandra; Shrubsole, Martha; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Tchatchou, Sandrine; Devilee, Peter; Tollenaar, Robert A.E.M.; Seynaeve, Caroline M.; García-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J.; Lissowska, Jolanta; Czene, Kamila; Darabi, Hartef; Eriksson, Kimael; Hooning, Maartje J.; Martens, John W.M.; van den Ouweland, Ans M.W.; van Deurzen, Carolien H.M.; Hall, Per; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Cox, Angela; Reed, Malcolm W.R.; Blot, William; Signorello, Lisa B.; Cai, Qiuyin; Pharoah, Paul D.P.; Ghoussaini, Maya; Harrington, Patricia; Tyrer, Jonathan; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K.; Noh, Dong-Young; Hartman, Mikael; Hui, Miao; Lim, Wei-Yen; Buhari, Shaik A.; Hamann, Ute; Försti, Asta; Rüdiger, Thomas; Ulmer, Hans-Ulrich; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Vachon, Celine; Slager, Susan; Fostira, Florentia; Pilarski, Robert; Shen, Chen-Yang; Hsiung, Chia-Ni; Wu, Pei-Ei; Hou, Ming-Feng; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Schoemaker, Minouk J.; Ponder, Bruce A.J.; Dunning, Alison M.; Easton, Douglas F.

    2013-01-01

    The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. We identified three statistically independent risk signals within the locus. Within risk signals 1 and 3, genetic analysis identified five and two variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and electrophoretic mobility shift assays to study protein-DNA binding, we identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit ERα to this site in an allele-specific manner, whereas E2F1 preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5 phosphorylated RNA polymerase II, suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region. A role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen-receptor-positive disease. PMID:24290378

  3. Identification of functional variants for cleft lip with or without cleft palate in or near PAX7, FGFR2, and NOG by targeted sequencing of GWAS loci.

    PubMed

    Leslie, Elizabeth J; Taub, Margaret A; Liu, Huan; Steinberg, Karyn Meltz; Koboldt, Daniel C; Zhang, Qunyuan; Carlson, Jenna C; Hetmanski, Jacqueline B; Wang, Hang; Larson, David E; Fulton, Robert S; Kousa, Youssef A; Fakhouri, Walid D; Naji, Ali; Ruczinski, Ingo; Begum, Ferdouse; Parker, Margaret M; Busch, Tamara; Standley, Jennifer; Rigdon, Jennifer; Hecht, Jacqueline T; Scott, Alan F; Wehby, George L; Christensen, Kaare; Czeizel, Andrew E; Deleyiannis, Frederic W-B; Schutte, Brian C; Wilson, Richard K; Cornell, Robert A; Lidral, Andrew C; Weinstock, George M; Beaty, Terri H; Marazita, Mary L; Murray, Jeffrey C

    2015-03-01

    Although genome-wide association studies (GWASs) for nonsyndromic orofacial clefts have identified multiple strongly associated regions, the causal variants are unknown. To address this, we selected 13 regions from GWASs and other studies, performed targeted sequencing in 1,409 Asian and European trios, and carried out a series of statistical and functional analyses. Within a cluster of strongly associated common variants near NOG, we found that one, rs227727, disrupts enhancer activity. We furthermore identified significant clusters of non-coding rare variants near NTN1 and NOG and found several rare coding variants likely to affect protein function, including four nonsense variants in ARHGAP29. We confirmed 48 de novo mutations and, based on best biological evidence available, chose two of these for functional assays. One mutation in PAX7 disrupted the DNA binding of the encoded transcription factor in an in vitro assay. The second, a non-coding mutation, disrupted the activity of a neural crest enhancer downstream of FGFR2 both in vitro and in vivo. This targeted sequencing study provides strong functional evidence implicating several specific variants as primary contributory risk alleles for nonsyndromic clefting in humans.

  4. Identification of Functional Variants for Cleft Lip with or without Cleft Palate in or near PAX7, FGFR2, and NOG by Targeted Sequencing of GWAS Loci

    PubMed Central

    Leslie, Elizabeth J.; Taub, Margaret A.; Liu, Huan; Steinberg, Karyn Meltz; Koboldt, Daniel C.; Zhang, Qunyuan; Carlson, Jenna C.; Hetmanski, Jacqueline B.; Wang, Hang; Larson, David E.; Fulton, Robert S.; Kousa, Youssef A.; Fakhouri, Walid D.; Naji, Ali; Ruczinski, Ingo; Begum, Ferdouse; Parker, Margaret M.; Busch, Tamara; Standley, Jennifer; Rigdon, Jennifer; Hecht, Jacqueline T.; Scott, Alan F.; Wehby, George L.; Christensen, Kaare; Czeizel, Andrew E.; Deleyiannis, Frederic W.-B.; Schutte, Brian C.; Wilson, Richard K.; Cornell, Robert A.; Lidral, Andrew C.; Weinstock, George M.; Beaty, Terri H.; Marazita, Mary L.; Murray, Jeffrey C.

    2015-01-01

    Although genome-wide association studies (GWASs) for nonsyndromic orofacial clefts have identified multiple strongly associated regions, the causal variants are unknown. To address this, we selected 13 regions from GWASs and other studies, performed targeted sequencing in 1,409 Asian and European trios, and carried out a series of statistical and functional analyses. Within a cluster of strongly associated common variants near NOG, we found that one, rs227727, disrupts enhancer activity. We furthermore identified significant clusters of non-coding rare variants near NTN1 and NOG and found several rare coding variants likely to affect protein function, including four nonsense variants in ARHGAP29. We confirmed 48 de novo mutations and, based on best biological evidence available, chose two of these for functional assays. One mutation in PAX7 disrupted the DNA binding of the encoded transcription factor in an in vitro assay. The second, a non-coding mutation, disrupted the activity of a neural crest enhancer downstream of FGFR2 both in vitro and in vivo. This targeted sequencing study provides strong functional evidence implicating several specific variants as primary contributory risk alleles for nonsyndromic clefting in humans. PMID:25704602

  5. A Study on Genetic Variants of Fibroblast Growth Factor Receptor 2 (FGFR2) and the Risk of Breast Cancer from North India

    PubMed Central

    Siddiqui, Sarah; Chattopadhyay, Shilpi; Akhtar, Md. Salman; Najm, Mohammad Zeeshan; Deo, S. V. S.; Shukla, N. K.; Husain, Syed Akhtar

    2014-01-01

    Genome-Wide Association Studies (GWAS) have identified Fibroblast growth factor receptor 2 (FGFR2) as a candidate gene for breast cancer with single nucleotide polymorphisms (SNPs) located in intron 2 region as the susceptibility loci strongly associated with the risk. However, replicate studies have often failed to extrapolate the association to diverse ethnic regions. This hints towards the existing heterogeneity among different populations, arising due to differential linkage disequilibrium (LD) structures and frequencies of SNPs within the associated regions of the genome. It is therefore important to revisit the previously linked candidates in varied population groups to unravel the extent of heterogeneity. In an attempt to investigate the role of FGFR2 polymorphisms in susceptibility to the risk of breast cancer among North Indian women, we genotyped rs2981582, rs1219648, rs2981578 and rs7895676 polymorphisms in 368 breast cancer patients and 484 healthy controls by Polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP) assay. We observed a statistically significant association with breast cancer risk for all the four genetic variants (P<0.05). In per-allele model for rs2981582, rs1219648, rs7895676 and in dominant model for rs2981578, association remained significant after bonferroni correction (P<0.0125). On performing stratified analysis, significant correlations with various clinicopathological as well as environmental and lifestyle characteristics were observed. It was evident that rs1219648 and rs2981578 interacted with exogenous hormone use and advanced clinical stage III (after Bonferroni correction, P<0.000694), respectively. Furthermore, combined analysis on these four loci revealed that compared to women with 0–1 risk loci, those with 2–4 risk loci had increased risk (OR = 1.645, 95%CI = 1.152–2.347, P = 0.006). In haplotype analysis, for rs2981578, rs2981582 and rs1219648, risk haplotype (GTG) was

  6. FGFR2 risk SNPs confer breast cancer risk by augmenting oestrogen responsiveness.

    PubMed

    Campbell, Thomas M; Castro, Mauro A A; de Santiago, Ines; Fletcher, Michael N C; Halim, Silvia; Prathalingam, Radhika; Ponder, Bruce A J; Meyer, Kerstin B

    2016-08-01

    The fibroblast growth factor receptor 2 (FGFR2) locus is consistently the top hit in genome-wide association studies for oestrogen receptor-positive (ER(+)) breast cancer. Yet, its mode of action continues to be controversial. Here, we employ a systems biology approach to demonstrate that signalling via FGFR2 counteracts cell activation by oestrogen. In the presence of oestrogen, the oestrogen receptor (ESR1) regulon (set of ESR1 target genes) is in an active state. However, signalling by FGFR2 is able to reverse the activity of the ESR1 regulon. This effect is seen in multiple distinct FGFR2 signalling model systems, across multiple cells lines and is dependent on the presence of FGFR2. Increased oestrogen exposure has long been associated with an increased risk of breast cancer. We therefore hypothesized that risk variants should reduce FGFR2 expression and subsequent signalling. Indeed, transient transfection experiments assaying the three independent variants of the FGFR2 risk locus (rs2981578, rs35054928 and rs45631563) in their normal chromosomal context show that these single-nucleotide polymorphisms (SNPs) map to transcriptional silencer elements and that, compared with wild type, the risk alleles augment silencer activity. The presence of risk variants results in lower FGFR2 expression and increased oestrogen responsiveness. We thus propose a molecular mechanism by which FGFR2 can confer increased breast cancer risk that is consistent with oestrogen exposure as a major driver of breast cancer risk. Our findings may have implications for the clinical use of FGFR2 inhibitors. PMID:27236187

  7. FGFR2 risk SNPs confer breast cancer risk by augmenting oestrogen responsiveness.

    PubMed

    Campbell, Thomas M; Castro, Mauro A A; de Santiago, Ines; Fletcher, Michael N C; Halim, Silvia; Prathalingam, Radhika; Ponder, Bruce A J; Meyer, Kerstin B

    2016-08-01

    The fibroblast growth factor receptor 2 (FGFR2) locus is consistently the top hit in genome-wide association studies for oestrogen receptor-positive (ER(+)) breast cancer. Yet, its mode of action continues to be controversial. Here, we employ a systems biology approach to demonstrate that signalling via FGFR2 counteracts cell activation by oestrogen. In the presence of oestrogen, the oestrogen receptor (ESR1) regulon (set of ESR1 target genes) is in an active state. However, signalling by FGFR2 is able to reverse the activity of the ESR1 regulon. This effect is seen in multiple distinct FGFR2 signalling model systems, across multiple cells lines and is dependent on the presence of FGFR2. Increased oestrogen exposure has long been associated with an increased risk of breast cancer. We therefore hypothesized that risk variants should reduce FGFR2 expression and subsequent signalling. Indeed, transient transfection experiments assaying the three independent variants of the FGFR2 risk locus (rs2981578, rs35054928 and rs45631563) in their normal chromosomal context show that these single-nucleotide polymorphisms (SNPs) map to transcriptional silencer elements and that, compared with wild type, the risk alleles augment silencer activity. The presence of risk variants results in lower FGFR2 expression and increased oestrogen responsiveness. We thus propose a molecular mechanism by which FGFR2 can confer increased breast cancer risk that is consistent with oestrogen exposure as a major driver of breast cancer risk. Our findings may have implications for the clinical use of FGFR2 inhibitors.

  8. FGFR2-amplified gastric cancer cell lines require FGFR2 and Erbb3 signaling for growth and survival.

    PubMed

    Kunii, Kaiko; Davis, Lenora; Gorenstein, Julie; Hatch, Harold; Yashiro, Masakazu; Di Bacco, Alessandra; Elbi, Cem; Lutterbach, Bart

    2008-04-01

    We have identified a critical role for amplified FGFR2 in gastric cancer cell proliferation and survival. In a panel of gastric cancer cell lines, fibroblast growth factor receptor 2 (FGFR2) was overexpressed and tyrosine phosphorylated selectively in FGFR2-amplified cell lines KatoIII, Snu16, and OCUM-2M. FGFR2 kinase inhibition by a specific small-molecule inhibitor resulted in selective and potent growth inhibition in FGFR2-amplified cell lines, resulting in growth arrest in KatoIII cells and prominent induction of apoptosis in both Snu16 and OCUM-2M cells. FGFR2-amplified cell lines also contained elevated phosphotyrosine in EGFR, Her2, and Erbb3, but the elevated phosphorylation in EGFR could not be inhibited by gefitinib or erlotinib. We show that the elevated EGFR, Her2, and Erbb3 phosphotyrosine is dependent on FGFR2, revealing EGFR family kinases to be downstream targets of amplified FGFR2. Moreover, shRNA to Erbb3 resulted in a loss of proliferation, confirming a functional role for the activated EGFR signaling pathway. These results reveal that both the FGFR2 and EGFR family signaling pathways are activated in FGFR2-amplified gastric cancer cell lines to drive cell proliferation and survival. Inhibitors of FGFR2 or Erbb3 signaling may have therapeutic efficacy in the subset of gastric cancers containing FGFR2 amplification. PMID:18381441

  9. FGFR2c-mediated ERK-MAPK activity regulates coronal suture development.

    PubMed

    Pfaff, Miles J; Xue, Ke; Li, Li; Horowitz, Mark C; Steinbacher, Derek M; Eswarakumar, Jacob V P

    2016-07-15

    Fibroblast growth factor receptor 2 (FGFR2) signaling is critical for proper craniofacial development. A gain-of-function mutation in the 2c splice variant of the receptor's gene is associated with Crouzon syndrome, which is characterized by craniosynostosis, the premature fusion of one or more of the cranial vault sutures, leading to craniofacial maldevelopment. Insight into the molecular mechanism of craniosynostosis has identified the ERK-MAPK signaling cascade as a critical regulator of suture patency. The aim of this study is to investigate the role of FGFR2c-induced ERK-MAPK activation in the regulation of coronal suture development. Loss-of-function and gain-of-function Fgfr2c mutant mice have overlapping phenotypes, including coronal synostosis and craniofacial dysmorphia. In vivo analysis of coronal sutures in loss-of-function and gain-of-function models demonstrated fundamentally different pathogenesis underlying coronal suture synostosis. Calvarial osteoblasts from gain-of-function mice demonstrated enhanced osteoblastic function and maturation with concomitant increase in ERK-MAPK activation. In vitro inhibition with the ERK protein inhibitor U0126 mitigated ERK protein activation levels with a concomitant reduction in alkaline phosphatase activity. This study identifies FGFR2c-mediated ERK-MAPK signaling as a key mediator of craniofacial growth and coronal suture development. Furthermore, our results solve the apparent paradox between loss-of-function and gain-of-function FGFR2c mutants with respect to coronal suture synostosis. PMID:27034231

  10. Fgfr2 is integral for bladder mesenchyme patterning and function

    PubMed Central

    Walker, K. A.; Ikeda, Y.; Zabbarova, I.; Schaefer, C. M.; Bushnell, D.; De Groat, W. C.; Kanai, A.

    2015-01-01

    While urothelial signals, including sonic hedgehog (Shh), drive bladder mesenchyme differentiation, it is unclear which pathways within the mesenchyme are critical for its development. Studies have shown that fibroblast growth factor receptor (Fgfr)2 is necessary for kidney and ureter mesenchymal development. The objective of the present study was to determine the role of Fgfr2 in the bladder mesenchyme. We used Tbx18cre mice to delete Fgfr2 in the bladder mesenchyme (Fgfr2BM−/−). We performed three-dimensional reconstructions, quantitative real-time PCR, in situ hybridization, immunolabeling, ELISAs, immunoblot analysis, void stain on paper, ex vivo bladder sheet assays, and in vivo decerebrated cystometry. Compared with control bladders, embryonic day 16.5 (E16.5) Fgfr2BM−/− bladders had thin muscle layers with less α-smooth muscle actin and thickened lamina propria with increased collagen type Ia and IIIa that intruded into the muscle. The reciprocal changes in mutant layer thicknesses appeared partly due to a cell fate switch. From postnatal days 1 to 30, Fgfr2BM−/− bladders demonstrated progressive muscle loss and increased collagen expression. Postnatal Fgfr2BM−/− bladder sheets exhibited decreased agonist-mediated contractility and increased passive stretch tension versus control bladder sheets. Cystometry revealed high baseline and threshold pressures and shortened intercontractile intervals in Fgfr2BM−/− versus control bladders. Mechanistically, whereas Shh expression appeared normal, mRNA and protein readouts of hedgehog activity were increased in E16.5 Fgfr2BM−/− versus control bladders. Moreover, E16.5 Fgfr2BM−/− bladders exhibited higher levels of Cdo and Boc, hedgehog coreceptors that enhance sensitivity to Shh, compared with control bladders. In conclusion, loss of Fgfr2 in the bladder mesenchyme leads to abnormal bladder morphology and decreased compliance and contractility. PMID:25656370

  11. FGFR2 mutation in 46,XY sex reversal with craniosynostosis.

    PubMed

    Bagheri-Fam, Stefan; Ono, Makoto; Li, Li; Zhao, Liang; Ryan, Janelle; Lai, Raymond; Katsura, Yukako; Rossello, Fernando J; Koopman, Peter; Scherer, Gerd; Bartsch, Oliver; Eswarakumar, Jacob V P; Harley, Vincent R

    2015-12-01

    Patients with 46,XY gonadal dysgenesis (GD) exhibit genital anomalies, which range from hypospadias to complete male-to-female sex reversal. However, a molecular diagnosis is made in only 30% of cases. Heterozygous mutations in the human FGFR2 gene cause various craniosynostosis syndromes including Crouzon and Pfeiffer, but testicular defects were not reported. Here, we describe a patient whose features we would suggest represent a new FGFR2-related syndrome, craniosynostosis with XY male-to-female sex reversal or CSR. The craniosynostosis patient was chromosomally XY, but presented as a phenotypic female due to complete GD. DNA sequencing identified the FGFR2c heterozygous missense mutation, c.1025G>C (p.Cys342Ser). Substitution of Cys342 by Ser or other amino acids (Arg/Phe/Try/Tyr) has been previously reported in Crouzon and Pfeiffer syndrome. We show that the 'knock-in' Crouzon mouse model Fgfr2c(C342Y/C342Y) carrying a Cys342Tyr substitution displays XY gonadal sex reversal with variable expressivity. We also show that despite FGFR2c-Cys342Tyr being widely considered a gain-of-function mutation, Cys342Tyr substitution in the gonad leads to loss of function, as demonstrated by sex reversal in Fgfr2c(C342Y/-) mice carrying the knock-in allele on a null background. The rarity of our patient suggests the influence of modifier genes which exacerbated the testicular phenotype. Indeed, patient whole exome analysis revealed several potential modifiers expressed in Sertoli cells at the time of testis determination in mice. In summary, this study identifies the first FGFR2 mutation in a 46,XY GD patient. We conclude that, in certain rare genetic contexts, maintaining normal levels of FGFR2 signaling is important for human testis determination. PMID:26362256

  12. Tissue-specific roles of Fgfr2 in development of the external genitalia

    PubMed Central

    Gredler, Marissa L.; Seifert, Ashley W.; Cohn, Martin J.

    2015-01-01

    Congenital anomalies frequently occur in organs that undergo tubulogenesis. Hypospadias is a urethral tube defect defined by mislocalized, oversized, or multiple openings of the penile urethra. Deletion of Fgfr2 or its ligand Fgf10 results in severe hypospadias in mice, in which the entire urethral plate is open along the ventral side of the penis. In the genital tubercle, the embryonic precursor of the penis and clitoris, Fgfr2 is expressed in two epithelial populations: the endodermally derived urethral epithelium and the ectodermally derived surface epithelium. Here, we investigate the tissue-specific roles of Fgfr2 in external genital development by generating conditional deletions of Fgfr2 in each of these cell types. Conditional deletion of Fgfr2 results in two distinct phenotypes: endodermal Fgfr2 deletion causes mild hypospadias and inhibits maturation of a complex urethral epithelium, whereas loss of ectodermal Fgfr2 results in severe hypospadias and absence of the ventral prepuce. Although these cell type-specific mutants exhibit distinctive genital anomalies, cellular analysis reveals that Fgfr2 regulates epithelial maturation and cell cycle progression in the urethral endoderm and in the surface ectoderm. The unexpected finding that ectodermal deletion of Fgfr2 results in the most severe hypospadias highlights a major role for Fgfr2 in the developing genital surface epithelium, where epithelial maturation is required for maintenance of a closed urethral tube. These results demonstrate that urethral tubulogenesis, prepuce morphogenesis, and sexually dimorphic patterning of the lower urethra are controlled by discrete regions of Fgfr2 activity. PMID:26081573

  13. Association between rs2981582 polymorphism in the FGFR2 gene and the risk of breast cancer in Mexican women

    PubMed Central

    Murillo-Zamora, Efrén; Moreno-Macías, Hortensia; Ziv, Elad; Romieu, Isabelle; Lazcano-Ponce, Eduardo; Ángeles-Llerenas, Angélica; Pérez-Rodríguez, Edelmiro; Vidal-Millán, Silvia; Fejerman, Laura; Torres-Mejía, Gabriela

    2014-01-01

    Background and Aims The rs2981582 single nucleotide polymorphism in the Fibroblast Growth Factor Receptor 2 gene has been consistently associated with an increased risk of breast cancer. We evaluated the effect of rs2981582 polymorphism in the FGFR2 gene on the risk of breast cancer and its interaction with non-genetic risk factors. Methods A population based case control study was conducted in Mexico. Data from 687 cases and 907 controls were analyzed. Results The T allele of the rs2981582 polymorphism was associated with an increased risk of breast cancer (OR per allele =1.24, 95% CI 1.06 – 1.46). There was also an interaction between this polymorphism and alcohol consumption (p = 0.043); the effect of alcohol consumption on the risk of breast cancer varied according to the allelic variants of the rs2981582 polymorphism in the FGFR2 gene: OR = 3.97 (95% CI 2.10 – 7.49), OR = 2.01 (95% CI 1.23 − 3.29) and OR = 1.21 (95% CI 0.48 − 3.05) for genotypes CC, CT and TT, respectively. Conclusions This is the first study exploring the association between rs2981582 polymorphism in the FGFR2 gene and breast cancer risk in Mexican women. The interaction found may be of great public health interest, since alcohol consumption is a modifiable breast cancer risk factor. Therefore, replication of this finding is of foremost importance. PMID:24054997

  14. S267P mutation in FGFR2: first report in a patient with Crouzon syndrome.

    PubMed

    Ke, Ronghu; Yang, Xianxian; Ge, Min; Cai, Tianyi; Lei, Jiaqi; Mu, Xiongzheng

    2015-03-01

    It has been known for several years that mutations in the fibroblast growth factor receptor (FGFR2) result in syndromic craniosynostosis including Apert, Crouzon, or Pfeiffer syndromes. Here, we report on a child with a clinically diagnosed Crouzon syndrome that shows the missense point mutation S267P in FGFR2 gene. The mutation is firstly identified in Crouzon syndrome. Our observations expand the molecular spectrum of FGFR2 mutations in the syndrome. PMID:25759927

  15. A reciprocal regulatory circuit between CD44 and FGFR2 via c-myc controls gastric cancer cell growth

    PubMed Central

    Kim, Ha-Jung; Kim, Kyoung-Mee; Choi, Eun Young; Kang, Myung-Soo

    2016-01-01

    Despite their suggested importance, the mechanistic roles of FGFR2 and gastric cancer stem cell (GCSC) marker CD44 remain unclear. We investigated cross talk between CD44 and FGFR2. FGFR2 and CD44 positively regulate each other's expression. While FGFR2 suppresses c-Myc transcription, CD44 activates it. c-Myc in turn augments FGFR2 transcription. CD44 knockdown (KD) depleted FGFR2 and other GCSC markers, decreased c-Myc and Sox2 expression, and suppressed tumor growth, whereas CD44 activation led to FGFR2 induction. FGFR2 KD decreased most GCSC marker expression, including CD44, but increased c-Myc and Sox2 expression and attenuated tumor growth. FGFR2 kinase inhibitor and FGFR2 neutralizing antibody decreased the CD44+/hi GCSC fraction. Conversely, FGFR2 overexpression increased CD44 and accelerated tumor growth in mice. FGFR2 was co-expressed and colocalized diffusively with CD44, EpCAM, and LGR5. In contrast, phospho-FGFR2 colocalized densely with CD44, forming an aggregated signaling complex that was prevented by FGFR2 inhibition. The c-Myc KD depleted FGFR2 but not CD44. Similarly to CD44+/hi phenotypes, sorted FGFR+/hi cells had larger volumes, formed more tumor spheres, grew faster in vivo with bigger tumor mass, and expressed more CD44, EpCAM, and HER2. These findings suggest that FGFR2+/hi cells have stemness properties. Moreover, in situ FGFR2 expression in patient-derived gastric cancer tissue correlated with tumorigenic potential in a xenograft model. In conclusion, CD44 and FGFR2 maintain stemness in gastric cancer by differentially regulating c-Myc transcription. PMID:27107424

  16. Antitumor effects and molecular mechanisms of ponatinib on endometrial cancer cells harboring activating FGFR2 mutations.

    PubMed

    Kim, Do-Hee; Kwak, Yeonui; Kim, Nam Doo; Sim, Taebo

    2016-01-01

    Aberrant mutational activation of FGFR2 is associated with endometrial cancers (ECs). AP24534 (ponatinib) currently undergoing clinical trials has been known to be an orally available multi-targeted tyrosine kinase inhibitor. Our biochemical kinase assay showed that AP24534 is potent against wild-type FGFR1-4 and 5 mutant FGFRs (V561M-FGFR1, N549H-FGFR2, K650E-FGFR3, G697C-FGFR3, N535K-FGFR4) and possesses the strongest kinase-inhibitory activity on N549H-FGFR2 (IC50 of 0.5 nM) among all FGFRs tested. We therefore investigated the effects of AP24534 on endometrial cancer cells harboring activating FGFR2 mutations and explored the underlying molecular mechanisms. AP24534 significantly inhibited the proliferation of endometrial cancer cells bearing activating FGFR2 mutations (N549K, K310R/N549K, S252W) and mainly induced G1/S cell cycle arrest leading to apoptosis. AP24534 also diminished the kinase activity of immunoprecipitated FGFR2 derived from MFE-296 and MFE-280 cells and reduced the phosphorylation of FGFR2 and FRS2 on MFE-296 and AN3CA cells. AP24534 caused substantial reductions in ERK phosphorylation, PLCγ signaling and STAT5 signal transduction on ECs bearing FGFR2 activating mutations. Akt signaling pathway was also deactivated by AP24534. AP24534 causes the chemotherapeutic effect through mainly the blockade of ERK, PLCγ and STAT5 signal transduction on ECs. Moreover, AP24534 inhibited migration and invasion of endometrial cancer cells with FGFR2 mutations. In addition, AP24534 significantly blocked anchorage-independent growth of endometrial cancer cells. We, for the first time, report the molecular mechanisms by which AP24534 exerts antitumor effects on ECs with FGFR2 activating mutations, which would provide mechanistic insight into ongoing clinical investigations of AP24534 for ECs.

  17. Switching addictions between HER2 and FGFR2 in HER2-positive breast tumor cells: FGFR2 as a potential target for salvage after lapatinib failure

    SciTech Connect

    Azuma, Koichi; Tsurutani, Junji; Sakai, Kazuko; Kaneda, Hiroyasu; Fujisaka, Yasuhito; Takeda, Masayuki; Watatani, Masahiro; Arao, Tokuzo; Satoh, Taroh; Okamoto, Isamu; Kurata, Takayasu; Nishio, Kazuto; Nakagawa, Kazuhiko

    2011-04-01

    Highlights: {yields} A lapatinib-resistant breast cancer cell line, UACC812 (UACC812/LR), was found to harbor amplification of the FGFR2 gene. {yields} Inhibition of the molecule by a specific inhibitor of FGFR dramatically induced growth inhibition accompanied by cell death. {yields} Immunohistochemical analysis of patients with HER2-positive breast cancer demonstrated an association between FGFR2 expression and poor outcome for lapatinib-containing chemotherapy. -- Abstract: Agents that target HER2 have improved the prognosis of patients with HER2-amplified breast cancers. However, patients who initially respond to such targeted therapy eventually develop resistance to the treatment. We have established a line of lapatinib-resistant breast cancer cells (UACC812/LR) by chronic exposure of HER2-amplified and lapatinib-sensitive UACC812 cells to the drug. The mechanism by which UACC812/LR acquired resistance to lapatinib was explored using comprehensive gene hybridization. The FGFR2 gene in UACC812/LR was highly amplified, accompanied by overexpression of FGFR2 and reduced expression of HER2, and a cell proliferation assay showed that the IC{sub 50} of PD173074, a small-molecule inhibitor of FGFR tyrosine kinase, was 10,000 times lower in UACC812/LR than in the parent cells. PD173074 decreased the phosphorylation of FGFR2 and substantially induced apoptosis in UACC812/LR, but not in the parent cells. FGFR2 appeared to be a pivotal molecule for the survival of UACC812/LR as they became independent of the HER2 pathway, suggesting that a switch of addiction from the HER2 to the FGFR2 pathway enabled cancer cells to become resistant to HER2-targeted therapy. The present study is the first to implicate FGFR in the development of resistance to lapatinib in cancer, and suggests that FGFR-targeted therapy might become a promising salvage strategy after lapatinib failure in patients with HER2-positive breast cancer.

  18. The C342R mutation in FGFR2 causes Crouzon syndrome with elbow deformity.

    PubMed

    Ke, Ronghu; Yang, Xianxian; Tianyi, Cai; Ge, Min; Lei, Jiaqi; Mu, Xiongzheng

    2015-03-01

    Crouzon syndrome is an autosomal dominant craniosynostosis syndrome caused by mutation in the fibroblast growth factor receptor 2 (FGFR-2). Numerous findings from animal studies imply a critical role for FGFRs in the regulation of skeletal development. Here, we report 2 unrelated patients with Crouzon syndrome accompanied by elbow deformity. Subsequently, we analyzed the sequence of the FGFR2 gene and found that both of the patients carried the Cys342Arg mutation. The findings suggest that the C342R mutation in FGFR2 may cause Crouzon syndrome and elbow deformity in Chinese patients. PMID:25759925

  19. Severe meningeal calcification in a Crouzon patient carrying a mutant C342W FGFR2.

    PubMed

    Ke, Ronghu; Lei, Jiaqi; Ge, Min; Cai, Tianyi; Yang, Junyi; Wu, Yingzhi; Mu, Xiongzheng

    2015-03-01

    Crouzon is an autosomal dominant craniosynostosis syndrome caused by mutation in the fibroblast growth factor receptor (FGFR)-2 gene. Recent findings from animal studies imply a critical role for FGFs in the regulation of mineralization. Here, we presented a 5-year-old girl with severe meningeal calcification. Subsequently, we analyzed FGFR2 mutation and identified a mutation of Cys342Tyr. The findings suggest that abnormal calcification was atypical phenotype of Crouzon patients with Cys342Tyr mutation in FGFR2. PMID:25692891

  20. Epithelial-Specific Requirement of FGFR2 Signaling During Tooth and Palate Development

    PubMed Central

    HOSOKAWA, RYOICHI; DENG, XUEMEI; TAKAMORI, KAZUNORI; XU, XUN; URATA, MARK; BRINGAS, PABLO; CHAI, YANG

    2010-01-01

    Reciprocal interactions between epithelium and mesenchyme are crucial for embryonic development. Fibroblast growth factors (FGFs) are a growth factor family that play an important role in epithelial–mesenchymal tissue interaction. We have generated epithelial-specific conditional knockout mice targeting Fibroblast growth factor receptor 2 (Fgfr2) to investigate the function of FGF signaling during craniofacial development. K14-Cre;Fgfr2fl/fl mice have skin defects, retarded tooth formation, and cleft palate. During the formation of the tooth primordium and palatal processes, cell proliferation in the epithelial cells of K14-Cre;Fgfr2fl/fl mice is reduced. Thus, FGF signaling via FGFR2 in the epithelium is crucial for cell proliferation activity during tooth and palate development. PMID:19235875

  1. Molecular analysis of exons 8, 9 and 10 of the fibroblast growth factor receptor 2 (FGFR2) gene in two families with index cases of Apert Syndrome

    PubMed Central

    Hernández, Gualberto; Barrera, Alejandro; Ospina, Sandra; Prada, Rolando

    2015-01-01

    Introduction: Apert syndrome (AS) is a craniosynostosis condition caused by mutations in the Fibroblast Growth Factor Receptor 2 (FGFR2) gene. Clinical features include cutaneous and osseous symmetric syndactily in hands and feet, with variable presentations in bones, brain, skin and other internal organs. Methods: Members of two families with an index case of Apert Syndrome were assessed to describe relevant clinical features and molecular analysis (sequencing and amplification) of exons 8, 9 and 10 of FGFR2 gen. Results: Family 1 consists of the mother, the index case and half -brother who has a cleft lip and palate. In this family we found a single FGFR2 mutation, S252W, in the sequence of exon 8. Although mutations were not found in the study of the patient affected with cleft lip and palate, it is known that these diseases share signaling pathways, allowing suspected alterations in shared genes. In the patient of family 2, we found a sequence variant T78.501A located near the splicing site, which could interfere in this process, and consequently with the protein function. PMID:26600631

  2. Molecular analysis of FGFR 2 and associated clinical observations in two Chinese families with Crouzon syndrome

    PubMed Central

    Lin, Ying; Gao, Hongbin; Ai, Siming; Eswarakumar, Jacob V.P.; Li, Tao; Liu, Bingqian; Jiang, Hongye; Liu, Yuhua; Liu, Xialin; Li, Yonghao; Ni, Yao; Chen, Jiangna; Lin, Zhuoling; Liang, Xiaoling; Jin, Chenjin; Huang, Xinhua; Lu, Lin; Liu, Yizhi

    2016-01-01

    Crouzon syndrome, a dominantly inherited disorder and the most common type of craniosynostosis syndrome, is caused by mutations in the fibroblast growth factor receptor 2 (FGFR 2) gene, and characterized by craniosynostosis, shallow orbits, ocular proptosis, midface hypoplasia and a curved, beak-like nose. The purpose of the present study was to investigate the fibroblast growth factor receptor 2 (FGFR 2) gene in two Chinese families with Crouzon syndrome and to characterize the associated clinical features. Two families underwent complete ophthalmic examination, and three patients in two families were diagnosed with Crouzon syndrome. Genomic DNA was extracted from leukocytes of peripheral blood samples, which were collected from the family members and 200 unrelated control subjects from the same population. Exons 8 and 10 of the FGFR 2 gene were amplified using polymerase chain reaction analysis and were directly sequenced. Ophthalmic examinations, including best-corrected visual acuity, slit-lamp examination, fundus examination and Computerized Tomography scans, and physical examinations were performed to exclude systemic diseases. These patients were affected with shallow orbits and ocular proptosis, accompanied by midface hypoplasia, craniosynostosis, strabismus or papilloedema, with clinically normal hands and feet. A heterozygous FGFR 2 missense mutation, c.811-812insGAG (p.273insGlu) in exon 8 was identified in the affected individual, but not in the unaffected family members or the normal control individuals in family 1. In family 2, another heterozygous FGFR 2 missense mutation, c.842A>G (P.Tyr281Cys or Y281C), in exon 8 was identified in the affected boy and his mother, but not in the unaffected family members or the normal control individuals. Although FGFR 2 gene mutations and polymorphisms have been reported in various ethnic groups, particularly in the area of osteology, the present study reported for the first time, to the best of our knowledge, the

  3. Novel mutation detection of fibroblast growth factor receptor 1 (FGFR1) gene, FGFR2IIIa, FGFR2IIIb, FGFR2IIIc, FGFR3, FGFR4 gene for craniosynostosis: A prospective study in Asian Indian patient

    PubMed Central

    Barik, Mayadhar; Bajpai, Minu; Malhotra, Arun; Samantaray, Jyotish Chandra; Dwivedi, Sadananda; Das, Sambhunath

    2015-01-01

    Background: Craniosynostosis (CS) syndrome is an autosomal dominant condition classically combining craniosynostosis and non-syndromic craniosynostosis with digital anomalies of the hands and feet. The majority of cases are caused by heterozygous mutations in the third immunoglobulin-like domain (IgIII) of FGFR2, whilst a larger number of cases can be attributed to mutations outside this region of the protein. Aims: To find out the FGFR1, FGFR2, FGFR3 and FGFR4 gene in craniosynostosis syndrome. Settings and Design: A hospital based prospective study. Materials and Methods: Prospective analysis of clinical records of patients registered in CS clinic from December 2007 to January 2015 was done in patients between 4 months to 13 years of age. We have performed genetic findings in a three generation Indian family with Craniosynostosis syndrome. Results: We report for the first time the clinical and genetic findings in a three generation Indian family with Craniosynostosis syndrome caused by a heterozygous missense mutation, Thr 392 Thr and ser 311 try, located in the IgII domain of FGFR2. FGFR 3 and 4 gene basis syndrome was eponymously named. Genetic analysis demonstrated that 51/56 families to be unrelated. In FGFR3 gene 10/TM location of 1172 the nucleotide changes C>A, Ala 391 Glu 19/56 and Exon-19, 5q35.2 at conserved linker region the changes occurred pro 246 Arg in 25/56 families. Conclusions: Independent genetic origins, but phenotypic similarities in the 51 families add to the evidence supporting the theory of selfish spermatogonial selective advantage for this rare gain-of-function FGFR2 mutation. PMID:26557159

  4. Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma.

    PubMed

    Sia, Daniela; Losic, Bojan; Moeini, Agrin; Cabellos, Laia; Hao, Ke; Revill, Kate; Bonal, Dennis; Miltiadous, Oriana; Zhang, Zhongyang; Hoshida, Yujin; Cornella, Helena; Castillo-Martin, Mireia; Pinyol, Roser; Kasai, Yumi; Roayaie, Sasan; Thung, Swan N; Fuster, Josep; Schwartz, Myron E; Waxman, Samuel; Cordon-Cardo, Carlos; Schadt, Eric; Mazzaferro, Vincenzo; Llovet, Josep M

    2015-01-22

    Intrahepatic cholangiocarcinoma (iCCA) is a fatal bile duct cancer with dismal prognosis and limited therapeutic options. By performing RNA- and exome-sequencing analyses, we report a novel fusion event, FGFR2-PPHLN1 (16%), and damaging mutations in the ARAF oncogene (11%). Here we demonstrate that the chromosomal translocation t(10;12)(q26;q12) leading to FGFR2-PPHLN1 fusion possesses transforming and oncogenic activity, which is successfully inhibited by a selective FGFR2 inhibitor in vitro. Among the ARAF mutations, N217I and G322S lead to activation of the pathway and N217I shows oncogenic potential in vitro. Screening of a cohort of 107 iCCA patients reveals that FGFR2 fusions represent the most recurrent targetable alteration (45%, 17/107), while they are rarely present in other primary liver tumours (0/100 of hepatocellular carcinoma (HCC); 1/21 of mixed iCCA-HCC). Taken together, around 70% of iCCA patients harbour at least one actionable molecular alteration (FGFR2 fusions, IDH1/2, ARAF, KRAS, BRAF and FGF19) that is amenable for therapeutic targeting.

  5. Ectrodactyly and Lethal Pulmonary Acinar Dysplasia Associated with Homozygous FGFR2 Mutations Identified by Exome Sequencing.

    PubMed

    Barnett, Christopher P; Nataren, Nathalie J; Klingler-Hoffmann, Manuela; Schwarz, Quenten; Chong, Chan-Eng; Lee, Young K; Bruno, Damien L; Lipsett, Jill; McPhee, Andrew J; Schreiber, Andreas W; Feng, Jinghua; Hahn, Christopher N; Scott, Hamish S

    2016-09-01

    Ectrodactyly/split hand-foot malformation is genetically heterogeneous with more than 100 syndromic associations. Acinar dysplasia is a rare congenital lung lesion of unknown etiology, which is frequently lethal postnatally. To date, there have been no reports of combinations of these two phenotypes. Here, we present an infant from a consanguineous union with both ectrodactyly and autopsy confirmed acinar dysplasia. SNP array and whole-exome sequencing analyses of the affected infant identified a novel homozygous Fibroblast Growth Factor Receptor 2 (FGFR2) missense mutation (p.R255Q) in the IgIII domain (D3). Expression studies of Fgfr2 in development show localization to the affected limbs and organs. Molecular modeling and genetic and functional assays support that this mutation is at least a partial loss-of-function mutation, and contributes to ectrodactyly and acinar dysplasia only in homozygosity, unlike previously reported heterozygous activating FGFR2 mutations that cause Crouzon, Apert, and Pfeiffer syndromes. This is the first report of mutations in a human disease with ectrodactyly with pulmonary acinar dysplasia and, as such, homozygous loss-of-function FGFR2 mutations represent a unique syndrome. PMID:27323706

  6. Bent bone dysplasia (BBD)-FGFR2 type: the radiologic manifestations in early gestation.

    PubMed

    Handa, Atsuhiko; Okajima, Yuka; Izumi, Noriko; Yamanaka, Michiko; Kurihara, Yasuyuki

    2016-02-01

    Bent bone dysplasia-fibroblast growth factor receptor 2 type (BBD-FGFR2) is a recently identified skeletal dysplasia caused by specific FGFR2 mutations, characterized by craniosynostosis and prenatal bowing of the long bones. Only a few cases have been published. We report an affected fetus terminated at 21 weeks of gestation. The clinical and radiologic manifestations mostly recapitulate previous descriptions; however we suggest additional hallmarks of this disorder in early gestation. These hallmarks include distinctive short, thick clavicles and wavy ribs, as well as vertebral bodies that showed striking anteroposterior shortening. Femoral fractures were also present in our case. Although craniosynostosis is a hallmark of the disease, clinicians should be aware that craniosynostosis might not be readily apparent on plain films early in gestation. PMID:26446305

  7. FGFR2 mutation in a Chinese family with unusual Crouzon syndrome

    PubMed Central

    Li, Zi-Li; Chen, Xue; Zhuang, Wen-Juan; Zhao, Wei; Liu, Ya-Ni; Zhang, Fang-Xia; Ha, Ruo-Shui; Wu, Jin-Hua; Zhao, Chen; Sheng, Xun-Lun

    2016-01-01

    AIM To describe the clinical characteristics with genetic lesions in a Chinese family with Crouzon syndrome. METHODS All five patients from this family were included and received comprehensive ophthalmic and systemic examinations. Direct sequencing of the FGFR2 gene was employed for mutation identification. Crystal structure analysis was applied to analyze the structural changes associated with the substitution. RESULTS All patients presented typical Crouzon features, including short stature, craniosynostosis, mandibular prognathism, shallow orbits with proptosis, and exotropia. Intrafamilial phenotypic diversities were observed. Atrophic optic nerves were exclusively detected in the proband and her son. Cranial magnetic resonance imaging (MRI) implied a cystic lesion in her sellar and third ventricular regions. A missense mutation, FGFR2 p.Cys342Trp, was found as disease causative. This substitution would generate conformational changes in the extracellular Ig-III domain of the FGFR-2 protein, thus altering its physical and biological properties. CONCLUSION We describe the clinical presentations and genotypic lesions in a Chinese family with Crouzon syndrome. The intrafamilial phenotypic varieties in this family suggest that other genetic modifiers may also play a role in the pathogenesis of Crouzon syndrome. PMID:27803855

  8. miR-494 inhibits ovarian cancer cell proliferation and promotes apoptosis by targeting FGFR2

    PubMed Central

    ZHAO, XIAOJUAN; ZHOU, YUN; CHEN, YU; YU, FENG

    2016-01-01

    MicroRNAs (miRs) have been reported to be key regulators in numerous types of cancer. The aim of the present study was to investigate the role of miR-494 in ovarian cancer. Expression of miR-494 was analyzed in ovarian cancer tissues and cell lines by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). miR-494 mimic or negative control was transiently transfected into A2780 and SKOV3 cell lines. A cell counting kit-8 assay was performed to assess the effects of miR-494 on cell proliferation, and flow cytometry was used to evaluate the apoptotic rate. The target gene of miR-494 was detected by luciferase assay. Expression of fibroblast growth factor receptor 2 (FGFR2) was identified using RT-qPCR and western blotting. In the present study, decreased expression of miR-494 was observed in ovarian cancer samples and cell lines. Overexpression of miR-494 inhibited ovarian cancer cell proliferation by inducing apoptosis. Additional investigation indicated that FGFR2 was a direct target of miR-494. Taken together, the results of the present study suggested that miR-494 suppressed ovarian cancer cell proliferation by inducing apoptosis via targeting FGFR2. PMID:27313773

  9. A novel exonic variant (221delT) in the LGALS13 gene encoding placental protein 13 (PP13) is associated with preterm labour in a low risk population.

    PubMed

    Gebhardt, S; Bruiners, N; Hillermann, R

    2009-11-01

    Predicting adverse pregnancy outcome in low risk patients in a community with poor socio-economic circumstances is difficult, yet about 5% of these pregnancies will result in preterm labour or severe pre-eclampsia. In this study we aimed to identify markers in pro- and anti-inflammatory genes that may contribute to disease and possibly disease prediction in a low risk community setting. A prospective study was undertaken on 450 consecutive low risk primigravid patients. Blood obtained at first booking was screened for known immunological gene variants (IL4 -590, IL1B +3953, IL1RN, IL10 -1082; -819; -592 and TNFA -308; -238; +488) as well as for novel variants in the LGALS13 gene coding for placental protein 13 (PP13). The incidence of preterm labour and pre-eclampsia was 7.1% and 6.8% respectively. A novel exonic variant (221delT) in the LGALS13 gene increased the risk for preterm labour in the total study group (relative risk RR 2.27). Maternal carriage of the interleukin-1 RN*2 allele was associated with an increased risk of hypertension in pregnancy in the Coloured subgroup of the study cohort (RR 2.53). There was an increased risk for preterm labour in the same subgroup with carriage of the TNFA -308 A-allele (TNF2) (RR 2.53). No significance was found for the other variants examined. We conclude that single nucleotide polymorphisms (SNPs) in certain genes regulating implantation and inflammation may contribute to the complex etiology of pre-eclampsia and preterm labour. The association between the 221delT deletion and adverse pregnancy outcome needs to be confirmed in different populations.

  10. FGFR2 Is Amplified in the NCI-H716 Colorectal Cancer Cell Line and Is Required for Growth and Survival

    PubMed Central

    Mathur, Anjili; Ware, Christopher; Davis, Lenora; Gazdar, Adi; Pan, Bo-Sheng; Lutterbach, Bart

    2014-01-01

    Aberrant kinase activation resulting from mutation, amplification, or translocation can drive growth and survival in a subset of human cancer. FGFR2 is amplified in breast and gastric cancer, and we report here the first characterization of FGFR2 gene amplification in colorectal cancer in the NCI-H716 colorectal cancer cell line. FGFR2 is highly expressed and activated in NCI-H716 cells, and FGFR selective small molecule inhibitors or FGFR2 shRNA strongly inhibited cell viability in vitro, indicating “addiction” of NCI-H716 cells to FGFR2. NCI-H716 growth in a xenograft model was also inhibited by an FGFR small molecule inhibitor. FGFR2 was required for activation of multiple downstream signaling proteins including AKT, ERK, S6RP and NFKB. Inhibition of downstream kinases such as AKT or ERK alone had modest effects on proliferation, whereas combined inhibition of AKT and ERK signaling resulted in a loss of viability similar to FGFR2 inhibition. We identified elevated FGFR2 expression in a small subset of primary colorectal cancer, however FGFR2 amplification was not observed. Although FGFR2 amplification is not common in primary colon cancer or lymph node and liver metastases, other subsets of colorectal cancer such as ascites, from which the NCI-H716 cell line was derived, have yet to be tested. These results suggest that emerging FGFR inhibitor therapeutics may have efficacy in a subset of colon cancer driven by FGFR2 amplification. PMID:24968263

  11. Fibroblast Growth Factor Receptor 2 (FGFR2) Is Required for Corneal Epithelial Cell Proliferation and Differentiation during Embryonic Development

    PubMed Central

    Zhang, Jinglin; Upadhya, Dinesh; Lu, Lin; Reneker, Lixing W.

    2015-01-01

    Fibroblast growth factors (FGFs) play important roles in many aspects of embryonic development. During eye development, the lens and corneal epithelium are derived from the same surface ectodermal tissue. FGF receptor (FGFR)-signaling is essential for lens cell differentiation and survival, but its role in corneal development has not been fully investigated. In this study, we examined the corneal defects in Fgfr2 conditional knockout mice in which Cre expression is activated at lens induction stage by Pax6 P0 promoter. The cornea in LeCre, Fgfr2loxP/loxP mice (referred as Fgfr2CKO) was analyzed to assess changes in cell proliferation, differentiation and survival. We found that Fgfr2CKO cornea was much thinner in epithelial and stromal layer when compared to WT cornea. At embryonic day 12.5–13.5 (E12.5–13.5) shortly after the lens vesicle detaches from the overlying surface ectoderm, cell proliferation (judged by labeling indices of Ki-67, BrdU and phospho-histone H3) was significantly reduced in corneal epithelium in Fgfr2CKO mice. At later stage, cell differentiation markers for corneal epithelium and underlying stromal mesenchyme, keratin-12 and keratocan respectively, were not expressed in Fgfr2CKO cornea. Furthermore, Pax6, a transcription factor essential for eye development, was not present in the Fgfr2CKO mutant corneal epithelial at E16.5 but was expressed normally at E12.5, suggesting that FGFR2-signaling is required for maintaining Pax6 expression in this tissue. Interestingly, the role of FGFR2 in corneal epithelial development is independent of ERK1/2-signaling. In contrast to the lens, FGFR2 is not required for cell survival in cornea. This study demonstrates for the first time that FGFR2 plays an essential role in controlling cell proliferation and differentiation, and maintaining Pax6 levels in corneal epithelium via ERK-independent pathways during embryonic development. PMID:25615698

  12. Attenuating endogenous Fgfr2b ligands during bleomycin-induced lung fibrosis does not compromise murine lung repair.

    PubMed

    MacKenzie, BreAnne; Henneke, Ingrid; Hezel, Stefanie; Al Alam, Denise; El Agha, Elie; Chao, Cho-Ming; Quantius, Jennifer; Wilhelm, Jochen; Jones, Matthew; Goth, Kerstin; Li, Xiaokun; Seeger, Werner; Königshoff, Melanie; Herold, Susanne; Rizvanov, Albert A; Günther, Andreas; Bellusci, Saverio

    2015-05-15

    Fibroblast growth factors (Fgfs) mediate organ repair. Lung epithelial cell overexpression of Fgf10 postbleomycin injury is both protective and therapeutic, characterized by increased survival and attenuated fibrosis. Exogenous administration of FGF7 (palifermin) also showed prophylactic survival benefits in mice. The role of endogenous Fgfr2b ligands on bleomycin-induced lung fibrosis is still elusive. This study reports the expression of endogenous Fgfr2b ligands, receptors, and signaling targets in wild-type mice following bleomycin lung injury. In addition, the impact of attenuating endogenous Fgfr2b-ligands following bleomycin-induced fibrosis was tested by using a doxycycline (dox)-based inducible, soluble, dominant-negative form of the Fgfr2b receptor. Double-transgenic (DTG) Rosa26(rtTA/+);tet(O)solFgfr2b mice were validated for the expression and activity of soluble Fgfr2b (failure to regenerate maxillary incisors, attenuated recombinant FGF7 signal in the lung). As previously reported, no defects in lung morphometry were detected in DTG (+dox) mice exposed from postnatal days (PN) 1 through PN105. Female single-transgenic (STG) and DTG mice were subjected to various levels of bleomycin injury (1.0, 2.0, and 3.0 U/kg). Fgfr2b ligands were attenuated either throughout injury (days 0-11; days 0-28) or during later stages (days 6-28 and 14-28). No significant changes in survival, weight, lung function, confluent areas of fibrosis, or hydroxyproline deposition were detected in DTG mice. These results indicate that endogenous Fgfr2b ligands do not significantly protect against bleomycin injury, nor do they expedite the resolution of bleomycin-induced lung injury in mice. PMID:25820524

  13. Attenuating endogenous Fgfr2b ligands during bleomycin-induced lung fibrosis does not compromise murine lung repair

    PubMed Central

    MacKenzie, BreAnne; Henneke, Ingrid; Hezel, Stefanie; Al Alam, Denise; El Agha, Elie; Chao, Cho-Ming; Quantius, Jennifer; Wilhelm, Jochen; Jones, Matthew; Goth, Kerstin; Li, Xiaokun; Seeger, Werner; Königshoff, Melanie; Herold, Susanne; Rizvanov, Albert A.; Günther, Andreas

    2015-01-01

    Fibroblast growth factors (Fgfs) mediate organ repair. Lung epithelial cell overexpression of Fgf10 postbleomycin injury is both protective and therapeutic, characterized by increased survival and attenuated fibrosis. Exogenous administration of FGF7 (palifermin) also showed prophylactic survival benefits in mice. The role of endogenous Fgfr2b ligands on bleomycin-induced lung fibrosis is still elusive. This study reports the expression of endogenous Fgfr2b ligands, receptors, and signaling targets in wild-type mice following bleomycin lung injury. In addition, the impact of attenuating endogenous Fgfr2b-ligands following bleomycin-induced fibrosis was tested by using a doxycycline (dox)-based inducible, soluble, dominant-negative form of the Fgfr2b receptor. Double-transgenic (DTG) Rosa26rtTA/+;tet(O)solFgfr2b mice were validated for the expression and activity of soluble Fgfr2b (failure to regenerate maxillary incisors, attenuated recombinant FGF7 signal in the lung). As previously reported, no defects in lung morphometry were detected in DTG (+dox) mice exposed from postnatal days (PN) 1 through PN105. Female single-transgenic (STG) and DTG mice were subjected to various levels of bleomycin injury (1.0, 2.0, and 3.0 U/kg). Fgfr2b ligands were attenuated either throughout injury (days 0–11; days 0–28) or during later stages (days 6–28 and 14–28). No significant changes in survival, weight, lung function, confluent areas of fibrosis, or hydroxyproline deposition were detected in DTG mice. These results indicate that endogenous Fgfr2b ligands do not significantly protect against bleomycin injury, nor do they expedite the resolution of bleomycin-induced lung injury in mice. PMID:25820524

  14. The role of fibroblast growth factor receptor 2 (FGFR2) in differentiation of bovine spermatogonial stem cells (SCC)

    PubMed Central

    Akbarinejad, Vahid; Tajik, Parviz; Movahedin, Mansoureh; Youssefi, Reza

    2016-01-01

    The receptors 1 and 2 of fibroblast growth factor (FGFR1 and FGFR2, respectively) have been observed in all types of testicular cells. Culture on extracellular matrix (ECM) has been observed to lead to initiation of differentiation in spermatogonial stem cells (SSCs). The present study was carried out to investigate whether FGFR1 and FGFR2 play a role in SSCs differentiation. Following isolation, bovine testicular cells were cultured on ECM-coated or uncoated (control) plates for 12 days. The gene expression of THY1, cKIT, FGFR1 and FGFR2 was evaluated using quantitative real-time polymerase chain reaction (PCR). Results related to the gene expression of markers of with undifferentiated (THY1) and differentiated (cKIT) spermatogonia implicated stimulation of self-renewal and differentiation in cells cultured on ECM-coated and uncoated plates, respectively (p < 0.05). Concomitantly, the expression of FGFR2 increased during culture in the ECM group (p < 0.05), whereas it did not change in the control group (p > 0.05). As a result, the gene expression of FGFR2 was greater in the ECM than control group (p < 0.05). Nevertheless, FGFR1 expression did not change during culture in the control and ECM groups (p > 0.05). In conclusion, the present study revealed the potential role of FGFR2 in differentiation of SSCs during culture on ECM. PMID:27482360

  15. The role of fibroblast growth factor receptor 2 (FGFR2) in differentiation of bovine spermatogonial stem cells (SCC).

    PubMed

    Akbarinejad, Vahid; Tajik, Parviz; Movahedin, Mansoureh; Youssefi, Reza

    2016-01-01

    The receptors 1 and 2 of fibroblast growth factor (FGFR1 and FGFR2, respectively) have been observed in all types of testicular cells. Culture on extracellular matrix (ECM) has been observed to lead to initiation of differentiation in spermatogonial stem cells (SSCs). The present study was carried out to investigate whether FGFR1 and FGFR2 play a role in SSCs differentiation. Following isolation, bovine testicular cells were cultured on ECM-coated or uncoated (control) plates for 12 days. The gene expression of THY1, cKIT, FGFR1 and FGFR2 was evaluated using quantitative real-time polymerase chain reaction (PCR). Results related to the gene expression of markers of with undifferentiated (THY1) and differentiated (cKIT) spermatogonia implicated stimulation of self-renewal and differentiation in cells cultured on ECM-coated and uncoated plates, respectively (p < 0.05). Concomitantly, the expression of FGFR2 increased during culture in the ECM group (p < 0.05), whereas it did not change in the control group (p > 0.05). As a result, the gene expression of FGFR2 was greater in the ECM than control group (p < 0.05). Nevertheless, FGFR1 expression did not change during culture in the control and ECM groups (p > 0.05). In conclusion, the present study revealed the potential role of FGFR2 in differentiation of SSCs during culture on ECM. PMID:27482360

  16. Suramin blocks interaction between human FGF1 and FGFR2 D2 domain and reduces downstream signaling activity.

    PubMed

    Wu, Zong-Sian; Liu, Che Fu; Fu, Brian; Chou, Ruey-Hwang; Yu, Chin

    2016-09-01

    The extracellular portion of the human fibroblast growth factor receptor2 D2 domain (FGFR2 D2) interacts with human fibroblast growth factor 1 (hFGF1) to activate a downstream signaling cascade that ultimately affects mitosis and differentiation. Suramin is an antiparasiticdrug and a potent inhibitor of FGF-induced angiogenesis. Suramin has been shown to bind to hFGF1, and might block the interaction between hFGF1 and FGFR2 D2. Here, we titrated hFGF1 with FGFR2 D2 and suramin to elucidate their interactions using the detection of NMR. The docking results of both hFGF1-FGFR2 D2 domain and hFGF1-suramin complex were superimposed. The results indicate that suramin blocks the interaction between hFGF1 and FGFR2 D2. We used the PyMOL software to show the hydrophobic interaction of hFGF1-suramin. In addition, we used a Water-soluble Tetrazolium salts assay (WST1) to assess hFGF1 bioactivity. The results will be useful for the development of new antimitogenic activity drugs.

  17. Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome

    SciTech Connect

    Slaney, S.F.; Oldridge, M.; Wilkie, A.O.M.

    1996-05-01

    Apert syndrome is a distinctive human malformation characterized by craniosynostosis and severe syndactyly of the hands and feet. It is caused by specific missense substitutions involving adjacent amino acids (Ser252Trp or Pro253Arg) in the linker between the second and third extracellular immunoglobulin domains of fibroblast growth factor receptor 2 (FGFR2). We have developed a simple PCR assay for these mutations in genomic DNA, based on the creation of novel SfiI and BstUI restriction sites. Analysis of DNA from 70 unrelated patients with Apert syndrome showed that 45 had the Ser252Trp mutation and 25 had the Pro253Arg mutation. Phenotypic differences between these two groups of patients were investigated. Significant differences were found for severity of syndactyly and presence of cleft palate. The syndactyly was more severe with the Pro253Arg mutation, for both the hands and the feet. In contrast, cleft palate was significantly more common in the Ser252Trp patients. No convincing differences were found in the prevalence of other malformations associated with Apert syndrome. We conclude that, although the phenotype attributable to the two mutations is very similar, there are subtle differences. The opposite trends for severity of syndactyly and cleft palate in relation to the two mutations may relate to the varying patterns of temporal and tissue-specific expression of different fibroblast growth factors, the ligands for FGFR2. 54 refs., 5 figs., 3 tabs.

  18. The IgLON Family Member Negr1 Promotes Neuronal Arborization Acting as Soluble Factor via FGFR2.

    PubMed

    Pischedda, Francesca; Piccoli, Giovanni

    2015-01-01

    IgLON proteins are GPI anchored adhesion molecules that control neurite outgrowth. In particular, Negr1 down-regulation negatively influences neuronal arborization in vitro and in vivo. In the present study, we found that the metalloprotease ADAM10 releases Negr1 from neuronal membrane. Ectodomain shedding influences several neuronal mechanisms, including survival, synaptogenesis, and the formation of neurite trees. By combining morphological analysis and virus-mediated selective protein silencing in primary murine cortical neurons, we found that pharmacologically inhibition of ADAM10 results in an impairment of neurite tree maturation that can be rescued upon treatment with soluble Negr1. Furthermore, we report that released Negr1 influences neurite outgrowth in a P-ERK1/2 and FGFR2 dependent manner. Together our findings suggest a role for Negr1 in regulating neurite outgrowth through the modulation of FGFR2 signaling pathway. Given the physiological and pathological role of ADAM10, Negr1, and FGFR2, the regulation of Negr1 shedding may play a crucial role in sustaining brain function and development.

  19. The IgLON Family Member Negr1 Promotes Neuronal Arborization Acting as Soluble Factor via FGFR2

    PubMed Central

    Pischedda, Francesca; Piccoli, Giovanni

    2016-01-01

    IgLON proteins are GPI anchored adhesion molecules that control neurite outgrowth. In particular, Negr1 down-regulation negatively influences neuronal arborization in vitro and in vivo. In the present study, we found that the metalloprotease ADAM10 releases Negr1 from neuronal membrane. Ectodomain shedding influences several neuronal mechanisms, including survival, synaptogenesis, and the formation of neurite trees. By combining morphological analysis and virus-mediated selective protein silencing in primary murine cortical neurons, we found that pharmacologically inhibition of ADAM10 results in an impairment of neurite tree maturation that can be rescued upon treatment with soluble Negr1. Furthermore, we report that released Negr1 influences neurite outgrowth in a P-ERK1/2 and FGFR2 dependent manner. Together our findings suggest a role for Negr1 in regulating neurite outgrowth through the modulation of FGFR2 signaling pathway. Given the physiological and pathological role of ADAM10, Negr1, and FGFR2, the regulation of Negr1 shedding may play a crucial role in sustaining brain function and development. PMID:26793057

  20. FGFR2 is overexpressed in myxoid liposarcoma and inhibition of FGFR signaling impairs tumor growth in vitro

    PubMed Central

    Künstlinger, Helen; Fassunke, Jana; Schildhaus, Hans-Ulrich; Brors, Benedikt; Heydt, Carina; Ihle, Michaela Angelika; Mechtersheimer, Gunhild; Wardelmann, Eva; Büttner, Reinhard; Merkelbach-Bruse, Sabine

    2015-01-01

    Myxoid liposarcomas account for more than one third of liposarcomas and about 10% of all adult soft tissue sarcomas. The tumors are characterized by specific chromosomal translocations leading to the chimeric oncogenes FUS-DDIT3 or EWS1R-DDIT3. The encoded fusion proteins act as aberrant transcription factors. Therefore, we implemented comparative expression analyses using whole-genome microarrays in tumor and fat tissue samples. We aimed at identifying differentially expressed genes which may serve as diagnostic or prognostic biomarkers or as therapeutic targets. Microarray analyses revealed overexpression of FGFR2 and other members of the FGF/FGFR family. Overexpression of FGFR2 was validated by qPCR, immunohistochemistry and western blot analysis in primary tumor samples. Treatment of the myxoid liposarcoma cell lines MLS 402 and MLS 1765 with the FGFR inhibitors PD173074, TKI258 (dovitinib) and BGJ398 as well as specific siRNAs reduced cell proliferation, induced apoptosis and delayed cell migration. Combination of FGFR inhibitors with trabectedin further increased the effect. Our study demonstrates overexpression of FGFR2 and a functional role of FGFR signaling in myxoid liposarcoma. As FGFR inhibition showed effects on proliferation and cell migration and induced apoptosis in vitro, our data indicate the potential use of FGFR inhibitors as a targeted therapy for these tumors. PMID:26036639

  1. Conditional Gene Inactivation Reveals Roles for Fgf10 and Fgfr2 in Establishing a Normal Pattern of Epithelial Branching in the Mouse Lung

    PubMed Central

    Abler, Lisa L.; Mansour, Suzanne L.; Sun, Xin

    2012-01-01

    Fibroblast growth factor 10 (FGF10) signaling through FGF receptor 2 (FGFR2) is required for lung initiation. While studies indicate that Fgf10 and Fgfr2 are also important at later stages of lung development, their roles in early branching events remain unclear. We addressed this question through conditional inactivation of both genes in mouse subsequent to lung initiation. Inactivation of Fgf10 in lung mesenchyme resulted in smaller lobes with a reduced number of branches. Inactivation of Fgfr2 in lung epithelium resulted in disruption of lobes and small epithelial outgrowths that arose arbitrarily along the main bronchi. In both mutants, there was an increase in cell death. Also, the expression patterns of key signaling molecules implicated in branching morphogenesis were altered and a proximal lung marker was expanded distally. Our results indicate that both Fgf10 and Fgfr2 are required for a normal branching program and for proper proximal-distal patterning of the lung. PMID:19618463

  2. A meta-analysis of genome-wide association studies for adiponectin levels in East Asians identifies a novel locus near WDR11-FGFR2.

    PubMed

    Wu, Ying; Gao, He; Li, Huaixing; Tabara, Yasuharu; Nakatochi, Masahiro; Chiu, Yen-Feng; Park, Eun Jung; Wen, Wanqing; Adair, Linda S; Borja, Judith B; Cai, Qiuyin; Chang, Yi-Cheng; Chen, Peng; Croteau-Chonka, Damien C; Fogarty, Marie P; Gan, Wei; He, Chih-Tsueng; Hsiung, Chao A; Hwu, Chii-Min; Ichihara, Sahoko; Igase, Michiya; Jo, Jaeseong; Kato, Norihiro; Kawamoto, Ryuichi; Kuzawa, Christophor W; Lee, Jeannette J M; Liu, Jianjun; Lu, Ling; McDade, Thomas W; Osawa, Haruhiko; Sheu, Wayne H-H; Teo, Yvonne; Vadlamudi, Swarooparani; Van Dam, Rob M; Wang, Yiqin; Xiang, Yong-Bing; Yamamoto, Ken; Ye, Xingwang; Young, Terri L; Zheng, Wei; Zhu, Jingwen; Shu, Xiao-Ou; Shin, Chol; Jee, Sun Ha; Chuang, Lee-Ming; Miki, Tetsuro; Yokota, Mitsuhiro; Lin, Xu; Mohlke, Karen L; Tai, E Shyong

    2014-02-15

    Blood levels of adiponectin, an adipocyte-secreted protein correlated with metabolic and cardiovascular risks, are highly heritable. Genome-wide association (GWA) studies for adiponectin levels have identified 14 loci harboring variants associated with blood levels of adiponectin. To identify novel adiponectin-associated loci, particularly those of importance in East Asians, we conducted a meta-analysis of GWA studies for adiponectin in 7827 individuals, followed by two stages of replications in 4298 and 5954 additional individuals. We identified a novel adiponectin-associated locus on chromosome 10 near WDR11-FGFR2 (P = 3.0 × 10(-14)) and provided suggestive evidence for a locus on chromosome 12 near OR8S1-LALBA (P = 1.2 × 10(-7)). Of the adiponectin-associated loci previously described, we confirmed the association at CDH13 (P = 6.8 × 10(-165)), ADIPOQ (P = 1.8 × 10(-22)), PEPD (P = 3.6 × 10(-12)), CMIP (P = 2.1 × 10(-10)), ZNF664 (P = 2.3 × 10(-7)) and GPR109A (P = 7.4 × 10(-6)). Conditional analysis at ADIPOQ revealed a second signal with suggestive evidence of association only after conditioning on the lead SNP (Pinitial = 0.020; Pconditional = 7.0 × 10(-7)). We further confirmed the independence of two pairs of closely located loci (<2 Mb) on chromosome 16 at CMIP and CDH13, and on chromosome 12 at GPR109A and ZNF664. In addition, the newly identified signal near WDR11-FGFR2 exhibited evidence of association with triglycerides (P = 3.3 × 10(-4)), high density lipoprotein cholesterol (HDL-C, P = 4.9 × 10(-4)) and body mass index (BMI)-adjusted waist-hip ratio (P = 9.8 × 10(-3)). These findings improve our knowledge of the genetic basis of adiponectin variation, demonstrate the shared allelic architecture for adiponectin with lipids and central obesity and motivate further studies of underlying mechanisms.

  3. A meta-analysis of genome-wide association studies for adiponectin levels in East Asians identifies a novel locus near WDR11-FGFR2

    PubMed Central

    Wu, Ying; Gao, He; Li, Huaixing; Tabara, Yasuharu; Nakatochi, Masahiro; Chiu, Yen-Feng; Park, Eun Jung; Wen, Wanqing; Adair, Linda S.; Borja, Judith B.; Cai, Qiuyin; Chang, Yi-Cheng; Chen, Peng; Croteau-Chonka, Damien C.; Fogarty, Marie P.; Gan, Wei; He, Chih-Tsueng; Hsiung, Chao A.; Hwu, Chii-Min; Ichihara, Sahoko; Igase, Michiya; Jo, Jaeseong; Kato, Norihiro; Kawamoto, Ryuichi; Kuzawa, Christophor W.; Lee, Jeannette J.M.; Liu, Jianjun; Lu, Ling; Mcdade, Thomas W.; Osawa, Haruhiko; Sheu, Wayne H-H.; Teo, Yvonne; Vadlamudi, Swarooparani; Van Dam, Rob M.; Wang, Yiqin; Xiang, Yong-Bing; Yamamoto, Ken; Ye, Xingwang; Young, Terri L.; Zheng, Wei; Zhu, Jingwen; Shu, Xiao-Ou; Shin, Chol; Jee, Sun Ha; Chuang, Lee-Ming; Miki, Tetsuro; Yokota, Mitsuhiro; Lin, Xu; Mohlke, Karen L; Tai, E Shyong

    2014-01-01

    Blood levels of adiponectin, an adipocyte-secreted protein correlated with metabolic and cardiovascular risks, are highly heritable. Genome-wide association (GWA) studies for adiponectin levels have identified 14 loci harboring variants associated with blood levels of adiponectin. To identify novel adiponectin-associated loci, particularly those of importance in East Asians, we conducted a meta-analysis of GWA studies for adiponectin in 7827 individuals, followed by two stages of replications in 4298 and 5954 additional individuals. We identified a novel adiponectin-associated locus on chromosome 10 near WDR11-FGFR2 (P = 3.0 × 10−14) and provided suggestive evidence for a locus on chromosome 12 near OR8S1-LALBA (P = 1.2 × 10−7). Of the adiponectin-associated loci previously described, we confirmed the association at CDH13 (P = 6.8 × 10−165), ADIPOQ (P = 1.8 × 10−22), PEPD (P = 3.6 × 10−12), CMIP (P = 2.1 × 10−10), ZNF664 (P = 2.3 × 10−7) and GPR109A (P = 7.4 × 10−6). Conditional analysis at ADIPOQ revealed a second signal with suggestive evidence of association only after conditioning on the lead SNP (Pinitial = 0.020; Pconditional = 7.0 × 10−7). We further confirmed the independence of two pairs of closely located loci (<2 Mb) on chromosome 16 at CMIP and CDH13, and on chromosome 12 at GPR109A and ZNF664. In addition, the newly identified signal near WDR11-FGFR2 exhibited evidence of association with triglycerides (P = 3.3 × 10−4), high density lipoprotein cholesterol (HDL-C, P = 4.9 × 10−4) and body mass index (BMI)-adjusted waist–hip ratio (P = 9.8 × 10−3). These findings improve our knowledge of the genetic basis of adiponectin variation, demonstrate the shared allelic architecture for adiponectin with lipids and central obesity and motivate further studies of underlying mechanisms. PMID:24105470

  4. The Fgfr2(S252W/+) mutation in mice retards mandible formation and reduces bone mass as in human Apert syndrome.

    PubMed

    Zhou, Xia; Pu, Dongquan; Liu, Ri; Li, Xiangjie; Wen, Xiujie; Zhang, Li; Chen, Lin; Deng, Manjing; Liu, Luchuan

    2013-05-01

    Apert syndrome is a common craniosynostosis caused by gain-of-function missense mutations of fibroblast growth factor receptor 2 (FGFR2). Mice with the FGFR2 S252W mutation can elucidate the mechanism by which the human Apert syndrome phenotypes arise. However, many studies have focused on mutant skull and long bone malformation, only few studies have focused on mandible changes. Bone formation and micro-architecture between 28- and 56-day-old mutant mice and controls were compared to investigate the changes in the mandibular micro-architecture caused by the Fgfr2(S252W/+) mutation to provide a basis for exploring the pathogenesis and therapeutic measures of human Apert syndrome. Fgfr2(S252W/+) mutant mice were established, and their general characteristics, including weight, naso-anal length, and calcium and phosphate content in serum and bone were tested. Calcein labeling, tartrate-resistant acid phosphatase staining and toluidine blue staining were used to detect osteoblast and osteoclast activities. H&E staining and micro-CT detection were used to test micro-architecture changes. The changes in mineral apposition rate and micro-architecture of the Fgfr2(S252W/+) mice were statistically significant; however, the magnitude of the micro-architecture became less with age. The Fgfr2(S252W/+) mutation may retard mandibular bone formation, decreased bone volume, and compromised skeletal architecture by regulating both osteoblastogenesis and osteoclastogenesis.

  5. Multiple receptor tyrosine kinase activation attenuates therapeutic efficacy of the fibroblast growth factor receptor 2 inhibitor AZD4547 in FGFR2 amplified gastric cancer

    PubMed Central

    Zhang, Zhe; Liu, Xinyang; Wu, Zheng; Geng, Ruixuan; Ge, Xiaoxiao; Dai, Congqi; Liu, Rujiao; Zhang, Qunling; Li, Wenhua; Li, Jin

    2015-01-01

    Fibroblast growth factor receptor 2 (FGFR2)-targeted therapy has attracted considerable attention as novel anticancer agents in gastric cancer (GC). However, intrinsic or acquired drug resistance has emerged as a major challenge to their clinical use. In this study, we demonstrated that several receptor tyrosine kinase (RTK), including EGFR, HER3 and MET, activations contributed to AZD4547 (a selective FGFR2 inhibitor) hyposensitivity in FGFR2 amplified GC cells. The rescue effect was abrogated by inhibiting these RTKs with their targeted tyrosine kinase inhibitors (TKIs). In addition, synergy in growth inhibition was observed when the GC cells were treated with a combination of AZD4547 and cetuximab (an EGFR monoclonal antibody) both in vitro and in vivo. More importantly, tissue microarray analysis revealed that these resistance-conferring RTKs were highly expressed in FGFR2 positive GC patients. Taken together, these observations demonstrated RTKs including EGFR, HER3 and MET activations as novel mechanisms of hyposensitivity to AZD4547. It will be clinically valuable to investigate the involvement of RTK-mediated signaling in intrinsicor acquired resistance to FGFR2 TKIs in GC. A combination targeted therapeutic strategy may be recommended for treating FGFR2 amplified GC patients with these RTK activations. PMID:25576915

  6. Molecular analysis of FGFR 2 and associated clinical observations in two Chinese families with Crouzon syndrome.

    PubMed

    Lin, Ying; Gao, Hongbin; Ai, Siming; Eswarakumar, Jacob V P; Li, Tao; Liu, Bingqian; Jiang, Hongye; Liu, Yuhua; Liu, Xialin; Li, Yonghao; Ni, Yao; Chen, Jiangna; Lin, Zhuoling; Liang, Xiaoling; Jin, Chenjin; Huang, Xinhua; Lu, Lin; Liu, Yizhi

    2016-09-01

    Crouzon syndrome, a dominantly inherited disorder and the most common type of craniosynostosis syndrome, is caused by mutations in the fibroblast growth factor receptor 2 (FGFR 2) gene, and characterized by craniosynostosis, shallow orbits, ocular proptosis, midface hypoplasia and a curved, beak‑like nose. The purpose of the present study was to investigate the fibroblast growth factor receptor 2 (FGFR 2) gene in two Chinese families with Crouzon syndrome and to characterize the associated clinical features. Two families underwent complete ophthalmic examination, and three patients in two families were diagnosed with Crouzon syndrome. Genomic DNA was extracted from leukocytes of peripheral blood samples, which were collected from the family members and 200 unrelated control subjects from the same population. Exons 8 and 10 of the FGFR 2 gene were amplified using polymerase chain reaction analysis and were directly sequenced. Ophthalmic examinations, including best‑corrected visual acuity, slit‑lamp examination, fundus examination and Computerized Tomography scans, and physical examinations were performed to exclude systemic diseases. These patients were affected with shallow orbits and ocular proptosis, accompanied by midface hypoplasia, craniosynostosis, strabismus or papilloedema, with clinically normal hands and feet. A heterozygous FGFR 2 missense mutation, c.811‑812insGAG (p.273insGlu) in exon 8 was identified in the affected individual, but not in the unaffected family members or the normal control individuals in family 1. In family 2, another heterozygous FGFR 2 missense mutation, c.842A>G (P.Tyr281Cys or Y281C), in exon 8 was identified in the affected boy and his mother, but not in the unaffected family members or the normal control individuals. Although FGFR 2 gene mutations and polymorphisms have been reported in various ethnic groups, particularly in the area of osteology, the present study reported for the first time, to the best of

  7. FGFR2 and other loci identified in genome-wide association studies are associated with breast cancer in African-American and younger women

    PubMed Central

    Barnholtz-Sloan, Jill S.; Shetty, Priya B.; Guan, Xiaowei; Nyante, Sarah J.; Luo, Jingchun; Brennan, Donal J.; Millikan, Robert C.

    2010-01-01

    Twenty-nine single-nucleotide polymorphisms (SNPs) from previously published genome-wide association studies (GWAS) and multiple ancestry informative markers were genotyped in the Carolina Breast Cancer Study (CBCS) (742 African-American (AA) cases, 1230 White cases; 658 AA controls, 1118 White controls). In the entire study population, 9/10 SNPs in fibroblast growth factor receptor 2 (FGFR2) were significantly associated with breast cancer after adjusting for age, race and European ancestry [odds ratios (OR) range 1.17–1.81]. Associations were observed for SNPs in FGFR2, LSP1, H19, TLR1/TLR6 and RELN for AA; FGFR2, TNRC9, H19 and MAP3K1 for Whites; FGFR2, TNRC9, Msc5A1 and chromosome 8q for women ≥50 years old and FGFR2 and TNRC9 for women <50 years old. FGFR2 haplotypes based upon rs11200014, rs2981579, rs1219648 and rs2420946 were associated with increased risk of breast cancer, including the GTGT haplotype in AAs [OR = 1.27, 95% confidence interval (CI) 1.04–1.56] and younger women of either race [OR = 1.35, 95% CI 1.02–1.78) and the ATGT haplotype in Whites (OR = 1.30, 95% CI 1.15–1.46). Recent GWAS hits for breast cancer in Europeans and Whites (i.e. women of European descent) thus showed evidence of replication among AAs and Whites in the CBCS. Several new haplotypes were associated with breast cancer in AA and younger women, particularly the FGFR2 GTGT haplotype. These results highlight the need to conduct GWAS among younger women and in a variety of racial–ethnic populations. PMID:20554749

  8. Transient Inhibition of FGFR2b-Ligands Signaling Leads to Irreversible Loss of Cellular β-Catenin Organization and Signaling in AER during Mouse Limb Development

    PubMed Central

    Tabatabai, Reza; Baptista, Sheryl; Tiozzo, Caterina; Carraro, Gianni; Wheeler, Matthew; Barreto, Guillermo; Braun, Thomas; Li, Xiaokun; Hajihosseini, Mohammad K.; Bellusci, Saverio

    2013-01-01

    The vertebrate limbs develop through coordinated series of inductive, growth and patterning events. Fibroblast Growth Factor receptor 2b (FGFR2b) signaling controls the induction of the Apical Ectodermal Ridge (AER) but its putative roles in limb outgrowth and patterning, as well as in AER morphology and cell behavior have remained unclear. We have investigated these roles through graded and reversible expression of soluble dominant-negative FGFR2b molecules at various times during mouse limb development, using a doxycycline/transactivator/tet(O)-responsive system. Transient attenuation (≤24 hours) of FGFR2b-ligands signaling at E8.5, prior to limb bud induction, leads mostly to the loss or truncation of proximal skeletal elements with less severe impact on distal elements. Attenuation from E9.5 onwards, however, has an irreversible effect on the stability of the AER, resulting in a progressive loss of distal limb skeletal elements. The primary consequences of FGFR2b-ligands attenuation is a transient loss of cell adhesion and down-regulation of P63, β1-integrin and E-cadherin, and a permanent loss of cellular β-catenin organization and WNT signaling within the AER. Combined, these effects lead to the progressive transformation of the AER cells from pluristratified to squamous epithelial-like cells within 24 hours of doxycycline administration. These findings show that FGFR2b-ligands signaling has critical stage-specific roles in maintaining the AER during limb development. PMID:24167544

  9. BRAF kinase inhibitor exerts anti-tumor activity against breast cancer cells via inhibition of FGFR2.

    PubMed

    Zhang, Zong Xin; Jin, Wen Jun; Yang, Sheng; Ji, Cun Li

    2016-01-01

    Most anti-angiogenic therapies currently being evaluated in clinical trials targetvascular endothelial growth factor (VEGF) pathway; however, the tumor vasculature can acquire resistance to VEGF-targeted therapy by shifting to other angiogenesis mechanisms. Therefore, other potential therapeutic agents that block non-VEGF angiogenic pathways need to be evaluated. Here we identified BRAF kinase inhibitor, vemurafenibas an agent with potential anti-angiogenic and anti-breast cancer activities. Vemurafenib demonstrated inhibition of endothelial cell proliferation, migration, and tube formation in response to basic fibroblast growth factor (bFGF). In ex vivo and in vivo angiogenesis assays, vemurafenib suppressed bFGF-induced microvessel sprouting of rat aortic rings and angiogenesis in vivo. To understand the underlying molecular basis, we examined the effects of vemurafenib on different molecular components in treated endothelial cell, and found that vemurafenib suppressed bFGF-triggered activation of FGFR2 and protein kinase B (AKT). Moreover, vemurafenib directly inhibited proliferation and blocked the oncogenic signaling pathways in breast cancer cell. In vivo, using xenograft models of breast cancer cells MDA-MB-231, vemurafenib showed growth-inhibitory activity associated with inhibition of tumor angiogenesis. Taken together, our results indicate that vemurafenib targets the FGFR2-mediated AKT signaling pathway in endothelial cells, leading to the suppression of tumor growth and angiogenesis.

  10. Fgf receptors Fgfr1a and Fgfr2 control the function of pharyngeal endoderm in late cranial cartilage development.

    PubMed

    Larbuisson, Arnaud; Dalcq, Julia; Martial, Joseph A; Muller, Marc

    2013-01-01

    Cranial cartilage derives mainly from cranial neural crest cells and its formation requires fibroblast growth factor (Fgf) signaling for early differentiation and survival of developing chondrocytes as well as patterning of the endodermal pouches. Here, we investigate the role of Fgf receptors in chondrocyte maturation at later stages, beyond 24 hpf. Using inducible expression of a dominant-negative Fgf receptor, we show that Fgf signaling is required around 30 hpf for correct cartilage formation. The receptor genes fgfr1a and fgr2 are expressed in pharyngeal endodermal pouches after 24 hpf or 26 hpf, respectively. Depletion of any of these two receptors by microinjection of antisense morpholinos results in severe defects in cartilage formation at 4 dpf and a decrease in expression of the late chondrocyte markers barx1 and runx2b. Although endodermal pouches are correctly formed and patterned, receptor knock down leads to decreased expression of runx3, egr1 and sox9b in this tissue, while expression of fsta, coding for a secreted BMP/Tgfß inhibitor, is clearly increased. Rescue experiments revealed that each Fgfr1a or Fgfr2 receptor is able to compensate for the loss of the other. Thus, we show that minimal amounts of Fgfr1a or Fgfr2 are required to initiate a regulatory cascade in pharyngeal endoderm reducing expression of fsta, thereby allowing correct BMP signaling to the maturing chondrocytes of the head cartilage. PMID:24176552

  11. BRAF kinase inhibitor exerts anti-tumor activity against breast cancer cells via inhibition of FGFR2

    PubMed Central

    Zhang, Zong Xin; Jin, Wen Jun; Yang, Sheng; Ji, Cun Li

    2016-01-01

    Most anti-angiogenic therapies currently being evaluated in clinical trials targetvascular endothelial growth factor (VEGF) pathway; however, the tumor vasculature can acquire resistance to VEGF-targeted therapy by shifting to other angiogenesis mechanisms. Therefore, other potential therapeutic agents that block non-VEGF angiogenic pathways need to be evaluated. Here we identified BRAF kinase inhibitor, vemurafenibas an agent with potential anti-angiogenic and anti-breast cancer activities. Vemurafenib demonstrated inhibition of endothelial cell proliferation, migration, and tube formation in response to basic fibroblast growth factor (bFGF). In ex vivo and in vivo angiogenesis assays, vemurafenib suppressed bFGF-induced microvessel sprouting of rat aortic rings and angiogenesis in vivo. To understand the underlying molecular basis, we examined the effects of vemurafenib on different molecular components in treated endothelial cell, and found that vemurafenib suppressed bFGF-triggered activation of FGFR2 and protein kinase B (AKT). Moreover, vemurafenib directly inhibited proliferation and blocked the oncogenic signaling pathways in breast cancer cell. In vivo, using xenograft models of breast cancer cells MDA-MB-231, vemurafenib showed growth-inhibitory activity associated with inhibition of tumor angiogenesis. Taken together, our results indicate that vemurafenib targets the FGFR2-mediated AKT signaling pathway in endothelial cells, leading to the suppression of tumor growth and angiogenesis. PMID:27293997

  12. A novel mutation (a886g) in exon 5 of FGFR2 in members of a family with Crouzon phenotype and plagiocephaly.

    PubMed Central

    Steinberger, D; Collmann, H; Schmalenberger, B; Müller, U

    1997-01-01

    We identified a novel mutation in members of a family with signs of Crouzon syndrome and plagiocephaly. In affected members of the family an A-->G transition was found at position 886 in exon 5 of the fibroblast growth factor receptor 2 (FGFR2) gene. The base change results in the replacement of a lysine by glutamic acid in Ig-like loop III of FGFR2. The unusual finding of plagiocephaly in these Crouzon patients may either be the result of the type of mutation or because of genetic and environmental factors that affect the phenotype in addition to the mutated FGF receptor. Images PMID:9152842

  13. Clinical and radiographic delineation of Bent Bone Dysplasia-FGFR2 type or Bent Bone Dysplasia with Distinctive Clavicles and Angel-shaped Phalanges.

    PubMed

    Krakow, Deborah; Cohn, Daniel H; Wilcox, William R; Noh, Grace J; Raffel, Leslie J; Sarukhanov, Anna; Ivanova, Margarita H; Danielpour, Moise; Grange, Dorothy K; Elliott, Alison M; Bernstein, Jonathan A; Rimoin, David L; Merrill, Amy E; Lachman, Ralph S

    2016-10-01

    Bent Bone Dysplasia-FGFR2 type is a relatively recently described bent bone phenotype with diagnostic clinical, radiographic, and molecular characteristics. Here we report on 11 individuals, including the original four patients plus seven new individuals with three longer-term survivors. The prenatal phenotype included stillbirth, bending of the femora, and a high incidence of polyhydramnios, prematurity, and perinatal death in three of 11 patients in the series. The survivors presented with characteristic radiographic findings that were observed among those with lethality, including bent bones, distinctive (moustache-shaped) small clavicles, angel-shaped metacarpals and phalanges, poor mineralization of the calvarium, and craniosynostosis. Craniofacial abnormalities, hirsutism, hepatic abnormalities, and genitourinary abnormalities were noted as well. Longer-term survivors all needed ventilator support. Heterozygosity for mutations in the gene that encodes Fibroblast Growth Factor Receptor 2 (FGFR2) was identified in the nine individuals with available DNA. Description of these patients expands the prenatal and postnatal findings of Bent Bone Dysplasia-FGFR2 type and adds to the phenotypic spectrum among all FGFR2 disorders. © 2016 Wiley Periodicals, Inc. PMID:27240702

  14. FGFR2 mutation in a patient without typical features of Pfeiffer syndrome--The emerging role of combined NGS and phenotype based strategies.

    PubMed

    Flöttmann, Ricarda; Knaus, Alexej; Zemojtel, Tomasz; Robinson, Peter N; Mundlos, Stefan; Horn, Denise; Spielmann, Malte

    2015-08-01

    Pfeiffer syndrome (MIM: #101600) is a rare autosomal dominant disorder classically characterized by limb and craniofacial anomalies. It is caused by heterozygous mutations in the fibroblast growth factor receptors types 1 and 2 (FGFR1 and FGFR2). We applied a next generation sequencing (NGS) panel approach comprising all 2877 genes currently known to be causative for one or more Mendelian diseases combined with the phenotype based computational tool PhenIX (Phenotypic Interpretation of eXomes). We report on a patient presenting with multiple anomalies of hands and feet including brachydactyly and symphalangism. No clinical diagnosis could be established based on the clinical findings and testing of several genes associated with brachydactyly and symphalangism failed to identify mutations. Via next generation sequencing (NGS) panel approach we then identified a novel de novo missense FGFR2 mutation affecting an amino acid reported to be mutated in Pfeiffer syndrome. Since our patient shows typical radiological findings of Pfeiffer syndrome in hands and feet but at the same time lacks several characteristic features such as clinical signs of craniosynostosis and prominent eyes we suggest introducing the term "FGFR2 associated phenotypes" for similar cases. Our results highlight the emerging role of combined NGS and phenotype based bioinformatics strategies to establish clinical diagnoses.

  15. Binding of FGF2 to FGFR2 in an autocrine mode in trophectoderm cells is indispensable for mouse blastocyst formation through PKC-p38 pathway

    PubMed Central

    Yang, Jing; Zhang, Dan; Yu, Ying; Zhang, Run-Ju; Hu, Xiao-Ling; Huang, He-Feng; Lu, Yong-Chao

    2015-01-01

    Fibroblast growth factors (FGF1, FGF2 and FGF4) and fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3 and FGFR4) have been reported to be expressed in preimplantation embryos and be required for their development. However, the functions of these molecules in trophectoderm cells (TEs) that lead to the formation of the blastocyst as well as the underlying mechanism have not been elucidated. The present study has demonstrated for the first time that endogenous FGF2 secreted by TEs can regulate protein expression and distribution in TEs via the FGFR2-mediated activation of PKC and p38, which are important for the development of expanded blastocysts. This finding provides the first explanation for the long-observed phenomenon that only high concentrations of exogenous FGFs have effects on embryonic development, but in vivo the amount of endogenous FGFs are trace. Besides, the present results suggest that FGF2/FGFR2 may act in an autocrine fashion and activate the downstream PKC/p38 pathway in TEs during expanded blastocyst formation. PMID:26378412

  16. FGFR2IIIb-MAPK Activity Is Required for Epithelial Cell Fate Decision in the Lower Müllerian Duct.

    PubMed

    Terakawa, Jumpei; Rocchi, Altea; Serna, Vanida A; Bottinger, Erwin P; Graff, Jonathan M; Kurita, Takeshi

    2016-07-01

    Cell fate of lower Müllerian duct epithelium (MDE), to become uterine or vaginal epithelium, is determined by the absence or presence of ΔNp63 expression, respectively. Previously, we showed that SMAD4 and runt-related transcription factor 1 (RUNX1) were independently required for MDE to express ΔNp63. Here, we report that vaginal mesenchyme directs vaginal epithelial cell fate in MDE through paracrine activation of fibroblast growth factor (FGF) receptor-MAPK pathway. In the developing reproductive tract, FGF7 and FGF10 were enriched in vaginal mesenchyme, whereas FGF receptor 2IIIb was expressed in epithelia of both the uterus and vagina. When Fgfr2 was inactivated, vaginal MDE underwent uterine cell fate, and this differentiation defect was corrected by activation of MEK-ERK pathway. In vitro, FGF10 in combination with bone morphogenetic protein 4 and activin A (ActA) was sufficient to induce ΔNp63 in MDE, and ActA was essential for induction of RUNX1 through SMAD-independent pathways. Accordingly, inhibition of type 1 receptors for activin in neonatal mice induced uterine differentiation in vaginal epithelium by down-regulating RUNX1, whereas conditional deletion of Smad2 and Smad3 had no effect on vaginal epithelial differentiation. In conclusion, vaginal epithelial cell fate in MDE is induced by FGF7/10-MAPK, bone morphogenetic protein 4-SMAD, and ActA-RUNX1 pathway activities, and the disruption in any one of these pathways results in conversion from vaginal to uterine epithelial cell fate. PMID:27164167

  17. Incorporating Known Genetic Variants Does Not Improve the Accuracy of PSA Testing to Identify High Risk Prostate Cancer on Biopsy

    PubMed Central

    Gilbert, Rebecca; Martin, Richard M.; Evans, David M.; Tilling, Kate; Davey Smith, George; Kemp, John P.; Lane, J. Athene; Hamdy, Freddie C.; Neal, David E.; Donovan, Jenny L.; Metcalfe, Chris

    2015-01-01

    Introduction Prostate-specific antigen (PSA) testing is a widely accepted screening method for prostate cancer, but with low specificity at thresholds giving good sensitivity. Previous research identified four single nucleotide polymorphisms (SNPs) principally associated with circulating PSA levels rather than with prostate cancer risk (TERT rs2736098, FGFR2 rs10788160, TBX3 rs11067228, KLK3 rs17632542). Removing the genetic contribution to PSA levels may improve the ability of the remaining biologically-determined variation in PSA to discriminate between high and low risk of progression within men with identified prostate cancer. We investigate whether incorporating information on the PSA-SNPs improves the discrimination achieved by a single PSA threshold in men with raised PSA levels. Materials and Methods Men with PSA between 3-10ng/mL and histologically-confirmed prostate cancer were categorised as high or low risk of progression (Low risk: Gleason score≤6 and stage T1-T2a; High risk: Gleason score 7–10 or stage T2C). We used the combined genetic effect of the four PSA-SNPs to calculate a genetically corrected PSA risk score. We calculated the Area under the Curve (AUC) to determine how well genetically corrected PSA risk scores distinguished men at high risk of progression from low risk men. Results The analysis includes 868 men with prostate cancer (Low risk: 684 (78.8%); High risk: 184 (21.2%)). Receiver operating characteristic (ROC) curves indicate that including the 4 PSA-SNPs does not improve the performance of measured PSA as a screening tool for high/low risk prostate cancer (measured PSA level AU C = 59.5% (95% CI: 54.7,64.2) vs additionally including information from the 4 PSA-SNPs AUC = 59.8% (95% CI: 55.2,64.5) (p-value = 0.40)). Conclusion We demonstrate that genetically correcting PSA for the combined genetic effect of four PSA-SNPs, did not improve discrimination between high and low risk prostate cancer in men with raised PSA levels (3-10ng

  18. Influenza Virus Infects Epithelial Stem/Progenitor Cells of the Distal Lung: Impact on Fgfr2b-Driven Epithelial Repair

    PubMed Central

    Quantius, Jennifer; Schmoldt, Carole; Vazquez-Armendariz, Ana I.; Becker, Christin; El Agha, Elie; Wilhelm, Jochen; Morty, Rory E.; Vadász, István; Mayer, Konstantin; Gattenloehner, Stefan; Fink, Ludger; Matrosovich, Mikhail; Li, Xiaokun; Seeger, Werner; Lohmeyer, Juergen; Bellusci, Saverio; Herold, Susanne

    2016-01-01

    Influenza Virus (IV) pneumonia is associated with severe damage of the lung epithelium and respiratory failure. Apart from efficient host defense, structural repair of the injured epithelium is crucial for survival of severe pneumonia. The molecular mechanisms underlying stem/progenitor cell mediated regenerative responses are not well characterized. In particular, the impact of IV infection on lung stem cells and their regenerative responses remains elusive. Our study demonstrates that a highly pathogenic IV infects various cell populations in the murine lung, but displays a strong tropism to an epithelial cell subset with high proliferative capacity, defined by the signature EpCamhighCD24lowintegrin(α6)high. This cell fraction expressed the stem cell antigen-1, highly enriched lung stem/progenitor cells previously characterized by the signature integrin(β4)+CD200+, and upregulated the p63/krt5 regeneration program after IV-induced injury. Using 3-dimensional organoid cultures derived from these epithelial stem/progenitor cells (EpiSPC), and in vivo infection models including transgenic mice, we reveal that their expansion, barrier renewal and outcome after IV-induced injury critically depended on Fgfr2b signaling. Importantly, IV infected EpiSPC exhibited severely impaired renewal capacity due to IV-induced blockade of β-catenin-dependent Fgfr2b signaling, evidenced by loss of alveolar tissue repair capacity after intrapulmonary EpiSPC transplantation in vivo. Intratracheal application of exogenous Fgf10, however, resulted in increased engagement of non-infected EpiSPC for tissue regeneration, demonstrated by improved proliferative potential, restoration of alveolar barrier function and increased survival following IV pneumonia. Together, these data suggest that tropism of IV to distal lung stem cell niches represents an important factor of pathogenicity and highlight impaired Fgfr2b signaling as underlying mechanism. Furthermore, increase of alveolar Fgf10

  19. Fibroblast Growth Factor (FGF-2) and Its Receptors FGFR-2 and FGFR-3 May Be Putative Biomarkers of Malignant Transformation of Potentially Malignant Oral Lesions into Oral Squamous Cell Carcinoma

    PubMed Central

    Nayak, Seema; Goel, Madhu Mati; Makker, Annu; Bhatia, Vikram; Chandra, Saumya; Kumar, Sandeep; Agarwal, S. P.

    2015-01-01

    There are several factors like angiogenesis, lymphangiogenesis, genetic alterations, mutational factors that are involved in malignant transformation of potentially malignant oral lesions (PMOLs) to oral squamous cell carcinoma (OSCC). Fibroblast growth factor-2 (FGF-2) is one of the prototypes of the large family of growth factors that bind heparin. FGF-2 induces angiogenesis and its receptors may play a role in synthesis of collagen. FGFs are involved in transmission of signals between the epithelium and connective tissue, and influence growth and differentiation of a wide variety of tissue including epithelia. The present study was undertaken to analyze expression of FGF-2 and its receptors FGFR-2 and FGFR-3 in 72 PMOLs, 108 OSCC and 52 healthy controls, and their role in risk assessment for malignant transformation of Leukoplakia (LKP) and Oral submucous fibrosis (OSMF) to OSCC. Immunohistochemistry was performed using antibodies against FGF-2, FGFR-2 and FGFR-3. IHC results were validated by Real Time PCR. Expression of FGF-2, FGFR-2 and FGFR-3 was upregulated from PMOLs to OSCC. While 90% (9/10) of PMOLs which showed malignant transformation (transformed) expressed FGF-2, only 24.19% cases (15/62) of PMOLs which were not transformed (untransformed) to OSCC expressed FGF-2. Similarly, FGFR-2 expression was seen in 16/62 (25.81%) of untransformed PMOLs and 8/10 (80%) cases of transformed PMOLs. FGFR-3 expression was observed in 23/62 (37.10%) cases of untransformed PMOLs and 6/10 (60%) cases of transformed PMOLs. A significant association of FGF-2 and FGFR-2 expression with malignant transformation from PMOLs to OSCC was observed both at phenotypic and molecular level. The results suggest that FGF-2 and FGFR-2 may be useful as biomarkers of malignant transformation in patients with OSMF and LKP. PMID:26465941

  20. Fibroblast Growth Factor (FGF-2) and Its Receptors FGFR-2 and FGFR-3 May Be Putative Biomarkers of Malignant Transformation of Potentially Malignant Oral Lesions into Oral Squamous Cell Carcinoma.

    PubMed

    Nayak, Seema; Goel, Madhu Mati; Makker, Annu; Bhatia, Vikram; Chandra, Saumya; Kumar, Sandeep; Agarwal, S P

    2015-01-01

    There are several factors like angiogenesis, lymphangiogenesis, genetic alterations, mutational factors that are involved in malignant transformation of potentially malignant oral lesions (PMOLs) to oral squamous cell carcinoma (OSCC). Fibroblast growth factor-2 (FGF-2) is one of the prototypes of the large family of growth factors that bind heparin. FGF-2 induces angiogenesis and its receptors may play a role in synthesis of collagen. FGFs are involved in transmission of signals between the epithelium and connective tissue, and influence growth and differentiation of a wide variety of tissue including epithelia. The present study was undertaken to analyze expression of FGF-2 and its receptors FGFR-2 and FGFR-3 in 72 PMOLs, 108 OSCC and 52 healthy controls, and their role in risk assessment for malignant transformation of Leukoplakia (LKP) and Oral submucous fibrosis (OSMF) to OSCC. Immunohistochemistry was performed using antibodies against FGF-2, FGFR-2 and FGFR-3. IHC results were validated by Real Time PCR. Expression of FGF-2, FGFR-2 and FGFR-3 was upregulated from PMOLs to OSCC. While 90% (9/10) of PMOLs which showed malignant transformation (transformed) expressed FGF-2, only 24.19% cases (15/62) of PMOLs which were not transformed (untransformed) to OSCC expressed FGF-2. Similarly, FGFR-2 expression was seen in 16/62 (25.81%) of untransformed PMOLs and 8/10 (80%) cases of transformed PMOLs. FGFR-3 expression was observed in 23/62 (37.10%) cases of untransformed PMOLs and 6/10 (60%) cases of transformed PMOLs. A significant association of FGF-2 and FGFR-2 expression with malignant transformation from PMOLs to OSCC was observed both at phenotypic and molecular level. The results suggest that FGF-2 and FGFR-2 may be useful as biomarkers of malignant transformation in patients with OSMF and LKP. PMID:26465941

  1. Breast cancer susceptibility variants alter risk in familial ovarian cancer.

    PubMed

    Latif, A; McBurney, H J; Roberts, S A; Lalloo, F; Howell, A; Evans, D G; Newman, W G

    2010-12-01

    Recent candidate gene and genome wide association studies have revealed novel loci associated with an increased risk of breast cancer. We evaluated the effect of these breast cancer associated variants on ovarian cancer risk in individuals with familial ovarian cancer both with and without BRCA1 or BRCA2 mutations. A total of 158 unrelated white British women (54 BRCA1/2 mutation positive and 104 BRCA1/2 mutation negative) with familial ovarian cancer were genotyped for FGFR2, TNRC9/TOX3 and CASP8 variants. The p.Asp302His CASP8 variant was associated with reduced ovarian cancer risk in the familial BRCA1/2 mutation negative ovarian cancer cases (P = 0.016). The synonymous TNRC9/TOX3 (Ser51) variant was present at a significantly lower frequency than in patients with familial BRCA1/2 positive breast cancer (P = 0.0002). Our results indicate that variants in CASP8 and TNRC9/TOX3 alter the risk of disease in individuals affected with familial ovarian cancer.

  2. Panel Endorses Active Monitoring for Low-Risk Prostate Cancer

    Cancer.gov

    An independent panel convened this week by NIH has concluded that many men with localized, low-risk prostate cancer should be closely monitored, permitting treatment to be delayed until warranted by disease progression. However, monitoring strategies—such

  3. Frequency of low-risk hospital admissions for heart failure.

    PubMed

    Butler, J; Hanumanthu, S; Chomsky, D; Wilson, J R

    1998-01-01

    Heart failure is one of the most common reasons for admission to acute care hospitals. A proportion of these admissions are probably low risk and could be managed in subacute care facilities, resulting in substantial cost savings. To investigate the proportion of low-risk hospital admissions for heart failure, all admissions for heart failure to Vanderbilt University Medical Center between July 1993 and June 1995 were identified (n = 743). One hundred twenty of these admissions were randomly selected, reviewed, and classified into a high-risk versus low-risk group on admission based on the severity of heart failure and the presence of life-threatening complications. Of the 120 admissions, 57 (48%) were classified as high risk based on the presence of moderate to severe heart failure for the first time or recurrent heart failure with a major complicating factor. Sixteen admissions (28%) were associated with adverse outcomes, including myocardial infarction in 5 (9%), intubation in 6 (11%), and death in 4 (7%). Sixty-three admissions (52%) were classified as low risk based on the presence of new-onset mild heart failure or mild to moderate recurrent heart failure with no complicating factors. Most of these admissions were for dyspnea without any life-threatening complication; 57 (91%) had no evidence of interstitial or alveolar pulmonary edema, and arterial oxygen saturation averaged 95 +/- 3%. Only 3 of these low risk admissions (5%) were associated with an adverse cardiovascular event. None of the patients died. These data suggest that over half of the patients admitted for heart failure to an acute care facility are low risk and probably could be managed in a subacute care setting, resulting in large cost savings. PMID:9462604

  4. MS ANTWERPEN: Emergency Management Training for Low-Risk Environments

    ERIC Educational Resources Information Center

    Strohschneider, Stefan; Gerdes, Jurgen

    2004-01-01

    Emergency management training programs have been developed mostly for trainees from high-risk environments such as aviation or the chemical industry. This article describes a training program for staff members from low-risk environments such as hospitals or hotels, where the awareness of potential dangers is usually low and emergency plans are…

  5. Active surveillance for low-risk prostate cancer.

    PubMed

    Klotz, Laurence

    2015-04-01

    There is ample evidence that low risk and many cases of low-/intermediate-risk prostate cancer, are indolent, have little or no metastatic potential, and do not pose a threat to the patient in his lifetime. Major strides have been made in understanding who these patients are and in encouraging the use of conservative management in such individuals. A component of conservative management is the early identification of those 'low-risk' patients who harbour higher risk disease, and benefit from definitive therapy. This represents about 30% of newly diagnosed low-risk patients. A further small proportion of patients with low-risk disease demonstrate biological progression to higher grade disease. Men with lower risk disease can defer treatment, in most cases for life. Men with higher risk disease that can be localized to a relatively small volume of the prostate can undergo selective therapy. The results of active surveillance, embodying conservative management with selective delayed intervention for the subset who are re-classified as higher risk overtime based on repeat biopsy, imaging or biomarker results have shown that this approach is safe in the intermediate to long term, with a 3% cancer specific mortality at 10-15 years. Further refinement of the surveillance approach is ongoing, incorporating MRI, targeted biopsies and molecular biomarkers.

  6. Cellulase variants

    DOEpatents

    Blazej, Robert; Toriello, Nicholas; Emrich, Charles; Cohen, Richard N.; Koppel, Nitzan

    2015-07-14

    This invention provides novel variant cellulolytic enzymes having improved activity and/or stability. In certain embodiments the variant cellulotyic enzymes comprise a glycoside hydrolase with or comprising a substitution at one or more positions corresponding to one or more of residues F64, A226, and/or E246 in Thermobifida fusca Cel9A enzyme. In certain embodiments the glycoside hydrolase is a variant of a family 9 glycoside hydrolase. In certain embodiments the glycoside hydrolase is a variant of a theme B family 9 glycoside hydrolase.

  7. LOW RISK PROSTATE CANCER: ACTIVE TREATMENT OR ACTIVE SURVEILLANCE?

    PubMed

    Tomašković, Igor

    2015-09-01

    The widely used screening for prostate cancer with prostate specific antigen has resulted in identification of potentially lethal prostate cancers at a much more curable stage and has been associated with significant falls in prostate cancer mortality. In spite of the fact that prostate cancer is one of the deadliest malignancies in men, the advent of sensitive diagnostic testing has also resulted in detection of low risk cancers due to the high incidence of latent prostate cancer in aging men and prolonged natural history of the disease. This, in turn, has entailed the problem of cancer overdiagnosis and subsequent overtreatment. Approximately 6 times as many men will be diagnosed with the disease as will die from it. Active surveillance appeared as a response to the clearly documented risks of overdiagnosis and overtreatment of low risk prostate cancer for localized prostate cancer. It entails initial expectant management rather than immediate therapy, with 'curative-intent' treatment deferred until there is evidence that the patient is at an increased risk of disease progression. This approach attempts to balance the risks and side effects of overtreatment against the possibility of disease progression and lost opportunity for cure. A systematic literature review brings current knowledge on the subject.

  8. Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants.

    PubMed

    Paumard-Hernández, Beatriz; Berges-Soria, Julia; Barroso, Eva; Rivera-Pedroza, Carlos I; Pérez-Carrizosa, Virginia; Benito-Sanz, Sara; López-Messa, Eva; Santos, Fernando; García-Recuero, Ignacio I; Romance, Ana; Ballesta-Martínez, Juliana María; López-González, Vanesa; Campos-Barros, Ángel; Cruz, Jaime; Guillén-Navarro, Encarna; Sánchez Del Pozo, Jaime; Lapunzina, Pablo; García-Miñaur, Sixto; Heath, Karen E

    2015-07-01

    Craniosynostosis, caused by the premature fusion of one or more of the cranial sutures, can be classified into non-syndromic or syndromic and by which sutures are affected. Clinical assignment is a difficult challenge due to the high phenotypic variability observed between syndromes. During routine diagnostics, we screened 182 Spanish craniosynostosis probands, implementing a four-tiered cascade screening of FGFR2, FGFR3, FGFR1, TWIST1 and EFNB1. A total of 43 variants, eight novel, were identified in 113 (62%) patients: 104 (92%) detected in level 1; eight (7%) in level 2 and one (1%) in level 3. We subsequently screened additional genes in the probands with no detected mutation: one duplication of the IHH regulatory region was identified in a patient with craniosynostosis Philadelphia type and five variants, four novel, were identified in the recently described TCF12, in probands with coronal or multisuture affectation. In the 19 Saethre-Chotzen syndrome (SCS) individuals in whom a variant was detected, 15 (79%) carried a TWIST1 variant, whereas four (21%) had a TCF12 variant. Thus, we propose that TCF12 screening should be included for TWIST1 negative SCS patients and in patients where the coronal suture is affected. In summary, a molecular diagnosis was obtained in a total of 119/182 patients (65%), allowing the correct craniosynostosis syndrome classification, aiding genetic counselling and in some cases provided a better planning on how and when surgical intervention should take place and, subsequently the appropriate clinical follow up.

  9. Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants.

    PubMed

    Paumard-Hernández, Beatriz; Berges-Soria, Julia; Barroso, Eva; Rivera-Pedroza, Carlos I; Pérez-Carrizosa, Virginia; Benito-Sanz, Sara; López-Messa, Eva; Santos, Fernando; García-Recuero, Ignacio I; Romance, Ana; Ballesta-Martínez, Juliana María; López-González, Vanesa; Campos-Barros, Ángel; Cruz, Jaime; Guillén-Navarro, Encarna; Sánchez Del Pozo, Jaime; Lapunzina, Pablo; García-Miñaur, Sixto; Heath, Karen E

    2015-07-01

    Craniosynostosis, caused by the premature fusion of one or more of the cranial sutures, can be classified into non-syndromic or syndromic and by which sutures are affected. Clinical assignment is a difficult challenge due to the high phenotypic variability observed between syndromes. During routine diagnostics, we screened 182 Spanish craniosynostosis probands, implementing a four-tiered cascade screening of FGFR2, FGFR3, FGFR1, TWIST1 and EFNB1. A total of 43 variants, eight novel, were identified in 113 (62%) patients: 104 (92%) detected in level 1; eight (7%) in level 2 and one (1%) in level 3. We subsequently screened additional genes in the probands with no detected mutation: one duplication of the IHH regulatory region was identified in a patient with craniosynostosis Philadelphia type and five variants, four novel, were identified in the recently described TCF12, in probands with coronal or multisuture affectation. In the 19 Saethre-Chotzen syndrome (SCS) individuals in whom a variant was detected, 15 (79%) carried a TWIST1 variant, whereas four (21%) had a TCF12 variant. Thus, we propose that TCF12 screening should be included for TWIST1 negative SCS patients and in patients where the coronal suture is affected. In summary, a molecular diagnosis was obtained in a total of 119/182 patients (65%), allowing the correct craniosynostosis syndrome classification, aiding genetic counselling and in some cases provided a better planning on how and when surgical intervention should take place and, subsequently the appropriate clinical follow up. PMID:25271085

  10. Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants

    PubMed Central

    Paumard-Hernández, Beatriz; Berges-Soria, Julia; Barroso, Eva; Rivera-Pedroza, Carlos I; Pérez-Carrizosa, Virginia; Benito-Sanz, Sara; López-Messa, Eva; Santos, Fernando; García-Recuero, Ignacio I; Romance, Ana; Ballesta-Martínez, Juliana María; López-González, Vanesa; Campos-Barros, Ángel; Cruz, Jaime; Guillén-Navarro, Encarna; Sánchez del Pozo, Jaime; Lapunzina, Pablo; García-Miñaur, Sixto; Heath, Karen E

    2015-01-01

    Craniosynostosis, caused by the premature fusion of one or more of the cranial sutures, can be classified into non-syndromic or syndromic and by which sutures are affected. Clinical assignment is a difficult challenge due to the high phenotypic variability observed between syndromes. During routine diagnostics, we screened 182 Spanish craniosynostosis probands, implementing a four-tiered cascade screening of FGFR2, FGFR3, FGFR1, TWIST1 and EFNB1. A total of 43 variants, eight novel, were identified in 113 (62%) patients: 104 (92%) detected in level 1; eight (7%) in level 2 and one (1%) in level 3. We subsequently screened additional genes in the probands with no detected mutation: one duplication of the IHH regulatory region was identified in a patient with craniosynostosis Philadelphia type and five variants, four novel, were identified in the recently described TCF12, in probands with coronal or multisuture affectation. In the 19 Saethre–Chotzen syndrome (SCS) individuals in whom a variant was detected, 15 (79%) carried a TWIST1 variant, whereas four (21%) had a TCF12 variant. Thus, we propose that TCF12 screening should be included for TWIST1 negative SCS patients and in patients where the coronal suture is affected. In summary, a molecular diagnosis was obtained in a total of 119/182 patients (65%), allowing the correct craniosynostosis syndrome classification, aiding genetic counselling and in some cases provided a better planning on how and when surgical intervention should take place and, subsequently the appropriate clinical follow up. PMID:25271085

  11. Fetal heart screening in low-risk pregnancies.

    PubMed

    Rustico, M A; Benettoni, A; D'Ottavio, G; Maieron, A; Fischer-Tamaro, I; Conoscenti, G; Meir, Y; Montesano, M; Cattaneo, A; Mandruzzato, G

    1995-11-01

    The aim of this study was to assess whether a screening program for fetal cardiac malformations is justified in a low-risk population, and which factors influence its accuracy. The fetal heart was evaluated in 7024 pregnant women at 20-22 weeks, and evaluation was repeated at a more advanced gestational age in 9% of cases. Cardiological follow-up was continued postnatally until 2 years of age. The overall prevalence of cardiac anomaly was 0.93%. The incidences of major and minor defects were 0.44% and 0.48%, respectively. There were 23 true positives (0.33%): in 20 cases, the diagnosis was made in the second trimester, and 13 women (65%) chose termination of pregnancy. Seventeen of the 20 cases identified in the second trimester were serious malformations. There were 42 false negatives (0.60%). Of these, 12 had signs of cardiac dysfunction at birth or within the 1st month of life, and three of them died as a result of their cardiac anomaly. There were eight false positives (0.11%), all of a minor type. Six abnormal karyotypes, out of a total of 21 performed in the true-positive group (28.5%), were found. In addition, five of the 42 newborns in the false-negative group had trisomy 21. The overall sensitivity was 35.4%, and 61.3% for major defects. The accuracy in two distinct periods was estimated because the level of experience of the operators was different: sensitivity was 45.2% in period 1 (1986-88) (77.8% for major defects) and 26.5% in period 2 (1989-92) (52.9% for major defects). We conclude that a fetal heart screening program in the obstetric population is justified. It defines a high-risk group for karyotyping, allows planning of delivery in a tertiary center or the choice of terminating the pregnancy for the parents and appears to have a positive cost-benefit ratio. A crucial factor is the level of training and experience of the operators, who need specific teaching support. PMID:8590200

  12. 29 CFR 99.530 - Criteria for a low-risk auditee.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 1 2010-07-01 2010-07-01 true Criteria for a low-risk auditee. 99.530 Section 99.530 Labor Office of the Secretary of Labor AUDITS OF STATES, LOCAL GOVERNMENTS, AND NON-PROFIT ORGANIZATIONS... part. A non-Federal entity that has biennial audits does not qualify as a low-risk auditee,...

  13. Hepatic splenosis diagnosed after inappropriate metastatic evaluation in patient with low-risk prostate cancer.

    PubMed

    Li, Hanhan; Snow-Lisy, Devon; Klein, Eric A

    2012-05-01

    A man interested in active surveillance of low-risk prostate cancer sought a second opinion after having undergone an inappropriate metastatic evaluation that demonstrated multiple enhancing liver masses. Because of his history of splenectomy for trauma, hepatic splenosis was suspected. Despite reassurance, the patient desired biopsy of the masses to confirm splenosis. The imaging features and pathophysiology of hepatic splenosis are presented. Owing to the low rates of metastatic disease, the current guidelines do not recommend diagnostic imaging for low-risk prostate cancer. The present case illustrates the dangers of the current widespread practice of inappropriate diagnostic imaging of patients with low-risk prostate cancer.

  14. Insights and clinical questions about the active surveillance of low-risk papillary thyroid microcarcinomas [Review].

    PubMed

    Ito, Yasuhiro; Oda, Hitomi; Miyauchi, Akira

    2016-04-25

    Over 20 years ago, two Japanese institutions initiated an active surveillance policy for papillary microcarcinomas (PMCs) without high-risk features (such as clinical lymph node and distant metastases) and suspected trachea or recurrent laryngeal nerve invasion. Since the most recent American Thyroid Association (ATA) guidelines adopt active surveillance as a therapy option for low-risk PMCs, the number of institutions worldwide carrying out this policy can be expected to increase. However, before adopting an active surveillance strategy, some important clinical questions must be considered. In this review, conceivable clinical questions with our answers based on the present accumulation of low-risk PMC surveillance data are presented. PMID:26632168

  15. Dispositional Empathy in High- and Low-Risk Parents for Child Physical Abuse.

    ERIC Educational Resources Information Center

    Perez-Albeniz, A.; de Paul, Joaquin

    2003-01-01

    Parents identified as either at high risk (n=36) or low-risk (n=38) for child physical abuse were assessed for dispositional empathy. High-risk parents showed lower total scores on the Hogan Empathy Scale and the Questionnaire Measure of Emotional Empathy. They also scored higher on the Interpersonal Reactivity Index "personal distress" dimension.…

  16. Visual Recognition Memory in High- and Low-Risk Infant Pigtailed Macaques (Macaca Nemestrina).

    ERIC Educational Resources Information Center

    Gunderson, Virginia M.; And Others

    1987-01-01

    Study looks at pigtailed macaque in the context of visual recognition problems adapted from a standardized test developed for use with human infants. Results demonstrate that the low-risk group easily differentiated novel from previously seen targets; the high-risk group gave no evidence of recognition. (Author/RWB)

  17. 48 CFR 1352.237-71 - Security processing requirements-low risk contracts.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Clauses 1352.237-71 Security processing requirements—low risk contracts. As prescribed in 48 CFR 1337.110... for less than 180 days require processing of Form OFI-86C Special Agreement Check (SAC), to be processed. The Sponsor will forward a completed Form OFI-86C, FD-258, Fingerprint Chart, and Credit...

  18. 48 CFR 1352.237-71 - Security processing requirements-low risk contracts.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... DEPARTMENT OF COMMERCE CLAUSES AND FORMS SOLICITATION PROVISIONS AND CONTRACT CLAUSES Text of Provisions and Clauses 1352.237-71 Security processing requirements—low risk contracts. As prescribed in 48 CFR 1337.110... before being eligible to work on the premises of any Department of Commerce owned, leased, or...

  19. Gender Differences in Empathy in Parents at High- and Low-Risk of Child Physical Abuse

    ERIC Educational Resources Information Center

    Perez-Albeniz, A.; de Paul, Joaquin

    2004-01-01

    Objectives: The present research was designed to study empathy in high-risk parents for child physical abuse. The main objective was to study if high-risk mothers and fathers, compared to low-risk mothers and fathers, presented more Personal distress, less Perspective-taking, less Empathic concern and a deficit in dispositional empathy toward…

  20. 48 CFR 1352.237-71 - Security processing requirements-low risk contracts.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Clauses 1352.237-71 Security processing requirements—low risk contracts. As prescribed in 48 CFR 1337.110... processed. The Sponsor will forward a completed Form OFI-86C, FD-258, Fingerprint Chart, and Credit Release... (DCII), FBI Fingerprint (FBIF), and the FBI Information Management Division (FBIN). (5) In addition,...

  1. Hemoglobin variants in Cyprus.

    PubMed

    Kyrri, Andreani R; Felekis, Xenia; Kalogerou, Eleni; Wild, Barbara J; Kythreotis, Loukas; Phylactides, Marios; Kleanthous, Marina

    2009-01-01

    Cyprus, located at the eastern end of the Mediterranean region, has been a place of eastern and western civilizations, and the presence of various hemoglobin (Hb) variants can be considered a testimony to past colonizations of the island. In this study, we report the structural Hb variants identified in the Cypriot population (Greek Cypriots, Maronites, Armenians, and Latinos) during the thalassemia screening of 248,000 subjects carried out at the Thalassaemia Centre, Nicosia, Cyprus, over a period of 26 years. A sample population of 65,668 people was used to determine the frequency and localization of several of the variants identified in Cyprus. The localization of some of the variants in regions where the presence of foreign people was most prevalent provides important clues to the origin of the variants. Twelve structural variants have been identified by DNA sequencing, nine concerning the beta-globin gene and three concerning the alpha-globin gene. The most common beta-globin variants identified were Hb S (0.2%), Hb D-Punjab (0.02%), and Hb Lepore-Washington-Boston (Hb Lepore-WB) (0.03%); the most common alpha-globin variant was Hb Setif (0.1%). The presence of some of these variants is likely to be directly linked to the history of Cyprus, as archeological monuments have been found throughout the island which signify the presence for many years of the Greeks, Syrians, Persians, Arabs, Byzantines, Franks, Venetians, and Turks. PMID:19373583

  2. CT coronary angiography: new risks for low-risk chest pain.

    PubMed

    Radecki, Ryan Patrick

    2013-10-01

    Widespread conservative management of low-risk chest pain has motivated the development of a rapid triage strategy based on CT coronary angiography (CTCA) in the Emergency Department (ED). Recently, three prominent trials using this technology in the ED setting have presented results in support of its routine use. However, these studies fail to show the incremental prognostic value of CTCA over clinical and biomarker-based risk-stratification strategies, demonstrate additional downstream costs and interventions, and result in multiple harms associated with radio-contrast and radiation exposure. Observing the widespread overdiagnosis of pulmonary embolism following availability of CT pulmonary angiogram as a practice pattern parallel, CTCA use for low-risk chest pain in the ED should be advanced only with caution.

  3. An Association of Human Papillomaviruses Low Risk and High Risk Subtypes with Skin Tag

    PubMed Central

    Pezeshkpoor, Fakhrozaman; Jafarian, Amir Hossein; Ghazvini, Kiarash; Yazdanpanah, Mohammad Javad; Sadeghian, Ali; Esmaili, Habiballah; Karrabi, Maryam; Rohani, Fatemeh; Joushan, Bahareh

    2012-01-01

    Objective(s) Human papillomavirus (HPV) infections are related to the genesis of various benign lesions and some malignant tumors, but no clear relationship has been identified so far between the subtypes of HPV and skin tag. Materials and Methods The present case-control study was designed to detect the existence of low risk and high risk HPV types in lesions of 50 patients with skin tag (case group) and normal skin around the melanocytic nevus of 30 patients (control group), using PCR. Results All of the samples were negative for HPV subtypes, except two samples in control group which were positive for high risk HPV. There was no significant relationship between the HPV subtypes and skin tag. Conclusion There is no association between skin tag and low risk and high risk human papillomaviruses. PMID:23493098

  4. Necrotizing fasciitis of anterior abdominal wall following cesarean section in a low-risk patient

    PubMed Central

    Chhetry, Manisha; Banerjee, Basudeb; Subedi, Shanti; Koirala, Ashok

    2016-01-01

    We report a case of a mono-microbial post-cesarean necrotizing fasciitis caused by methicillin resistant Staphylococcus aureus, in a low-risk healthy woman who presented with acute fulminant infection, sepsis and features of multi-organ dysfunction syndrome on sixth post-operative day. Aggressive management with multiple surgical debridement and supportive therapy was the key to favorable outcome in this case. PMID:27402541

  5. Increasing use of observation among men at low risk for prostate cancer mortality

    PubMed Central

    Ritch, Chad R.; Graves, Amy J.; Keegan, Kirk A.; Ni, Shenghua; Bassett, Jeffrey C.; Chang, Sam S.; Resnick, Matthew J.; Penson, David F.; Barocas, Daniel A.

    2015-01-01

    Purpose There are growing concerns regarding the overtreatment of localized prostate cancer. It is also relatively unknown whether there has been increased uptake of observational strategies for disease management. We assessed the temporal trend in use of observation for clinically localized prostate cancer, particularly among men with low-risk disease, who were young and healthy enough to undergo treatment. Materials and Methods We conducted a retrospective cohort study using the Surveillance Epidemiology, and End Results cancer registry linked to Medicare claims (SEER-Medicare database) in 66,499 men with localized prostate cancer between 2004 and 2009. The main outcome was use of observation within one year following diagnosis. We performed multivariable analysis to develop a predictive model for use of observation adjusting for diagnosis year, age, risk and comorbidity. Results Observation was used in 12,007 men (18%) with a slight increase over time from 17% to 20%. However, there was marked increase in the use of observation from 18% in 2004 to 29% in 2009 for men with low-risk disease. Men 66–69 years old, with low-risk disease and no comorbidities, had twice the odds of undergoing observation in 2009 versus 2004 (OR = 2.12; 95% CI = 1.73–2.59). In addition to the diagnosis year, age, risk group, comorbidity and race were independent predictors of undergoing observation (all P<.001). Conclusions We identified increasing use of observation for low-risk prostate cancer between 2004 and 2009, even among men young and healthy enough for treatment, suggesting growing acceptance of surveillance in this group of patients. PMID:25196658

  6. Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer

    PubMed Central

    Guiducci, Candace; Segrè, Ayellet V.; McGee, Kate; McGuffog, Lesley; Kartsonaki, Christiana; Morrison, Jonathan; Healey, Sue; Sinilnikova, Olga M.; Stoppa-Lyonnet, Dominique; Mazoyer, Sylvie; Gauthier-Villars, Marion; Sobol, Hagay; Longy, Michel; Frenay, Marc; GEMO Study Collaborators; Hogervorst, Frans B. L.; Rookus, Matti A.; Collée, J. Margriet; Hoogerbrugge, Nicoline; van Roozendaal, Kees E. P.; Piedmonte, Marion; Rubinstein, Wendy; Nerenstone, Stacy; Van Le, Linda; Blank, Stephanie V.; Caldés, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Lazaro, Conxi; Blanco, Ignacio; Arason, Adalgeir; Johannsson, Oskar T.; Barkardottir, Rosa B.; Devilee, Peter; Olopade, Olofunmilayo I.; Neuhausen, Susan L.; Wang, Xianshu; Fredericksen, Zachary S.; Peterlongo, Paolo; Manoukian, Siranoush; Barile, Monica; Viel, Alessandra; Radice, Paolo; Phelan, Catherine M.; Narod, Steven; Rennert, Gad; Lejbkowicz, Flavio; Flugelman, Anath; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Toland, Amanda E.; Montagna, Marco; D'Andrea, Emma; Friedman, Eitan; Laitman, Yael; Borg, Ake; Beattie, Mary; Ramus, Susan J.; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Tim; Spurdle, Amanda B.; Chen, Xiaoqing; Holland, Helene; John, Esther M.; Hopper, John L.; Buys, Saundra S.; Daly, Mary B.; Southey, Melissa C.; Terry, Mary Beth; Tung, Nadine; Overeem Hansen, Thomas V.; Nielsen, Finn C.; Greene, Mark I.; Mai, Phuong L.; Osorio, Ana; Durán, Mercedes; Andres, Raquel; Benítez, Javier; Weitzel, Jeffrey N.; Garber, Judy; Hamann, Ute; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Platte, Radka; Evans, D. Gareth; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Walker, Lisa; Eason, Jacqueline; Barwell, Julian; Godwin, Andrew K.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engert, Stefanie; Arnold, Norbert; Gadzicki, Dorothea; Dean, Michael; Gold, Bert; Klein, Robert J.; Couch, Fergus J.; Chenevix-Trench, Georgia; Easton, Douglas F.; Daly, Mark J.; Antoniou, Antonis C.; Altshuler, David M.; Offit, Kenneth

    2010-01-01

    The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10−5 and 39 SNPs had p-values<10−4. These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66–0.86, ) and for rs311499 was 0.72 (95% CI 0.61–0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18–1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer. PMID:21060860

  7. [Clinical guideline for management of patients with low risk differentiated thyroid carcinoma].

    PubMed

    Díez, Juan José; Oleaga, Amelia; Álvarez-Escolá, Cristina; Martín, Tomás; Galofré, Juan Carlos

    2015-01-01

    Incidence of thyroid cancer is increasing in Spain and worldwide. Overall thyroid cancer survival is very high, and stratification systems to reliably identify patients with worse prognosis have been developed. However, marked differences exist between the different specialists in clinical management of low-risk patients with thyroid carcinoma. Almost half of all papillary thyroid carcinomas are microcarcinomas, and 90% are tumors < 2 cm that have a particularly good prognosis. However, they are usually treated more aggressively than needed, despite the lack of adequate scientific support. Surgery remains the gold standard treatment for these tumors. However, lobectomy may be adequate in most patients, without the need for total thyroidectomy. Similarly, prophylactic lymph node dissection of the central compartment is not required in most cases. This more conservative approach prevents postoperative complications such as hypoparathyroidism or recurrent laryngeal nerve injury. Postoperative radioiodine remnant ablation and strict suppression of serum thyrotropin, although effective for the more aggressive forms of thyroid cancer, have not been shown to be beneficial for the treatment of low risk patients, and may impair their quality of life. This guideline provides recommendations from the task force on thyroid cancer of the Spanish Society of Endocrinology and Nutrition for adequate management of patients with low-risk thyroid cancer.

  8. Deep venous thrombosis after total hip or knee arthroplasty in a "low-risk" Chinese population.

    PubMed

    Ko, P S; Chan, W F; Siu, T H; Khoo, J; Wu, W C; Lam, J J

    2003-02-01

    Scarcely any information has been published on deep vein thrombosis (DVT) in Chinese patients after total hip arthroplasty (THA) or total knee arthroplasty (TKA). However, generally, no prophylaxis is given to patients who do not have conventional high-risk factors because they are believed to be at "low risk." We performed a prospective study on 80 such "low risk" patients undergoing THA or TKA (58 TKA and 22 THA) without prophylaxis and performed duplex ultrasonography on both lower limbs 6 to 8 days after surgery. A total of 22 patients (27.5%) showed ultrasonographic evidence of DVT. Eighteen (31%) TKAs and 4 (18.1%) THAs were complicated by DVT. Three patients showed bilateral involvement, all of whom underwent TKA. Two patients had symptomatic pulmonary embolism. The sensitivity and positive predictive value of the clinical examination was 27.2% and 31.6%, respectively. This study showed that patients who are labeled "low risk" for DVT actually had a significant risk and suggests that the current practice of providing prophylaxis to only patients deemed at "high risk" should be revised.

  9. [Postoperative radioiodine ablation in patients with low risk differentiated thyroid carcinoma].

    PubMed

    Díez, Juan J; Grande, Enrique; Iglesias, Pedro

    2015-01-01

    Most patients with newly diagnosed differentiated thyroid carcinoma have tumors with low risk of mortality and recurrence. Standard therapy has been total or near total thyroidectomy followed by postoperative radioiodine remnant ablation (RRA). Although RRA provides benefits, current clinical guidelines do not recommend it universally, since an increase in disease-free survival or a decrease in mortality in low risk patients has not been demonstrated so far. Advancements in our understanding of the biological behavior of thyroid cancer have been translated into the clinic in a personalized approach to the patients based on their individual risk of recurrence and mortality. Current evidence suggests that RRA is not indicated in most low-risk patients, especially those with papillary carcinomas smaller than 1cm, without extrathyroidal extension, unfavorable histology, lymph node involvement or distant metastases. Follow-up of these patients with serial measurements of serum thyroglobulin and neck ultrasound is adequate. Careful evaluation of all risk factors of clinical relevance will allow a more realistic assessment of each individual patient.

  10. Prognosis of Low-Risk Young Women Presenting to the Emergency Department With Chest Pain.

    PubMed

    Stauber, Stacey M; Teleten, Aleksander; Li, Zhongmin; Venugopal, Sandhya; Amsterdam, Ezra A

    2016-01-01

    Identification of patients at low risk presenting to the emergency department with chest pain is a continuing challenge. We examined a cohort of low-risk women with negative cardiac injury markers, electrocardiogram with normal results, and clinical stability. We hypothesized that these patients can be safely and accurately managed in a chest pain unit (CPU), may not require predischarge cardiac testing, and have an excellent short-term prognosis. The primary end point was major cardiovascular events during index admission or follow-up. Mean age of the 403 women was 42 ± 4.3 years (30 to 50 years). No patient had a cardiovascular event in the CPU, and none of the 321 patients followed for 6 months had a late cardiovascular event. Most (211, 52%) did not receive predischarge cardiac testing. The remaining 192 patients (48%) had predischarge exercise treadmill test, stress imaging, or cardiac catheterization. Of those patients who underwent treadmill testing, almost 90% had no exercise-induced chest pain and approximately 50% had functional capacity 8 to 14 METs. In addition, 166 patients (41%) were discharged from the CPU after <2 hours and 21% (n = 86) within 2 to 8 hours. In conclusion, this group of low-risk women was safely and accurately managed in the CPU and discharged promptly. There were no cardiac events on index admission or 6-month follow-up, and in most patients, predischarge cardiac testing was unnecessary.

  11. SY 04-1 CVD RISK PREDICTION IN HIGH-RISK VERSUS LOW-RISK POPULATIONS.

    PubMed

    Kim, Hyeon Chang

    2016-09-01

    Disease risk prediction models have been developed to assess the impact of multiple risk factors and to estimate an individual's absolute disease risk. Accurate disease prediction is essential for personalized prevention, because the benefits, risks, and costs of alternative strategies must be weighed to choose the best preventive strategy for individual patients. Cardiovascular disease (CVD) prediction is the earliest example of individual risk predictions. Since the Framingham study reported a CVD risk prediction method in 1976, an increasing number of risk assessment tools have been developed to CVD risk in various settings. The Framingham study results are fundamental evidence for the prediction of CVD risk. However, the clinical utility of a disease prediction model can be population-specific because the baseline disease risk, subtype distribution of the disease, and level of exposure to risk factors differ by region and ethnicity.It has been proved that CVD prediction models which were developed in high-risk populations, such as the Framingham Risk Score, overestimate an individual's disease risk when applied to a low-risk population without re-calibration. Thus countries of relatively low CVD risk are trying to re-calibrate the existing CVD prediction models or to develop a new prediction model analyzing their own population data. However, even the re-calibrated or newly-developed CVD prediction models are often of little clinical value in a low-risk population. A good example is the CVD prediction in the Korean population. Compared to Western populations, the Korean population has much lower incidence of coronary heart disease. Therefore, the vast majority of individuals fall into the low-risk group when their disease risk is assessed with a prediction model. Even a well-validated prediction model may not identify high-risk individuals who merit aggressive preventive treatment.A few alternative approaches have been suggested for CVD risk prediction in a low-risk

  12. Antiplatelet therapy versus observation in low-risk essential thrombocythemia with a CALR mutation

    PubMed Central

    Alvarez-Larrán, Alberto; Pereira, Arturo; Guglielmelli, Paola; Hernández-Boluda, Juan Carlos; Arellano-Rodrigo, Eduardo; Ferrer-Marín, Francisca; Samah, Alimam; Griesshammer, Martin; Kerguelen, Ana; Andreasson, Bjorn; Burgaleta, Carmen; Schwarz, Jiri; García-Gutiérrez, Valentín; Ayala, Rosa; Barba, Pere; Gómez-Casares, María Teresa; Paoli, Chiara; Drexler, Beatrice; Zweegman, Sonja; McMullin, Mary F.; Samuelsson, Jan; Harrison, Claire; Cervantes, Francisco; Vannucchi, Alessandro M.; Besses, Carlos

    2016-01-01

    The role of antiplatelet therapy as primary prophylaxis of thrombosis in low-risk essential thrombocythemia has not been studied in randomized clinical trials. We assessed the benefit/risk of low-dose aspirin in 433 patients with low-risk essential thrombocythemia (271 with a CALR mutation, 162 with a JAK2V617F mutation) who were on antiplatelet therapy or observation only. After a follow up of 2215 person-years free from cytoreduction, 25 thrombotic and 17 bleeding episodes were recorded. In CALR-mutated patients, antiplatelet therapy did not affect the risk of thrombosis but was associated with a higher incidence of bleeding (12.9 versus 1.8 episodes per 1000 patient-years, P=0.03). In JAK2V617F-mutated patients, low-dose aspirin was associated with a reduced incidence of venous thrombosis with no effect on the risk of bleeding. Coexistence of JAK2V617F-mutation and cardiovascular risk factors increased the risk of thrombosis, even after adjusting for treatment with low-dose aspirin (incidence rate ratio: 9.8; 95% confidence interval: 2.3–42.3; P=0.02). Time free from cytoreduction was significantly shorter in CALR-mutated patients with essential thrombocythemia than in JAK2V617F-mutated ones (median time 5 years and 9.8 years, respectively; P=0.0002) and cytoreduction was usually necessary to control extreme thrombocytosis. In conclusion, in patients with low-risk, CALR-mutated essential thrombocythemia, low-dose aspirin does not reduce the risk of thrombosis and may increase the risk of bleeding. PMID:27175028

  13. Unilateral Prostate Cancer Cannot be Accurately Predicted in Low-Risk Patients

    SciTech Connect

    Isbarn, Hendrik; Karakiewicz, Pierre I.; Vogel, Susanne

    2010-07-01

    Purpose: Hemiablative therapy (HAT) is increasing in popularity for treatment of patients with low-risk prostate cancer (PCa). The validity of this therapeutic modality, which exclusively treats PCa within a single prostate lobe, rests on accurate staging. We tested the accuracy of unilaterally unremarkable biopsy findings in cases of low-risk PCa patients who are potential candidates for HAT. Methods and Materials: The study population consisted of 243 men with clinical stage {<=}T2a, a prostate-specific antigen (PSA) concentration of <10 ng/ml, a biopsy-proven Gleason sum of {<=}6, and a maximum of 2 ipsilateral positive biopsy results out of 10 or more cores. All men underwent a radical prostatectomy, and pathology stage was used as the gold standard. Univariable and multivariable logistic regression models were tested for significant predictors of unilateral, organ-confined PCa. These predictors consisted of PSA, %fPSA (defined as the quotient of free [uncomplexed] PSA divided by the total PSA), clinical stage (T2a vs. T1c), gland volume, and number of positive biopsy cores (2 vs. 1). Results: Despite unilateral stage at biopsy, bilateral or even non-organ-confined PCa was reported in 64% of all patients. In multivariable analyses, no variable could clearly and independently predict the presence of unilateral PCa. This was reflected in an overall accuracy of 58% (95% confidence interval, 50.6-65.8%). Conclusions: Two-thirds of patients with unilateral low-risk PCa, confirmed by clinical stage and biopsy findings, have bilateral or non-organ-confined PCa at radical prostatectomy. This alarming finding questions the safety and validity of HAT.

  14. Mucopolysaccharidosis: A New Variant?

    ERIC Educational Resources Information Center

    Primrose, D. A.

    1972-01-01

    Described is a possibly new variant of mucopolysaccharidosis characterized by progressive mental and motor deficiency, bone abnormalities, a generalized skin lesion, and abnormal mucopolysaccharides in the urine as seen in a 20-year-old female. (DB)

  15. Normal Variants in Echocardiography.

    PubMed

    Sanchez, Daniel R; Bryg, Robert J

    2016-11-01

    Echocardiography is a powerful and convenient tool used routinely in the cardiac evaluation of many patients. Improved resolution and visualization of cardiac anatomy has led to the discovery of many normal variant structures that have no known pathologic consequence. Importantly, these findings may masquerade as pathology prompting unnecessary further evaluation at the expense of anxiety, cost, or potential harm. This review provides an updated and comprehensive collection of normal anatomic variants on both transthoracic and transesophageal imaging. PMID:27612473

  16. Elective induction of labour increases caesarean section rate in low risk multiparous women.

    PubMed

    Jacquemyn, Y; Michiels, I; Martens, G

    2012-04-01

    The aim of this study was to compare the risk of secondary caesarean section in induced versus spontaneous labour in the second delivery of low risk women who had a vaginal delivery in their first pregnancy. The data were retrospective cohort from an existing regional database, comparing term (between 37 and 42 gestational weeks) second deliveries in cephalic position in women who had previously given vaginal birth. Diabetes, hypertension and multiple pregnancy were excluded as were those with a birth weight less than 2500 g or more than 4500 g. The difference was not significant when induction was performed after 41 weeks. The results showed a total number of 29693 deliveries were included, 21243 in spontaneous labour and 8450 after induction of labour. In the spontaneous group 312 (1.5%) underwent secondary caesarean section, as compared to 237 (2.8%) in the induced group, p < 0.001, OR 1.93 (95% confidence interval 1.63-2.29). It was concluded that elective induction of labour in low risk women who have previously given vaginal birth is associated with an almost doubled rate of secondary caesarean section if performed before 41 weeks.

  17. Measurement of ethical behavior in leisure among high- and low-risk adolescents.

    PubMed

    Widmer, M A; Ellis, G D; Trunnell, E P

    1996-01-01

    Based on Aristotelian ethics, an "Adolescent Ethical Behavior in Leisure Scale" (AEBLS) was developed. Sixty-two items were created and reviewed by a panel of experts for content-related evidence of validity. Two validity studies were then conducted. In Study 1, data from 419 high- and low-risk adolescents were used to examine correlations between the AEBLS scores and measures of substance use, school bonding, and dispositional leisure boredom. All hypotheses about relations between these variables and the AEBLS were supported. In Study 2, an experiment was conducted to assess construct-related evidence of validity. Seventy-one adolescents completed the AEBLS and evaluated images of sensory and cortical recreation activities to which they were exposed. Consistent with the hypotheses, significant positive correlations were found between the AEBLS and evaluation of cortical activities, and significant negative correlations were found between the AEBLS and evaluation of sensory activities. Results support the use of AEBLS scores to discriminate between ethical leisure behaviors of high- and low-risk adolescents. PMID:8726898

  18. Genetic polymorphisms in the cytokine genes and risk of hepatocellular carcinoma in low-risk non-Asians of USA

    PubMed Central

    Ognjanovic, Simona; Yuan, Jian-Min; Chaptman, Ann K.; Fan, Yunhua; Yu, Mimi C.

    2009-01-01

    Polymorphisms in cytokine genes responsible for inflammatory and immune responses are associated with risk of hepatocellular carcinoma (HCC) in high-risk Chinese population. Similar data in low-risk populations are lacking. A population-based case–control study of HCC was conducted including 120 HCC patients and 230 matched control subjects of non-Asian residents in Los Angeles County, California. Genetic variants in the interferon γ (IFNγ), tumor necrosis factor-α (TNFα), interleukin-2 (IL-2), IL-4, IL-6, IL-10, IL-12 and IL-18 genes were determined by Taqman assays. The logistic regression method was used to analyze the data. For T helper (Th) 1 genes (IFNγ, IL-6 and IL-12), relative to the putative high-activity genotypes, individual low-activity genotypes were associated with statistically non-significant increases in HCC risk. The odds ratio (OR) was 1.53 [95% confidence interval (CI) = 0.53–4.39] for three versus zero low-activity genotypes. For Th2 cytokines (IL-4 and IL-10), low- versus high-activity genotypes were associated with statistically non-significant decreases in HCC risk. The OR was 0.64 (95% CI = 0.27–1.55) for two versus zero low-activity genotypes. When the Th1 and Th2 genotypes were examined simultaneously, the highest level of risk was observed in individuals jointly possessing the highest number of low-activity Th1 genotypes and the lowest number of low-activity Th2 genotypes. There was a roughly doubling of risk between these two extreme genetic profiles, which did not reach statistical significance (OR = 1.98, 95% CI = 0.50–7.84, P = 0.08). In contrast to high-risk Chinese, Th1 and Th2 genotypes did not impact in a major way on risk of HCC in USA non-Asians. PMID:19126646

  19. Identification of de novo copy number variants associated with human disorders of sexual development.

    PubMed

    Tannour-Louet, Mounia; Han, Shuo; Corbett, Sean T; Louet, Jean-Francois; Yatsenko, Svetlana; Meyers, Lindsay; Shaw, Chad A; Kang, Sung-Hae L; Cheung, Sau Wai; Lamb, Dolores J

    2010-01-01

    Disorders of sexual development (DSD), ranging in severity from genital abnormalities to complete sex reversal, are among the most common human birth defects with incidence rates reaching almost 3%. Although causative alterations in key genes controlling gonad development have been identified, the majority of DSD cases remain unexplained. To improve the diagnosis, we screened 116 children born with idiopathic DSD using a clinically validated array-based comparative genomic hybridization platform. 8951 controls without urogenital defects were used to compare with our cohort of affected patients. Clinically relevant imbalances were found in 21.5% of the analyzed patients. Most anomalies (74.2%) evaded detection by the routinely ordered karyotype and were scattered across the genome in gene-enriched subtelomeric loci. Among these defects, confirmed de novo duplication and deletion events were noted on 1p36.33, 9p24.3 and 19q12-q13.11 for ambiguous genitalia, 10p14 and Xq28 for cryptorchidism and 12p13 and 16p11.2 for hypospadias. These variants were significantly associated with genitourinary defects (P = 6.08×10(-12)). The causality of defects observed in 5p15.3, 9p24.3, 22q12.1 and Xq28 was supported by the presence of overlapping chromosomal rearrangements in several unrelated patients. In addition to known gonad determining genes including SRY and DMRT1, novel candidate genes such as FGFR2, KANK1, ADCY2 and ZEB2 were encompassed. The identification of risk germline rearrangements for urogenital birth defects may impact diagnosis and genetic counseling and contribute to the elucidation of the molecular mechanisms underlying the pathogenesis of human sexual development. PMID:21048976

  20. Elective amniocentesis in low-risk pregnancies: decision making in the era of information and uncertainty.

    PubMed Central

    Lesser, Y; Rabinowitz, J

    2001-01-01

    OBJECTIVES: Rational choice theory was applied to explain women's use of amniocentesis. Variables included knowledge about prenatal diagnostics, attitudes, and emotional preferences. METHODS: Using structured instruments at 9 to 14 and at 29 to 34 weeks' gestation, we interviewed 232 Israeli women who had low-risk pregnancies. RESULTS: Women who had elective amniocentesis (n = 39) were more knowledgeable about prenatal diagnostics, risks of invasive procedures, and probability of fetal abnormality in high maternal age; had fewer children; and had less favorable attitudes toward parenthood than those who had medically indicated amniocentesis (n = 57) and those who did not have amniocentesis (n = 136). CONCLUSIONS: The use and possible overuse of amniocentesis were associated with having more information about prenatal diagnostics and definite emotional preferences. PMID:11291381

  1. SY 04-4 HOW TO IMPROVE CVD RISK PREDICTION IN A LOW-RISK POPULATION.

    PubMed

    Chia, Yook Chin

    2016-09-01

    : Many cardiovascular disease (CVD) risk prediction tools have been developed in an attempt to identify those at highest risk in order for them to benefit from interventional treatment. The first CVD risk tool that was developed was the coronary heart disease risk tool by the Framingham Heart Study in 1998 (1). However the Framingham Risk Score could overestimate (or underestimate) risk in populations other than the US population. Hence several other risk engines have also been developed, primarily for a better fit in the communities in which the tools are to be used (2, 3). Having said that the Framingham Heart Study risk tool has been validated in several populations (4, 5) and found to work reasonably well after some recalibration.Most risk prediction tools predict short term risk ie over a period of 10 years but since more recently risk tools now attempt to predict life-time risk or at least risk over the next 30 years. (6-8). The practical use of these risk prediction tools is that it is able to separate those at high risk (ie > 20% risk of a CVD event fatal or non-fatal event in the next 10 years) from those with the lowest risk (< 10% risk over 10 years). It then helps practitioners to triage them to either receive preventive therapy (high risk group) or none at all (low risk group) respectively. However in those with medium risk ie between 10-20%, the decision to offer treatment or not is less clear. In such a situation, other CVD risk factors for example family history of premature coronary heart disease, other biomarkers like elevated hs-CRP, presence of chronic kidney disease or albuminuria can be employed to further stratify risk.It is known that risk prediction tools are very much age dependent and in a younger individual with mildly raised CVD risk factors, his global CVD risk may be grossly under-estimated. Here additional CVD risk factors beyond those traditionally used in risk engines should be sought in order to recalibrate that individual

  2. A Multi-Institutional Evaluation of Active Surveillance for Low-Risk Prostate Cancer

    PubMed Central

    Eggener, Scott E; Mueller, Alex; Berglund, Ryan K; Ayyathurai, Raj; Soloway, Cindy; Soloway, Mark S; Abouassaly, Robert; Klein, Eric A; Jones, Steven J; Zappavigna, Chris; Goldenberg, Larry; Scardino, Peter T; Eastham, James A; Guillonneau, Bertrand

    2014-01-01

    Purpose For select men with low-risk prostate cancer, active surveillance (AS) is more often being considered a management strategy. In a multicenter retrospective study we evaluated the actuarial rates and predictors of remaining on AS, incidence of cancer progression, and pathologic findings of delayed radical prostatectomy. Methods A cohort of 262 men from four institutions met the following inclusion criteria: age ≤75, PSA ≤10 ng/ml, clinical stage T1-T2a, biopsy Gleason sum ≤6, ≤3 positive cores at diagnostic biopsy, a repeat biopsy before AS, and no treatment for six months following the repeat biopsy. AS started on the date of the second biopsy. Actuarial rates of remaining on AS were calculated and univariate Cox regression used to assess predictors of discontinuing AS. Results With a median follow-up of 29 months 43 patients ultimately received active treatment. The two and five-year probabilities of remaining on AS were 91% and 75%, respectively. Patients with cancer on the second biopsy (HR=2.23; 95% CI: 1.23–4.06; p=0.007) and a higher number of cancerous cores from the two biopsies combined (p=0.002) were more likely to undergo treatment. Age, PSA, clinical stage, prostate volume, and number of total biopsy cores sampled were not predictive of outcome. One patient developed skeletal metastases 38 months after starting AS. Of the 43 patients undergoing delayed treatment, 41 (95%) are without disease progression at a median of 23 months following treatment. Conclusions With a median follow-up of 29 months, AS for select patients appears to be safe and associated with a low risk of systemic progression. Cancer at restaging biopsy and a higher total number of cancerous cores are associated with a lower likelihood of remaining on AS. A restaging biopsy should be strongly considered to finalize eligibility for AS. PMID:19233410

  3. [Conservation of erectile function following brachytherapy for low-risk prostate cancer].

    PubMed

    Gilberti, C; Gallo, F; Chiono, L; Gastaldi, E; Ninotta, G; Rosso, G

    2009-01-01

    Brachytherapy (BT) is an effective option to treat low-risk prostate cancer (CaP). While oncological results are consistent with those reported following radical retropubic prostatectomy (RRP), attention may be given to the advantages in terms of functional results that a less invasive approach can ensure. The aim of this study is to assess the impact of the conservation of erectile function (EF) in patients who underwent BT with a short and medium term follow-up. MATERIALS AND METHODS. Between May 1999 and January 2005, 170 patients underwent BT for low-risk CaP (intracapsular prostate cancer, PSA , 10 ng/mL, Gleason score , 6). Among them, 58 patients (average age 65.6) with good preoperative erectile function (IIEF>22) and a minimum follow-up of 5 years were selected. The results were evaluated by comparing the values of pre- and postoperative IIEF questionnaire at 3 months, 1 and 5 years of medium follow-up. RESULTS. At a mean 3-month follow-up, a spontaneous recovery of EF (IIEF> 17), strongly influenced by urinary irritative disorders, was reported by 34/58 patients (58%). At 1 and 5 years, good EF (IIEF >22) was reported by 45/58 (78%) and 39/58 (68%) patients, respectively. DISCUSSION AND CONCLUSIONS. The recovery of EF was good one year after BT (78%). Urinary disorders are a significant limiting factor on this recovery. The deterioration of EF during the follow-up, which was already described in literature, is due not only to ageing but also to a delayed radioactive effect on pelvic structures.

  4. Antenatal Care Utilisation and Content between Low-Risk and High-Risk Pregnant Women

    PubMed Central

    Yeoh, Ping Ling; Hornetz, Klaus; Dahlui, Maznah

    2016-01-01

    Background The purpose of antenatal care is to monitor and improve the wellbeing of the mother and foetus. The World Health Organization recommends risk-oriented strategy that includes: (i) routine care to all women, (ii) additional care for women with moderately severe diseases and complications, (iii) specialised obstetrical and neonatal care for women with severe diseases and complications. Antenatal care is concerned with adequate care in order to be effective. Measurement for adequacy of antenatal care often applies indexes that assess initiation of care and number of visits. In addition, adequacy of care content should also be assessed. Results of studies in developed settings demonstrate that women without risk factors use antenatal services more frequently than recommended. Such over-utilisation is problematic for low-resourced settings. Moreover, studies show that a substantial proportion of high-risk women had utilisation or content of care below the recommended standard. Yet studies in developing countries have seldom included a comparison between low-risk and high-risk women. The purpose of the study was therefore to assess adequacy of care and pregnancy outcomes for the different risk groups. Methods A retrospective study using a multistage sampling technique, at public-funded primary health care clinics was conducted. Antenatal utilisation level was assessed using a modified Adequacy of Prenatal Care Utilisation index that measures the timing for initiation of care and observed-to-expected visits ratio. Adequacy of antenatal care content assessed compliance to routine care based on the local guidelines. Results Intensive or “adequate-plus” antenatal care utilisation as defined by the modified index was noted in over half of the low-risk women. On the other hand, there were 26% of the high-risk women without the expected intensive utilisation. Primary- or non-educated high-risk women were less likely to have a higher antenatal care utilisation

  5. Role of blood cells dynamism on hemostatic complications in low-risk patients with essential thrombocythemia.

    PubMed

    Piccin, Andrea; Steurer, Michael; Mitterer, Manfred; Blöchl, Elisabeth Maria; Marcheselli, Luigi; Pusceddu, Irene; Marabese, Alessandra; Bertozzi, Irene; Corvetta, Daisy; Randi, Maria Luigia; Elli, Elena; Pogliani, Enrico Maria; Veneri, Dino; Perbellini, Omar; Krampera, Mauro; Pacquola, Enrica; Gottardi, Michele; Tiribelli, Mario; Guella, Anna; Innella, Barbara; Vivaldi, Paolo; De Biasi, Ercole; Sancetta, Rosaria; Rocconi, Roberta; Bassan, Renato; Gherlinzoni, Filippo; Pizzolo, Giovanni; Gastl, Günther; Cortelazzo, Sergio

    2015-06-01

    Patients with essential thrombocythemia (ET) aged less than 60 years, who have not suffered a previous vascular event (low-risk patients), may develop thrombotic or hemorrhagic events. So far, it has not been possible to identify useful markers capable of predicting which of these patients are more likely to develop an event and therefore who needs to be treated. In the present study, we analysed the relationship between vascular complications and longitudinal blood counts of 136 low-risk ET patients taken over a sustained period of time (blood cells dynamism). After a median follow-up of 60 months, 45 out of 136 patients (33%) suffered 40 major thrombotic and 5 severe hemorrhagic complications. A total number of 5,781 blood counts were collected longitudinally. Thrombotic and hemorrhagic events were studied together (primary endpoint) but also separately (thrombotic alone = secondary endpoint; hemorrhagic alone = tertiary endpoint). The primary endpoint showed no significant association between platelet and WBC count at diagnosis and risk of any event (platelet, p = 0.797; WBC, p = 0.178), while Hb at baseline did show an association (p = 0.024). In the dynamic analysis with Cox regression model, where the blood count values were studied by time of follow-up, we observed that the risk for Hb was 1.49 (95% CI 1.13-1.97) for every increase of 1 g/dL, and that this risk then marginally decreased during follow-up. WBC was associated with an increased risk at baseline for every increase of 1 × 10(9)/L (hazard ratio (HR) 1.07, 95% CI 1.01-1.13, p = 0.034), the risk was stable during follow-up (HR 0.95, p = 0.187 at 60 months). Also, for each increment at baseline of 100 × 10(9) platelets/L, HR was increased by 1.08 (95% CI 0.97-1.22, p = 0.159) and decreases during follow-up. In conclusion, this study is the first to evaluate in ET low-risk patients, the risk of developing a thrombotic/hemorrhagic event considering blood counts over time. Overall our study shows that

  6. Comparing variation in hospital rates of cesarean delivery among low-risk women using 3 different measures.

    PubMed

    Armstrong, Joanne C; Kozhimannil, Katy B; McDermott, Patricia; Saade, George R; Srinivas, Sindhu K

    2016-02-01

    This report describes the development of a measure of low-risk cesarean delivery by the Society for Maternal-Fetal Medicine (SMFM). Safely lowering the cesarean delivery rate is a priority for maternity care clinicians and health care delivery systems. Therefore, hospital quality assurance programs are increasingly tracking cesarean delivery rates among low-risk pregnancies. Two commonly used definitions of "low risk" are available, the Joint Commission (JC) and the Agency for Healthcare Research and Quality (AHRQ) measures, but these measures are not clinically comprehensive. We sought to refine the definition of the low-risk cesarean delivery rate to enhance the validity of the metric for quality measurement. We created this refined definition-called the SMFM definition-and compared it to the JC and AHRQ measures using claims-based data from the 2011 Nationwide Inpatient Sample of >863,000 births in 612 hospitals. Using these definitions, we calculated means and interquartile ranges (25th-75th percentile range) for hospital low-risk cesarean delivery rates, stratified by hospital size, teaching status, urban/rural location, and payer mix. Across all hospitals, the mean low-risk cesarean delivery rate was lowest for the SMFM definition (12.65%), but not substantially different from the JC and AHRQ measures (13.12% and 13.29%, respectively). We empirically examined the SMFM definition to ensure its validity and utility. This refined definition performs similarly to existing measures and has the added advantage of clinical perspective, enhanced face validity, and ease of use. PMID:26593970

  7. Impact of educational strategies in low-risk prenatal care: systematic review of randomized clinical trials.

    PubMed

    Silva, Esther Pereira da; Lima, Roberto Teixeira de; Osório, Mônica Maria

    2016-09-01

    This study aimed to analyze the impact of educational strategies developed in low-risk prenatal care on obstetric outcomes from a systematic literature review. This review consulted databases PubMed, Medline, SciELO and Lilacs, analyzing randomized clinical trials with the following birth outcomes: birth weight, prematurity and breastfeeding, using the following combination of keywords: pre-natal, antenatal visits, education, health education, pregnancy outcomes, birth weight, prematurity, breastfeeding and randomized clinical trial. Nine studies were included following quality evaluation. Actions prove to be more effective when extended to the postpartum period. Most of them occurred during home visits and had a positive impact on breastfeeding and birth weight. The establishment of groups of pregnant women contributed to lower prevalence of prematurity. Breastfeeding was found to be the outcome most sensitive to educational strategies. Educational practices during the prenatal period contributed to favorable obstetric outcomes as they minimized pregnant women concerns and anxiety during the pregnancy process, preparing them for childbirth and postpartum, and should be incorporated into health services' work process. PMID:27653079

  8. Periodontal disease and some adverse perinatal outcomes in a cohort of low risk pregnant women

    PubMed Central

    2010-01-01

    Objective To evaluate the association of periodontal disease (PD) in pregnancy with some adverse perinatal outcomes. Method This cohort study included 327 pregnant women divided in groups with or without PD. Indexes of plaque and gingival bleeding on probing, probing pocket depth, clinical attachment level and gingival recession were evaluated at one periodontal examination below 32 weeks of gestation. The rates of preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA) neonates and prelabor rupture of membranes (PROM) were evaluated using Risk Ratios (95%CI) and Population Attributable Risk Fractions. Results PD was associated with a higher risk of PTB (RRadj. 3.47 95%CI 1.62-7.43), LBW (RRadj. 2.93 95%CI 1.36-6.34) and PROM (RRadj. 2.48 95%CI 1.35-4.56), but not with SGA neonates (RR 2.38 95%CI 0.93 - 6.10). Conclusions PD was a risk factor for PT, LBW and PROM among Brazilian low risk pregnant women. PMID:21047427

  9. Assessment of Febrile Neonates According to Low Risk Criteria for Serious Bacterial Infection

    PubMed Central

    Zarkesh, Marjaneh; Hashemian, Houman; Momtazbakhsh, Mohammad; Rostami, Tahereh

    2011-01-01

    Objective It is propounded that febrile neonates with low risk criteria (LRC) can be carefully observed without parenteral antimicrobial therapy; but yet, reliability of LRC to exclude serious bacterial infection (SBI) is uncertain. Methods The records of all febrile term neonates, seen in the emergency room and admitted in neonatal ward of 17 Shahrivar children's hospital of Rasht, Iran from January 2004 to January 2009 were reviewed. All of them underwent full sepsis workup. The prevalence of SBI in total population and LRC positive and negative neonates were calculated Findings A total of 202 records of previously healthy febrile neonates were evaluated. SBI was shown in 38 (18.8%). The most common type of SBI was urinary tract infection (UTI). Sixty-two (31%) neonates had LRC, and only one (1.6%) had SBI (UTI with E. coli). SBI was significantly more common in neonates without LRC (26.6% versus 1.6%, P<0.001). The negative predictive value (NPV) of LRC to exclude SBI was 98.4% (95%confidence interval: 96.7% to 100%). Conclusion These findings suggest that LRC may be relied upon to exclude SBI in febrile neonates. We propose that all febrile neonates be admitted, ill or LRC negative neonates should undergo a full sepsis work up and be administered systemic antibiotics immediately. LRC positive neonates should be under close observation. PMID:23056828

  10. Strategies for obstacle crossing in older adults with high and low risk of falling

    PubMed Central

    Pan, Hui-Fen; Hsu, Horng-Chaung; Chang, Wei-Ning; Renn, Jenn-Huei; Wu, Hong-Wen

    2016-01-01

    [Purpose] Tripping is a frequent cause of falls among aging adults. Appropriate limb movements while negotiating obstacles are critical to trip avoidance. The aim of our study was to investigate the mechanics of obstacle crossing in older adults at low or high risk of falling. [Subjects and Methods] Twenty community-dwelling adults aged ≥55 years, were evaluated with the Tinetti Balance and Gait scale and classified as being at high or low risk of falling. Between-group comparisons of kinematics were evaluated for obstacle heights of 10%, 20%, and 30% of leg length. [Results] The high-risk group demonstrated greater toe-obstacle clearance of the leading leg. Increasing obstacle height led to increased maximal toe-obstacle clearance, toe-obstacle distance, and shortened swing phase of the leading limb. Adaptation of clearance height was greater for the trailing leg. Individuals at high risk of falling demonstrated less symmetry between the leading and trailing legs and a narrower step width, features that increase the likelihood of tripping. [Conclusion] Kinematic parameters of obstacle clearance, including the symmetry index described in our study, could provide clinicians with a quick screening tool to identify patients at risk of falling and to evaluate outcomes of training programs. PMID:27313384

  11. Associations of Anogenital Low-Risk Human Papillomavirus Infection With Cancer and Acquisition of HIV.

    PubMed

    Bennetts, Liga E; Wagner, Monika; Giuliano, Anna R; Palefsky, Joel M; Steben, Marc; Weiss, Thomas W

    2015-10-01

    α-Mucosal human papillomavirus (HPV) types are implicated in a range of clinical conditions and categorized as "low-risk" (LR) and "high-risk" (HR) types according to their degree of association with cervical cancers. The causative role of LR HPV infection in the development of anogenital warts and in low-grade squamous intraepithelial lesions is well established. In addition, there is a growing body of evidence that infection with LR HPV types may be associated with an elevated risk of cancers and potentiation of coinfections. Prospective and case-control studies consistently report a higher risk of anogenital cancers in men and women with a history of anogenital warts. Based on currently available evidence, this higher risk may be due to shared exposure to HR HPV types or an underlying immune impairment, rather than a direct role of LR HPV types in subsequent cancer risk. Data also suggest that infection with LR HPV, HR HPV, or both may increase the risk of HIV acquisition, although the relative contribution of different HPV types is not yet known. There is also evidence implicating HPV clearance, rather than HPV infection, in increased risk of HIV acquisition. PMID:26372925

  12. Brain changes in older adults at very low risk for Alzheimer's disease.

    PubMed

    Fjell, Anders M; McEvoy, Linda; Holland, Dominic; Dale, Anders M; Walhovd, Kristine B

    2013-05-01

    Alzheimer's disease (AD) has a slow onset, so it is challenging to distinguish brain changes in healthy elderly persons from incipient AD. One-year brain changes with a distinct frontotemporal pattern have been shown in older adults. However, it is not clear to what extent these changes may have been affected by undetected, early AD. To address this, we estimated 1-year atrophy by magnetic resonance imaging (MRI) in 132 healthy elderly persons who had remained free of diagnosed mild cognitive impairment or AD for at least 3 years. We found significant volumetric reductions throughout the brain. The sample was further divided into low-risk groups based on clinical, biomarker, genetic, or cognitive criteria. Although sample sizes varied, significant reductions were observed in all groups, with rates and topographical distribution of atrophy comparable to that of the full sample. Volume reductions were especially pronounced in the default mode network, closely matching the previously described frontotemporal pattern of changes in healthy aging. Atrophy in the hippocampus predicted change in memory, with no additional default mode network contributions. In conclusion, reductions in regional brain volumes can be detected over the course of 1 year even in older adults who are unlikely to be in a presymptomatic stage of AD.

  13. The characteristics of large bowel cancer in the low-risk black population of the Witwatersrand.

    PubMed

    Boytchev, H; Marcovic, S; Oettle, G J

    1999-12-01

    Sporadic colorectal cancer may follow a different pathogenic pathway in low-risk populations. The black population of the Witwatersrand has been urbanized for a long time, and has a westernized lifestyle, but colorectal cancer is still infrequent. This study aimed to define the characteristics of the disease in this group. All histologically proven large bowel cancers arising in blacks resident in the Witwatersrand in 1991 and 1996 were extracted from the registry records. Mean age was 54.3 years (range 16-90 years); 6% occurred before 30 years and 22% before 40 years. Male:female ratio was 1.32:1. Over three-quarters of the tumours arose in the rectum and sigmoid; there was no evidence of a right-sided preponderance. More than half the cases were advanced at presentation, and nearly one third were mucinous or signet ring on pathological assessment. Associated adenomata were rare (5.2%), suggesting a different pathogenic pathway from the classical adenoma-carcinoma sequence.

  14. Strategies for obstacle crossing in older adults with high and low risk of falling.

    PubMed

    Pan, Hui-Fen; Hsu, Horng-Chaung; Chang, Wei-Ning; Renn, Jenn-Huei; Wu, Hong-Wen

    2016-05-01

    [Purpose] Tripping is a frequent cause of falls among aging adults. Appropriate limb movements while negotiating obstacles are critical to trip avoidance. The aim of our study was to investigate the mechanics of obstacle crossing in older adults at low or high risk of falling. [Subjects and Methods] Twenty community-dwelling adults aged ≥55 years, were evaluated with the Tinetti Balance and Gait scale and classified as being at high or low risk of falling. Between-group comparisons of kinematics were evaluated for obstacle heights of 10%, 20%, and 30% of leg length. [Results] The high-risk group demonstrated greater toe-obstacle clearance of the leading leg. Increasing obstacle height led to increased maximal toe-obstacle clearance, toe-obstacle distance, and shortened swing phase of the leading limb. Adaptation of clearance height was greater for the trailing leg. Individuals at high risk of falling demonstrated less symmetry between the leading and trailing legs and a narrower step width, features that increase the likelihood of tripping. [Conclusion] Kinematic parameters of obstacle clearance, including the symmetry index described in our study, could provide clinicians with a quick screening tool to identify patients at risk of falling and to evaluate outcomes of training programs. PMID:27313384

  15. Malaria morbidity and temperature variation in a low risk Kenyan district: a case of overdiagnosis?

    NASA Astrophysics Data System (ADS)

    Njuguna, John; Muita, James; Mundia, George

    2009-05-01

    Diagnosis of malaria using only clinical means leads to overdiagnosis. This has implications due to safety concerns and the recent introduction of more expensive drugs. Temperature is a major climatic factor influencing the transmission dynamics of malaria. This study looked at trends in malaria morbidity in the low risk Kenyan district of Nyandarua, coupled with data on temperature and precipitation for the years 2003-2006. July had the highest number of cases (12.2% of all cases) followed by August (10.2% of all cases). July and August also had the lowest mean maximum temperatures, 20.1 and 20.2 °C respectively. April, July and August had the highest rainfall, with daily means of 4.0, 4.3 and 4.9 mm, respectively. Observation showed that the coldest months experienced the highest number of cases of malaria. Despite the high rainfall, transmission of malaria tends to be limited by low temperatures due to the long duration required for sporogony, with fewer vectors surviving. These cold months also tend to have the highest number of cases of respiratory infections. There is a possibility that some of these were misdiagnosed as malaria based on the fact that only a small proportion of malaria cases were diagnosed using microscopy or rapid diagnostic tests. We conclude that overdiagnosis may be prevalent in this district and there may be a need to design an intervention to minimise it.

  16. Quantification of fetal magnetoencephalographic activity in low-risk fetuses using burst duration and interburst interval

    PubMed Central

    Vairavan, Srinivasan; Govindan, Rathinaswamy B.; Haddad, Naim; Preissl, Hubert; Lowery, Curtis L.; Siegel, Eric; Eswaran, Hari

    2014-01-01

    Objective To identify quantitative MEG indices of spontaneous brain activity for fetal neurological maturation in normal pregnancies and examine the effect of fetal state on these indices. Methods Spontaneous MEG brain activity was examined in 22 low-risk fetal recordings with gestational age (GA) ranging from 30-37 weeks. As major quantitative characteristics of spontaneous activity, burst duration (BD) and interburst interval (IBI) were studied in correlation with GA and fetal state. Results IBI showed a decrease with gestational age (−0.21 sec/week, P= 0.0031). This trend was only maintained in the quiet-sleep state. With respect to BD, no significant trends were detected with GA and state. Conclusion IBI can be quantified as a fetal brain maturational parameter. The decrease in IBI over gestation was similar to the trend reported in the preterm neonatal EEG studies. Quiet sleep could be the optimal state to study such MEG maturational indices. Significance With further investigation, indices extracted from spontaneous fetal brain activity may serve as an early warning for fetal neurological distress. PMID:24361251

  17. Impact of educational strategies in low-risk prenatal care: systematic review of randomized clinical trials.

    PubMed

    Silva, Esther Pereira da; Lima, Roberto Teixeira de; Osório, Mônica Maria

    2016-09-01

    This study aimed to analyze the impact of educational strategies developed in low-risk prenatal care on obstetric outcomes from a systematic literature review. This review consulted databases PubMed, Medline, SciELO and Lilacs, analyzing randomized clinical trials with the following birth outcomes: birth weight, prematurity and breastfeeding, using the following combination of keywords: pre-natal, antenatal visits, education, health education, pregnancy outcomes, birth weight, prematurity, breastfeeding and randomized clinical trial. Nine studies were included following quality evaluation. Actions prove to be more effective when extended to the postpartum period. Most of them occurred during home visits and had a positive impact on breastfeeding and birth weight. The establishment of groups of pregnant women contributed to lower prevalence of prematurity. Breastfeeding was found to be the outcome most sensitive to educational strategies. Educational practices during the prenatal period contributed to favorable obstetric outcomes as they minimized pregnant women concerns and anxiety during the pregnancy process, preparing them for childbirth and postpartum, and should be incorporated into health services' work process.

  18. Obstetric interventions during labor and childbirth in Brazilian low-risk women.

    PubMed

    Carmo Leal, Maria do; Pereira, Ana Paula Esteves; Domingues, Rosa Maria Soares Madeira; Theme Filha, Mariza Miranda; Dias, Marcos Augusto Bastos; Nakamura-Pereira, Marcos; Bastos, Maria Helena; Gama, Silvana Granado Nogueira da

    2014-08-01

    This study evaluated the use of best practices (eating, movement, use of nonpharmacological methods for pain relief and partograph) and obstetric interventions in labor and delivery among low-risk women. Data from the hospital-based survey Birth in Brazil conducted between 2011 and 2012 was used. Best practices during labor occurred in less than 50% of women and prevalence of the use of these practices was lower in the North, Northeast and Central West Regions. The rate of use of oxytocin drips and amniotomy was 40%, and was higher among women admitted to public hospitals and in women with a low level of education. The uterine fundal pressure, episiotomy and lithotomy were used in 37%, 56% and 92% of women, respectively. Caesarean section rates were lower in women using the public health system, nonwhites, women with a low level of education and multiparous women. To improve the health of mothers and newborns and promote quality of life, a change of approach to labor and childbirth that focuses on evidence-based care is required in both the public and private health sectors.

  19. The role of rHuEpo in low-risk myelodysplastic syndrome patients.

    PubMed

    Rigolin, Gian Matteo; Castoldi, Gianluigi

    2005-06-01

    Myelodysplastic syndromes (MDS) are clonal disorders of the haemopoietic stem cell characterized by peripheral cytopenias that are the result of abnormal haemopoietic differentiation and maturation. Approximately 90% of MDS patients present with anemia at the beginning or during the course of the disease and often require transfusions. The rationale for treating anemic MDS patients with recombinant human erythropoietin (rHuEpo), alone or in combination with other growth factors, is based on the possibility of overcoming the defective proliferation and maturation of erythroid precursors through the inhibition of bone marrow apoptosis, the enhancement of the differentiation of preleukemic progenitor cells or the stimulation of the growth of residual normal haematopoietic cells. Clinical trails have shown that rHuEpo, alone or in combination with recombinant human granulocyte colony-stimulating factor, is a useful drug for the treatment of anemia in low-risk MDS patients, and the same trials have identified patients who are more likely to respond to maximize benefits, to minimize adverse effects, and to avoid misuse or abuse. However, further research is required to determine whether this treatment has any real impact on quality of life and on life expectancy, thus allowing recommendations to be made about rHuEpo use in MDS patients with a degree of certainty. PMID:16019526

  20. Variants of glycoside hydrolases

    DOEpatents

    Teter, Sarah; Ward, Connie; Cherry, Joel; Jones, Aubrey; Harris, Paul; Yi, Jung

    2011-04-26

    The present invention relates to variants of a parent glycoside hydrolase, comprising a substitution at one or more positions corresponding to positions 21, 94, 157, 205, 206, 247, 337, 350, 373, 383, 438, 455, 467, and 486 of amino acids 1 to 513 of SEQ ID NO: 2, and optionally further comprising a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2 a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2, wherein the variants have glycoside hydrolase activity. The present invention also relates to nucleotide sequences encoding the variant glycoside hydrolases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  1. Variants of glycoside hydrolases

    SciTech Connect

    Teter, Sarah; Ward, Connie; Cherry, Joel; Jones, Aubrey; Harris, Paul; Yi, Jung

    2013-02-26

    The present invention relates to variants of a parent glycoside hydrolase, comprising a substitution at one or more positions corresponding to positions 21, 94, 157, 205, 206, 247, 337, 350, 373, 383, 438, 455, 467, and 486 of amino acids 1 to 513 of SEQ ID NO: 2, and optionally further comprising a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2 a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2, wherein the variants have glycoside hydrolase activity. The present invention also relates to nucleotide sequences encoding the variant glycoside hydrolases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  2. Empathic responsiveness and affective reactivity to infant stimuli in high- and low-risk for physical child abuse mothers.

    PubMed

    Milner, J S; Halsey, L B; Fultz, J

    1995-06-01

    Empathic responsiveness and affective reactivity to infant stimuli were examined in matched groups of high- and low-risk for physical child abuse mothers. Hypotheses were generated based on models of aggression and the child abuse literature. Although no between-group differences were found in empathy, within-group differences were observed. Compared to baseline, high-risk mothers reported no change (p > .05) in empathy across infant conditions (baseline, smiling, quiet, and crying), while low-risk mothers reported an increase (p < .0005) in empathy following presentation of the crying infant. Although there was no change in empathy, high-risk mothers reported more sadness, distress, hostility, unhappiness, and less quietness following presentation of the crying infant. Low-risk mothers reported no changes in sadness, distress, and hostility. The data for high-risk mothers are congruent with reports that physical child abusers are less empathic and more hostile in response to a crying child. The findings support aggression models which suggest the lack of empathy and the presence of negative affectivity precede abusive behavior. Post-hoc analyses also provide support for an emotional contagion perspective, where high-risk parents, compared to low-risk parents, are thought to more frequently reflect the emotional state of the infant.

  3. A Comparative Study of Two Groups of Sex Offenders Identified as High and Low Risk on the Static-99

    ERIC Educational Resources Information Center

    Coxe, Ray; Holmes, William

    2009-01-01

    The purpose of this study was to identify possible differences between high- and low-risk sex offenders. The subjects included 285 sex offenders on probation. They were evaluated with the Static-99, Abel Assessment, Raven's, and MMPI-2. A criminal history review identified the number of prior offenses and the age/sex category in the index offense.…

  4. Arguments against Chemoprophylaxis in Areas at Low Risk for Chloroquine-Resistant Plasmodium falciparum.

    PubMed

    Armengaud

    1995-03-01

    Chemoprophylaxis of malaria prevents the disease not the infection (suppressive chemoprophylaxis) with "high levels of confusion and low levels of compliance." The magnitude of danger of contracting malaria for travelers varies in several endemic zones. In West Africa, without prophylaxis, malaria is estimated to have an incidence of 1.4% per person per month. In South and Central America, the incidence is 0.05 and 0.01% per month, respectively. In Asia, the transmission and percentage of infection due to Plasmodium falciparum is much lower. The dangers of chemoprophylaxis in an area at low risk for chloroquine resistant P. falciparum are a reality. Incompletely active drugs change clinical manifestations, and changes in clinical manifestations delay the establishment of a correct diagnosis. The rate of adverse events is 15-20%, and hospitalization due to side effects of prophylaxis occurs in one in 10,000 travelers. Neuropsychiatric side effects have been reported with both mefloquine and chloroquine. A false sense of security can hinder a physician practicing in a nonendemic area from thinking of malaria when a traveler returns with fever. To complicate the picture, in many countries, there is an emerging drug resistance in P. falciparum as well as an emerging chloroquine resistance in P. vivax strains (20% in New Guinea and Irian Jaya). In short, no available chemoprophylaxis is free from toxicity, and its efficacy is never 100%. Alternatives to conventional chemoprophylaxis are encouraged in areas of low morbidity of malaria. In areas where P. vivax occurs primarily, and when the risk of serious side effects from chemoprophylaxis outweighs the risk of life threatening P. falciparum infection, there are four alternative strategies.2,3 The first strategy is that the traveler avoid mosquito bites. With a compulsive attitude, a high degree of protection can be realized with the proper use of pyrethrum-impregnated mosquito netting, topical DEET-containing insect

  5. Applicator-guided volumetric-modulated arc therapy for low-risk endometrial cancer

    SciTech Connect

    Cilla, Savino; Macchia, Gabriella; Sabatino, Domenico; Digesù, Cinzia; Deodato, Francesco; Piermattei, Angelo; De Spirito, Marco; Morganti, Alessio G.

    2013-04-01

    The aim of this study was to report the feasibility of volumetric-modulated arc therapy (VMAT) in the postoperative irradiation of the vaginal vault. Moreover, the VMAT technique was compared with 3D conformal radiotherapy (3D-CRT) and fixed-field intensity-modulated radiotherapy (IMRT), in terms of target coverage and organs at risk sparing. The number of monitor units and the delivery time were analyzed to score the treatment efficiency. All plans were verified in a dedicated solid water phantom using a 2D array of ionization chambers. Twelve patients with endometrial carcinoma who underwent radical hystero-adenexectomy and fixed-field IMRT treatments were retrospectively included in this analysis; for each patient, plans were compared in terms of dose-volume histograms, homogeneity index, and conformity indexes. All techniques met the prescription goal for planning target volume coverage, with VMAT showing the highest level of conformity at all dose levels. VMAT resulted in significant reduction of rectal and bladder volumes irradiated at all dose levels compared with 3D-CRT. No significant differences were found with respect to IMRT. Moreover, a significant improvement of the dose conformity was reached by VMAT technique not only at the 95% dose level (0.74 vs. 0.67 and 0.62) but also at 50% and 75% levels of dose prescription. In addition, VMAT plans showed a significant reduction of monitor units by nearly 28% with respect to IMRT, and reduced treatment time from 11 to <3 minutes for a single 6-Gy fraction. In conclusion, VMAT plans can be planned and carried out with high quality and efficiency for the irradiation of vaginal vault alone, providing similar or better sparing of organs at risk to fixed-field IMRT and resulting in the most efficient treatment option. VMAT is currently our standard approach for radiotherapy of low-risk endometrial cancer.

  6. Clinical decision aids for chest pain in the emergency department: identifying low-risk patients

    PubMed Central

    Alley, William; Mahler, Simon A

    2015-01-01

    Chest pain is one of the most common presenting complaints in the emergency department, though only a small minority of patients are subsequently diagnosed with acute coronary syndrome (ACS). However, missing the diagnosis has potential for significant morbidity and mortality. ACS presentations can be atypical, and their workups are often prolonged and costly. In order to risk-stratify patients and better direct the workup and care given, many decision aids have been developed. While each may have merit in certain clinical settings, the most useful aid in the emergency department is one that finds all cases of ACS while also identifying a substantial subset of patients at low risk who can be discharged without stress testing or coronary angiography. This review describes several of the chest pain decision aids developed and studied through the recent past, starting with the thrombolysis in myocardial infarction (TIMI) risk score and Global Registry of Acute Coronary Events (GRACE) scores, which were developed as prognostic aids for patients already diagnosed with ACS, then subsequently validated in the undifferentiated chest pain population. Asia-Pacific Evaluation of Chest Pain Trial (ASPECT); Accelerated Diagnostic Protocol to Assess Patients With Chest Pain Symptoms Using Contemporary Troponins (ADAPT); North American Chest Pain Rule (NACPR); and History, Electrocardiogram, Age, Risk factors, Troponin (HEART) score have been developed exclusively for use in the undifferentiated chest pain population as well, with improved performance compared to their predecessors. This review describes the relative merits and limitations of these decision aids so that providers can determine which tool fits the needs of their clinical practice setting. PMID:27147894

  7. Preoperative Laboratory Testing in Patients Undergoing Elective, Low-Risk Ambulatory Surgery

    PubMed Central

    Benarroch-Gampel, Jaime; Sheffield, Kristin M.; Duncan, Casey B.; Brown, Kimberly M.; Han, Yimei; Townsend, Courtney M.; Riall, Taylor S.

    2012-01-01

    Background Routine preoperative laboratory testing for ambulatory surgery is not recommended. Methods Patients who underwent elective hernia repair (N = 73,596) were identified from the National Surgical Quality Improvement Program (NSQIP) database (2005–2010). Patterns of preoperative testing were examined. Multivariate analyses were used to identify factors associated with testing and postoperative complications. Results A total of 46,977 (63.8%) patients underwent testing, with at least one abnormal test recorded in 61.6% of patients. In patients with no NSQIP comorbidities (N = 25,149) and no clear indication for testing, 54% received at least one test. In addition, 15.3% of tested patients underwent laboratory testing the day of the operation. In this group, surgery was done despite abnormal results in 61.6% of same day tests. In multivariate analyses, testing was associated with older age, ASA (American Society of Anesthesiologists) class >1, hypertension, ascites, bleeding disorders, systemic steroids, and laparoscopic procedures. Major complications (reintubation, pulmonary embolus, stroke, renal failure, coma, cardiac arrest, myocardial infarction, septic shock, bleeding, or death) occurred in 0.3% of patients. After adjusting for patient and procedure characteristics, neither testing nor abnormal results were associated with postoperative complications. Conclusions Preoperative testing is overused in patients undergoing low-risk, ambulatory surgery. Neither testing nor abnormal results were associated with postoperative outcomes. On the basis of high rates of testing in healthy patients, physician and/or facility preference and not only patient condition currently dictate use. Involvement from surgical societies is necessary to establish guidelines for preoperative testing. PMID:22868362

  8. Costing Alternative Birth Settings for Women at Low Risk of Complications: A Systematic Review

    PubMed Central

    Scarf, Vanessa; Catling, Christine; Viney, Rosalie; Homer, Caroline

    2016-01-01

    Background There is demand from women for alternatives to giving birth in a standard hospital setting however access to these services is limited. This systematic review examines the literature relating to the economic evaluations of birth setting for women at low risk of complications. Methods Searches of the literature to identify economic evaluations of different birth settings of the following electronic databases: MEDLINE, CINAHL, EconLit, Business Source Complete and Maternity and Infant care. Relevant English language publications were chosen using keywords and MeSH terms between 1995 and 2015. Inclusion criteria included studies focussing on the comparison of birth setting. Data were extracted with respect to study design, perspective, PICO principles, and resource use and cost data. Results Eleven studies were included from Australia, Canada, the Netherlands, Norway, the USA, and the UK. Four studies compared costs between homebirth and the hospital setting and the remaining seven focussed on the cost of birth centre care and the hospital setting. Six studies used a cost-effectiveness analysis and the remaining five studies used cost analysis and cost comparison methods. Eight of the 11 studies found a cost saving in the alternative settings. Two found no difference in the cost of the alternative settings and one found an increase in birth centre care. Conclusions There are few studies that compare the cost of birth setting. The variation in the results may be attributable to the cost data collection processes, difference in health systems and differences in which costs were included. A better understanding of the cost of birth setting is needed to inform policy makers and service providers. PMID:26891444

  9. A Low Risk Strategy for the Exploration of Near-Earth Objects

    NASA Technical Reports Server (NTRS)

    Landis, Rob R.

    2011-01-01

    The impetus for asteroid exploration is scientific, political, and pragmatic. The notion of sending human explorers to asteroids is not new. Piloted missions to these primitive bodies were first discussed in the 1960s, pairing Saturn V rockets with enhanced Apollo spacecraft to explore what were then called "Earth-approaching asteroids." Two decades ago, NASA's Space Exploration Initiative (SEI) also briefly examined the possibility of visiting these small celestial bodies. Most recently, the U.S. Human Space Flight Review Committee (the second Augustine Commission) suggested that near-Earth objects (NEOs) represent a target-rich environment for exploration via the "Flexible Path" option. However, prior to seriously considering human missions to NEOs, it has become clear that we currently lack a robust catalog of human accessible targets. The majority of the NEOs identified by a study team across several NASA centers as "human-accessible" are probably too small and have orbits that are too uncertain to consider mounting piloted expeditions to these small worlds. The first step in developing such a catalog is, therefore, to complete a space-based NEO survey. The resulting catalog of candidate NEOs would then be transformed into a matrix of opportunities for robotic and human missions for the next several decades. This initial step of a space-based NEO survey first is the linchpin to laying the foundation of a low-risk architecture to venture out and explore these primitive bodies. We suggest such a minimalist framework architecture from 1) extensive ground-based and precursor spacecraft investigations (while applying operational knowledge from science-driven robotic missions), 2) astronaut servicing of spacecraft operating at geosynchronous Earth orbit to retain essential skills and experience, and 3) applying the sum of these skills, knowledge and experience to piloted missions to NEOs.

  10. Analysis of expanded criteria to select candidates for active surveillance of low-risk prostate cancer

    PubMed Central

    Jo, Jung Ki; Lee, Han Sol; Lee, Young Ik; Lee, Sang Eun; Hong, Sung Kyu

    2015-01-01

    We aimed to analyze the value of each criterion for clinically insignificant prostate cancer (PCa) in the selection of men for active surveillance (AS) of low-risk PCa. We identified 532 men who were treated with radical prostatectomy from 2006 to 2013 who met 4 or all 5 of the criteria for clinically insignificant PCa (clinical stage ≤ T1, prostate specific antigen [PSA] density ≤ 0.15, biopsy Gleason score ≤ 6, number of positive biopsy cores ≤ 2, and no core with > 50% involvement) and analyzed their pathologic and biochemical outcomes. Patients who met all 5 criteria for clinically insignificant PCa were designated as group A (n = 172), and those who met 4 of 5 criteria were designated as group B (n = 360). The association of each criterion with adverse pathologic features was assessed via logistic regression analyses. Comparison of group A and B and also logistic regression analyses showed that PSA density > 0.15 ng ml−1 and high (≥7) biopsy Gleason score were associated with adverse pathologic features. Higher (> T1c) clinical stage was not associated with any adverse pathologic features. Although ≤ 3 positive cores were not associated with any adverse pathology, ≥4 positive cores were associated with higher risk of extracapsular extension. Among potential candidates for AS, PSA density > 0.15 ng ml−1 and biopsy Gleason score > 6 pose significantly higher risks of harboring more aggressive disease. The eligibility criteria for AS may be expanded to include men with clinical stage T2 tumor and 3 positive cores. PMID:25432498

  11. Portrayal of Alcohol Consumption in Movies and Drinking Initiation in Low-Risk Adolescents

    PubMed Central

    Sargent, James D.; Hunt, Kate; Sweeting, Helen; Engels, Rutger C.M.E.; Scholte, Ron H.J.; Mathis, Federica; Florek, Ewa; Morgenstern, Matthis

    2014-01-01

    OBJECTIVES: To investigate the hypothesis that exposure to alcohol consumption in movies affects the likelihood that low-risk adolescents will start to drink alcohol. METHODS: Longitudinal study of 2346 adolescent never drinkers who also reported at baseline intent to not to do so in the next 12 months (mean age 12.9 years, SD = 1.08). Recruitment was carried out in 2009 and 2010 in 112 state-funded schools in Germany, Iceland, Italy, Netherlands, Poland, and Scotland. Exposure to movie alcohol consumption was estimated from 250 top-grossing movies in each country in the years 2004 to 2009. Multilevel mixed-effects Poisson regressions assessed the relationship between baseline exposure to movie alcohol consumption and initiation of trying alcohol, and binge drinking (≥ 5 consecutive drinks) at follow-up. RESULTS: Overall, 40% of the sample initiated alcohol use and 6% initiated binge drinking by follow-up. Estimated mean exposure to movie alcohol consumption was 3653 (SD = 2448) occurrences. After age, gender, family affluence, school performance, TV screen time, personality characteristics, and drinking behavior of peers, parents, and siblings were controlled for, exposure to each additional 1000 movie alcohol occurrences was significantly associated with increased relative risk for trying alcohol, incidence rate ratio = 1.05 (95% confidence interval, 1.02–1.08; P = .003), and for binge drinking, incidence rate ratio = 1.13 (95% confidence interval, 1.06–1.20; P < .001). CONCLUSIONS: Seeing alcohol depictions in movies is an independent predictor of drinking initiation, particularly for more risky patterns of drinking. This result was shown in a heterogeneous sample of European youths who had a low affinity for drinking alcohol at the time of exposure. PMID:24799536

  12. Analysis of expanded criteria to select candidates for active surveillance of low-risk prostate cancer.

    PubMed

    Jo, Jung Ki; Lee, Han Sol; Lee, Young Ik; Lee, Sang Eun; Hong, Sung Kyu

    2015-01-01

    We aimed to analyze the value of each criterion for clinically insignificant prostate cancer (PCa) in the selection of men for active surveillance (AS) of low-risk PCa. We identified 532 men who were treated with radical prostatectomy from 2006 to 2013 who met 4 or all 5 of the criteria for clinically insignificant PCa (clinical stage ≤ T1, prostate specific antigen [PSA] density ≤ 0.15, biopsy Gleason score ≤ 6, number of positive biopsy cores ≤ 2, and no core with > 50% involvement) and analyzed their pathologic and biochemical outcomes. Patients who met all 5 criteria for clinically insignificant PCa were designated as group A (n = 172), and those who met 4 of 5 criteria were designated as group B (n = 360). The association of each criterion with adverse pathologic features was assessed via logistic regression analyses. Comparison of group A and B and also logistic regression analyses showed that PSA density > 0.15 ng ml-1 and high (≥7) biopsy Gleason score were associated with adverse pathologic features. Higher (> T1c) clinical stage was not associated with any adverse pathologic features. Although ≤ 3 positive cores were not associated with any adverse pathology, ≥4 positive cores were associated with higher risk of extracapsular extension. Among potential candidates for AS, PSA density > 0.15 ng ml-1 and biopsy Gleason score > 6 pose significantly higher risks of harboring more aggressive disease. The eligibility criteria for AS may be expanded to include men with clinical stage T2 tumor and 3 positive cores.

  13. Utilization of prostate brachytherapy for low risk prostate cancer: Is the decline overstated?

    PubMed Central

    Wong, Andrew; Weiner, Joseph P.; Schwartz, David; Schreiber, David

    2016-01-01

    Purpose Several prior studies have suggested that brachytherapy utilization has markedly decreased, coinciding with the recent increased utilization of intensity modulated radiation therapy, as well as an increase in urologist-owned centers. We sought to investigate the brachytherapy utilization in a large, hospital-based registry. Material and methods Men with prostate cancer diagnosed between 2004-2012 and treated with either external beam radiation and/or prostate brachytherapy were abstracted from the National Cancer Database. In order to be included, men had to be clinically staged as T1c-T2aNx-0Mx-0, Gleason 6, PSA ≤ 10.0 ng/ml. Descriptive statistics were used to analyze brachytherapy utilization over time and were compared via χ2. Multivariate logistic regression was used to assess for covariables associated with increased brachytherapy usage. Results There were 89,413 men included in this study, of which 37,054 (41.6%) received only external beam radiation, and 52,089 (58.4%) received prostate brachytherapy. The use of brachytherapy declined over time from 62.9% in 2004 to 51.3% in 2012 (p < 0.001). This decline was noted in both academic facilities (60.8% in 2004 to 47.0% in 2012, p < 0.001) as well as in non-academic facilities (63.7% in 2004 to 53.0% in 2012, p < 0.001). The decline was more pronounced in patients who lived closer to treatment facilities than those who lived further. The use of intensity modulated radiation therapy increased during this same time period from 18.4% in 2004 to 38.2% in 2012 (p < 0.001). On multivariate analysis, treatment at an academic center, increasing age, decreasing distance from the treatment center, and years of diagnosis from 2006-2012 were significantly associated with reduced brachytherapy usage. Conclusions In this hospital-based registry, prostate brachytherapy usage has declined for low risk prostate cancer as intensity modulated radiation therapy usage has increased. However, it still remains the

  14. Utilization of prostate brachytherapy for low risk prostate cancer: Is the decline overstated?

    PubMed Central

    Wong, Andrew; Weiner, Joseph P.; Schwartz, David; Schreiber, David

    2016-01-01

    Purpose Several prior studies have suggested that brachytherapy utilization has markedly decreased, coinciding with the recent increased utilization of intensity modulated radiation therapy, as well as an increase in urologist-owned centers. We sought to investigate the brachytherapy utilization in a large, hospital-based registry. Material and methods Men with prostate cancer diagnosed between 2004-2012 and treated with either external beam radiation and/or prostate brachytherapy were abstracted from the National Cancer Database. In order to be included, men had to be clinically staged as T1c-T2aNx-0Mx-0, Gleason 6, PSA ≤ 10.0 ng/ml. Descriptive statistics were used to analyze brachytherapy utilization over time and were compared via χ2. Multivariate logistic regression was used to assess for covariables associated with increased brachytherapy usage. Results There were 89,413 men included in this study, of which 37,054 (41.6%) received only external beam radiation, and 52,089 (58.4%) received prostate brachytherapy. The use of brachytherapy declined over time from 62.9% in 2004 to 51.3% in 2012 (p < 0.001). This decline was noted in both academic facilities (60.8% in 2004 to 47.0% in 2012, p < 0.001) as well as in non-academic facilities (63.7% in 2004 to 53.0% in 2012, p < 0.001). The decline was more pronounced in patients who lived closer to treatment facilities than those who lived further. The use of intensity modulated radiation therapy increased during this same time period from 18.4% in 2004 to 38.2% in 2012 (p < 0.001). On multivariate analysis, treatment at an academic center, increasing age, decreasing distance from the treatment center, and years of diagnosis from 2006-2012 were significantly associated with reduced brachytherapy usage. Conclusions In this hospital-based registry, prostate brachytherapy usage has declined for low risk prostate cancer as intensity modulated radiation therapy usage has increased. However, it still remains the

  15. Early sac shrinkage predicts a low risk of late complications after endovascular aortic aneurysm repair

    PubMed Central

    Bastos Gonçalves, F; Baderkhan, H; Verhagen, H J M; Wanhainen, A; Björck, M; Stolker, R J; Hoeks, S E; Mani, K

    2014-01-01

    Background Aneurysm shrinkage has been proposed as a marker of successful endovascular aneurysm repair (EVAR). Patients with early postoperative shrinkage may experience fewer subsequent complications, and consequently require less intensive surveillance. Methods Patients undergoing EVAR from 2000 to 2011 at three vascular centres (in 2 countries), who had two imaging examinations (postoperative and after 6–18 months), were included. Maximum diameter, complications and secondary interventions during follow-up were registered. Patients were categorized according to early sac dynamics. The primary endpoint was freedom from late complications. Secondary endpoints were freedom from secondary intervention, postimplant rupture and direct (type I/III) endoleaks. Results Some 597 EVARs (71·1 per cent of all EVARs) were included. No shrinkage was observed in 284 patients (47·6 per cent), moderate shrinkage (5–9 mm) in 142 (23·8 per cent) and major shrinkage (at least 10 mm) in 171 patients (28·6 per cent). Four years after the index imaging, the rate of freedom from complications was 84·3 (95 per cent confidence interval 78·7 to 89·8), 88·1 (80·6 to 95·5) and 94·4 (90·1 to 98·7) per cent respectively. No shrinkage was an independent risk factor for late complications compared with major shrinkage (hazard ratio (HR) 3·11; P < 0·001). Moderate compared with major shrinkage (HR 2·10; P = 0·022), early postoperative complications (HR 3·34; P < 0·001) and increasing abdominal aortic aneurysm baseline diameter (HR 1·02; P = 0·001) were also risk factors for late complications. Freedom from secondary interventions and direct endoleaks was greater for patients with major sac shrinkage. Conclusion Early change in aneurysm sac diameter is a strong predictor of late complications after EVAR. Patients with major sac shrinkage have a very low risk of complications for up to 5 years. This parameter may be used to tailor postoperative surveillance. PMID:24752772

  16. Identification of Patients at Very Low Risk of Local Recurrence After Breast-Conserving Surgery

    SciTech Connect

    Smith, Sally L.; Truong, Pauline T.; Lu, Linghong; Lesperance, Mary; Olivotto, Ivo A.

    2014-07-01

    Purpose: To identify clinical and pathological factors that identify groups of women with stage I breast cancer with a 5-year risk of local recurrence (LR) ≤1.5% after breast-conserving therapy (BCS) plus whole-breast radiation therapy (RT). Methods and Materials: Study subjects were 5974 patients ≥50 years of age whose cancer was diagnosed between 1989 and 2006, and were referred with pT1 pN0 invasive breast cancer treated with BCS and RT. Cases of 5- and 10-year LR were examined using Kaplan-Meier methods. Recursive partitioning analysis was performed in patients treated with and without endocrine therapy to identify combinations of factors associated with a 5-year LR risk ≤1.5%. Results: The median follow-up was 8.61 years. Median age was 63 years of age (range, 50 to 91). Overall 5-year LR was 1.5% (95% confidence interval [CI], 1.2%-1.9%) and 10-year LR was 3.4% (95% CI, 2.8%-4.0%). Of 2830 patients treated with endocrine therapy, patient subsets identified with 5-year LR ≤1.5% included patients with grade 1 histology (n=1038; LR, 0.2%; 95% CI, 0%-0.5%) or grade 2 histology plus ≥60 years of age (n=843; LR, 0.5%; 95% CI, 0%-1.0%). Ten-year LR for these groups were 0.8% (95% CI, 0.1%-1.6%) and 0.9% (95% CI, 0.2%-1.6%), respectively. Of 3144 patients treated without endocrine therapy, patients with grade 1 histology plus clear margins had 5-year LR ≤1.5% (n=821; LR, 0.6%; 95% CI, 0.1%-1.2%). Ten-year LR for this group was 2.2% (95% CI, 1.0%-3.4%). Conclusions: Histologic grade, age, margin status, and use of endocrine therapy identified 45% of a population-based cohort of female patients over age 50 with stage I breast cancer with a 5-year LR risk ≤1.5% after BCS plus RT. Prospective study is needed to evaluate the safety of omitting RT in patients with such a low risk of LR.

  17. Impact of Relative Contraindications to Home Management in Emergency Department Patients with Low-Risk Pulmonary Embolism

    PubMed Central

    Drenten, Carrieann E.; Huang, Jie; Morley, J. Eileen; Anderson, Megan L.; Reed, Mary E.; Nishijima, Daniel K.; Liu, Vincent

    2015-01-01

    Rationale: Studies of adults presenting to the emergency department (ED) with acute pulmonary embolism (PE) suggest that those who are low risk on the PE Severity Index (classes I and II) can be managed safely without hospitalization. However, the impact of relative contraindications to home management on outcomes has not been described. Objectives: To compare 5-day and 30-day adverse event rates among low-risk ED patients with acute PE without and with outpatient ineligibility criteria. Methods: We conducted a retrospective multicenter cohort study of adults presenting to the ED with acute low-risk PE between 2010 and 2012. We evaluated the association between outpatient treatment eligibility criteria based on a comprehensive list of relative contraindications and 5-day adverse events and 30-day outcomes, including major hemorrhage, recurrent venous thromboembolism, and all-cause mortality. Measurements and Main Results: Of 423 adults with acute low-risk PE, 271 (64.1%) had no relative contraindications to outpatient treatment (outpatient eligible), whereas 152 (35.9%) had at least one contraindication (outpatient ineligible). Relative contraindications were categorized as PE-related factors (n = 112; 26.5%), comorbid illness (n = 42; 9.9%), and psychosocial barriers (n = 19; 4.5%). There were no 5-day events in the outpatient-eligible group (95% upper confidence limit, 1.7%) and two events (1.3%; 95% confidence interval [CI], 0.1–5.0%) in the outpatient-ineligible group (P = 0.13). At 30 days, there were five events (two recurrent venous thromboemboli and three major bleeding events) in the outpatient-eligible group (1.8%; 95% CI, 0.7–4.4%) compared with nine in the ineligible group (5.9%; 95% CI, 2.7–10.9%; P < 0.05). This difference remained significant when controlling for PE severity class. Conclusions: Nearly two-thirds of adults presenting to the ED with low-risk PE were potentially eligible for outpatient therapy. Relative

  18. How to avoid venous thromboembolism in women at increased risk--with special focus on low-risk periods.

    PubMed

    Lindqvist, Pelle G; von Känel, Roland

    2015-09-01

    Venous thromboembolism (VTE) is a major cause of mortality during Western women's fertile life. Although half of thromboembolic events occur during times of low-risk situations, almost all our knowledge is focused on medical thromboprophylaxis during high-risk situations. Thus, since we only use medical thromboprophylaxis at high-risk periods, lifestyle advice could be an attractive complement both during high- and low-risk situations. The knowledge of how lifestyle factors affect VTE risk has grown in recent years, and women at high risk are often highly motivated to make changes in order to reduce their risk. This review is focused on modifiable risk factors for VTE and advice that may be given to women at increased risk of VTE.

  19. Variants of windmill nystagmus.

    PubMed

    Choi, Kwang-Dong; Shin, Hae Kyung; Kim, Ji-Soo; Kim, Sung-Hee; Choi, Jae-Hwan; Kim, Hyo-Jung; Zee, David S

    2016-07-01

    Windmill nystagmus is characterized by a clock-like rotation of the beating direction of a jerk nystagmus suggesting separate horizontal and vertical oscillators, usually 90° out of phase. We report oculographic characteristics in three patients with variants of windmill nystagmus in whom the common denominator was profound visual loss due to retinal diseases. Two patients showed a clock-like pattern, while in the third, the nystagmus was largely diagonal (in phase or 180° out of phase) but also periodically changed direction by 180°. We hypothesize that windmill nystagmus is a unique manifestation of "eye movements of the blind." It emerges when the central structures, including the cerebellum, that normally keep eye movements calibrated and gaze steady can no longer perform their task, because they are deprived of the retinal image motion that signals a need for adaptive recalibration.

  20. Variants of windmill nystagmus.

    PubMed

    Choi, Kwang-Dong; Shin, Hae Kyung; Kim, Ji-Soo; Kim, Sung-Hee; Choi, Jae-Hwan; Kim, Hyo-Jung; Zee, David S

    2016-07-01

    Windmill nystagmus is characterized by a clock-like rotation of the beating direction of a jerk nystagmus suggesting separate horizontal and vertical oscillators, usually 90° out of phase. We report oculographic characteristics in three patients with variants of windmill nystagmus in whom the common denominator was profound visual loss due to retinal diseases. Two patients showed a clock-like pattern, while in the third, the nystagmus was largely diagonal (in phase or 180° out of phase) but also periodically changed direction by 180°. We hypothesize that windmill nystagmus is a unique manifestation of "eye movements of the blind." It emerges when the central structures, including the cerebellum, that normally keep eye movements calibrated and gaze steady can no longer perform their task, because they are deprived of the retinal image motion that signals a need for adaptive recalibration. PMID:27159990

  1. An alternate low risk technique for esophageal transection in the Sugiura-Futagawa procedure.

    PubMed

    Mercado, M A; Takahashi, T; Orozco, H

    1993-07-01

    The Sugiura-Futagawa procedure is an effective non-shunting operation to treat bleeding esophageal varices. The goal of the esophageal transection is the interruption of submucosal varices. The rate of esophageal fistula reported after transection is 5 to 8 per cent. This complication has high morbidity and mortality rates. The technique and results of an alternate variant of the esophageal transection are described. After devascularization of the esophagus is achieved, the anterior muscular layer is opened, and the entire mucosal cylinder is dissected free from the muscular layer. Without opening the mucosa, a circumferential continuous running suture with fine non-absorbable material is placed, involving both mucosa and submucosa, interrupting the varicose veins. Our experience with this technique has been encouraging, having observed no stenosis or fistulization in 10 patients on whom we operated. Re-bleeding rate is low (10% in this series). The advantages of this modification are: 1) since we do not cut open the mucosal layer, we believe that the risk of fistulization is reduced, and 2) it allows an early initiation of oral feeding, thus reducing the hospital stay.

  2. Evidence that putative ADHD low risk alleles at SNAP25 may increase the risk of schizophrenia.

    PubMed

    Carroll, L S; Kendall, K; O'Donovan, M C; Owen, M J; Williams, N M

    2009-10-01

    Synaptosomal Associated Protein 25 kDa (SNAP25) has been implicated in the pathogenesis of schizophrenia by numerous neuropathological studies and genetic variation at SNAP25 has been reported to be associated with ADHD. Expression levels of the putative schizophrenia susceptibility gene DTNBP1 has been shown to influence the levels of SNAP25 in vitro. We undertook directed mutation screening of SNAP25 in UK schizophrenic cases followed by direct association analysis of all variants identified and identified known exonic SNPs that showed evidence for association (rs3746544 P = 0.004 OR = 1.26, rs8636 P = 0.003 OR = 1.27), although these SNPs are highly correlated (r(2) > 0.99). We additionally genotyped a further 31 tag SNPs spanning the SNAP25 locus and identified several independent SNPs that were nominally associated with schizophrenia (strongest association at rs3787283, P = 0.006, OR = 1.25) however, due to the number of tests performed no SNP met experiment-wise significance (minimum permuted P-value = 0.1). Post hoc analysis revealed that the SNPs nominally associated with schizophrenia (rs3787283, rs3746544) were the same as those previously demonstrated to be associated with ADHD but with the opposite alleles, allowing the intriguing hypothesis that genetic variation at SNAP25 may be differentially associated with both schizophrenia and ADHD. PMID:19132710

  3. Alternative versus standard packages of antenatal care for low-risk pregnancy

    PubMed Central

    Dowswell, Therese; Carroli, Guillermo; Duley, Lelia; Gates, Simon; Gülmezoglu, A Metin; Khan-Neelofur, Dina; Piaggio, Gilda GP

    2014-01-01

    Background The number of visits for antenatal (prenatal) care developed without evidence of how many visits are necessary. The content of each visit also needs evaluation. Objectives To compare the effects of antenatal care programmes with reduced visits for low-risk women with standard care. Search methods We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (April 2010), reference lists of articles and contacted researchers in the field. Selection criteria Randomised trials comparing a reduced number of antenatal visits, with or without goal-oriented care, with standard care. Data collection and analysis Two authors assessed trial quality and extracted data independently. Main results We included seven trials (more than 60,000 women): four in high-income countries with individual randomisation; three in low- and middle-income countries with cluster randomisation (clinics as the unit of randomisation). The number of visits for standard care varied, with fewer visits in low- and middle- income country trials. In studies in high-income countries, women in the reduced visits groups, on average, attended between 8.2 and 12 times. In low- and middle- income country trials, many women in the reduced visits group attended on fewer than five occasions, although in these trials the content as well as the number of visits was changed, so as to be more ‘goal oriented’. Perinatal mortality was increased for those randomised to reduced visits rather than standard care, and this difference was borderline for statistical significance (five trials; risk ratio (RR) 1.14; 95% confidence interval (CI) 1.00 to 1.31). In the subgroup analysis, for high-income countries the number of deaths was small (32/5108), and there was no clear difference between the groups (2 trials; RR 0.90; 95% CI 0.45 to 1.80); for low- and middle-income countries perinatal mortality was significantly higher in the reduced visits group (3 trials RR 1.15; 95% CI 1.01 to 1

  4. The role of genetic breast cancer susceptibility variants as prognostic factors

    PubMed Central

    Fasching, Peter A.; Pharoah, Paul D.P.; Cox, Angela; Nevanlinna, Heli; Bojesen, Stig E.; Karn, Thomas; Broeks, Annegien; van Leeuwen, Flora E.; van 't Veer, Laura J.; Udo, Renate; Dunning, Alison M.; Greco, Dario; Aittomäki, Kristiina; Blomqvist, Carl; Shah, Mitul; Nordestgaard, Børge G.; Flyger, Henrik; Hopper, John L.; Southey, Melissa C.; Apicella, Carmel; Garcia-Closas, Montserrat; Sherman, Mark; Lissowska, Jolanta; Seynaeve, Caroline; Huijts, Petra E.A.; Tollenaar, Rob A.E.M.; Ziogas, Argyrios; Ekici, Arif B.; Rauh, Claudia; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Andrulis, Irene L.; Ozcelik, Hilmi; Mulligan, Anna-Marie; Glendon, Gord; Hall, Per; Czene, Kamila; Liu, Jianjun; Chang-Claude, Jenny; Wang-Gohrke, Shan; Eilber, Ursula; Nickels, Stefan; Dörk, Thilo; Schiekel, Maria; Bremer, Michael; Park-Simon, Tjoung-Won; Giles, Graham G.; Severi, Gianluca; Baglietto, Laura; Hooning, Maartje J.; Martens, John W.M.; Jager, Agnes; Kriege, Mieke; Lindblom, Annika; Margolin, Sara; Couch, Fergus J.; Stevens, Kristen N.; Olson, Janet E.; Kosel, Matthew; Cross, Simon S.; Balasubramanian, Sabapathy P.; Reed, Malcolm W.R.; Miron, Alexander; John, Esther M.; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Chenevix-Trench, Georgia; Lambrechts, Diether; Dieudonne, Anne-Sophie; Hatse, Sigrid; van Limbergen, Erik; Benitez, Javier; Milne, Roger L.; Zamora, M. Pilar; Pérez, José Ignacio Arias; Bonanni, Bernardo; Peissel, Bernard; Loris, Bernard; Peterlongo, Paolo; Rajaraman, Preetha; Schonfeld, Sara J.; Anton-Culver, Hoda; Devilee, Peter; Beckmann, Matthias W.; Slamon, Dennis J.; Phillips, Kelly-Anne; Figueroa, Jonine D.; Humphreys, Manjeet K.; Easton, Douglas F.; Schmidt, Marjanka K.

    2012-01-01

    Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09–1.35, P=0.0002 and HR=1.29; 95% CI: 1.12–1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility. PMID:22532573

  5. Cellobiohydrolase variants and polynucleotides encoding same

    SciTech Connect

    Wogulis, Mark

    2014-10-14

    The present invention relates to variants of a parent cellobiohydrolase II. The present invention also relates to polynucleotides encoding the variants; nucleic acid constructs, vectors, and host cells comprising the polynucleotides; and methods of using the variants.

  6. Cellobiohydrolase variants and polynucleotides encoding the same

    SciTech Connect

    Wogulis, Mark

    2014-09-09

    The present invention relates to variants of a parent cellobiohydrolase. The present invention also relates to polynucleotides encoding the cellobiohydrolase variants; nucleic acid constructs, vectors, and host cells comprising the polynucleotides; and methods of using the cellobiohydrolase variants.

  7. Cellobiohydrolase variants and polynucleotides encoding same

    DOEpatents

    Wogulis, Mark

    2013-09-24

    The present invention relates to variants of a parent cellobiohydrolase II. The present invention also relates to polynucleotides encoding the variants; nucleic acid constructs, vectors, and host cells comprising the polynucleotides; and methods of using the variants.

  8. Rare Copy Number Variants

    PubMed Central

    Grozeva, Detelina; Kirov, George; Ivanov, Dobril; Jones, Ian R.; Jones, Lisa; Green, Elaine K.; St Clair, David M.; Young, Allan H.; Ferrier, Nicol; Farmer, Anne E.; McGuffin, Peter; Holmans, Peter A.; Owen, Michael J.; O’Donovan, Michael C.; Craddock, Nick

    2015-01-01

    Context Recent studies suggest that copy number variation in the human genome is extensive and may play an important role in susceptibility to disease, including neuropsychiatric disorders such as schizophrenia and autism. The possible involvement of copy number variants (CNVs) in bipolar disorder has received little attention to date. Objectives To determine whether large (>100 000 base pairs) and rare (found in <1% of the population) CNVs are associated with susceptibility to bipolar disorder and to compare with findings in schizophrenia. Design A genome-wide survey of large, rare CNVs in a case-control sample using a high-density microarray. Setting The Wellcome Trust Case Control Consortium. Participants There were 1697 cases of bipolar disorder and 2806 nonpsychiatric controls. All participants were white UK residents. Main Outcome Measures Overall load of CNVs and presence of rare CNVs. Results The burden of CNVs in bipolar disorder was not increased compared with controls and was significantly less than in schizophrenia cases. The CNVs previously implicated in the etiology of schizophrenia were not more common in cases with bipolar disorder. Conclusions Schizophrenia and bipolar disorder differ with respect to CNV burden in general and association with specific CNVs in particular. Our data are consistent with the possibility that possession of large, rare deletions may modify the phenotype in those at risk of psychosis: those possessing such events are more likely to be diagnosed as having schizophrenia, and those without them are more likely to be diagnosed as having bipolar disorder. PMID:20368508

  9. Heteromorphic variants of chromosome 9

    PubMed Central

    2013-01-01

    Background Heterochromatic variants of pericentromere of chromosome 9 are reported and discussed since decades concerning their detailed structure and clinical meaning. However, detailed studies are scarce. Thus, here we provide the largest ever done molecular cytogenetic research based on >300 chromosome 9 heteromorphism carriers. Results In this study, 334 carriers of heterochromatic variants of chromosome 9 were included, being 192 patients from Western Europe and the remainder from Easter-European origin. A 3-color-fluorescence in situ hybridization (FISH) probe-set directed against for 9p12 to 9q13~21.1 (9het-mix) and 8 different locus-specific probes were applied for their characterization. The 9het-mix enables the characterization of 21 of the yet known 24 chromosome 9 heteromorphic patterns. In this study, 17 different variants were detected including five yet unreported; the most frequent were pericentric inversions (49.4%) followed by 9qh-variants (23.9%), variants of 9ph (11.4%), cenh (8.2%), and dicentric- (3.8%) and duplication-variants (3.3%). For reasons of simplicity, a new short nomenclature for the yet reported 24 heteromorphic patterns of chromosome 9 is suggested. Six breakpoints involved in four of the 24 variants could be narrowed down using locus-specific probes. Conclusions Based on this largest study ever done in carriers of chromosome 9 heteromorphisms, three of the 24 detailed variants were more frequently observed in Western than in Eastern Europe. Besides, there is no clear evidence that infertility is linked to any of the 24 chromosome 9 heteromorphic variants. PMID:23547710

  10. Variants of beta-glucosidases

    SciTech Connect

    Fidantsef, Ana; Lamsa, Michael; Gorre-Clancy, Brian

    2014-10-07

    The present invention relates to variants of a parent beta-glucosidase, comprising a substitution at one or more positions corresponding to positions 142, 183, 266, and 703 of amino acids 1 to 842 of SEQ ID NO: 2 or corresponding to positions 142, 183, 266, and 705 of amino acids 1 to 844 of SEQ ID NO: 70, wherein the variant has beta-glucosidase activity. The present invention also relates to nucleotide sequences encoding the variant beta-glucosidases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  11. Variants of beta-glucosidase

    SciTech Connect

    Fidantsef, Ana; Lamsa, Michael; Gorre-Clancy, Brian

    2015-07-14

    The present invention relates to variants of a parent beta-glucosidase, comprising a substitution at one or more positions corresponding to positions 142, 183, 266, and 703 of amino acids 1 to 842 of SEQ ID NO: 2 or corresponding to positions 142, 183, 266, and 705 of amino acids 1 to 844 of SEQ ID NO: 70, wherein the variant has beta-glucosidase activity. The present invention also relates to nucleotide sequences encoding the variant beta-glucosidases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  12. Variants of beta-glucosidase

    SciTech Connect

    Fidantsef, Ana; Lamsa, Michael; Gorre-Clancy, Brian

    2009-12-29

    The present invention relates to variants of a parent beta-glucosidase, comprising a substitution at one or more positions corresponding to positions 142, 183, 266, and 703 of amino acids 1 to 842 of SEQ ID NO: 2 or corresponding to positions 142, 183, 266, and 705 of amino acids 1 to 844 of SEQ ID NO: 70, wherein the variant has beta-glucosidase activity. The present invention also relates to nucleotide sequences encoding the variant beta-glucosidases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  13. Variants of beta-glucosidases

    DOEpatents

    Fidantsef, Ana; Lamsa, Michael; Clancy, Brian Gorre

    2008-08-19

    The present invention relates to variants of a parent beta-glucosidase, comprising a substitution at one or more positions corresponding to positions 142, 183, 266, and 703 of amino acids 1 to 842 of SEQ ID NO: 2 or corresponding to positions 142, 183, 266, and 705 of amino acids 1 to 844 of SEQ ID NO: 70, wherein the variant has beta-glucosidase activity. The present invention also relates to nucleotide sequences encoding the variant beta-glucosidases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  14. High-dose-rate brachytherapy delivered in two fractions as monotherapy for low-risk prostate cancer

    PubMed Central

    Alwers, Elizabeth; Cifuentes, Javier; Bobadilla, Ivan; Torres, Felipe; Arbelaez, Juan; Gaitan, Armando; Cortes, Helber; Acevedo, Yenny; Quintero, Paulo; Vasquez, Jaider

    2015-01-01

    Purpose High-dose-rate (HDR) brachytherapy has been accepted as an effective and safe method to treat prostate cancer. The aim of this study was to describe acute toxicity following HDR brachytherapy to the prostate, and to examine the association between dosimetric parameters and urinary toxicity in low-risk prostate cancer patients. Material and methods Patients with low-risk prostate cancer were given HDR brachytherapy as monotherapy in two 12.5 Gy fractions. Planning objectives for the planning target volume (PTV) were V100% ≥ 90% and V150% ≤ 35%. Planning objectives for organs at risk were V75% ≤ 1 cc for the bladder, rectum and perineum, and V125% ≤ 1 cc for the urethra. Toxicity was assessed three months after treatment using the Common Terminology Criteria for Adverse Events. Results Seventy-three patients were included in the analysis. Thirty-three patients (45%) reported having any type of toxicity in the three months following HDR brachytherapy. Most toxicity cases (26%) were grade 1 urinary toxicity. Mean coverage index was 0.89 and mean V100 was 88.85. Doses administered to the urethra were associated with urinary toxicity. Patients who received more than 111.3% of the prescribed dose in 1 cc of the urethra were four times more likely to have urinary toxicity compared to patients receiving less than 111.3% (OR = 4.71, 95% CI: 1.43-15.6; p = 0.011). Conclusions High-dose-rate brachytherapy administered as monotherapy for prostate cancer proved to be a safe alternative treatment for patients with low-risk prostate cancer. Urinary toxicity was associated with the dose administered to 1 cc and 0.1 cc of the urethra and was remarkably inferior to the reported toxicity in similar studies. PMID:25829931

  15. Molecular genotyping of HPV L1 gene in low-risk and high-risk populations in Bangkok

    PubMed Central

    Leaungwutiwong, Pornsawan; Bamrungsak, Busara; Jittmittraphap, Akanitt; Maneekan, Pannamas; Kosoltanapiwat, Nathamon; Kalambaheti, Thareerat; Kelley, James F.

    2015-01-01

    Background Human papillomavirus (HPV) infections in Thailand are a public health concern but information on HPV infection in sex workers and men who have sex with men (MSM) is limited. The aim of this study was to measure the prevalence and genotype distribution of HPV among low- and high-risk, HIV-negative populations. Methods A total of 300 participants were categorized as general women, female sex workers, MSM, and MSM sex workers. HPV infections were identified by the Papanicolaou (Pap) test and nested-PCR. A phylogenetic analysis of partial HPV L1 genes was performed. Results Abnormal cytology was found in 5% of general women, 10% of female sex workers, 24% of MSM and 28% of MSM sex workers. HPV was detected in 9% of general women, 13% of female sex workers and 30% in both MSM and the MSM sex workers. The prevalence of HPV high-risk genotypes was significantly higher in female sex workers and MSM while low-risk genotypes and genital warts were significantly higher in MSM sex workers. Significantly more patients with genital warts and CIN I/AIN I harbored low-risk genotypes while those with CIN II/AIN II harbored high-risk genotypes. Conclusion High- and low-risk HPV genotypes persist in high-risk groups in Bangkok. Some genotypes infecting at-risk populations are not vaccine-preventable. These findings may help to elucidate the prevalence of HPV infections in Thailand and serve as the basis for additional investigations into risk factors for these populations. PMID:25763674

  16. Gene Variants Reduce Opioid Risks

    MedlinePlus

    ... Charts Emerging Trends and Alerts Alcohol Club Drugs Cocaine Hallucinogens Heroin Inhalants Marijuana MDMA (Ecstasy/Molly) Methamphetamine ... a decreased risk for addiction to heroin or cocaine. The other linked variants in two genes— OPRM1 , ...

  17. Freestanding midwifery unit versus obstetric unit: a matched cohort study of outcomes in low-risk women

    PubMed Central

    Møller, Anna Margrethe; Fenger-Grøn, Morten; Knudsen, Lisbeth B; Sandall, Jane

    2011-01-01

    Objective To compare perinatal and maternal morbidity and birth interventions in low-risk women giving birth in two freestanding midwifery units (FMUs) and two obstetric units (OUs). Design A cohort study with a matched control group. Setting The region of North Jutland, Denmark. Participants 839 low-risk women intending FMU birth and a matched control group of 839 low-risk women intending OU birth were included at the start of care in labour. OU women were individually chosen to match selected obstetric/socio-economic characteristics of FMU women. Analysis was by intention to treat. Main outcome measures Perinatal and maternal morbidity and interventions. Results No significant differences in perinatal morbidity were observed between groups (Apgar scores <7/5, <9/5 or <7/1, admittance to neonatal unit, asphyxia or readmission). Adverse outcomes were rare and occurred in both groups. FMU women were significantly less likely to experience an abnormal fetal heart rate (RR: 0.3, 95% CI 0.2 to 0.5), fetal–pelvic complications (0.2, 0.05 to 0.6), shoulder dystocia (0.3, 0.1 to 0.9), occipital–posterior presentation (0.5, 0.3 to 0.9) and postpartum haemorrhage >500 ml (0.4, 0.3 to 0.6) compared with OU women. Significant reductions were found for the FMU group's use of caesarean section (0.6, 0.3 to 0.9), instrumental delivery (0.4, 0.3 to 0.6), and oxytocin augmentation (0.5, 0.3 to 0.6) and epidural analgesia (0.4, 0.3 to 0.6). Transfer during or <2 h after birth occurred in 14.8% of all FMU births but more frequently in primiparas than in multiparas (36.7% vs 7.2%). Conclusion Comparing FMU and OU groups, there was no increase in perinatal morbidity, but there were significantly reduced incidences of maternal morbidity, birth interventions including caesarean section, and increased likelihood of spontaneous vaginal birth. FMU care may be considered as an adequate alternative to OU care for low-risk women. Pregnant prospective mothers should be given an

  18. Single-Nucleotide Polymorphism–Based Noninvasive Prenatal Screening in a High-Risk and Low-Risk Cohort

    PubMed Central

    Pergament, Eugene; Cuckle, Howard; Zimmermann, Bernhard; Banjevic, Milena; Sigurjonsson, Styrmir; Ryan, Allison; Hall, Megan P.; Dodd, Michael; Lacroute, Phil; Stosic, Melissa; Chopra, Nikhil; Hunkapiller, Nathan; Prosen, Dennis E.; McAdoo, Sallie; Demko, Zachary; Siddiqui, Asim; Hill, Matthew; Rabinowitz, Matthew

    2014-01-01

    Objective To estimate performance of a single-nucleotide-polymorphism–based noninvasive prenatal screen for fetal aneuploidy in high-risk and low-risk populations upon single venopuncture. Methods One thousand sixty-four maternal blood samples from 7 weeks of gestation and beyond were included; one thousand fifty-one were within specifications, 518 (49.3%) low-risk. Cell-free DNA was amplified, sequenced, and analyzed using the Next-generation Aneuploidy Test Using SNPs algorithm. Samples were called as trisomies 21, 18, 13, or monosomy X, or euploid, and male or female. Results Nine hundred sixty-six samples (91.9%) successfully generated a cell-free DNA result. Among these, sensitivity was 100% for trisomy 21 (58/58, CI: 93.8–100%), trisomy 13 (12/12, CI: 73.5–100%), and fetal sex (358/358 female, CI:99.0–100%; 418/418 male, CI: 99.1–100%), 96.0% for trisomy 18 (24/25, CI: 79.7–99.9%), and 90% for monosomy X (9/10, CI: 55.5–99.8%). Specificity for trisomies 21 and 13 was 100% (905/905 [CI: 99.6–100%] and 953/953 [CI: 99.6–100%], respectively) and for trisomy 18 and monosomy X was 99.9% (938/939 [CI: 99.4–100%] and 953/954 [CI: 99.4–100%], respectively). However, 16% (20/125) of aneuploid samples did not return a result; 50% (10/20) had a fetal fraction below the 1.5th percentile of euploid pregnancies. Aneuploidy rate was significantly higher in these samples (p<0.001, odds ratio: 9.2, CI: 4.4–19.0). Sensitivity and specificity did not differ in low-risk and high-risk populations. Conclusions This noninvasive prenatal screen performed with high sensitivity and specificity in high-risk and low-risk cohorts. Aneuploid samples were significantly more likely to not return a result; the number of aneuploidy samples was especially increased among samples with low fetal fraction. This underscores the importance of redraws or, in rare cases, invasive procedures based on low fetal fraction. PMID:25004354

  19. [Focal Laser Ablation and Photodynamic Vascular Therapy with soluble TOOKAD® in the treatment of low risk prostate cancer].

    PubMed

    Domínguez-Escrig, J L; Casanova Ramón-Borja, J

    2016-07-01

    The increase of the diagnosis of low risk prostate cancer translates into a new clinical entity, for which active surveillance may not be always enough and conventional therapies are clearly overtreatment. Faced with the necessity of giving a therapeutic answer to these patients, and facilitated by the technological advances in the imaging field and new energy sources, the interest is centered in the clinical development of focal therapies as an alternative with minimal morbidity and oncologically safe. As a part of the review carried out in this monographic issue, this article focus on the features relative to the preclinical and clinical development of laser ablative therapy and the innovative photodynamic vascular therapy with soluble TOOKAD®. With this aim we performed an exhaustive bibliographic search, updated to February 2016, in the greater databases, including original articles and reviews in reference to the object of this review, without restrictions for year of publication. This article reviews the preclinical and clinical development of these innovative ablative techniques in the field of focal therapy for low risk prostate cancer. PMID:27416636

  20. Swallow-breath interaction and phase of respiration with swallow during nonnutritive suck among low-risk preterm infants.

    PubMed

    Reynolds, Eric W; Grider, Debbie; Caldwell, Rhonda; Capilouto, Gilson; Vijaygopal, Pooja; Patwardhan, Abhijit; Charnigo, Richard

    2010-11-01

    This study describes swallow-breath interaction and phase of respiration with swallow during nonnutritive suck (NNS) in low-risk preterm infants. Suckle and swallow, thoracic motion, and airflow were measured in 16 infants during NNS. Logistic regression models were used to describe swallow-breath interaction and phase of respiration with swallow. One hundred seventy-six swallows occurred in 35 NNS periods. Swallow-breath interaction occurred as: central apnea (CA), obstructive apnea (OA), or attenuated respiration (AR). AR was associated with increased weeks post-first nipple feeding. OA occurred less often in males and with increased weeks post-first nipple feeding. In looking at the phase of respiration, more swallows occurred at beginning expiration with increased gestational age, increased weeks post-first nipple feed, and increased weeks before first nipple feed. More swallows occurred at midexpiration with more swallows per study, increased birth weight (BWT), and weeks before first nipple feed. Fewer swallows occurred at end expiration with increased weeks before first nipple feed. Fewer swallows occurred at midinspiration with increased swallows per study. Fewer swallows occurred at apnea with increasing BWT, more occurred with increased swallows per study. In low-risk preterm infants, swallow-breath interaction progresses from CA and OA to AR. The phase of respiration with swallow shows a maturation progression.

  1. Screening for lung cancer using low-dose computed tomography: concerns about the application in low-risk individuals

    PubMed Central

    Li, Wei; Han, Fu-Jun; Liu, Yu-Di

    2015-01-01

    Low-dose computed tomography (LDCT) has been increasingly accepted as an efficient screening method for high-risk individuals to reduce lung cancer mortality. However, there remains a gap of knowledge in the practical implementation of screening on a larger scale, especially for low-risk individuals. The aim of this study is to initiate discussion through an evidence-based analysis and provide valuable suggestions on LDCT screening for lung cancer in clinical practice. Among previously published randomized controlled trials (RCTs), the National Lung Screening Trial (NLST) is the only one demonstrating positive results in a high-risk population of old age and heavy smokers. It is also shown that the potential harms include false-positive findings, radiation exposure etc., but its magnitude is uncertain. In the meantime, the current risk stratification system is inadequate, and is difficult to define selection criteria. Thus, the efficacy of LDCT in lung cancer screening needs to be confirmed in future trials, and the procedure should not be proposed to individuals without comparable risk to those in the NLST. Furthermore, there is a lack of evidence to support the expansion of LDCT screening to low-risk individuals. Therefore, recommendation of LDCT screening for these patients could be premature in clinical practice although some of them might be missed based on current definition of risk factors. Further studies and advances in risk assessment tools are urgently needed to address the concerns about lung cancer screening in order to improve the outcomes of lung cancer. PMID:26207215

  2. Management of low risk and low PSA prostate cancer: long term results from the prostate cancer intervention versus observation trial.

    PubMed

    Wilt, Timothy J

    2014-01-01

    Management of localized prostate cancer is controversial due in part to the lack of randomized controlled trial information in men diagnosed with prostate specific antigen (PSA) testing. Men with low risk or low PSA (<10 ng/ml) prostate cancer comprise up to 70 % of men currently diagnosed. Evidence suggests an excellent long-term prognosis with observation though nearly 90 % are treated with surgery (radical prostatectomy), external beam radiation, or brachytherapy. Results from the Prostate cancer Intervention Versus Observation Trial (PIVOT) provide high quality Level 1 evidence that observation compared to surgery results in similar long-term overall and prostate cancer survival, prevention of bone metastases and avoidance of surgery related harms. Combined with emerging evidence from screening, natural history, decision analysis and cost-effectiveness modeling studies, these data demonstrate that observation is the preferred treatment option for men with low risk and possibly low PSA prostate cancer. Recommending against PSA testing or, in men who still desire testing, raising thresholds of PSA values used to define abnormal, lengthening intervals between PSA tests and discontinuing testing in men with a life expectancy less than 15 years will reduce diagnostic and treatment related harms without adversely impacting overall or disease specific mortality and morbidity. PMID:24531789

  3. A comparison of genetic variants between proficient low- and high-risk sport participants.

    PubMed

    Thomson, Cynthia J; Power, Rebecca J; Carlson, Scott R; Rupert, Jim L; Michel, Grégory

    2015-01-01

    Athletes participating in high-risk sports consistently report higher scores on sensation-seeking measures than do low-risk athletes or non-athletic controls. To determine whether genetic variants commonly associated with sensation seeking were over-represented in such athletes, proficient practitioners of high-risk (n = 141) and low-risk sports (n = 132) were compared for scores on sensation seeking and then genotyped at 33 polymorphic loci in 14 candidate genes. As expected, athletes participating in high-risk sports score higher on sensation seeking than did low-risk sport athletes (P < .01). Genotypes were associated with high-risk sport participation for two genes (stathmin, (P = .004) and brain-derived neurotrophic factor (P = .03)) as well as when demographically matched subsets of the sport cohorts were compared (P < .05); however, in all cases, associations did not survive correction for multiple testing.

  4. A comparison of genetic variants between proficient low- and high-risk sport participants.

    PubMed

    Thomson, Cynthia J; Power, Rebecca J; Carlson, Scott R; Rupert, Jim L; Michel, Grégory

    2015-01-01

    Athletes participating in high-risk sports consistently report higher scores on sensation-seeking measures than do low-risk athletes or non-athletic controls. To determine whether genetic variants commonly associated with sensation seeking were over-represented in such athletes, proficient practitioners of high-risk (n = 141) and low-risk sports (n = 132) were compared for scores on sensation seeking and then genotyped at 33 polymorphic loci in 14 candidate genes. As expected, athletes participating in high-risk sports score higher on sensation seeking than did low-risk sport athletes (P < .01). Genotypes were associated with high-risk sport participation for two genes (stathmin, (P = .004) and brain-derived neurotrophic factor (P = .03)) as well as when demographically matched subsets of the sport cohorts were compared (P < .05); however, in all cases, associations did not survive correction for multiple testing. PMID:25751253

  5. A new proposal to risk stratify urothelial carcinomas of the upper urinary tract (UTUCs) in a predefinitive treatment setting: low-risk versus high-risk UTUCs.

    PubMed

    Rouprêt, Morgan; Colin, Pierre; Yates, David R

    2014-08-01

    Risk stratification of upper tract urothelial carcinoma (UTUC) patients and tumours is crucial for highlighting that an alternative to radical extirpative surgery now exists and should be considered for all patients who qualify as having low-risk UTUC.

  6. Management of low-risk well-differentiated thyroid cancer based only on thyroglobulin measurement after recombinant human thyrotropin.

    PubMed

    Wartofsky, Leonard

    2002-07-01

    A multicenter study was undertaken to ascertain prevalence and significance of recombinant human thyrotropin (rhTSH)-stimulated increases in thyroglobulin (Tg) levels in thyroid cancer patients classified to be at low risk for recurrence. Patients were eligible for enrollment if they had undergone near-total or total thyroidectomy and remnant ablation between 1-10 years prior to enrollment and had received thyroxine suppression therapy (THST) with a TSH level of < 0.5 mU/L and Tg level less than or equal to 5 ng/mL within the prior year. Patients with anti-Tg antibodies, distant metastases, or other evidence of residual disease were excluded. Four hundred eighty-six patients were entered into the study, and 300 were considered eligible and comprise the study population. TSH, Tg, and anti-Tg antibody levels were obtained at baseline, followed by intramuscular injection of 0.9 mg of rhTSH on days 1 and 2 and measurement of Tg on day 5. After rhTSH, 53 patients (18%) had elevations in Tg of at least 2 ng/mL, including 33 patients (11%) with increases from baseline of equal to or greater than 5 ng/mL. Patients with an initial advanced stage of disease were more likely to display elevations in Tg after rhTSH. One third of those with stage III disease displayed elevations in Tg of 2 ng/mL or more. Patients within 5 years of thyroidectomy were as likely to display elevations in rhTSH-stimulated Tg as those 5-10 years from surgery. In conclusion, these data suggest rhTSH-stimulated Tg testing without scan may be a useful tool in the follow-up of patients with low-risk thyroid cancer, and may serve to identify patients previously thought free of disease on the basis of undetectable Tg levels while undergoing THST. A strategy is presented for incorporation of this approach into the management of patients with low-risk well-differentiated thyroid cancer.

  7. Randomized trial of pragmatic education for low-risk COPD patients: impact on hospitalizations and emergency department visits

    PubMed Central

    Siddique, Haamid H; Olson, Raymond H; Parenti, Connie M; Rector, Thomas S; Caldwell, Michael; Dewan, Naresh A; Rice, Kathryn L

    2012-01-01

    Background: Most interventions aimed at reducing hospitalizations and emergency department (ED) visits in patients with chronic obstructive pulmonary disease (COPD) have employed resource-intense programs in high-risk individuals. Although COPD is a progressive disease, little is known about the effectiveness of proactive interventions aimed at preventing hospitalizations and ED visits in the much larger population of low-risk (no known COPD-related hospitalizations or ED visits in the prior year) patients, some of whom will eventually become high-risk. Methods: We tested the effect of a simple educational and self-efficacy intervention (n = 2243) versus usual care (n = 2182) on COPD/breathing-related ED visits and hospitalizations in a randomized study of low-risk patients at three Veterans Affairs (VA) medical centers in the upper Midwest. Administrative data was used to track VA admissions and ED visits. A patient survey was used to determine health-related events outside the VA. Results: Rates of COPD-related VA hospitalizations in the education and usual care group were not significantly different (3.4 versus 3.6 admissions per 100 person-years, respectively; 95% CI of difference −1.3 to 1.0, P = 0.77). The much higher patient-reported rates of non-VA hospitalizations for breathing-related problems were lower in the education group (14.0 versus 19.0 per 100 person-years; 95% CI −8.6 to −1.4, P = 0.006). Rates of COPD-related VA ED visits were not significantly different (6.8 versus 5.3; 95% CI −0.1 to 3.0, P = 0.07), nor were non-VA ED visits (32.4 versus 36.5; 95% CI −9.3 to 1.1, P = 0.12). All-cause VA admission and ED rates did not differ. Mortality rates (6.9 versus 8.3 per 100 person-years, respectively; 95% CI −3.0 to 0.4, P = 0.13) did not differ. Conclusion: An educational intervention that is practical for large numbers of low-risk patients with COPD may reduce the rate of breathing-related hospitalizations. Further research that more

  8. Short-term neurodevelopmental outcome of babies operated on for low-risk esophageal atresia: a pilot study.

    PubMed

    Aite, L; Bevilacqua, F; Zaccara, A; Ravà, L; Valfrè, L; Conforti, A; Braguglia, A; Bagolan, P

    2014-01-01

    Data on the neurodevelopmental outcome of esophageal atresia (EA) survivors are scarce, controversial, and based on small samples. This is an observational prospective longitudinal study on a selected cohort of low-risk EA survivors. We considered a low-risk EA survivor a patient with the following characteristics: gestational age >32 weeks, no long gap, no genetic or chromosomic anomaly associated with neurodevelopmental delay, and no further major surgical congenital anomalies. Infants were evaluated with scales derived from the Bayley Scales of Infant and Toddler Development - 3rd Edition at 6 and 12 months, with a score of 100 considered normal for each scale. Analysis of variance was used to assess differences of cognitive and motor development. Linear regression was used to assess the impact of the following clinical and sociodemographic variables: gender, birthweight, gestational age, length of hospital stay, number of surgeries and number of esophageal dilatations during first hospitalization, days of mechanical ventilation, weight at follow up, number of surgeries and esophageal dilatations at follow up, parental age, educational level, and socioeconomic status. Thirty children form the object of the study. The mean (standard deviation [SD]) cognitive scale's score was 93.7 (7.5) and 98.2 (9.6) at 6 and 12 months, respectively (P < 0.05). The mean (SD) motor scale's score was 97.6 (9.3) and 98.0 (12.1) at 6 and 12 months, respectively (P = n.s.). Children with a body weight <5° percentile at 12 months showed a mean (SD) cognitive score significantly lower when compared with those with a body weight >5° percentile: 88.8 (6.3) and 100.5 (8.9), respectively. At 12 months, children with unemployed mothers had a mean (SD) motor score significantly lower when compared with those in the other socioeconomic classes: 87.7 (9.8) and 100.6 (12.4), respectively. In conclusion, parents of babies operated on for low-risk EA can be reassured about neurodevelopmental

  9. Common Variants for Heart Failure

    PubMed Central

    Shen, Shutong; Tao, Lichan; Wang, Xiuzhi; Kong, Xiangqing; Li, Xinli

    2015-01-01

    Heart failure (HF) is a common disease with high morbidity and mortality; however, none of the drugs available are now entirely optimal for the treatment of HF. In addition to various clinical diseases and environment influences, genetic factors also contribute to the development and progression of HF. Identifying the common variants for HF by genome-wide association studies will facilitate the understanding of pathophysiological mechanisms underlying HF. This review summarizes the recently identified common variants for HF risk and outcome and discusses their implications for the clinic therapy. PMID:26085806

  10. A SIS reaction-diffusion-advection model in a low-risk and high-risk domain

    NASA Astrophysics Data System (ADS)

    Ge, Jing; Kim, Kwang Ik; Lin, Zhigui; Zhu, Huaiping

    2015-11-01

    A simplified SIS model is proposed and investigated to understand the impact of spatial heterogeneity of environment and advection on the persistence and eradication of an infectious disease. The free boundary is introduced to model the spreading front of the disease. The basic reproduction number associated with the diseases in the spatial setting is introduced. Sufficient conditions for the disease to be eradicated or to spread are given. Our result shows that if the spreading domain is high-risk at some time, the disease will continue to spread till the whole area is infected; while if the spreading domain is low-risk, the disease may be vanishing or keep spreading depending on the expanding capability and the initial number of the infective individuals. The spreading speeds are also given when spreading happens, numerical simulations are presented to illustrate the impacts of the advection and the expanding capability on the spreading fronts.

  11. Isolated port-site metastasis after surgical staging for low-risk endometrioid endometrial cancer: A case report

    PubMed Central

    MAUTONE, DANIELE; DALL'ASTA, ANDREA; MONICA, MICHELA; GALLI, LETIZIA; CAPOZZI, VITO ANDREA; MARCHESI, FEDERICO; GIORDANO, GIOVANNA; BERRETTA, ROBERTO

    2016-01-01

    Port-site metastases (PSMs) are well-known potential complications of laparoscopic surgery for gynaecologic malignancies. The present case study reports PSM following laparoscopic surgery for Stage IA Grade 1 endometrioid endometrial cancer (EEC). The recurrence developed within 7 months following primary surgery and required surgical excision followed by adjuvant chemo-radio therapy. After 9 months, the patient remains disease-free. PSMs are rare complications following laparoscopic surgery. Amongst the 23 cases of endometrial cancer PSMs reported so far, only 4 followed EEC Stage IA Grade 1–2. The present study reports a rare case of PSM after Stage IA Grade 1 EEC. The clinical and prognostic relevance of PSMs has not been identified so far; and it is not known whether PSMs represent a local recurrence or a systemic recurrence. Surgeons should be aware that even low-risk EEC may be followed by PSMs and should take steps to prevent these rare recurrences. PMID:27347138

  12. The Effect of Parenting Style on Social Smiling in Infants at High and Low Risk for ASD.

    PubMed

    Harker, Colleen M; Ibañez, Lisa V; Nguyen, Thanh P; Messinger, Daniel S; Stone, Wendy L

    2016-07-01

    This study examined how parenting style at 9 months predicts growth in infant social engagement (i.e., social smiling) between 9 and 18 months during a free-play interaction in infants at high (HR-infants) and low (LR-infants) familial risk for autism spectrum disorder (ASD). Results indicated that across all infants, higher levels of maternal responsiveness were concurrently associated with higher levels of social smiling, while higher levels of maternal directiveness predicted slower growth in social smiling. When accounting for maternal directiveness, which was higher in mothers of HR-infants, HR-infants exhibited greater growth in social smiling than LR-infants. Overall, each parenting style appears to make a unique contribution to the development of social engagement in infants at high- and low-risk for ASD.

  13. Intelligence, classroom behavior, and academic achievement in children at high and low risk for psychopathology: a structural equation analysis.

    PubMed

    Worland, J; Weeks, D G; Janes, C L; Strock, B D

    1984-09-01

    The intelligence, academic achievement, and classroom behavior of 158 children were assessed in a sample that is being followed longitudinally. The sample included children at high risk for mental disorder by virtue of having a parent with a psychiatric diagnosis of schizophrenia or affective disorder, children at moderate risk, and children at low risk. A series of path analyses indicated that in this sample (1) classroom behavior was more likely an affect that a cause of academic achievement, and (2) the influence of parental psychopathology on classroom behavior was mediated by a child's intelligence and academic achievement. We were unable to substantiate an unmediated causal link between parental psychopathology and children's academic achievement or classroom behavior.

  14. Placental calcifications: a clue for the identification of high-risk fetuses in the low-risk pregnant population?

    PubMed

    Mastrolia, Salvatore Andrea; Weintraub, Adi Yehuda; Sciaky-Tamir, Yael; Tirosh, Dan; Loverro, Giuseppe; Hershkovitz, Reli

    2016-03-01

    "What does it mean, Doctor?" and "Is it going to affect my baby in some way?". Those are the most typical questions of pregnant women to obstetricians. Answering is sometimes easier but placental calcification is not the case, since placental architecture and disease are two different faces of the same coin and the association between them is not completely clear. Placenta can function properly, even in the presence of architectural alterations, without any fetal consequences. So, remains the question, when does a placental structural anomaly become a sign of increased attention to maternal conditions, fetal development and well-being? The present review will analyze these concepts, with emphasis on placental calcification, its pathogenesis, and the state-of-the-art regarding the influence of this finding on pregnancy outcomes among low-risk pregnant patients.

  15. Outcomes of Low-Risk Ductal Carcinoma In Situ in Southeast Asian Women Treated With Breast Conservation Therapy

    SciTech Connect

    Wong, Fuh Yong; Wang, Fuqiang; Chen, John Ju; Tan, Chiew Har; Tan, Puay Hoon

    2014-04-01

    Purpose: To examine the outcomes of Southeast Asian (SEA) women with low-risk ductal carcinoma in situ (DCIS) treated with breast-conserving surgery (BCS) and adjuvant radiation therapy. Methods and Materials: Retrospective chart reviews of patients treated with BCS for DCIS from 1995 to 2011 were performed. Patients meeting the selection criteria from Eastern Cooperative Oncology Group 5194 were included. Most patients received adjuvant radiation therapy (RT) consisting of whole-breast RT delivered to 50 Gy followed by a 10-Gy boost to the tumor bed. Results: Of 744 patients with pathologic diagnosis of pure DCIS identified, 273 met the selection criteria: low-intermediate grade (LIG), n=219; high grade (HG), n=54. Median follow-up for these patients was 60 months. There were 8 ipsilateral breast tumor recurrences (IBTRs) in total, 7 of which were DCIS. The estimated actuarial IBTR rates at 5 and 10 years for the entire cohort are 1.8% and 4.3%, respectively. Of the 219 patients with LIG DCIS, 210 received RT and 9 did not. There were 7 IBTRs in LIG DCIS, 2 among the 9 patients who did not receive RT. The IBTR rates in LIG DCIS at 5 and 10 years are 2.3% and 4.2%, respectively. All patients with HG DCIS received RT. There was only 1 IBTR occurring beyond 5 years, giving an estimated IBTR rate of 4.5% at 10 years. Conclusions: SEA women with screen-detected DCIS have exceedingly low rates of IBTR after BCS, comparable to that observed in reports of similar patients with low-risk DCIS treated with adjuvant radiation.

  16. Overweight Is a Major Contributor to Atherosclerosis in Systemic Lupus Erythematosus Patients at Apparent Low Risk for Cardiovascular Disease

    PubMed Central

    Sacre, Karim; Escoubet, Brigitte; Zennaro, Maria-Christina; Chauveheid, Marie-Paule; Gayat, Etienne; Papo, Thomas

    2015-01-01

    Abstract Cardiovascular disease (CVD) is the main cause of death in systemic lupus erythematosus (SLE) patients. We aimed to determine whether overweight (defined as a body mass index [BMI] > 25 kg/m2) contributed to subclinical atherosclerosis in SLE patients at low risk for CVD according to traditional factors. Wall thickness of the internal carotid artery (ICWT) measured at the carotid bulb and carotid plaques were assessed in 49 SLE patients asymptomatic for CVD and 49 controls matched on Framingham score. Factors associated to ICWT were identified and multivariate analysis was performed. SLE patients and controls displayed a low 10-year risk for CVD according to Framingham score (mean 1.9 ± 3.5 in SLE vs 1.8 ± 3.2% in controls, P = 0.37). ICWT (P < 0.001) and number of patients with carotid plaques (P = 0.015) were, however, higher in SLE patients as compared to controls. In multivariable analysis, SLE was an independent risk for a carotid atherosclerosis (OR [95% confidence interval, CI]: 3.53 [1.36–9.14]; P = 0.009). Older age, higher BMI, and higher Framingham score were associated with atherosclerosis in SLE patients in univariate analysis. In multivariate analysis, only the association with overweight remained significant (OR [95% CI]: 4.13 [1.02–16.75]; P = 0.047). Overweight is a major contributor to atherosclerosis in SLE patients at apparent low risk for CVD. PMID:26632902

  17. Preserved Offshore Tsunami Deposits Recognized in a 'Low Risk' Zone: an undocumented tsunami in the northern Red Sea

    NASA Astrophysics Data System (ADS)

    Goodman Tchernov, Beverly; Katz, Timor; Yonaton, Shaked; Qupty, Nairooz; Kanari, Mor; Niemi, Tina; Agnon, Amotz

    2016-04-01

    The Red Sea generally, despite all of the necessary components for tsunami production, has been generally defined as 'low-risk' with regard to tsunami damage on the basis of historical records, observations of small-scale tsunami production in recent periods, and a lack of field evidence. While some regions are known to be prone to tsunami events, other areas are considered safe because of their geographic and bathymetric settings, seismic disposition, and lack of written descriptions of past tsunamis. Models that are produced to estimate said risk rely on catalogues of written records and field studies that summarize known events. There are multiple failures in this approach. First, written records are not evenly distributed worldwide, nor has writing always existed; thereby limiting the possible timeframe for reference. Field studies of preserved tsunami deposits focus primarily on terrestrial or coastal deposits, which modern observations of post-tsunami deposit diagenesis are determining that they are quickly eroded and rarely preserved, thus leading to a considerably patchy record, ultimately underrepresenting the actual number of past tsunamis. Offshore sedimentary deposits may hold promise as better recorders of these events. Here we present recently published evidence for a rare, yet significant and potentially very destructive tsunami event that impacted a presumed low-risk location in the northern Red Sea's Gulf of Aqaba. The anomalous deposits were recognized within sediment cores collected offshore (-16 to -12 msl) and were identified using a suite of common tsunamigenic indicators such as sedimentological characterization, granulometry and micropaleontology. Given rapidly expanding coastal populations in the region and worldwide, these findings are a warning that the current practice of determining risk based solely on models and historical catalogues, without offshore field studies, is insufficient.

  18. Adverse outcomes in maternity care for women with a low risk profile in The Netherlands: a case series analysis

    PubMed Central

    2013-01-01

    Background This study aimed to perform a structural analysis of determinants of risk of critical incidents in care for women with a low risk profile at the start of pregnancy with a view on improving patient safety. Methods We included 71 critical incidents in primary midwifery care and subsequent hospital care in case of referral after 36 weeks of pregnancy that were related to substandard care and for that reason were reported to the Health Care Inspectorate in The Netherlands in 36 months (n = 357). We performed a case-by-case analysis, using a previously validated instrument which covered five broad domains: healthcare organization, communication between healthcare providers, patient risk factors, clinical management, and clinical outcomes. Results Determinants that were associated with risk concerned healthcare organization (n = 20 incidents), communication about treatment procedures (n = 39), referral processes (n = 19), risk assessment by telephone triage (n = 10), and clinical management in an out of hours setting (n = 19). The 71 critical incidents included three cases of maternal death, eight cases of severe maternal morbidity, 42 perinatal deaths and 12 critical incidents with severe morbidity for the child. Suboptimal prenatal risk assessment, a delay in availability of health care providers in urgent situations, miscommunication about treatment between care providers, and miscommunication with patients in situations with a language barrier were associated with safety risks. Conclusions Systematic analysis of critical incidents improves insight in determinants of safety risk. The wide variety of determinants of risk of critical incidents implies that there is no single intervention to improve patient safety in the care for pregnant women with initially a low risk profile. PMID:24286376

  19. Rhinovirus wheezing illness in infancy is associated with medically attended third year wheezing in low risk infants: results of a healthy birth cohort study.

    PubMed

    de Winter, Janneke J H; Bont, Louis; Wilbrink, Berry; van der Ent, Cornelis K; Smit, Henriette A; Houben, Michiel L

    2015-12-01

    Rhinoviruses may be pathogens contributing to the development of childhood wheezing. However, their role in low risk infants without an asthmatic predisposition is unknown. Knowing which healthy, low risk children are at increased risk for childhood wheezing after rhinovirus wheezing illness (RV-WI) in infancy, might help in developing prevention and treatment strategies for childhood wheezing. The aim of this study was to determine the association of medically attended wheezing at the age of three with RV-WI in the first year of life in low risk children without parental asthma. In a low risk, prospective birth cohort study, we followed 181 healthy born children from birth through the third year of life. We considered children 'low risk' if neither parent had a doctor's diagnosis of asthma. We determined infant RV-WI by parent-reported wheezing (based on daily logs) and simultaneous molecular rhinovirus detection in the first year of life. Respiratory function and blood eosinophil count were both measured in the first month of life. The primary outcome, third year wheezing, was defined as the use of prescribed inhaled asthma medications together with a doctor's visit for respiratory symptoms in the third year of life. We calculated the association of RV-WI with medically attended third year wheezing and other known possible risk factors for wheezing at the age of three. Among low risk children, third year wheezing was observed in 7 out of 18 (39%) children with versus 10 out of 163 (6%) children without infant RV-WI (OR 9.7, 95% CI 3.1-33.5, P < 0.0001). The association between RV-WI and third year wheezing was unchanged after adjustment for potential confounders such as eosinophilia and atopic eczema. RV-WI is a robust and independent risk factor for third year wheezing in low risk children without parental asthma. Future research will identify and protect those children at increased risk for RV-WI.

  20. Sterile α Motif Domain Containing 9 Is a Novel Cellular Interacting Partner to Low-Risk Type Human Papillomavirus E6 Proteins

    PubMed Central

    Wang, Jia; Dupuis, Crystal; Tyring, Stephen K.; Underbrink, Michael P.

    2016-01-01

    Low-risk type human papillomavirus (HPV) 6 and 11 infection causes recurrent respiratory papillomatosis (RRP) and genital warts. RRP is the most common benign tumor of the larynx in children with frequent relapses. Repeated surgeries are often needed to improve vocal function and prevent life-threatening respiratory obstruction. Currently, there are no effective treatments available to completely eliminate these diseases, largely due to limited knowledge regarding their viral molecular pathogenesis. HPV E6 proteins contribute to cell immortalization by interacting with a variety of cellular proteins, which have been well studied for the high-risk type HPVs related to cancer progression. However, the functions of low-risk HPV E6 proteins are largely unknown. In this study, we report GST-pulldown coupled mass spectrometry analysis with low-risk HPV E6 proteins that identified sterile alpha motif domain containing 9 (SAMD9) as a novel interacting partner. We then confirmed the interaction between HPV-E6 and SAMD9 using co-immunoprecipitation, proximity ligation assay, and confocal immunofluorescence staining. The SAMD9 gene is down-regulated in a variety of neoplasms and deleteriously mutated in normophosphatemic familial tumoral calcinosis. Interestingly, SAMD9 also has antiviral functions against poxvirus. Our study adds to the limited knowledge of the molecular properties of low-risk HPVs and describes new potential functions for the low-risk HPV E6 protein. PMID:26901061

  1. Different pituitary. beta. -endorphin and adrenal cortisol response to ethanol in individuals with high and low risk for future development of alcoholism

    SciTech Connect

    Gianoulakis, C.G.; Beliveau, D.; Angelogianni, P.; Meaney, M.; Thavundayil, J.; Tawar, V.; Dumas, M. )

    1989-01-01

    The purpose of the present studies was to investigate the activity of the adrenal gland and the pituitary {beta}-endorphin system in individuals from families with a 3 generation history of alcoholism, High Risk group, or from families without history of alcoholism, Low Risk group. On the day of testing, blood sample was taken at 9:00 a.m., then the subject drank a placebo drink or an ethanol solution. Additional blood samples were taken at 15, 45 and 120 minutes post-drink. Results indicated that individuals of the High Risk group had lower basal levels of {beta}-endorphin like immunoreactivity ({beta}-EPLIR) than individuals of the Low Risk group. The dose of 0.5 g ethanol/kg B.Wt. induced an induce an increase in the plasma content of {beta}-EPLIR of the High Risk group, but not of the Low Risk group. In the Low Risk group ethanol did not induce an increase above the 9:00 a.m. levels, however, it attenuated the {beta}-endorphin decrease overtime, observed following the placebo drink. Analysis of {beta}-endorphin-like peptides in the plasma of the High Risk group, with Sephadex G-75 chromatography indicated that the major component of the plasma {beta}-EPLIR was {beta}-lipotropin. Plasma cortisol levels, following ethanol intake, presented a small increase in the High Risk group but not in the Low Risk group.

  2. Variant (Swine Origin) Influenza Viruses in Humans

    MedlinePlus

    ... What's this? Submit Button Past Newsletters Variant Influenza Viruses: Background and CDC Risk Assessment and Reporting Language: ... Background CDC Assessment Reporting Background On Variant Influenza Viruses Swine flu viruses do not normally infect humans. ...

  3. Swine Influenza/Variant Influenza Viruses

    MedlinePlus

    ... Humans Key Facts about Human Infections with Variant Viruses Interim Guidance for Clinicians on Human Infections Background, Risk Assessment & Reporting Reported Infections with Variant Influenza Viruses in the United States since 2005 Prevention Treatment ...

  4. Cultural variant interaction in teaching and transmission.

    PubMed

    Abrams, Marshall

    2015-01-01

    Focus on the way in which cultural variants affect other variants' probabilities of transmission in modeling and empirical work can enrich Kline's conceptualization of teaching. For example, the problem of communicating complex cumulative culture is an adaptive problem; teaching methods that manage transmission so that acquisition of some cultural variants increases the probability of acquiring others, provide a partial solution. PMID:26786769

  5. Variant Humicola grisea CBH1.1

    DOEpatents

    Goedegebuur, Frits; Gualfetti, Peter; Mitchinson, Colin; Larenas, Edmund

    2011-05-31

    Disclosed are variants of Humicola grisea Cel7A (CBH1.1), H. jecorina CBH1 variant or S. thermophilium CBH1, nucleic acids encoding the same and methods for producing the same. The variant cellulases have the amino acid sequence of a glycosyl hydrolase of family 7A wherein one or more amino acid residues are substituted.

  6. Variant Humicola grisea CBH1.1

    DOEpatents

    Goedegebuur, Frits; Gualfetti, Peter; Mitchinson, Colin; Larenas, Edmund

    2008-12-02

    Disclosed are variants of Humicola grisea Cel7A (CBH1.1), H. jecorina CBH1 variant or S. thermophilium CBH1, nucleic acids encoding the same and methods for producing the same. The variant cellulases have the amino acid sequence of a glycosyl hydrolase of family 7A wherein one or more amino acid residues are substituted.

  7. Variant Humicola grisea CBH1.1

    DOEpatents

    Goedegebuur, Frits; Gualfetti, Peter; Mitchinson, Colin; Larenas, Edmund

    2012-08-07

    Disclosed are variants of Humicola grisea Cel7A (CBH1.1), H. jecorina CBH1 variant or S. thermophilium CBH1, nucleic acids encoding the same and methods for producing the same. The variant cellulases have the amino acid sequence of a glycosyl hydrolase of family 7A wherein one or more amino acid residues are substituted.

  8. Variant Humicola grisea CBH1.1

    DOEpatents

    Goedegebuur, Frits; Gualfetti, Peter; Mitchinson, Colin; Larenas, Edmund

    2011-08-16

    Disclosed are variants of Humicola grisea Cel7A (CBH1.1), H. jecorina CBH1 variant or S. thermophilium CBH1, nucleic acids encoding the same and methods for producing the same. The variant cellulases have the amino acid sequence of a glycosyl hydrolase of family 7A wherein one or more amino acid residues are substituted.

  9. Variant Humicola grisea CBH1.1

    SciTech Connect

    Goedegebuur, Frits; Gualfetti, Peter; Mitchinson, Colin; Larenas, Edmund

    2014-03-18

    Disclosed are variants of Humicola grisea Cel7A (CBH1.1), H. jecorina CBH1 variant or S. thermophilium CBH1, nucleic acids encoding the same and methods for producing the same. The variant cellulases have the amino acid sequence of a glycosyl hydrolase of family 7A wherein one or more amino acid residues are substituted.

  10. Variant humicola grisea CBH1.1

    SciTech Connect

    Goedegebuur, Frits; Gualfetti, Peter; Mitchinson, Colin; Edmund, Larenas

    2014-09-09

    Disclosed are variants of Humicola grisea Cel7A (CBH1.1), H. jecorina CBH1 variant or S. thermophilium CBH1, nucleic acids encoding the same and methods for producing the same. The variant cellulases have the amino acid sequence of a glycosyl hydrolase of family 7A wherein one or more amino acid residues are substituted.

  11. Variant Humicola grisea CBH1.1

    SciTech Connect

    Goedegeburr, Frits; Gualfetti, Peter; Mitchinson, Colin; Larenas, Edmund

    2013-02-19

    Disclosed are variants of Humicola grisea Cel7A (CBH1.1), H. jecorina CBH1 variant or S. thermophilium CBH1, nucleic acids encoding the same and methods for producing the same. The variant cellulases have the amino acid sequence of a glycosyl hydrolase of family 7A wherein one or more amino acid residues are substituted.

  12. Oncotator: cancer variant annotation tool.

    PubMed

    Ramos, Alex H; Lichtenstein, Lee; Gupta, Manaswi; Lawrence, Michael S; Pugh, Trevor J; Saksena, Gordon; Meyerson, Matthew; Getz, Gad

    2015-04-01

    Oncotator is a tool for annotating genomic point mutations and short nucleotide insertions/deletions (indels) with variant- and gene-centric information relevant to cancer researchers. This information is drawn from 14 different publicly available resources that have been pooled and indexed, and we provide an extensible framework to add additional data sources. Annotations linked to variants range from basic information, such as gene names and functional classification (e.g. missense), to cancer-specific data from resources such as the Catalogue of Somatic Mutations in Cancer (COSMIC), the Cancer Gene Census, and The Cancer Genome Atlas (TCGA). For local use, Oncotator is freely available as a python module hosted on Github (https://github.com/broadinstitute/oncotator). Furthermore, Oncotator is also available as a web service and web application at http://www.broadinstitute.org/oncotator/.

  13. [Mirizzi syndrome and its variants].

    PubMed

    Meyer, G J; Runge, D; Gebhardt, J

    1990-04-01

    Between 1981 and 1987 5434 patients were studied by ERCP in Allgemeines Krankenhaus Hamburg-Barmbeck. 26 (i.e. 0.43%) suffered from Mirizze syndrome with the triad of cholelithiasis, cholecystitis and obstructive biliary disease. They were classified in four different types according to the variable localisation and origin of the biliary obstruction. 16 patients corresponded to the classical type (I and II) with compression, penetration, and obturation by the concrement, five patients matched borderline with infiltration (III) and five patients were classified as variants of this syndrome. A mild elevation of serum bilirubine and alkaline phosphatase indicated more likely the benign etiology of type I to III, however, a marked elevation of alkaline phosphatase in the variants suggested more likely a malignant underlying disease. The diagnosis was ascertained in all cases by ERC and sonography preoperatively and was verified by laparotomy (n = 18) and follow-up (n = 6).

  14. A new variant of blepharospasm.

    PubMed

    Elston, J S

    1992-05-01

    Ten patients who were unable to initiate or sustain eye opening in the absence of overt spasm of the orbicularis oculi, were investigated. In five, the problem was isolated. Three had Parkinson's disease and two progressive supra-nuclear palsy for between one to six years before the eye opening difficulty developed. The clinical features and electrophysiological investigation suggested that the disorder is a variant of blepharospasm due to abnormal contraction in the pre-tarsal orbicularis oculi. PMID:1602309

  15. Dorsal variant blister aneurysm repair.

    PubMed

    Couldwell, William T; Chamoun, Roukoz

    2012-01-01

    Dorsal variant proximal carotid blister aneurysms are treacherous lesions to manage. It is important to recognize this variant on preoperative angiographic imaging, in anticipation of surgical strategies for their treatment. Strategies include trapping the involved segment and revascularization if necessary. Other options include repair of the aneurysm rupture site directly. Given that these are not true berry aneurysms, repair of the rupture site involves wrapping or clip-grafting techniques. The case presented here was a young woman with a subarachnoid hemorrhage from a ruptured dorsal variant blister aneurysm. The technique used is demonstrated in the video and is a modified clip-wrap technique using woven polyester graft material. The patient was given aspirin preoperatively as preparation for the clip-wrap technique. It is the authors' current protocol to attempt a direct repair with clip-wrapping and leaving artery sacrifice with or without bypass as a salvage therapy if direct repair is not possible. Assessment of vessel patency after repair is performed by intraoperative Doppler and indocyanine green angiography. Intraoperative somatosensory and motor evoked potential monitoring is performed in all cases. The video can be found here: http://youtu.be/crUreWGQdGo.

  16. Fibroblast Growth Factor Receptor-2 Expression in Thyroid Tumor Progression: Potential Diagnostic Application

    PubMed Central

    Redler, Adriano; Di Rocco, Giorgio; Giannotti, Domenico; Frezzotti, Francesca; Bernieri, Maria Giulia; Ceccarelli, Simona; D’Amici, Sirio; Vescarelli, Enrica; Mitterhofer, Anna Paola; Angeloni, Antonio; Marchese, Cinzia

    2013-01-01

    Fibroblast growth factor receptor-2 (FGFR-2) plays an important role in tumorigenesis. In thyroid cancer it has been observed a FGFR-2 down-modulation, but the role of this receptor has not been yet clarified. Therefore, we decided to examine the expression of both FGFR-2 isoform, FGFR-2-IIIb and FGFR-2-IIIc, in different histological thyroid variants such as hyperplasia, follicular adenoma and papillary carcinoma. Immunohistochemistry and quantitative Real-Time PCR analyses were performed on samples of hyperplasia, follicular adenoma and papillary carcinoma, compared with normal thyroid tissue. Thyroid hyperplasia did not show statistically significant reduction in FGFR-2 protein and mRNA levels. Interestingly, in both follicular adenoma and papillary carcinoma samples we observed a strongly reduced expression of both FGFR-2 isoforms. We speculate that FGFR-2 down-modulation might be an early event in thyroid carcinogenesis. Furthermore, we suggest the potential use of FGFR-2 as an early marker for thyroid cancer diagnosis. PMID:23977259

  17. Fibroblast growth factor receptor-2 expression in thyroid tumor progression: potential diagnostic application.

    PubMed

    Redler, Adriano; Di Rocco, Giorgio; Giannotti, Domenico; Frezzotti, Francesca; Bernieri, Maria Giulia; Ceccarelli, Simona; D'Amici, Sirio; Vescarelli, Enrica; Mitterhofer, Anna Paola; Angeloni, Antonio; Marchese, Cinzia

    2013-01-01

    Fibroblast growth factor receptor-2 (FGFR-2) plays an important role in tumorigenesis. In thyroid cancer it has been observed a FGFR-2 down-modulation, but the role of this receptor has not been yet clarified. Therefore, we decided to examine the expression of both FGFR-2 isoform, FGFR-2-IIIb and FGFR-2-IIIc, in different histological thyroid variants such as hyperplasia, follicular adenoma and papillary carcinoma. Immunohistochemistry and quantitative Real-Time PCR analyses were performed on samples of hyperplasia, follicular adenoma and papillary carcinoma, compared with normal thyroid tissue. Thyroid hyperplasia did not show statistically significant reduction in FGFR-2 protein and mRNA levels. Interestingly, in both follicular adenoma and papillary carcinoma samples we observed a strongly reduced expression of both FGFR-2 isoforms. We speculate that FGFR-2 down-modulation might be an early event in thyroid carcinogenesis. Furthermore, we suggest the potential use of FGFR-2 as an early marker for thyroid cancer diagnosis. PMID:23977259

  18. Comparison of hepatitis B, core, HBc, and hepatitis B antibody, anti HBs, in a presumed low risk donor population.

    PubMed

    Heck, Ellen; Cavanagh, H Dwight

    2014-09-01

    Donors screened by medical social history interview negative for high risk behavior or communicable disease history, but subsequently exhibiting reactive serological markers, emphasize importance of duel safe guarding factors for determining donor suitability. This report examines a relationship between two immunoabsorption assay tests, hepatitis B core (HBc) antibody, a required food and drug administration (FDA) test, and hepatitis B antibody (anti HBs), non-required test. Reactive serology results, 129 cases, 3,581 donors (2008-2012) for HBc as the only initially positive serological marker were subjected to anti HBs testing in this history pre-screened donor population. Enzyme linked immunoabsorption assay kits hepatitis B, core and antibody, were used in this study. All samples were initially tested for human immunodeficiency virus, hepatitis B, and hepatitis C, utilizing nucleic acid testing and antigen antibody immunoabsorption assay. Testing was performed by a FDA-registered CLEA-certified reference laboratory. Samples were deceased donor blood samples and a limited number of pre-mortem samples, separated, stored and analyzed according to manufacturer recommendation and FDA regulations. 129 reactive HBc only samples, were subsequently tested for anti HBs. Of these 129, 94 were found to be reactive for anti HBs. This represented 72 % of samples tested for antibody, a higher percentage than anticipated for a medical history negative, low risk population. PMID:24374389

  19. Preemptive therapy in the prevention of cytomegalovirus disease in high- and low-risk heart transplant recipients.

    PubMed

    Casquero, S; Rangel, D; Lage, E; Sobrino, M; Cristobo, P; Cordero, E; Cisneros, J M

    2012-09-01

    Cytomegalovirus (CMV) infection remains a major complication in recipients of solid organ transplantation. Based on available evidence, most centers are committed to an aggressive strategy, especially in high-risk patients, consisting of the use of universal prophylaxis in the posttransplantation period of maximum risk (3 months). In seropositive recipients there is no ideal model for prevention, although there is more acceptance in the international community for preemptive therapy. This paper shows the results obtained after analysis of a cohort of 86 patients undergoing heart transplantation in 2005-2011 at the Virgen del Rocío University Hospital, Seville. The 86 patients followed a strategy of preemptive therapy for both high- and low-risk recipients based on the use of antivirals for a variable period of ∼3 weeks when rising antigenemia was detected, determined by polymerase chain reaction above a set threshold. The incidence of CMV disease in our cohort was 4.6%. There are no data available from randomized clinical trials to establish which of the 2 strategies is more effective and safer in these patients, although there is a little experience with preemptive therapy in high-risk patients. Given our positive results and considering the adverse effects of antiviral prophylaxis derivatives, together with the development of resistance and the economic cost, we suggest an individualized prevention strategy at each center.

  20. Offshore Evidence for an Undocumented Tsunami Event in the 'Low Risk' Gulf of Aqaba-Eilat, Northern Red Sea.

    PubMed

    Goodman Tchernov, Beverly; Katz, Timor; Shaked, Yonathan; Qupty, Nairooz; Kanari, Mor; Niemi, Tina; Agnon, Amotz

    2016-01-01

    Although the Gulf of Aqaba-Eilat is located in the tectonically active northern Red Sea, it has been described as low-risk with regard to tsunami activity because there are no modern records of damaging tsunami events and only one tsunami (1068 AD) referred to in historical records. However, this assessment may be poorly informed given that the area was formed by and is located along the seismically active Dead Sea Fault, its population is known to fluctuate in size and literacy in part due to its harsh hyper-arid climate, and there is a dearth of field studies addressing the presence or absence of tsunamigenic deposits. Here we show evidence from two offshore cores for a major paleotsunami that occurred ~2300 years ago with a sedimentological footprint that far exceeds the scarce markers of the historically mentioned 1068 AD event. The interpretation is based on the presence of a laterally continuous and synchronous, anomalous sedimentological deposit that includes allochtonous inclusions and unique structural characteristics. Based on sedimentological parameters, these deposits could not be accounted for by other transport events, or other known background sedimentological processes.

  1. Characterization of the transport signals that mediate the nucleocytoplasmic traffic of low risk HPV11 E7

    SciTech Connect

    McKee, Courtney H.; Onder, Zeynep; Ashok, Aditya; Cardoso, Rebeca; Moroianu, Junona

    2013-08-15

    We previously discovered that nuclear import of low risk HPV11 E7 is mediated by its zinc-binding domain via a pathway that is independent of karyopherins/importins (Piccioli et al., 2010. Virology 407, 100–109). In this study we mapped and characterized a leucine-rich nuclear export signal (NES), {sub 76}IRQLQDLLL{sub 84}, within the zinc-binding domain that mediates the nuclear export of HPV11 E7 in a CRM1-dependent manner. We also identified a mostly hydrophobic patch {sub 65}VRLVV{sub 69} within the zinc-binding domain that mediates nuclear import of HPV11 E7 via hydrophobic interactions with the FG-repeats domain of Nup62. Substitutions of hydrophobic residues to alanine within the {sub 65}VRLVV{sub 69} sequence disrupt the nuclear localization of 11E7, whereas the R66A mutation has no effect. Overall the data support a model of nuclear entry of HPV11 E7 protein via hydrophobic interactions with FG nucleoporins at the nuclear pore complex. - Highlights: • HPV11 E7 has a leucine-rich nuclear export signal that mediates its nuclear export via CRM1. • HPV11 E7 interacts via its unique cNLS with the FG domain of Nup62. • Identification of a hydrophobic patch essential for nuclear localization of HPV11 E7.

  2. Offshore Evidence for an Undocumented Tsunami Event in the 'Low Risk' Gulf of Aqaba-Eilat, Northern Red Sea.

    PubMed

    Goodman Tchernov, Beverly; Katz, Timor; Shaked, Yonathan; Qupty, Nairooz; Kanari, Mor; Niemi, Tina; Agnon, Amotz

    2016-01-01

    Although the Gulf of Aqaba-Eilat is located in the tectonically active northern Red Sea, it has been described as low-risk with regard to tsunami activity because there are no modern records of damaging tsunami events and only one tsunami (1068 AD) referred to in historical records. However, this assessment may be poorly informed given that the area was formed by and is located along the seismically active Dead Sea Fault, its population is known to fluctuate in size and literacy in part due to its harsh hyper-arid climate, and there is a dearth of field studies addressing the presence or absence of tsunamigenic deposits. Here we show evidence from two offshore cores for a major paleotsunami that occurred ~2300 years ago with a sedimentological footprint that far exceeds the scarce markers of the historically mentioned 1068 AD event. The interpretation is based on the presence of a laterally continuous and synchronous, anomalous sedimentological deposit that includes allochtonous inclusions and unique structural characteristics. Based on sedimentological parameters, these deposits could not be accounted for by other transport events, or other known background sedimentological processes. PMID:26815553

  3. New Prospective for the Management of Low-Risk Pulmonary Embolism: Prognostic Assessment, Early Discharge, and Single-Drug Therapy with New Oral Anticoagulants

    PubMed Central

    2012-01-01

    Patients with pulmonary embolism (PE) can be stratified into two different prognostic categories, based on the presence or absence of shock or sustained arterial hypotension. Some patients with normotensive PE have a low risk of early mortality, defined as <1% at 30 days or during hospital stay. In this paper, we will discuss the new prospective for the optimal management of low-risk PE: prognostic assessment, early discharge, and single-drug therapy with new oral anticoagulants. Several parameters have been proposed and investigated to identify low-risk PE: clinical prediction rules, imaging tests, and laboratory markers of right ventricular dysfunction or injury. Moreover, outpatient management has been suggested for low-risk PE: it may lead to a decrease in unnecessary hospitalizations, acquired infections, death, and costs and to an improvement in health-related quality of life. Finally, the main characteristics of new oral anticoagulant drugs and the most recent published data on phase III trials on PE suggest that the single-drug therapy is a possible suitable option. Oral administration, predictable anticoagulant responses, and few drug-drug interactions of direct thrombin and factor Xa inhibitors may further simplify PE home therapy avoiding administration of low-molecular-weight heparin. PMID:24278706

  4. Left Visual Field Biases when Infants Process Faces: A Comparison of Infants at High- and Low-Risk for Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    Dundas, Eva; Gastgeb, Holly; Strauss, Mark S.

    2012-01-01

    While it is well-known that individuals with autism spectrum disorder (ASD) have difficulties processing faces, very little is known about the origins of these deficits. The current study focused on 6- and 11-month-old infants who were at either high-risk (n = 43) or low-risk (n = 31) for developing ASD based on having a sibling already diagnosed…

  5. Attractive toxic sugar baits: Control of mosquitoes with the low risk active ingredient dinotefuran and potential impacts on non-target organisms in Morocco

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We evaluated the efficacy of ATSB in the laboratory and the field with the low risk active ingredient dinotefuran against mosquito populations. Assays indicated that dinotefuran in solution with the sugar baits was ingested and resulted in high mortality of female Culex quinquefasciatus and Aedes a...

  6. The Mother-Infant Feeding Relationship across the First Year and the Development of Feeding Difficulties in Low-Risk Premature Infants

    ERIC Educational Resources Information Center

    Silberstein, Dalia; Feldman, Ruth; Gardner, Judith M.; Karmel, Bernard Z.; Kuint, Jacob; Geva, Ronny

    2009-01-01

    Although feeding problems are common during infancy and are typically accompanied by relational difficulties, little research observed the mother-infant feeding relationship across the first year as an antecedent to the development of feeding difficulties. We followed 76 low-risk premature infants and their mothers from the transition to oral…

  7. Human Papillomavirus - Prevalence of High-Risk and Low-Risk Types among Females Aged 14-59 Years, National Health and ...

    MedlinePlus

    ... Archive Data & Statistics Sexually Transmitted Diseases Figure 45. Human Papillomavirus — Prevalence of High-risk and Low-risk Types Among Females Aged 14 – 59 Years, National Health and Nutrition Examination Survey, 2003 – 2006 Recommend on Facebook Tweet ...

  8. Low-Risk Lifestyle Behaviors and All-Cause Mortality: Findings From the National Health and Nutrition Examination Survey III Mortality Study

    PubMed Central

    Zhao, Guixiang; Tsai, James; Li, Chaoyang

    2011-01-01

    Objectives. We examined the relationship between 4 low-risk behaviors—never smoked, healthy diet, adequate physical activity, and moderate alcohol consumption—and mortality in a representative sample of people in the United States. Methods. We used data from 16958 participants aged 17 years and older in the National Health and Nutrition Examination Survey III Mortality Study from 1988 to 2006. Results. The number of low-risk behaviors was inversely related to the risk for mortality. Compared with participants who had no low-risk behaviors, those who had all 4 experienced reduced all-cause mortality (adjusted hazard ratio [AHR]=0.37; 95% confidence interval [CI]=0.28, 0.49), mortality from malignant neoplasms (AHR=0.34; 95% CI=0.20, 0.56), major cardiovascular disease (AHR=0.35; 95% CI=0.24, 0.50), and other causes (AHR=0.43; 95% CI=0.25, 0.74). The rate advancement periods, representing the equivalent risk from a certain number of years of chronological age, for participants who had all 4 high-risk behaviors compared with those who had none were 11.1 years for all-cause mortality, 14.4 years for malignant neoplasms, 9.9 years for major cardiovascular disease, and 10.6 years for other causes. Conclusions. Low-risk lifestyle factors exert a powerful and beneficial effect on mortality. PMID:21852630

  9. Impact of Stress and Mitigating Information on Evaluations, Attributions, Affect, Disciplinary Choices, and Expectations of Compliance in Mothers at High and Low Risk for Child Physical Abuse

    ERIC Educational Resources Information Center

    De Paul, Joaquin; Asla, Nagore; Perez-Albeniz, Alicia; De Cadiz, Barbara Torres-Gomez

    2006-01-01

    The objective is to know if high-risk mothers for child physical abuse differ in their evaluations, attributions, negative affect, disciplinary choices for children's behavior, and expectations of compliance. The effect of a stressor and the introduction of mitigating information are analyzed. Forty-seven high-risk and 48 matched low-risk mothers…

  10. Expressed Emotion in Mothers of Currently Depressed, Remitted, High-Risk, and Low-Risk Youth: Links to Child Depression Status and Longitudinal Course

    ERIC Educational Resources Information Center

    Silk, Jennifer S.; Ziegler, Melissa L.; Whalen, Diana J.; Dahl, Ronald E.; Ryan, Neal D.; Dietz, Laura J.; Birmaher, Boris; Axelson, David A.; Williamson, Douglas E.

    2009-01-01

    This study examined expressed emotion in the families of children and adolescents who were (a) in a current episode of Major Depressive Disorder (MDD), (b) in remission from a past episode of MDD, (c) at high familial risk for developing MDD, and (d) low-risk controls. Participants were 109 mother-child dyads (children ages 8-19). Expressed…

  11. Identification of an obese eating style in 4-year-old children born at high and low risk for obesity.

    PubMed

    Berkowitz, Robert I; Moore, Renee' H; Faith, Myles S; Stallings, Virginia A; Kral, Tanja V E; Stunkard, Albert J

    2010-03-01

    This study tested whether children's eating behavior and parental feeding prompts during a laboratory test meal differ among children born at high risk (HR) or low risk (LR) for obesity and are associated with excess child weight gain. At 4 years of age, 32 HR children (mean maternal prepregnancy BMI = 30.4 kg/m(2)) and 29 LR children (maternal BMI = 19.6 kg/m(2)) consumed a test meal in which their eating behavior was assessed, including rate of caloric consumption, mouthfuls/min, and requests for food. Parental prompts for the child to eat also were measured at year 4, and child body composition was measured at ages 4 and 6 years. T-tests, and logistic and multiple regression analyses tested study aims. Results indicated that HR and LR children did not differ in eating rate or parental feeding prompts. Greater maternal BMI, child mouthfuls of food/min, and total caloric intake/min during the test meal predicted an increased risk of being overweight or obese at age 6, whereas greater active mealtime was associated with a reduced risk of being overweight or obese. Regression analyses indicated that only mouthfuls of food/min predicted changes in BMI from 4 to 6 years, and mouthfuls of food/min and gender predicted 2-year changes in sum of skinfolds and total body fat. Thus, a rapid eating style, characterized by increased mouthfuls of food/min, may be a behavioral marker for the development of childhood obesity. PMID:19779474

  12. Energy density at a buffet-style lunch differs for adolescents born at high and low risk of obesity.

    PubMed

    Kral, Tanja V E; Stunkard, Albert J; Berkowitz, Robert I; Stettler, Nicolas; Stallings, Virginia A; Kabay, April; Faith, Myles S

    2009-12-01

    The energy density (ED; kcal/g) of foods, when manipulated in the laboratory, affects short-term energy intake. The aim of this study was to examine if, when given a choice, dietary ED (foods only) and energy intake (expressed as a percentage of subjects' estimated daily energy requirement; EER) at a self-selected, single meal differ for teens born with a different familial predisposition to obesity and as a function of their sex. Subjects (13 males, 17 females) were 12years of age and born at high risk (HR; n=15) or low risk (LR; n=15) for obesity based on maternal pre-pregnancy body mass index (BMI; kg/m(2)). The buffet meal, served for lunch and consumed ad libitum, consisted of a variety of foods and beverages with a range in ED. HR subjects consumed a more energy-dense meal (foods only) than LR subjects (1.84 vs. 1.42kcal/g; P=0.02) and males consumed a more energy-dense meal than females (1.83 vs. 1.43kcal/g; P=0.03). Total energy intake, when expressed as a percentage of subjects' daily EER, did not differ between HR and LR subjects (42% vs. 33%; P=0.16). Males, compared to females, consumed ~59% more energy from foods and beverages during the meal (46 vs. 29%; P=0.008). During a single multi-item lunch meal, teens with a familial predisposition to obesity and males, independent of their obesity risk status, self-selected a more energy-dense meal. Familial risk for obesity, through either genetic or environmental pathways, may facilitate a more energy-dense diet. PMID:19778749

  13. Long-Term Outcomes From a Prospective Trial of Stereotactic Body Radiotherapy for Low-Risk Prostate Cancer

    SciTech Connect

    King, Christopher R.; Brooks, James D.; Gill, Harcharan; Presti, Joseph C.

    2012-02-01

    Purpose: Hypofractionated radiotherapy has an intrinsically different normal tissue and tumor radiobiology. The results of a prospective trial of stereotactic body radiotherapy (SBRT) for prostate cancer with long-term patient-reported toxicity and tumor control rates are presented. Methods and Materials: From 2003 through 2009, 67 patients with clinically localized low-risk prostate cancer were enrolled. Treatment consisted of 36.25 Gy in 5 fractions using SBRT with the CyberKnife as the delivery technology. No patient received hormone therapy. Patient self-reported bladder and rectal toxicities were graded on the Radiation Therapy Oncology Group scale (RTOG). Results: Median follow-up was 2.7 years. There were no grade 4 toxicities. Radiation Therapy Oncology Group Grade 3, 2, and 1 bladder toxicities were seen in 3% (2 patients), 5% (3 patients), and 23% (13 patients) respectively. Dysuria exacerbated by urologic instrumentation accounted for both patients with Grade 3 toxicity. Urinary incontinence, complete obstruction, or persistent hematuria was not observed. Rectal Grade 3, 2, and 1 toxicities were seen in 0, 2% (1 patient), and 12.5% (7 patients), respectively. Persistent rectal bleeding was not observed. Low-grade toxicities were substantially less frequent with QOD vs. QD dose regimen (p = 0.001 for gastrointestinal and p = 0.007 for genitourinary). There were two prostate-specific antigen (PSA), biopsy-proven failures with negative metastatic workup. Median PSA at follow-up was 0.5 {+-} 0.72 ng/mL. The 4-year Kaplan-Meier PSA relapse-free survival was 94% (95% confidence interval, 85%-102%). Conclusion: Significant late bladder and rectal toxicities from SBRT for prostate cancer are infrequent. PSA relapse-free survival compares favorably with other definitive treatments. The current evidence supports consideration of stereotactic body radiotherapy among the therapeutic options for localized prostate cancer.

  14. Energy density at a buffet-style lunch differs for adolescents born at high and low risk of obesity

    PubMed Central

    Kral, Tanja V.E.; Stunkard, Albert J.; Berkowitz, Robert I.; Stettler, Nicolas; Stallings, Virginia A.; Kabay, April; Faith, Myles S.

    2009-01-01

    The energy density (ED; kcal/g) of foods, when manipulated in the laboratory, affects short-term energy intake. The aim of this study was to examine if, when given a choice, dietary ED (foods only) and energy intake (expressed as a percentage of subjects’ estimated daily energy requirement) at a self-selected, single meal differs for teens born with a different familial predisposition to obesity and as a function of their sex. Subjects (13 males, 17 females) were 12 years of age and born at high-risk (HR; n = 15) or low-risk (LR; n = 15) for obesity based on maternal pre-pregnancy body mass index (BMI; kg/m2). The buffet meal, served for lunch and consumed ad libitum, consisted of a variety of foods and beverages with a range in ED. HR subjects consumed a more energy-dense meal (foods only) than LR subjects (1.84 vs. 1.42 kcal/g; P = 0.02) and males consumed a more energy-dense meal than females (1.83 vs. 1.43 kcal/g; P = 0.03). Total energy intake, when expressed as a percentage of subjects’ daily EER, did not differ between HR and LR subjects (42% vs. 33%; P = 0.16). Males, compared to females, consumed ∼ 59% more energy from foods and beverages during the meal (46 vs. 29%; P = 0.008). During a single multi-item lunch meal, teens with a familial predisposition to obesity and males, independent of their obesity risk status, self-selected a more energy-dense meal. Familial risk for obesity, through either genetic or environmental pathways, may facilitate a more energy-dense diet. PMID:19778749

  15. The Effect of ABO Blood Incompatibility on Corneal Transplant Failure in Conditions with Low Risk of Graft Rejection

    PubMed Central

    Dunn, Steven P.; Stark, Walter J.; Doyle Stulting, R.; Lass, Jonathan H.; Sugar, Alan; Pavilack, Mark A.; Smith, Patricia W.; Tanner, Jean Paul; Dontchev, Mariya; Gal, Robin L.; Beck, Roy W.; Kollman, Craig; Mannis, Mark J.; Holland, Edward J.

    2009-01-01

    Purpose To determine whether corneal graft survival over a five-year follow-up period was affected by ABO blood type compatibility in participants in the Cornea Donor Study undergoing corneal transplantation principally for Fuchs’ dystrophy or pseudophakic corneal edema, conditions at low risk for graft rejection. Design Multi-center prospective, double-masked, clinical trial Methods ABO blood group compatibility was determined for 1,002 donors and recipients. During a five-year follow-up period, episodes of graft rejection were documented, and graft failures were classified as to whether or not they were due to immunologic rejection. Endothelial cell density was determined by a central reading center for a subset of subjects. Results ABO donor-recipient incompatibility was not associated with graft failure due to any cause including graft failure due to rejection, or with the occurrence of a rejection episode. The five-year cumulative incidence of graft failure due to rejection was 6% for recipients with ABO recipient-donor compatibility and 4% for those with ABO incompatibility (hazard ratio 0.65, 95% confidence interval 0.33 to 1.25, p=0.20). The five-year incidence for a definite rejection episode, irrespective of whether graft failure ultimately occurred, was 12% for ABO compatible compared with 8% for ABO incompatible cases (p=0.09). Among clear grafts at five years, percent loss of endothelial cells was similar in ABO compatible and incompatible cases. Conclusions In patients undergoing penetrating keratoplasty for Fuchs’ dystrophy or pseudophakic corneal edema, ABO matching is not indicated since ABO incompatibility does not increase the risk of transplant failure due to graft rejection. PMID:19056078

  16. Radioiodine remnant ablation in low-risk differentiated thyroid cancer patients who had R0 dissection is an over treatment

    PubMed Central

    Bal, Chandrasekhar; Ballal, Sanjana; Soundararajan, Ramya; Chopra, Saurav; Garg, Aayushi

    2015-01-01

    Low-risk (LR) differentiated thyroid cancer (DTC) patients should be ablated or not, albeit, with small dose of radioiodine is highly controversial. We hypothesized that those LR DTC patients who were surgically ablated need no radioiodine remnant ablation (RRA). This study aims to evaluate the long-term outcome in these two groups of patients. Retrospective cohort study conducted from January 1991 to December 2012. Based on extent of surgical resection and histopathology, LR DTC patients were classified as Gr-1: 169 patients, who were surgically ablated; Gr-2: 153 patients, who had significant remnant in thyroid bed. Basal parameters were comparable between two groups except pretherapy 24 h radioiodine uptake (0.16 ± 0.01% vs. 5.64 ± 0.46%; P < 0.001). No patient received RRA in Gr-1; Gr-2 patients were administered 30 mCi 131I. Total number of events (recurrence, persistent, and progression of disease), with median follow up of 10.3 years, was observed in 10/322 (3.1%) of LR DTC patients. Only one patient had disease recurrence from Gr-1, who became disease-free after radioiodine therapy. Similarly, one patient from 126, who was ablated with single dose of RRA, had recurrence from Gr-2. However, 8/27 (29.7%) patients from Gr-2 had persistent disease; even two of them subsequently developed disease progression, who failed first-dose of RRA. The event-free survival rates were 99.4% and 94.1% (P = 0.006) in Gr-1 and Gr-2, respectively. RRA is an overtreatment in surgically ablated LR DTC patients. Successfully ablated RRA patients also had similar long-term outcome, however, those who failed, should be re-stratified as intermediate-risk category, and managed aggressively. PMID:25755077

  17. Echocardiographic Predictors for Left Ventricular Remodeling after Acute ST Elevation Myocardial Infarction with Low Risk Group: Speckle Tracking Analysis

    PubMed Central

    Na, Hyun-Min; Lee, Joo Myung; Cha, Myung-Jin; Yoon, Yeonyee E.; Lee, Seung-Pyo; Kim, Hyung-Kwan; Kim, Yong-Jin; Sohn, Dae-Won

    2016-01-01

    Background We sought to assess echocardiographic predictors of left ventricular (LV) adverse remodeling after successfully reperfused acute ST elevation myocardial infarction (STEMI). LV remodeling is commonly found in STEMI patients and it may suggest adverse outcome in acute myocardial infarction. We sought to identify whether 2D strain and torsion be independent parameters for prediction of LV adverse remodeling. Methods We investigated 208 patients with low-risk STEMI patients who had follow up echocardiography at 6 or more months. After clinical assessments, all patients received revascularization according to current guideline. LV remodeling was defined as > 20% increase in end-diastolic volume (EDV) at follow up. Results During the follow-up (11.9 ± 5.3 months), 53 patients (25.5%) showed LV remodeling. In univariate analysis, EDV, end-systolic volume, deceleration time (DT), CK-MB, and global longitudinal strain (GLS) were associated with LV remodeling. In multivariate analysis, EDV [hazard ratio (HR): 0.922, 95% confidence interval (CI): 0.897–0.948, p< 0.001], GLS (HR: 0.842, 95% CI: 0.728–0.974, p = 0.020), DT (HR: 0.989, 95% CI: 0.980–0.998, p = 0.023) and CK-MB (HR: 1.003, 95% CI: 1.000–1.005, p = 0.033) independently predicted LV remodeling. However, global circumferential strain, net twist, and twist or untwist rate were not associated with remodeling. Conclusion Of various parameters of speckle strain, only GLS predicted adverse remodeling in STEMI patients. PMID:27358705

  18. Prognostic significance of early ischemia after acute myocardial infarction in low-risk patients. IRES (Ischemia Residua) Study Group.

    PubMed

    Silva, P; Galli, M; Campolo, L

    1993-05-15

    Early postinfarction angina is generally believed to imply an unfavorable prognosis. However, most of the published information devices from data collected in the prethrombolytic era, with widely differing populations and definitions of early angina, and very little data pertinent to low-risk patients are available. This collaborative study prospectively assessed the incidence of early recurrent ischemia after thrombolysis, as well as its prognostic significance, in 453 consecutive patients aged < or = 70 years with an uncomplicated course in the first 24 hours of a first myocardial infarction participating in the second Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2) trial. Early recurrent ischemia (spontaneous, transient ST depression or elevation of > 1 mm and/or T-wave inversion), assessed in the coronary care unit with continuous clinical and electrocardiographic monitoring, was documented in 35 of 453 patients (8%) and was unrelated to sex, age, electrocardiographic location, Q-wave or non-Q-wave infarction, thrombolytic agent and time to its administration. In-hospital cardiac events (7 deaths, 19 nonfatal reinfarctions and 8 urgent revascularizations) occurred in 15 of 35 patients (43%) with versus 19 of 418 without (4.5%) recurrent ischemia (p < 0.001). At the 6-month follow-up of 352 medically treated patients who did not have in-hospital events, the incidence of death, reinfarction and recurrent angina was comparable between patients with (2 of 18, 11%) and without (62 of 334, 19%) early ischemia (p = NS). With use of stepwise multivariate analysis, early ischemia was the only significant predictor of in-hospital cardiac events (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Outpatient treatment of low-risk venous thromboembolism with monotherapy oral anticoagulation: patient quality of life outcomes and clinician acceptance

    PubMed Central

    Kline, Jeffrey A; Kahler, Zachary P; Beam, Daren M

    2016-01-01

    Background Oral monotherapy anticoagulation has facilitated home treatment of venous thromboembolism (VTE) in outpatients. Objectives The aim of this study was to measure efficacy, safety, as well as patient and physician perceptions produced by a protocol that selected VTE patients as low-risk patients by the Hestia criteria, and initiated home anticoagulation with an oral factor Xa antagonist. Methods Patients were administered the Venous Insufficiency Epidemiological and Economic Study Quality of life/Symptoms questionnaire [VEINEs QoL/Sym] and the physical component summary [PCS] from the Rand 36-Item Short Form Health Survey [SF36]). The primary outcomes were VTE recurrence and hemorrhage at 30 days. Secondary outcomes compared psychometric test scores between patients with deep vein thrombosis (DVT) to those with pulmonary embolism (PE). Patient perceptions were abstracted from written comments and physician perceptions specific to PE outpatient treatment obtained from structured survey. Results From April 2013 to September 2015, 253 patients were treated, including 67 with PE. Within 30 days, 2/253 patients had recurrent DVT and 2/253 had major hemorrhage; all four had DVT at enrollment. The initial PCS scores did not differ between DVT and PE patients (37.2±13.9 and 38.0±12.1, respectively) and both DVT and PE patients had similar improvement over the treatment period (42.2±12.9 and 43.4±12.7, respectively), consistent with prior literature. The most common adverse event was menorrhagia, present in 15% of women. Themes from patient-written responses reflected satisfaction with increased autonomy. Physicians’ (N=116) before-to-after protocol comfort level with home treatment of PE increased 48% on visual analog scale. Conclusion Hestia-negative VTE patients treated with oral monotherapy at home had low rates of VTE recurrence and bleeding, as well as quality of life measurements similar to prior reports. PMID:27143861

  20. SERIAL NECK ULTRASOUND IS MORE LIKELY TO IDENTIFY FALSE-POSITIVE ABNORMALITIES THAN CLINICALLY SIGNIFICANT DISEASE IN LOW-RISK PAPILLARY THYROID CANCER PATIENTS

    PubMed Central

    Yang, Samantha Peiling; Bach, Ariadne M.; Tuttle, R. Michael; Fish, Stephanie A.

    2016-01-01

    Objective American Thyroid Association (ATA) low-risk papillary thyroid cancer (PTC) patients without structural evidence of disease on initial posttreatment evaluation have a low risk of recurrence. Despite this, most patients undergo frequent surveillance neck ultrasound (US). The objective of the study was to evaluate the clinical utility of routine neck US in ATA low-risk PTC patients with no structural evidence of disease after their initial thyroid surgery. Methods We performed a retrospective review of 171 ATA low-risk PTC patients after total thyroidectomy, with or without radioactive iodine (RAI) ablation, who had a neck US without suspicious findings after therapy. The main outcome measure was a comparison of the frequency of finding false-positive US abnormalities and the frequency of identifying structural disease recurrence. Results Over a median follow-up of 8 years, 171 patients underwent a median of 5 neck US (range 2–17). Structural recurrence with low-volume disease (≤1 cm) was identified in 1.2% (2/171) of patients at a median of 2.8 years (range 1.6–4.1 years) after their initial diagnosis. Recurrence was associated with rising serum thyroglobulin (Tg) level in 1 of the 2 patients and was detected without signs of biochemical recurrence in the other patient. Conversely, false-positive US abnormalities were identified in 67% (114/171) of patients after therapy, leading to additional testing without identifying clinically significant disease. Conclusion In ATA low-risk patients without structural evidence of disease on initial surveillance evaluation, routine screening US is substantially more likely to identify false-positive results than clinically significant structural disease recurrence. PMID:26372300

  1. Anal Cytology and Human Papillomavirus Genotyping in Women With a History of Lower Genital Tract Neoplasia Compared With Low-Risk Women

    PubMed Central

    Robison, Katina; Cronin, Beth; Bregar, Amy; Luis, Christine; DiSilvestro, Paul; Schechter, Steven; Pisharodi, Latha; Raker, Christina; Clark, Melissa

    2016-01-01

    OBJECTIVE To compare the prevalence of abnormal anal cytology and high-risk human papillomavirus (HPV) among women with a history of HPV-related genital neoplasia with women without a history of HPV-related genital neoplasia. METHODS A cross-sectional cohort study was performed from December 2012 to February 2014. Women were recruited from outpatient clinics at an academic medical center. Women with a history of high-grade cervical, vulvar, or vaginal cytology, dysplasia, or cancer were considered the high-risk group. Women with no history of high-grade anogenital dysplasia or cancer were considered the low-risk group. Human immunodeficiency virus–positive women were excluded. Anal cytology and HPV genotyping were performed. Women with abnormal anal cytology were referred for high-resolution anoscopy. RESULTS There were 190 women in the high-risk group and 83 in the low-risk group. The high-risk group was slightly older: 57 years compared with 47 years (P=.045); 21.7% of low-risk women had abnormal anal cytology compared with 41.2% of high-risk women (P=.006). High-risk HPV was detected in the anal canal of 1.2% of the low-risk group compared with 20.8% of the high-risk group (P<.001). Among women who underwent anoscopy, no anal dysplasia was detected in the low-risk group, whereas 13.4% in the high-risk group had anal dysplasia with 4.2% having anal intraepithelial neoplasia 2 or greater (P<.001). CONCLUSION Human immunodeficiency virus–negative women with a history of lower genital tract neoplasia are more likely to have positive anal cytology, anal high-risk HPV, and anal intraepithelial neoplasia. Anal cancer screening should be considered for these high-risk women. PMID:26551180

  2. Currarino syndrome: Rare clinical variants

    PubMed Central

    Kumar, Bindey; Sinha, Amit Kumar; Kumar, Prem; Kumar, Anil

    2016-01-01

    Currarino syndrome (CS) is a rare clinical condition. The classical presentation includes a triad of sacral anomaly, anorectal malformations, and presacral mass. This syndrome belongs to the group of persistent neuroenteric malformations. This article presents two cases of Currarino syndrome, where there was rare clinical variants such as rectal atresia in the first case and rectal stenosis in the second case. The clinical presentations were very deceptive as the first case presented as high anorectal malformation and the second case was simulating Hirschprung's disease.

  3. Currarino syndrome: Rare clinical variants

    PubMed Central

    Kumar, Bindey; Sinha, Amit Kumar; Kumar, Prem; Kumar, Anil

    2016-01-01

    Currarino syndrome (CS) is a rare clinical condition. The classical presentation includes a triad of sacral anomaly, anorectal malformations, and presacral mass. This syndrome belongs to the group of persistent neuroenteric malformations. This article presents two cases of Currarino syndrome, where there was rare clinical variants such as rectal atresia in the first case and rectal stenosis in the second case. The clinical presentations were very deceptive as the first case presented as high anorectal malformation and the second case was simulating Hirschprung's disease. PMID:27695213

  4. Histone variants: emerging players in cancer biology

    PubMed Central

    Vardabasso, Chiara; Hasson, Dan; Ratnakumar, Kajan; Chung, Chi-Yeh; Duarte, Luis F.

    2014-01-01

    Histone variants are key players in shaping chromatin structure, and, thus, in regulating fundamental cellular processes such as chromosome segregation and gene expression. Emerging evidence points towards a role for histone variants in contributing to tumor progression, and, recently, the first cancer-associated mutation in a histone variant-encoding gene was reported. In addition, genetic alterations of the histone chaperones that specifically regulate chromatin incorporation of histone variants are rapidly being uncovered in numerous cancers. Collectively, these findings implicate histone variants as potential drivers of cancer initiation and/or progression, and, therefore, targeting histone deposition or the chromatin remodeling machinery may be of therapeutic value. Here, we review the mammalian histone variants of the H2A and H3 families in their respective cellular functions, and their involvement in tumor biology. PMID:23652611

  5. Reliably Detecting Clinically Important Variants Requires Both Combined Variant Calls and Optimized Filtering Strategies

    PubMed Central

    Field, Matthew A.; Cho, Vicky

    2015-01-01

    A diversity of tools is available for identification of variants from genome sequence data. Given the current complexity of incorporating external software into a genome analysis infrastructure, a tendency exists to rely on the results from a single tool alone. The quality of the output variant calls is highly variable however, depending on factors such as sequence library quality as well as the choice of short-read aligner, variant caller, and variant caller filtering strategy. Here we present a two-part study first using the high quality ‘genome in a bottle’ reference set to demonstrate the significant impact the choice of aligner, variant caller, and variant caller filtering strategy has on overall variant call quality and further how certain variant callers outperform others with increased sample contamination, an important consideration when analyzing sequenced cancer samples. This analysis confirms previous work showing that combining variant calls of multiple tools results in the best quality resultant variant set, for either specificity or sensitivity, depending on whether the intersection or union, of all variant calls is used respectively. Second, we analyze a melanoma cell line derived from a control lymphocyte sample to determine whether software choices affect the detection of clinically important melanoma risk-factor variants finding that only one of the three such variants is unanimously detected under all conditions. Finally, we describe a cogent strategy for implementing a clinical variant detection pipeline; a strategy that requires careful software selection, variant caller filtering optimizing, and combined variant calls in order to effectively minimize false negative variants. While implementing such features represents an increase in complexity and computation the results offer indisputable improvements in data quality. PMID:26600436

  6. A new high activity plasma cholinesterase variant.

    PubMed Central

    Krause, A; Lane, A B; Jenkins, T

    1988-01-01

    A South African Afrikaans speaking family is reported in which a new high activity plasma cholinesterase variant was found to occur in the mother and son. The variant has the same electrophoretic mobility as the "usual' enzyme, but greater heat stability. Its higher specific activity is associated with a normal number of enzyme molecules. The variant may be inherited as a dominant trait, though its locus is uncertain. Images PMID:3225823

  7. Subtotal Gastrectomy With Billroth II Anastomosis Is Associated With a Low Risk of Ischemic Stroke in Peptic Ulcer Disease Patients

    PubMed Central

    Chen, Chien-Hua; Lin, Cheng-Li; Kao, Chia-Hung

    2016-01-01

    Abstract Duodenal diversion can ameliorate lipid and glucose metabolism. We assessed the risk of stroke after subtotal gastrectomy with Billroth II anastomosis (SGBIIA) in peptic ulcer disease (PUD). We identified 6425 patients who received SGBIIA for PUD between 1998 and 2010 from the Taiwan National Health Insurance Research Database as the study cohort; we frequency-matched them with 25,602 randomly selected controls from the PUD population who did not receive SGBIIA according to age, sex, index year, and comorbidities including hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease, congestive heart failure, chronic kidney disease, chronic obstructive pulmonary disease (COPD), and obesity. All patients were followed until the end of 2011 to determine the incidence of stroke. The incidence of stroke was lower in patients in the SGBIIA cohort than in those in the non-SGBIIA cohort (18.9 vs 22.9 per 1000 person-years, adjusted hazard ratio [aHR] 0.80, 95% confidence interval [CI] 0.72–0.89, P < 0.001). The risk of ischemic stroke (aHR 0.77, 95% CI 0.69–0.86, P < 0.001), rather than hemorrhagic stroke (aHR 1.00, 95% CI 0.78–1.28), was lower for the SGBIIA cohort than for the non-SGBIIA cohort according to the multivariable Cox proportional hazard regression analysis. The relative risk of ischemic stroke after SGBIIA was lower in men (aHR 0.77, 95% CI 0.69–0.86) than in women (aHR 0.80, 95% CI 0.65–0.99) and in patients aged ≥65 years (aHR 0.72, 95% CI 0.63–0.81) than in those of other age groups (≤49 years, aHR 0.82, 95% CI 0.48–1.39; 50–64 years, aHR 1.01, 95% CI 0.79–1.28). The relative risk of ischemic stroke after SGBIIA was also reduced in patients with comorbidities (aHR 0.84, 5% CI 0.75–0.95) rather than in those without comorbidities (aHR 0.81, 95% CI 0.59–1.12). SGBIIA is associated with a low risk of ischemic stroke for PUD patients, and its protective effect is prominent in men, patients aged ≥65

  8. Early Discharge in Low-Risk Patients Hospitalized for Acute Coronary Syndromes: Feasibility, Safety and Reasons for Prolonged Length of Stay

    PubMed Central

    Laurencet, Marie-Eva; Girardin, François; Rigamonti, Fabio; Bevand, Anne; Meyer, Philippe; Carballo, David; Roffi, Marco; Noble, Stéphane

    2016-01-01

    Introduction Length of hospital stay (LHS) is an indicator of clinical effectiveness. Early hospital discharge (≤72 hours) is recommended in patients with acute coronary syndromes (ACS) at low risk of complications, but reasons for prolonged LHS poorly reported. Methods We collected data of ACS patients hospitalized at the Geneva University Hospitals from 1st July 2013 to 30th June 2015 and used the Zwolle index score to identify patients at low risk (≤ 3 points). We assessed the proportion of eligible patients who were successfully discharged within 72 hours and the reasons for prolonged LHS. Outcomes were defined as adherence to recommended therapies, major adverse events at 30 days and patients' satisfaction using a Likert-scale patient-reported questionnaire. Results Among 370 patients with ACS, 255 (68.9%) were at low-risk of complications but only 128 (50.2%)were eligible for early discharge, because of other clinical reasons for prolonged LHS (e.g. staged coronary revascularization, cardiac monitoring) in 127 patients (49.8%). Of the latter, only 45 (35.2%) benefitted from an early discharge. Reasons for delay in discharge in the remaining 83 patients (51.2%) were mainly due to delays in additional investigations, titration of medical therapy, admission or discharge during weekends. In the early discharge group, at 30 days, only one patient (2.2%) had an adverse event (minor bleeding), 97% of patients were satisfied by the medical care. Conclusion Early discharge was successfully achieved in one third of eligible ACS patients at low risk of complications and appeared sufficiently safe while being overall appreciated by the patients. PMID:27551861

  9. Pathological Examination of Radical Prostatectomy Specimens in Men with Very Low Risk Disease at Biopsy Reveals Distinct Zonal Distribution of Cancer in Black American Men

    PubMed Central

    Sundi, Debasish; Kryvenko, Oleksandr N.; Carter, H. Ballentine; Ross, Ashley E.; Epstein, Jonathan I.; Schaeffer, Edward M.

    2014-01-01

    Purpose Of men with very low risk prostate cancer at biopsy recent evidence shows that black American men are at greater risk for adverse oncologic outcomes after radical prostatectomy. We studied radical prostatectomy specimens from black and white men at very low risk to determine whether there are systematic pathological differences. Materials and Methods Radical prostatectomy specimens were evaluated in men with National Comprehensive Cancer Network® (NCCN) very low risk prostate cancer. At diagnosis all men underwent extended biopsy sampling (10 or more cores) and were treated in the modern Gleason grade era. We analyzed tumor volume, grade and location in 87 black and 89 white men. For each specimen the dominant nodule was defined as the largest tumor with the highest grade. Results Compared to white men, black men were more likely to have significant prostate cancer (61% vs 29%), Gleason 7 or greater (37% vs 11%, each p <0.001) and a volume of greater than 0.5 cm3 (45% vs 21%, p = 0.001). Dominant nodules in black men were larger (median 0.28 vs 0.13 cm3, p = 0.002) and more often anterior (51% vs 29%, p = 0.003). In men who underwent pathological upgrading the dominant nodule was also more frequently anterior in black than in white men (59% vs 0%, p = 0.001). Conclusions Black men with very low risk prostate cancer at diagnosis have a significantly higher prevalence of anterior cancer foci that are of higher grade and larger volume. Enhanced imaging or anterior zone sampling may detect these significant anterior tumors, improving the outcome in black men considering active surveillance. PMID:23770146

  10. Admission rates for emergency department patients with venous thromboembolism and estimation of the proportion of low risk pulmonary embolism patients: a US perspective

    PubMed Central

    Singer, Adam J.; Thode, Henry C.; Peacock, W. Frank

    2016-01-01

    Objective Introduction of target specific anticoagulants and recent guidelines encourage outpatient management of low risk patients with venous thromboembolism. We describe hospital admission rates over time for patients presenting to US emergency departments (EDs) with deep vein thrombosis (DVT) and pulmonary embolism (PE) and estimate the proportion of low-risk PE patients who could potentially be managed as outpatients. Methods We performed a structured analysis of the National Hospital Ambulatory Medical Care Survey (a nationally representative weighted sampling of US ED visits) database for the years 2006–2010 including all adult patients with a primary diagnosis of DVT or PE. Simplified pulmonary embolus scoring index (sPESI) scores were determined in patients with PE to identify low risk patients. Results There were an estimated 652,000 and 394,000 ED visits for DVT and PE over the 5-year period (0.17%). Mean (SE) age was 59 (1.3), 50% were female, and 40% were > 65 years. Admission rates for DVT and PE were 52% and 90% respectively with no significant changes over time. In patients with DVT, predictors for admission were age (odds ratio, 1.03 per year of age [95% confidence interval, 1.01 to 1.05]) and race (odds ratio, 4.1 [95% confidence interval, 0.9 to 19.8] for Hispanics and 2.9 [1.2 to 7.4] for Blacks). Of all ED patients with PE, 51% were low risk based on sPESI scores. Conclusion Admission rates for DVT and PE have remained high and unchanged, especially with PE, minorities, and in older patients. Based on sPESI scores, up to half of PE patients might be eligible for early discharge or outpatient therapy. PMID:27752630

  11. Impact of SNP array karyotyping on the diagnosis and the outcome of chronic myelomonocytic leukemia with low risk cytogenetic features or no metaphases.

    PubMed

    Palomo, Laura; Xicoy, Blanca; Garcia, Olga; Mallo, Mar; Ademà, Vera; Cabezón, Marta; Arnan, Montse; Pomares, Helena; José Larrayoz, María; José Calasanz, María; Maciejewski, Jaroslaw P; Huang, Dayong; Shih, Lee-Yung; Ogawa, Seishi; Cervera, Jose; Such, Esperanza; Coll, Rosa; Grau, Javier; Solé, Francesc; Zamora, Lurdes

    2016-02-01

    Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic disorder with heterogeneous clinical, morphological and genetic characteristics. Clonal cytogenetic abnormalities are found in 20-30% of patients with CMML. Patients with low risk cytogenetic features (normal karyotype and isolated loss of Y chromosome) account for ∼80% of CMML patients and often fall into the low risk categories of CMML prognostic scores. We hypothesized that single nucleotide polymorphism arrays (SNP-A) karyotyping could detect cryptic chromosomal alterations with prognostic impact in these subgroup of patients. SNP-A were performed at diagnosis in 128 CMML patients with low risk karyotypes or uninformative results for conventional G-banding cytogenetics (CC). Copy number alterations (CNAs) and regions of copy number neutral loss of heterozygosity (CNN-LOH) were detected in 67% of patients. Recurrent CNAs included gains in regions 8p12 and 21q22 as well as losses in 10q21.1 and 12p13.2. Interstitial CNN-LOHs were recurrently detected in the following regions: 4q24-4q35, 7q32.1-7q36.3, and 11q13.3-11q25. Statistical analysis showed that some of the alterations detected by SNP-A associated with the patients' outcome. A shortened overall survival (OS) and progression free survival (PFS) was observed in cases where the affected size of the genome (considering CNAs and CNN-LOHs) was >11 Mb. In addition, presence of interstitial CNN-LOH was predictive of poor OS. Presence of CNAs (≥1) associated with poorer OS and PFS in the patients with myeloproliferative CMML. Overall, SNP-A analysis increased the diagnostic yield in patients with low risk cytogenetic features or uninformative CC and added prognostic value to this subset of patients. PMID:26509444

  12. Rare hemoglobin variants in Tunisian population.

    PubMed

    Zorai, A; Moumni, I; Mosbahi, I; Douzi, K; Chaouachi, D; Guemira, F; Abbes, S

    2015-04-01

    During the last 30 years, many studies concerning hemoglobinopathies were realized among Tunisians. More than twenty different thalassemic alleles were detected on the β-globin gene, and less are affecting the α-globin genes. Unusual hemoglobin (Hb) variants other than Hb S, Hb C, and Hb O-arab, which are the most frequent variants in Tunisia, were also detected. Eight Tunisian subjects were studied at phenotypic and molecular levels. Hematological indices and hemoglobin (Hb) pattern were performed by alkaline electrophoresis and isoelectric focusing (IEF),and the Hb fractions were quantitated by cation exchange HPLC. On genomic level, coding regions were amplified by polymerase chain reaction (PCR) followed by a sequencing of the purified PCR products using the dye terminator method. Seven uncommon Hb variants were detected and described for the first time among Tunisians. HbA2-Tunis [δ46(CD5), Gly → Glu, GGG → GAG] is the newly described δ-chain variant in our laboratory, and some other variants (Hb Constant Spring, G San Jose, and Hb J-Bangkok) are very uncommon in the Mediterranean region. We present here an updated review of the Hb variants detected among Tunisians. Twenty-one rare Hb variants were detected affecting the α1-, α2-, δ-, γ-, and β-globin genes, leading in some cases to a severe phenotype especially when the stability is completely altered. The ethnical history of Tunisia could explain this important variability of the observed rare Hb variants. PMID:24905386

  13. MTDH genetic variants in colorectal cancer patients

    PubMed Central

    Gnosa, Sebastian; Ticha, Ivana; Haapaniemi, Staffan; Sun, Xiao-Feng

    2016-01-01

    The colorectal carcinogenesis is a complex process encompassing genetic alterations. The oncoprotein AEG-1, encoded by the MTDH gene, was shown previously to be involved in colorectal cancer (CRC). The aim of this study was to determine the frequency and the spectrum of MTDH variants in tumor tissue, and their relationship to clinicopathological variables in CRC patients. The study included tumors from 356 unselected CRC patients. Mutation analysis of the MTDH gene, including coding region and adjacent intronic sequences, was performed by direct DNA sequencing. The corresponding normal colorectal tissue was analyzed in the carriers of exonic variant to confirm germline or somatic origin. We detected 42 intronic variants, where 25 were novel. Furthermore, we found 8 exonic variants of which four, one missense (c.977C > G-germline) and three frameshift mutations (c.533delA-somatic, c.1340dupA-unknown origin, c.1731delA-unknown origin), were novel. In silico prediction analyses suggested four deleterious variants (c.232G > T, c.533delA, c.1340dupA, and c.1731delA). There were no correlations between the MTDH variants and tumor stage, differentiation or patient survival. We described several novel exonic and intronic variants of the MTDH gene. The detection of likely pathogenic truncating mutations and alterations in functional protein domains indicate their clinical significance, although none of the variants had prognostic potential. PMID:26983693

  14. Beta-glucosidase I variants with improved properties

    DOEpatents

    Bott, Richard R.; Kaper, Thijs; Kelemen, Bradley; Goedegebuur, Frits; Hommes, Ronaldus Wilhelmus; Kralj, Slavko; Kruithof, Paulien; Nikolaev, Igor; Van Der Kley, Wilhelmus Antonious Hendricus; Van Lieshout, Johannes Franciscus Thomas; Van Stigt Thans, Sander

    2016-09-20

    The present disclosure is generally directed to enzymes and in particular beta-glucosidase variants. Also described are nucleic acids encoding beta-glucosidase variants, compositions comprising beta-glucosidase variants, methods of using beta-glucosidase variants, and methods of identifying additional useful beta-glucosidase variants.

  15. Obese sedentary patients with dyspnoea on exertion who are at low risk for coronary artery disease by clinical criteria have a very low prevalence of coronary artery disease.

    PubMed

    Bruckel, J T; Larsen, G; Benson, M R

    2014-06-01

    Dyspnoea, a much less specific symptom of ischaemia than chest discomfort, is common among obese patients. Patients with dyspnoea often undergo stress testing as part of their evaluation. We sought to examine the yield of stress testing in non-elderly, obese, sedentary patients with dyspnoea on exertion (DOE) as a chief complaint.We reviewed stress echocardiograms carried out on 203 patients in a stress testing laboratory at a major tertiary care centre. Of these, 81 (40%) fell into a group that was at low risk for coronary artery disease (CAD) by clinical criteria. Ischaemia was detected in two patients in the low-risk group (2.5%), and these results were likely false positives. In the higher risk group, 9.0% of functional tests showed ischaemia; after further testing, 2.5% of the higher risk patients were found to have obstructive coronary lesions. Clinical follow-up was performed for a mean of 815 days. New obstructive coronary disease was detected in 1.6% of all patients, and these patients were from the higher risk group. In obese sedentary patients with DOE but otherwise at low risk of coronary disease stress testing is of very low yield. DOE is generally not an anginal equivalent in this patient population.

  16. KIT Mutation and Loss of 14q May Be Sufficient for the Development of Clinically Symptomatic Very Low-Risk GIST

    PubMed Central

    Baldwin, Gouri; Bancel, Brigitte; Devouassoux-Shisheboran, Mojgan; Scoazec, Jean-Yves; Bringuier, Pierre-Paul; Feederle, Regina; Jauch, Anna; Hinderhofer, Katrin; Taniere, Philippe; Delecluse, Henri-Jacques

    2015-01-01

    The aim of this study was to determine the minimal set of genetic alterations required for the development of a very low risk clinically symptomatic gastro-intestinal stromal tumour within the stomach wall. We studied the genome of a very low-risk gastric gastro-intestinal stromal tumour by whole-genome sequencing, comparative genomic hybridisation and methylation profiling. The studied tumour harboured two typical genomic lesions: loss of the long arm of chromosome 14 and an activating mutation in exon 11 of KIT. Besides these genetic lesions, only two point mutations that may affect tumour progression were identified: A frame-shift deletion in RNF146 and a missense mutation in a zinc finger of ZNF407. Whilst the frameshift deletion in RNF146 seemed to be restricted to this particular tumour, a similar yet germline mutation in ZNF407 was found in a panel of 52 gastro-intestinal stromal tumours from different anatomical sites and different categories. Germline polymorphisms in the mitotic checkpoint proteins Aurora kinase A and BUB1 kinase B may have furthered tumour growth. The epigenetic profile of the tumour matches that of other KIT-mutant tumours. We have identified mutations in three genes and loss of the long arm of chromosome 14 as the so far minimal set of genetic abnormalities sufficient for the development of a very low risk clinically symptomatic gastric stromal tumour. PMID:26102504

  17. Management of low-risk early-stage cervical cancer: Should conization, simple trachelectomy, or simple hysterectomy replace radical surgery as the new standard of care?

    PubMed Central

    Ramirez, Pedro T.; Pareja, Rene; Rendón, Gabriel J.; Millan, Carlos; Frumovitz, Michael; Schmeler, Kathleen M.

    2014-01-01

    The standard treatment for women with early-stage cervical cancer (IA2-IB1) remains radical hysterectomy with pelvic lymphadenectomy. In select patients interested in future fertility, the option of radical trachelectomy with pelvic lymphadenectomy is also considered a viable option. The possibility of less radical surgery may be appropriate not only for patients desiring to preserve fertility but also for all patients with low-risk early-stage cervical cancer. Recently, a number of studies have explored less radical surgical options for early-stage cervical cancer, including simple hysterectomy, simple trachelectomy, and cervical conization with or without sentinel lymph node biopsy and pelvic lymph node dissection. Such options may be available for patients with low-risk early-stage cervical cancer. Criteria that define this low-risk group include: squamous carcinoma, adenocarcinoma, or adenosquamous carcinoma, tumor size <2 cm, stromal invasion <10mm, and no lymph-vascular space invasion. In this report, we provide a review of the existing literature on the conservative management of cervical cancer and describe ongoing multi-institutional trials evaluating the role of conservative surgery in selected patients with early-stage cervical cancer. PMID:24041877

  18. Disease variants in genomes of 44 centenarians.

    PubMed

    Freudenberg-Hua, Yun; Freudenberg, Jan; Vacic, Vladimir; Abhyankar, Avinash; Emde, Anne-Katrin; Ben-Avraham, Danny; Barzilai, Nir; Oschwald, Dayna; Christen, Erika; Koppel, Jeremy; Greenwald, Blaine; Darnell, Robert B; Germer, Soren; Atzmon, Gil; Davies, Peter

    2014-09-01

    To identify previously reported disease mutations that are compatible with extraordinary longevity, we screened the coding regions of the genomes of 44 Ashkenazi Jewish centenarians. Individual genome sequences were generated with 30× coverage on the Illumina HiSeq 2000 and single-nucleotide variants were called with the genome analysis toolkit (GATK). We identified 130 coding variants that were annotated as "pathogenic" or "likely pathogenic" based on the ClinVar database and that are infrequent in the general population. These variants were previously reported to cause a wide range of degenerative, neoplastic, and cardiac diseases with autosomal dominant, autosomal recessive, and X-linked inheritance. Several of these variants are located in genes that harbor actionable incidental findings, according to the recommendations of the American College of Medical Genetics. In addition, we found risk variants for late-onset neurodegenerative diseases, such as the APOE ε4 allele that was even present in a homozygous state in one centenarian who did not develop Alzheimer's disease. Our data demonstrate that the incidental finding of certain reported disease variants in an individual genome may not preclude an extraordinarily long life. When the observed variants are encountered in the context of clinical sequencing, it is thus important to exercise caution in justifying clinical decisions.

  19. A RESISTANT VARIANT OF MUMPS VIRUS

    PubMed Central

    Ginsberg, Harold S.; Horsfall, Frank L.

    1949-01-01

    Serial passage of mumps virus in the presence of inhibitory quantities of the capsular polysaccharide of Friediänder bacillus type B results in the appearance of a variant strain of the virus. Multiplication of the variant virus is not inhibited by the polysaccharide. A similar resistant variant is obtained with polysaccharide in a single cycle of multiplication when very large inocula of mumps virus are employed. The resistant variant is indistinguishable from the parent strain as to infectivity, reactivity with erythrocytes, and immunological properties, but appears to have a somewhat slower rate of multiplication. Serial passage of the resistant variant in the absence of polysaccharide results in the reappearance of a sensitive strain. It is suggested that mumps virus populations are inhomogeneous; that naturally occurring variants are present in such populations and possess distinctive properties; that the use of a chemical inhibitor of mumps virus multiplication makes possible the selection of a variant possessing a predictable property. The findings are discussed in relation to the mechanism of inhibition of mumps virus multiplication by polysaccharide. PMID:18143585

  20. Histone H3 Variants in Trichomonas vaginalis

    PubMed Central

    Zubáčová, Zuzana; Hostomská, Jitka

    2012-01-01

    The parabasalid protist Trichomonas vaginalis is a widespread parasite that affects humans, frequently causing vaginitis in infected women. Trichomonad mitosis is marked by the persistence of the nuclear membrane and the presence of an asymmetric extranuclear spindle with no obvious direct connection to the chromosomes. No centromeric markers have been described in T. vaginalis, which has prevented a detailed analysis of mitotic events in this organism. In other eukaryotes, nucleosomes of centromeric chromatin contain the histone H3 variant CenH3. The principal aim of this work was to identify a CenH3 homolog in T. vaginalis. We performed a screen of the T. vaginalis genome to retrieve sequences of canonical and variant H3 histones. Three variant histone H3 proteins were identified, and the subcellular localization of their epitope-tagged variants was determined. The localization of the variant TVAG_185390 could not be distinguished from that of the canonical H3 histone. The sequence of the variant TVAG_087830 closely resembled that of histone H3. The tagged protein colocalized with sites of active transcription, indicating that the variant TVAG_087830 represented H3.3 in T. vaginalis. The third H3 variant (TVAG_224460) was localized to 6 or 12 distinct spots at the periphery of the nucleus, corresponding to the number of chromosomes in G1 phase and G2 phase, respectively. We propose that this variant represents the centromeric marker CenH3 and thus can be employed as a tool to study mitosis in T. vaginalis. Furthermore, we suggest that the peripheral distribution of CenH3 within the nucleus results from the association of centromeres with the nuclear envelope throughout the cell cycle. PMID:22408228

  1. Histone H3 Variants in Trichomonas vaginalis.

    PubMed

    Zubácová, Zuzana; Hostomská, Jitka; Tachezy, Jan

    2012-05-01

    The parabasalid protist Trichomonas vaginalis is a widespread parasite that affects humans, frequently causing vaginitis in infected women. Trichomonad mitosis is marked by the persistence of the nuclear membrane and the presence of an asymmetric extranuclear spindle with no obvious direct connection to the chromosomes. No centromeric markers have been described in T. vaginalis, which has prevented a detailed analysis of mitotic events in this organism. In other eukaryotes, nucleosomes of centromeric chromatin contain the histone H3 variant CenH3. The principal aim of this work was to identify a CenH3 homolog in T. vaginalis. We performed a screen of the T. vaginalis genome to retrieve sequences of canonical and variant H3 histones. Three variant histone H3 proteins were identified, and the subcellular localization of their epitope-tagged variants was determined. The localization of the variant TVAG_185390 could not be distinguished from that of the canonical H3 histone. The sequence of the variant TVAG_087830 closely resembled that of histone H3. The tagged protein colocalized with sites of active transcription, indicating that the variant TVAG_087830 represented H3.3 in T. vaginalis. The third H3 variant (TVAG_224460) was localized to 6 or 12 distinct spots at the periphery of the nucleus, corresponding to the number of chromosomes in G(1) phase and G(2) phase, respectively. We propose that this variant represents the centromeric marker CenH3 and thus can be employed as a tool to study mitosis in T. vaginalis. Furthermore, we suggest that the peripheral distribution of CenH3 within the nucleus results from the association of centromeres with the nuclear envelope throughout the cell cycle. PMID:22408228

  2. Kuru and "new variant" CJD.

    PubMed

    Verdrager, J

    1997-09-01

    Acquired transmissible spongiform encephalopathies in humans include Kuru (a disease which was associated with ritualistic cannibalism in Papua New Guinea), iatrogenic Creutzfeldt-Jakob disease and a newly recognized variant form of Creutzfeldt-Jakob disease (nvCJD). Clinical and neuropathological features of nvCJD are reminiscent of Kuru: early and progressive cerebellar ataxia and numerous characteristic Kuru-type amyloid plaques surrounded by spongiform change. In contrast to typical cases of sporadic CJD, Kuru and nvCJD affect young patients. The newly recognized form of CJD has been identified in ten young people in the UK in 1996, approximately 10 years after the beginning of the bovine spongiform encephalopathy (BSE) epidemic in the UK. Molecular analysis has shown that nvCJD has strain characteristics that are distinct from other types of CJD but similar to those of BSE. In the UK an estimated half a million BSE-infected cows entered the human food chain before the bovine offal ban of 1989. To be effective the oral route probably requires high-infectivity titers which are encountered only in the brain, spinal cord and eyes of naturally infected cows. In patients with Kuru, titers of more than 10(8) infectious doses per gram were reported in the brain tissues. As a result of the estimated very long incubation period of nvCJD (10 to 30 years or more) the predicted nvCJD epidemic will have the shape of a normal distribution curve with a peak expected in 2009. The epidemic may extend until 2030. There is already an example to illustrate such a curve in its descending line: the decline of Kuru deaths following the interruption of ritual cannibalism. PMID:9561604

  3. Directed Evolution of Streptavidin Variants Using IVC

    PubMed Central

    Levy, M.; Ellington, A.D.

    2008-01-01

    Summary We have developed and implemented an in vitro compartmentalization (IVC) selection scheme for the identification of streptavidin (SA) variants with altered specificities for the biotin analog desthiobiotin. Wild-type SA and selected variants bind desthiobiotin with similar affinities (~10−13 M), but the variants have off-rates almost 50 times slower and a half-life for dissociation of 24 hours at 25°C. The utility of streptavidin variants with altered specificities and kinetic properties was demonstrated by constructing protein microarrays that could be used to differentially organize and immobilize DNAs bearing these ligands. The methods we have developed should prove to be generally useful for generating a variety of novel SA reagents, and for evolving other extremely high affinity protein:ligand couples. PMID:18804035

  4. Environmental responses mediated by histone variants.

    PubMed

    Talbert, Paul B; Henikoff, Steven

    2014-11-01

    Fluctuations in the ambient environment can trigger chromatin disruptions, involving replacement of nucleosomes or exchange of their histone subunits. Unlike canonical histones, which are available only during S-phase, replication-independent histone variants are present throughout the cell cycle and are adapted for chromatin repair. The H2A.Z variant mediates responses to environmental perturbations including fluctuations in temperature and seasonal variation. Phosphorylation of histone H2A.X rapidly marks double-strand DNA breaks for chromatin repair, which is mediated by both H2A and H3 histone variants. Other histones are used as weapons in conflicts between parasites and their hosts, which suggests broad involvement of histone variants in environmental responses beyond chromatin repair. PMID:25150594

  5. Written Informed Consent for Computed Tomography of the Abdomen/Pelvis is Associated with Decreased CT Utilization in Low-Risk Emergency Department Patients

    PubMed Central

    Merck, Lisa H.; Ward, Laura A.; Applegate, Kimberly E.; Choo, Esther; Lowery-North, Douglas W.; Heilpern, Katherine L.

    2015-01-01

    Introduction The increasing rate of patient exposure to radiation from computerized tomography (CT) raises questions about appropriateness of utilization. There is no current standard to employ informed consent for CT (ICCT). Our study assessed the relationship between informed consent and CT utilization in emergency department (ED) patients. Methods An observational multiphase before-after cohort study was completed from 4/2010–5/2011. We assessed CT utilization before and after (Time I/Time II) the implementation of an informed consent protocol. Adult patients were included if they presented with symptoms of abdominal/pelvic pathology or completed ED CT. We excluded patients with pregnancy, trauma, or altered mental status. Data on history, exam, diagnostics, and disposition were collected via standard abstraction tool. We generated a multivariate logistic model via stepwise regression, to assess CT utilization across risk groups. Logistic models, stratified by risk, were generated to include study phase and a propensity score that controlled for potential confounders of CT utilization. Results 7,684 patients met inclusion criteria. In PHASE 2, there was a 24% (95% CI [10–36%]) reduction in CT utilization in the low-risk patient group (p<0.002). ICCT did not affect CT utilization in the high-risk group (p=0.16). In low-risk patients, the propensity score was significant (p<0.001). There were no adverse events reported during the study period. Conclusion The implementation of ICCT was associated with reduced CT utilization in low-risk ED patients. ICCT has the potential to increase informed, shared decision making with patients, as well as to reduce the risks and cost associated with CT. PMID:26759646

  6. Gateway Effects: Why the Cited Evidence Does Not Support Their Existence for Low-Risk Tobacco Products (and What Evidence Would).

    PubMed

    Phillips, Carl V

    2015-05-21

    It is often claimed that low-risk drugs still create harm because of "gateway effects", in which they cause the use of a high-risk alternative. Such claims are popular among opponents of tobacco harm reduction, claiming that low-risk tobacco products (e.g., e-cigarettes, smokeless tobacco) cause people to start smoking, sometimes backed by empirical studies that ostensibly support the claim. However, these studies consistently ignore the obvious alternative causal pathways, particularly that observed associations might represent causation in the opposite direction (smoking causes people to seek low-risk alternatives) or confounding (the same individual characteristics increase the chance of using any tobacco product). Due to these complications, any useful analysis must deal with simultaneity and confounding by common cause. In practice, existing analyses seem almost as if they were designed to provide teaching examples about drawing simplistic and unsupported causal conclusions from observed associations. The present analysis examines what evidence and research strategies would be needed to empirically detect such a gateway effect, if there were one, explaining key methodological concepts including causation and confounding, examining the logic of the claim, identifying potentially useful data, and debunking common fallacies on both sides of the argument, as well as presenting an extended example of proper empirical testing. The analysis demonstrates that none of the empirical studies to date that are purported to show a gateway effect from tobacco harm reduction products actually does so. The observations and approaches can be generalized to other cases where observed association of individual characteristics in cross-sectional data could result from any of several causal relationships.

  7. The effects of high- and low-risk environments on cognitive function in rats following 2-vessel occlusion of the carotid arteries: a behavioral study.

    PubMed

    Winocur, Gordon; Thompson, Charlie; Hakim, Antoine; Greenwood, Carol

    2013-09-01

    In a prospective study of environmental factors affecting cognitive recovery from stroke, adult male rats were reared for 3 months in a high-risk (relatively isolated, low activity, high-fat diet, high-stress) or low-risk (social, healthy diet, low-stress, physically active) environment. They then received cognitive testing to assess various aspects of learning and memory before undergoing 2-vessel occlusion (2VO) of the carotid arteries, or sham surgery. Rats were returned to their respective environments post-operatively. Relative to pre-operative levels, 2VO rats exhibited significant cognitive losses that were consistently greater in the high-risk group than its low-risk counterpart. As well, the high-risk 2VO group was impaired, relative to the low-risk 2VO group on tests of new learning introduced post-operatively. At 3-month follow-up testing, rats that had undergone 2VO surgery exhibited further decline on some tests but recovery on others, with recovery generally slower in the high-risk 2VO group. The high-risk environment also affected rats' pre-operative cognitive performance and, to a lesser extent, their performance following sham surgery. Overall, the study shows that rats experiencing cerebral ischemia are more likely to experience severe cognitive deficits if exposed to a high-risk environment and recover more slowly than ischemic rats in a more favorable environment. The results underscore the importance of lifestyle factors with respect to the impact of stroke on cognition and in assessing prospects for recovery of function.

  8. Molecular beacon-based real-time PCR method for detection of 15 high-risk and 5 low-risk HPV types.

    PubMed

    Takács, Tibor; Jeney, Csaba; Kovács, Laura; Mózes, Johanna; Benczik, Márta; Sebe, Attila

    2008-04-01

    Detection of HPV infections requires a robust time-effective single-step method for efficient screening. A molecular beacon-based one-step multiplex real-time PCR system was developed to detect 15 high-risk (HPV types 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68) and 5 low-risk HPV types (HPV types 6, 11, 42, 43, 44). Molecular beacons detecting high-risk types are 5'-FAM-3'-DABCYL-labelled, molecular beacons for low-risk detection are 5'-TET-3'-DABCYL-labelled, while the internal control added before sample DNA extraction is detected by a 5'-FAM-TexasRed-3'-DABCYL wavelength-shifting molecular beacon. Accordingly, fluorescent data for HPV detection are collected at 530 nm for high-risk types, 560 nm in case of low-risk types and the reaction internal control is detected at 610 nm on a Roche LightCycler 2.0 instrument. The sensitivity for detected types varies between 22 and 700 copies/reaction. The clinical performance was tested on 161 clinical sample DNAs. The MB-RT PCR results were compared to the typing results obtained by the L1F/L1R PCR and hybridization-based system described previously, and the concordance rate between the two systems was 89.44%. The favorable characteristics shown by this multiplex single-step real-time HPV detection system make this promising approach worthy for further development and application for clinical screening.

  9. Bisalbuminemia. A new molecular variant, albumin Vancouver.

    PubMed

    Frohlich, J; Kozier, J; Campbell, D J; Curnow, J V; Tárnoky, A L

    1978-11-01

    Of 18 members of a Fiji Indian family investigated, eight of the 12 males and two of the six females had an electrophoretically slow-type bisalbuminemia (alloalbuminemia). The albumin was characterized by the hiterto unique ratio of the two bands (Al A 35%: variant 65%), and by dye-binding studies and electrophoretic mobility in different media. The data suggest that this is a new variant, which we propose to call albumin Vancouver (Al Va).

  10. Association of smoking, alcohol drinking and dietary factors with esophageal cancer in high- and low-risk areas of Jiangsu Province, China

    PubMed Central

    Wu, Ming; Zhao, Jin-Kou; Hu, Xiao-Shu; Wang, Pei-Hua; Qin, Yu; Lu, Yin-Chang; Yang, Jie; Liu, Ai-Min; Wu, De-Lin; Zhang, Zuo-Feng; Frans, Kok J; Veer, Pieter van’t

    2006-01-01

    AIM: To study the main environmental and lifestyle factors that account for the regional differences in esophageal cancer (EC) risk in low- and high-risk areas of Jiangsu Province, China. METHODS: Since 2003, a population-based case-control study has been conducted simultaneously in low-risk (Ganyu County) and high-risk (Dafeng County) areas of Jiangsu Province, China. Using identical protocols and pre-tested standardized questionnaire, following written informed consent, eligible subjects were inquired about their detail information on potential determinants of EC, including demographic information, socio-economic status, living conditions, disease history, family cancer history, smoking, alcohol drinking, dietary habits, frequency, amount of food intake, etc. Conditional logistic regression with maximum likelihood estimation was used to obtain Odds ratio (OR) and 95 % confidence interval (95% CI), after adjustment for potential confounders. RESULTS: In the preliminary analysis of the ongoing study, we recruited 291 pairs of cases and controls in Dafeng and 240 pairs of cases and controls in Ganyu, respectively. In both low-risk and high-risk areas, EC was inversely associated with socio-economic status, such as level of education, past economic status and body mass index. However, this disease was more frequent among those who had a family history of cancer or encountered misfortune in the past 10 years. EC was also more frequent among smokers, alcohol drinkers and fast eaters. Furthermore, there was a geographic variation of the associations between smoking, alcohol drinking and EC risk despite the similar prevalence of these risk factors in both low-risk and high-risk areas. The dose-response relationship of smoking and smoking related variables, such as age of the first smoking, duration and amount were apparent only in high-risk areas. On the contrary, a dose-response relationship on the effect of alcohol drinking on EC was observed only in low-risk areas

  11. Discovery of rare variants for complex phenotypes.

    PubMed

    Kosmicki, Jack A; Churchhouse, Claire L; Rivas, Manuel A; Neale, Benjamin M

    2016-06-01

    With the rise of sequencing technologies, it is now feasible to assess the role rare variants play in the genetic contribution to complex trait variation. While some of the earlier targeted sequencing studies successfully identified rare variants of large effect, unbiased gene discovery using exome sequencing has experienced limited success for complex traits. Nevertheless, rare variant association studies have demonstrated that rare variants do contribute to phenotypic variability, but sample sizes will likely have to be even larger than those of common variant association studies to be powered for the detection of genes and loci. Large-scale sequencing efforts of tens of thousands of individuals, such as the UK10K Project and aggregation efforts such as the Exome Aggregation Consortium, have made great strides in advancing our knowledge of the landscape of rare variation, but there remain many considerations when studying rare variation in the context of complex traits. We discuss these considerations in this review, presenting a broad range of topics at a high level as an introduction to rare variant analysis in complex traits including the issues of power, study design, sample ascertainment, de novo variation, and statistical testing approaches. Ultimately, as sequencing costs continue to decline, larger sequencing studies will yield clearer insights into the biological consequence of rare mutations and may reveal which genes play a role in the etiology of complex traits. PMID:27221085

  12. Histone variants: key players of chromatin.

    PubMed

    Biterge, Burcu; Schneider, Robert

    2014-06-01

    Histones are fundamental structural components of chromatin. Eukaryotic DNA is wound around an octamer of the core histones H2A, H2B, H3, and H4. Binding of linker histone H1 promotes higher order chromatin organization. In addition to their structural role, histones impact chromatin function and dynamics by, e.g., post-translational histone modifications or the presence of specific histone variants. Histone variants exhibit differential expression timings (DNA replication-independent) and mRNA characteristics compared to canonical histones. Replacement of canonical histones with histone variants can affect nucleosome stability and help to create functionally distinct chromatin domains. In line with this, several histone variants have been implicated in the regulation of cellular processes such as DNA repair and transcriptional activity. In this review, we focus on recent progress in the study of core histone variants H2A.X, H2A.Z, macroH2A, H3.3, and CENP-A, as well as linker histone H1 variants, their functions and their links to development and disease.

  13. Characterizing Genetic Variants for Clinical Action

    PubMed Central

    Ramos, Erin M.; Din-Lovinescu, Corina; Berg, Jonathan S.; Brooks, Lisa D.; Duncanson, Audrey; Dunn, Michael; Good, Peter; Hubbard, Tim; Jarvik, Gail P.; O'Donnell, Christopher; Sherry, Stephen T.; Aronson, Naomi; Biesecker, Leslie G.; Blumberg, Bruce; Calonge, Ned; Colhoun, Helen M.; Epstein, Robert S.; Flicek, Paul; Gordon, Erynn S.; Green, Eric D.; Green, Robert C.; Hurles, Matthew; Kawamoto, Kensaku; Knaus, William; Ledbetter, David H.; Levy, Howard P.; Lyon, Elaine; Maglott, Donna; McLeod, Howard L.; Rahman, Nazneen; Randhawa, Gurvaneet; Wicklund, Catherine; Manolio, Teri A.; Chisholm, Rex L.; Williams, Marc S.

    2014-01-01

    Genome-wide association studies, DNA sequencing studies, and other genomic studies are finding an increasing number of genetic variants associated with clinical phenotypes that may be useful in developing diagnostic, preventive, and treatment strategies for individual patients. However, few common variants have been integrated into routine clinical practice. The reasons for this are several, but two of the most significant are limited evidence about the clinical implications of the variants and a lack of a comprehensive knowledge base that captures genetic variants, their phenotypic associations, and other pertinent phenotypic information that is openly accessible to clinical groups attempting to interpret sequencing data. As the field of medicine begins to incorporate genome-scale analysis into clinical care, approaches need to be developed for collecting and characterizing data on the clinical implications of variants, developing consensus on their actionability, and making this information available for clinical use. The National Human Genome Research Institute (NHGRI) and the Wellcome Trust thus convened a workshop to consider the processes and resources needed to: 1) identify clinically valid genetic variants; 2) decide whether they are actionable and what the action should be; and 3) provide this information for clinical use. This commentary outlines the key discussion points and recommendations from the workshop. PMID:24634402

  14. Genetic Variants Associated with Colorectal Adenoma Susceptibility

    PubMed Central

    Abulí, Anna; Castells, Antoni; Bujanda, Luis; Lozano, Juan José; Bessa, Xavier; Hernández, Cristina; Álvarez-Urturi, Cristina; Pellisé, Maria; Esteban-Jurado, Clara; Hijona, Elizabeth; Burón, Andrea; Macià, Francesc; Grau, Jaume; Guayta, Rafael

    2016-01-01

    Background Common low-penetrance genetic variants have been consistently associated with colorectal cancer risk. Aim To determine if these genetic variants are associated also with adenoma susceptibility and may improve selection of patients with increased risk for advanced adenomas and/or multiplicity (≥ 3 adenomas). Methods We selected 1,326 patients with increased risk for advanced adenomas and/or multiplicity and 1,252 controls with normal colonoscopy from population-based colorectal cancer screening programs. We conducted a case-control association study analyzing 30 colorectal cancer susceptibility variants in order to investigate the contribution of these variants to the development of subsequent advanced neoplasia and/or multiplicity. Results We found that 14 of the analyzed genetic variants showed a statistically significant association with advanced adenomas and/or multiplicity: the probability of developing these lesions increased with the number of risk alleles reaching a 2.3-fold risk increment in individuals with ≥ 17 risk alleles. Conclusions Nearly half of the genetic variants associated with colorectal cancer risk are also related to advanced adenoma and/or multiplicity predisposition. Assessing the number of risk alleles in individuals within colorectal cancer screening programs may help to identify better a subgroup with increased risk for advanced neoplasia and/or multiplicity in the general population. PMID:27078840

  15. Comparative study of lifestyles of residents in high and low risk areas for gastric cancer in Jiangsu Province, China; with special reference to allium vegetables.

    PubMed

    Takezaki, T; Gao, C M; Ding, J H; Liu, T K; Li, M S; Tajima, K

    1999-11-01

    There is a low risk area for gastric cancer in Jiangsu Province, China, where people frequently consume raw allium vegetables. As a first step epidemiological study to clarify the factors involved in the low incidence of gastric cancer, we conducted a comparative study of the ecological factors in a high risk area (HRA), Yangzhong, and a low risk area (LRA), Pizhou, using a questionnaire. Subjects were selected from the general population according to age and sex, and comprised 414 residents of the HRA and 425 residents of the LRA. Ecological factors were compared for the two areas by Cochran-Mantel-Haenszel method, age-adjusted. Smoking and drinking habits were found to be more common in the LRA. On the other hand, allium vegetables were consumed in the LRA much more frequently, with high consumption of raw vegetables fruit, tomatoes, kidney beans and soybean products. People who consumed garlic en masse 3 times or more per week were 82% of men and 75% of women in the LRA, and 1% of men and women in the HRA. The results of the survey suggest that frequent consumption of allium vegetables, in addition to other anticancer foods, may be a factor in low mortality for gastric cancer. PMID:10616262

  16. Is the peripheral arterial disease in low risk type 2 diabetic patients influenced by body mass index, lipidemic control, and statins?

    PubMed Central

    Solanki, Jayesh Dalpatbhai; Makwana, Amit H.; Mehta, Hemant B.; Gokhale, Pradnya A.; Shah, Chinmay J.

    2016-01-01

    Objective: To correlate BMI, lipidemic control, and statin therapy with PAD measured by ABI in low risk type 2 diabetics. Materials and Methods: A sample of 101 nonsmoking, asymptomatic type 2 diabetics (50 males, 51 females) with known glycemic (fasting blood sugar, postprandial blood sugar, glycosylated hemoglobin) and lipidemic (total cholesterol, lipoproteins, and triglycerides [TGAs]) control was taken. Vascular Doppler was used to derive ABI and PAD was defined as ABI <0.9. ABI values were compared amongst groups and P < 0.05 was considered statistically significant. Results: We found fairly good lipid but poor glycemic control and prevalence of PAD 30%. There was insignificantly low ABI profile in patient having BMI ≥25, hyperlipidemia and absent statin therapy with odds ratio being highest for TGAs ≥150 (3.23) followed by BMI ≥25 (2.61), high-density lipoprotein ≤50 (1.61), low-density lipoprotein ≥100 (1.20), and disuse of statin (1.14) with significance only for BMI. Conclusion: We observed small, insignificant PAD risk by dyslipidemia or non-use of statins in low-risk ambulatory T2DM patients, not so by BMI. This suggests importance of good glycemic control, maintenance of optimum weight, and lifestyle modifications as primary prevention rather than opting for costly and inefficient secondary prevention. PMID:27440953

  17. The experience of labor, maternal perception of the infant, and the mother's postpartum mood in a low-risk community cohort.

    PubMed

    Weisman, Omri; Granat, Adi; Gilboa-Schechtman, Eva; Singer, Magi; Gordon, Ilanit; Azulay, Hila; Kuint, Jacob; Feldman, Ruth

    2010-12-01

    Postpartum negative mood interferes with maternal-infant bonding and carries long-term negative consequences for infant growth. We examined the effects of birth-related risks on mother's postpartum anxiety and depression. A community cohort of 1,844 low-risk women who delivered a singleton term baby completed measures assessing delivery, emotions during labor, attitudes toward pregnancy and infant, mood regulation, and postpartum anxiety and depression. Under conditions of low risk, 20.5% of parturient women reported high levels of depressive symptoms. Following Cesarean Section Delivery (CSD), 23% reported high depressive symptoms, compared to 19% following Vaginal Delivery (VGD), and 21% after Assisted Vaginal Delivery (AVGD). State anxiety was highest in CSD and lowest in VGD. Mothers undergoing CSD experienced labor as most negative, reported highest somatic symptoms during the last trimester, and were least efficient in regulating negative mood. Postpartum depression was independently associated with higher maternal age, CSD, labor pain, lower negative and higher positive emotions during labor, inefficient mood regulation, somatic symptoms, and more negative and less positive perception of fetus during last trimester. Results demonstrate that elevated depressive symptoms are prevalent in the postpartum even under optimal socioeconomic and health conditions and increase following CSD. Interventions to increase positive infant-related perceptions and emotions may be especially important for promoting bond formation following CSD.

  18. Frequency of thermostability variants: estimation of total rare variant frequency in human populations

    SciTech Connect

    Mohrenweiser, H.W.; Neel, J.V.

    1981-09-01

    Eight erythrocyte enzymes were examine for thermostability in an unselected sample of 100 newborn infants. Three thermolabile variants, one each of lactate dehydrogenase, glucosephosphate isomerase, and glucose-6-phosphate dehydrogenase, were identified, none of which was detectable as a variant by standard electrophoretic techniques. All were inherited. This frequency of 3.8 heritable thermostability variants per 1000 determinations is to be compared with a frequency of electrophoretically detectable variants of 1.1 per 1000 determinations, a frequency of 2.4 enzyme-deficiency variants per 1000 determinations, and a frequency of individuals with rare enzyme deficiency or electrophoretic or thermostability (or both) variants at these loci is 8.4 per 1000 determinations. A similar distribution and frequency is seen when the comparison is limited to the seven loci studied by all techniques. it is clear that not all of the electrophoretic and thermostability variants present in the population are detected by the techniques used in this study. Accordingly, it is estimated that the true frequency of carriers of a rare variant for each of these enzyme-coding loci averages greater than 10/1000. Some implications of these frequencies for human disease are discussed.

  19. Sequence Variant Descriptions: HGVS Nomenclature and Mutalyzer.

    PubMed

    den Dunnen, Johan T

    2016-01-01

    Consistent and unambiguous description of sequence variants is essential to report and exchange information on the analysis of a genome, in particular in DNA diagnostics. The HGVS nomenclature-recommendations for the description of sequence variants as originally proposed by the Human Genome Variation Society-has gradually been accepted as the international standard for variant description. In this unit, we describe the current recommendations (HGVS version 15.11) regarding how to describe variants at the DNA, RNA, and protein level. We explain the rationale and give example descriptions for all variant types: substitution, deletion, duplication, insertion, inversion, conversion, and complex, as well as special types occurring only on the RNA (splicing) or protein level (nonsense, frame shift, extension). Finally, we point users to available support tools and give examples for the use of the freely available Mutalyzer suite. An extensive version of the HGVS recommendations is available online at http://varnomen.hgvs.org/. © 2016 by John Wiley & Sons, Inc. PMID:27367167

  20. Coding Variants at Hexa-allelic Amino Acid 13 of HLA-DRB1 Explain Independent SNP Associations with Follicular Lymphoma Risk

    PubMed Central

    Foo, Jia Nee; Smedby, Karin E.; Akers, Nicholas K.; Berglund, Mattias; Irwan, Ishak D.; Jia, Xiaoming; Li, Yi; Conde, Lucia; Darabi, Hatef; Bracci, Paige M.; Melbye, Mads; Adami, Hans-Olov; Glimelius, Bengt; Khor, Chiea Chuen; Hjalgrim, Henrik; Padyukov, Leonid; Humphreys, Keith; Enblad, Gunilla; Skibola, Christine F.; de Bakker, Paul I.W.; Liu, Jianjun

    2013-01-01

    Non-Hodgkin lymphoma represents a diverse group of blood malignancies, of which follicular lymphoma (FL) is a common subtype. Previous genome-wide association studies (GWASs) have identified in the human leukocyte antigen (HLA) class II region multiple independent SNPs that are significantly associated with FL risk. To dissect these signals and determine whether coding variants in HLA genes are responsible for the associations, we conducted imputation, HLA typing, and sequencing in three independent populations for a total of 689 cases and 2,446 controls. We identified a hexa-allelic amino acid polymorphism at position 13 of the HLA-DR beta chain that showed the strongest association with FL within the major histocompatibility complex (MHC) region (multiallelic p = 2.3 × 10−15). Out of six possible amino acids that occurred at that position within the population, we classified two as high risk (Tyr and Phe), two as low risk (Ser and Arg), and two as moderate risk (His and Gly). There was a 4.2-fold difference in risk (95% confidence interval = 2.9–6.1) between subjects carrying two alleles encoding high-risk amino acids and those carrying two alleles encoding low-risk amino acids (p = 1.01 × 10−14). This coding variant might explain the complex SNP associations identified by GWASs and suggests a common HLA-DR antigen-driven mechanism for the pathogenesis of FL and rheumatoid arthritis. PMID:23791106

  1. Coding variants at hexa-allelic amino acid 13 of HLA-DRB1 explain independent SNP associations with follicular lymphoma risk.

    PubMed

    Foo, Jia Nee; Smedby, Karin E; Akers, Nicholas K; Berglund, Mattias; Irwan, Ishak D; Jia, Xiaoming; Li, Yi; Conde, Lucia; Darabi, Hatef; Bracci, Paige M; Melbye, Mads; Adami, Hans-Olov; Glimelius, Bengt; Khor, Chiea Chuen; Hjalgrim, Henrik; Padyukov, Leonid; Humphreys, Keith; Enblad, Gunilla; Skibola, Christine F; de Bakker, Paul I W; Liu, Jianjun

    2013-07-11

    Non-Hodgkin lymphoma represents a diverse group of blood malignancies, of which follicular lymphoma (FL) is a common subtype. Previous genome-wide association studies (GWASs) have identified in the human leukocyte antigen (HLA) class II region multiple independent SNPs that are significantly associated with FL risk. To dissect these signals and determine whether coding variants in HLA genes are responsible for the associations, we conducted imputation, HLA typing, and sequencing in three independent populations for a total of 689 cases and 2,446 controls. We identified a hexa-allelic amino acid polymorphism at position 13 of the HLA-DR beta chain that showed the strongest association with FL within the major histocompatibility complex (MHC) region (multiallelic p = 2.3 × 10⁻¹⁵). Out of six possible amino acids that occurred at that position within the population, we classified two as high risk (Tyr and Phe), two as low risk (Ser and Arg), and two as moderate risk (His and Gly). There was a 4.2-fold difference in risk (95% confidence interval = 2.9-6.1) between subjects carrying two alleles encoding high-risk amino acids and those carrying two alleles encoding low-risk amino acids (p = 1.01 × 10⁻¹⁴). This coding variant might explain the complex SNP associations identified by GWASs and suggests a common HLA-DR antigen-driven mechanism for the pathogenesis of FL and rheumatoid arthritis.

  2. In silico comparative characterization of pharmacogenomic missense variants

    PubMed Central

    2014-01-01

    Background Missense pharmacogenomic (PGx) variants refer to amino acid substitutions that potentially affect the pharmacokinetic (PK) or pharmacodynamic (PD) response to drug therapies. The PGx variants, as compared to disease-associated variants, have not been investigated as deeply. The ability to computationally predict future PGx variants is desirable; however, it is not clear what data sets should be used or what features are beneficial to this end. Hence we carried out a comparative characterization of PGx variants with annotated neutral and disease variants from UniProt, to test the predictive power of sequence conservation and structural information in discriminating these three groups. Results 126 PGx variants of high quality from PharmGKB were selected and two data sets were created: one set contained 416 variants with structural and sequence information, and, the other set contained 1,265 variants with sequence information only. In terms of sequence conservation, PGx variants are more conserved than neutral variants and much less conserved than disease variants. A weighted random forest was used to strike a more balanced classification for PGx variants. Generally structural features are helpful in discriminating PGx variant from the other two groups, but still classification of PGx from neutral polymorphisms is much less effective than between disease and neutral variants. Conclusions We found that PGx variants are much more similar to neutral variants than to disease variants in the feature space consisting of residue conservation, neighboring residue conservation, number of neighbors, and protein solvent accessibility. Such similarity poses great difficulty in the classification of PGx variants and polymorphisms. PMID:25057096

  3. Hemoglobin Variants: Biochemical Properties and Clinical Correlates

    PubMed Central

    Thom, Christopher S.; Dickson, Claire F.; Gell, David A.; Weiss, Mitchell J.

    2013-01-01

    Diseases affecting hemoglobin synthesis and function are extremely common worldwide. More than 1000 naturally occurring human hemoglobin variants with single amino acid substitutions throughout the molecule have been discovered, mainly through their clinical and/or laboratory manifestations. These variants alter hemoglobin structure and biochemical properties with physiological effects ranging from insignificant to severe. Studies of these mutations in patients and in the laboratory have produced a wealth of information on hemoglobin biochemistry and biology with significant implications for hematology practice. More generally, landmark studies of hemoglobin performed over the past 60 years have established important paradigms for the disciplines of structural biology, genetics, biochemistry, and medicine. Here we review the major classes of hemoglobin variants, emphasizing general concepts and illustrative examples. PMID:23388674

  4. Hemoglobin variants: biochemical properties and clinical correlates.

    PubMed

    Thom, Christopher S; Dickson, Claire F; Gell, David A; Weiss, Mitchell J

    2013-03-01

    Diseases affecting hemoglobin synthesis and function are extremely common worldwide. More than 1000 naturally occurring human hemoglobin variants with single amino acid substitutions throughout the molecule have been discovered, mainly through their clinical and/or laboratory manifestations. These variants alter hemoglobin structure and biochemical properties with physiological effects ranging from insignificant to severe. Studies of these mutations in patients and in the laboratory have produced a wealth of information on hemoglobin biochemistry and biology with significant implications for hematology practice. More generally, landmark studies of hemoglobin performed over the past 60 years have established important paradigms for the disciplines of structural biology, genetics, biochemistry, and medicine. Here we review the major classes of hemoglobin variants, emphasizing general concepts and illustrative examples.

  5. Human mitochondrial variants influence on oxygen consumption.

    PubMed

    Marcuello, Ana; Martínez-Redondo, Diana; Dahmani, Yahya; Casajús, José A; Ruiz-Pesini, Eduardo; Montoya, Julio; López-Pérez, Manuel J; Díez-Sánchez, Carmen

    2009-02-01

    This work investigates if human mitochondrial variants influence on maximal oxygen consumption (VO(2max)). With this purpose we recruited, as a uniform population in term of nutritional habits and life style, 114 healthy male Spanish subjects that practiced fitness exercises 3-4 times a week. Once mtDNA haplogroups were determined, we found that J presents with lower VO(2max) (P=0.02) than nonJ variants. J has been related with a lower efficiency of electron transport chain (ETC), diminished ATP and ROS production. Thus, the difficult to compensate the mitochondrial energetic deficiency could explain the accumulation of J haplogroup in LHON and multiple sclerosis. Furthermore, the lower ROS production associated to J could also account for the accrual of this variant in elderly people consequent to a decreased oxidative damage.

  6. Blockade of CCR7 leads to decreased dendritic cell migration to draining lymph nodes and promotes graft survival in low-risk corneal transplantation.

    PubMed

    Hos, D; Dörrie, J; Schaft, N; Bock, F; Notara, M; Kruse, F E; Krautwald, S; Cursiefen, C; Bachmann, B O

    2016-05-01

    The chemokine receptor CCR7 is essential for migration of mature dendritic cells (DCs) to the regional lymph nodes, and it has been shown that blocking of CCR7 improves graft survival after high-risk corneal transplantation in vascularized recipient corneas. However, it is so far unknown whether blocking of CCR7 reduces migration of DCs from the avascular cornea to the draining lymph nodes and whether this leads to improved graft survival also in the low-risk setting of corneal transplantation, which accounts for the majority of perforating transplantations performed. Therefore, in this study, pellets containing Freund's adjuvant and bovine serum albumin (BSA) conjugated to Alexa488 fluorescent dye were implanted into the corneal stroma of BALB/c mice to analyze antigen uptake by corneal DCs and their migration to the regional lymph nodes. After pellet implantation, mice were either treated by local administration of a CCR7 blocking fusion protein that consisted of CCL19 fused to the Fc part of human IgG1 or a control-IgG. In vivo fluorescence microscopy showed uptake of Alexa488-conjugated BSA by corneal DCs within 8 h. Furthermore, analysis of single cell suspensions of draining lymph nodes prepared after 48 h revealed that 2.1 ± 0.3% of CD11c(+) cells were also Alexa488(+). Importantly, DC migration was significantly reduced after topical administration of CCL19-IgG (1.2 ± 0.2%; p < 0.05). To test the effect of CCR7 blockade on graft rejection after allogeneic low-risk keratoplasty, corneal transplantations were performed using C57BL/6-mice as donors and BALB/c-mice as recipients. Treatment mice received two intraperitoneal loading doses of CCL19-IgG prior to transplantation, followed by local treatment with CCL19-IgG containing eye drops for the first two weeks after transplantation. Control mice received same amounts of control-IgG. Kaplan-Meier survival analysis showed that in the CCL19-IgG treated group, 76% of the grafts survived through the end

  7. The importance of active surveillance, and immediate re-biopsy in low-risk prostate cancer: The largest series from Turkey

    PubMed Central

    Bayar, Göksel; Horasanlı, Kaya; Acinikli, Hüseyin; Tanrıverdi, Orhan; Dalkılıç, Ayhan; Arısan, Serdar

    2016-01-01

    Objective To evaluate long-term outcomes of active surveillance (AS) applied in low-risk prostate cancer patients, and the impact of re-biopsy results on the prediction of progression. Material and methods In our clinic, patients who had undergone AS for low-risk localized prostate cancer between the years 2005–2013 were included in the study. Our AS criteria are Gleason score ≤6, prostate-specific antigen (PSA) level <10 ng/mL, number of positive cores <3, maximum cancer involvement ratio <50% each core. Immediate re-biopsy (within 3 months) was performed to 65 patients who accepted AS. Finally, 43 patients who met re-biopsy criteria were included in the study. Prostate biopsy specimens were harvested from 12 cores under the guidance of transrectal ultrasound (TRUS). Re-biopsy was performed within 3 months (1–12 weeks). In re-biopsy, a total of 20 core biopsies were performed including the far lateral (6 cores) and transition zone (2 cores) in addition to standard 12 core biopsy. Our follow-up protocol is PSA measurement and digital rectal examination (DRE) every 3 months within the first 2 years, than every 6 months. Control biopsies was performed one year later and once upon every 3 years to patients whose PSA levels and DREs were normal at follow-up visits. More than 2 tumor invaded cores or 50% tumor in one core, and Gleason score exceeding 6 points were accepted as indications for definitive treatment. Patients were divided into two groups by re-biopsy results and compared according to the time to progression. We have done multivariate regression analysis to predict prognosis by using data on age, PSA level, and detection of tumor in re-biopsy specimens. Results Patients’ median age was 61 years and PSA level was 5 (2.7–9) ng/mL. Tumor was detected in 22 (34%) patients at re-biopsy and they underwent definitive treatment. Additionally tumor was detected in 9 patients, but active surveillance was maintained because their pathologic results met active

  8. Distinguishing Low-Risk Luminal A Breast Cancer Subtypes with Ki-67 and p53 Is More Predictive of Long-Term Survival.

    PubMed

    Lee, Se Kyung; Bae, Soo Youn; Lee, Jun Ho; Lee, Hyun-Chul; Yi, Hawoo; Kil, Won Ho; Lee, Jeong Eon; Kim, Seok Won; Nam, Seok Jin

    2015-01-01

    Overexpression of p53 is the most frequent genetic alteration in breast cancer. Recently, many studies have shown that the expression of mutant p53 differs for each subtype of breast cancer and is associated with different prognoses. In this study, we aimed to determine the suitable cut-off value to predict the clinical outcome of p53 overexpression and its usefulness as a prognostic factor in each subtype of breast cancer, especially in luminal A breast cancer. Approval was granted by the Institutional Review Board of Samsung Medical Center. We analyzed a total of 7,739 patients who were surgically treated for invasive breast cancer at Samsung Medical Center between Dec 1995 and Apr 2013. Luminal A subtype was defined as ER&PR + and HER2- and was further subclassified according to Ki-67 and p53 expression as follows: luminal A (Ki-67-,p53-), luminal A (Ki-67+, p53-), luminal A (Ki-67 -, p53+) and luminal A (Ki-67+, p53+). Low-risk luminal A subtype was defined as negative for both Ki-67 and p53 (luminal A [ki-67-, p53-]), and others subtypes were considered to be high-risk luminal A breast cancer. A cut-off value of 10% for p53 was a good predictor of clinical outcome in all patients and luminal A breast cancer patients. The prognostic role of p53 overexpression for OS and DFS was only significant in luminal A subtype. The combination of p53 and Ki-67 has been shown to have the best predictive power as calculated by the area under curve (AUC), especially for long-term overall survival. In this study, we have shown that overexpression of p53 and Ki-67 could be used to discriminate low-risk luminal A subtype in breast cancer. Therefore, using the combination of p53 and Ki-67 expression in discriminating low-risk luminal A breast cancer may improve the prognostic power and provide the greatest clinical utility.

  9. Phenotypic extremes in rare variant study designs.

    PubMed

    Peloso, Gina M; Rader, Daniel J; Gabriel, Stacey; Kathiresan, Sekar; Daly, Mark J; Neale, Benjamin M

    2016-06-01

    Currently, next-generation sequencing studies aim to identify rare and low-frequency variation that may contribute to disease. For a given effect size, as the allele frequency decreases, the power to detect genes or variants of interest also decreases. Although many methods have been proposed for the analysis of such data, study design and analytic issues still persist in data interpretation. In this study we present sequencing data for ABCA1 that has known rare variants associated with high-density lipoprotein cholesterol (HDL-C). We contrast empirical findings from two study designs: a phenotypic extreme sample and a population-based random sample. We found differing strengths of association with HDL-C across the two study designs (P=0.0006 with n=701 phenotypic extremes vs P=0.03 with n=1600 randomly sampled individuals). To explore this apparent difference in evidence for association, we performed a simulation study focused on the impact of phenotypic selection on power. We demonstrate that the power gain for an extreme phenotypic selection study design is much greater in rare variant studies than for studies of common variants. Our study confirms that studying phenotypic extremes is critical in rare variant studies because it boosts power in two ways: the typical increases from extreme sampling and increasing the proportion of relevant functional variants ascertained and thereby tested for association. Furthermore, we show that when combining statistical evidence through meta-analysis from an extreme-selected sample and a second separate population-based random sample, power is lower when a traditional sample size weighting is used compared with weighting by the noncentrality parameter. PMID:26350511

  10. Predominant fatty variant of myofibroblastoma of breast

    PubMed Central

    Baxendine-Jones, J; Theaker, J; Baldwin, L

    2001-01-01

    Myofibroblastoma of the breast is an uncommon but well defined benign stromal tumour. This report describes a case in which the predominant histological component was mature adipose tissue and two further cases with a major adipocytic component. Although small foci of adipose tissue are a recognised feature of this tumour, the dominance of the histological pattern by fat has not been described previously, and the recognition of this variant is important to allow confident diagnosis and avoid confusion with other primary adipocytic or stromal lesions, especially in the setting of potential needle core biopsy of such a lesion. Key Words: myofibroblastoma • variant • fatty PMID:11429434

  11. Histone variants and melanoma: facts and hypotheses.

    PubMed

    Konstantinov, Nikifor K; Ulff-Møller, Constance J; Dimitrov, Stefan

    2016-07-01

    Melanoma is the most aggressive form of skin cancer with rising incidence and morbidity. Despite advances in treatment, the 10-yr survival for patients with metastatic disease is less than 10%. During the past few years, ongoing research on different epigenomic aberrations in melanoma has catalyzed better understanding of its pathogenesis and identification of new therapeutics. In our review, we will focus on the role of histone variants, key epigenetic players in melanoma initiation and progression. Specifically, incorporation of histone variants enables additional layers of chromatin structure, and here, we will describe how alterations in this epigenetic behavior impact melanoma.

  12. Targeted Sequencing of an Epidemiologically Low Risk patient defines Fibroblast Growth Factor Family Aberrations as a putative driver of Head and Neck Squamous Cell Carcinoma

    PubMed Central

    Tillman, Brittny N.; Yanik, Megan; Birkeland, Andrew C.; Liu, Chia-Jen; Hovelson, Daniel H.; Cani, Andi K.; Palanisamy, Nallasivam; Carskadon, Shannon; Carey, Thomas E.; Bradford, Carol R.; Tomlins, Scott A.; McHugh, Jonathan B.; Spector, Matthew E.; Brenner, J. Chad

    2016-01-01

    Background Targeted sequencing of epidemiologically low risk (ELR) HNSCC patients could help identify novel drivers or lost suppressors leading to precision medicine protocols and improved survival rates. Methods An ELR-HNSCC patient was selected for targeted sequencing. We then assessed next generation sequencing cohorts from the Oncomine Powertool Database, which contains pan-cancer data from The Cancer Genome Atlas(TCGA). Results Targeted sequencing revealed FGFR1 amplifications as a putative driver of the patient’s tumor. HNSCC patients from TCGA data demonstrated FGF family mutations, rearrangements or amplifications in over 35% of HNSCC cases, with a statistically significant higher frequency in African American populations. FGF alterations were unique from activating PIK3CA mutations. Conclusion Together, this data suggests that FGF signaling may be critical for a subset of HNSCC patients independent of other known pathways and provides rationale for leveraging ELR-HNSCC patients to define molecular subsets of high risk HNSCC. PMID:26849095

  13. Local Control With Reduced-Dose Radiotherapy for Low-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group D9602 Study

    SciTech Connect

    Breneman, John; Meza, Jane; Donaldson, Sarah S.; Raney, R. Beverly; Wolden, Suzanne; Michalski, Jeff; Laurie, Fran; Rodeberg, David A.; Meyer, William

    2012-06-01

    Purpose: To analyze the effect of reduced-dose radiotherapy on local control in children with low-risk rhabdomyosarcoma (RMS) treated in the Children's Oncology Group D9602 study. Methods and Materials: Patients with low-risk RMS were nonrandomly assigned to receive radiotherapy doses dependent on the completeness of surgical resection of the primary tumor (clinical group) and the presence of involved regional lymph nodes. After resection, most patients with microscopic residual and uninvolved nodes received 36 Gy, those with involved nodes received 41.4 to 50.4 Gy, and those with orbital primary tumors received 45 Gy. All patients received vincristine and dactinomycin, with cyclophosphamide added for patient subsets with a higher risk of relapse in Intergroup Rhabdomyosarcoma Study Group III and IV studies. Results: Three hundred forty-two patients were eligible for analysis; 172 received radiotherapy as part of their treatment. The cumulative incidence of local/regional failure was 15% in patients with microscopic involved margins when cyclophosphamide was not part of the treatment regimen and 0% when cyclophosphamide was included. The cumulative incidence of local/regional failure was 14% in patients with orbital tumors. Protocol-specified omission of radiotherapy in girls with Group IIA vaginal tumors (n = 5) resulted in three failures for this group. Conclusions: In comparison with Intergroup Rhabdomyosarcoma Study Group III and IV results, reduced-dose radiotherapy does not compromise local control for patients with microscopic tumor after surgical resection or with orbital primary tumors when cyclophosphamide is added to the treatment program. Girls with unresected nonbladder genitourinary tumors require radiotherapy for postsurgical residual tumor for optimal local control to be achieved.

  14. Association between Hospital Birth Volume and Maternal Morbidity among Low-Risk Pregnancies in Rural, Urban, and Teaching Hospitals in the United States.

    PubMed

    Kozhimannil, Katy B; Thao, Viengneesee; Hung, Peiyin; Tilden, Ellen; Caughey, Aaron B; Snowden, Jonathan M

    2016-05-01

    Objectives This study aims to examine the relationship between hospital birth volume and multiple maternal morbidities among low-risk pregnancies in rural hospitals, urban non-teaching hospitals, and urban teaching hospitals, using a representative sample of U.S. hospitals. Study Design Using the 2011 Nationwide Inpatient Sample from 607 hospitals, we identified 508,146 obstetric deliveries meeting low-risk criteria and compared outcomes across hospital volume categories. Outcomes include postpartum hemorrhage (PPH), chorioamnionitis, endometritis, blood transfusion, severe perineal laceration, and wound infection. Results Hospital birth volume was more consistently related to PPH than to other maternal outcomes. Lowest-volume rural (< 200 births) and non-teaching (< 650 births) hospitals had 80% higher odds (adjusted odds ratio [AOR] = 1.80; 95% CI = 1.56-2.08) and 39% higher odds (AOR = 1.39; 95% CI = 1.26-1.53) of PPH respectively, than those in corresponding high-volume hospitals. However, in urban teaching hospitals, delivering in a lower-volume hospital was associated with 14% lower odds of PPH (AOR = 0.86; 95% CI = 0.80-0.93). Deliveries in rural hospitals had 31% higher odds of PPH than urban teaching hospitals (AOR = 1.31; 95% CI = 1.13-1.53). Conclusions Low birth volume was a risk factor for PPH in both rural and urban non-teaching hospitals, but not in urban teaching hospitals, where higher volume was associated with greater odds of PPH. PMID:26731180

  15. Home treatment of patients with low-risk pulmonary embolism with the oral factor Xa inhibitor rivaroxaban. Rationale and design of the HoT-PE Trial.

    PubMed

    Barco, Stefano; Lankeit, Mareike; Binder, Harald; Schellong, Sebastian; Christ, Michael; Beyer-Westendorf, Jan; Duerschmied, Daniel; Bauersachs, Rupert; Empen, Klaus; Held, Matthias; Schwaiblmair, Martin; Fonseca, Cândida; Jiménez, David; Becattini, Cecilia; Quitzau, Kurt; Konstantinides, Stavros

    2016-07-01

    Pulmonary embolism (PE) is a potentially life-threatening acute cardiovascular syndrome. However, more than 95 % of patients are haemodynamically stable at presentation, and among them are patients at truly low risk who may qualify for immediate or early discharge. The Home Treatment of Pulmonary Embolism (HoT-PE) study is a prospective international multicentre single-arm phase 4 management (cohort) trial aiming to determine whether home treatment of acute low-risk PE with the oral factor Xa inhibitor rivaroxaban is feasible, effective, and safe. Patients with confirmed PE, who have no right ventricular dysfunction or free floating thrombi in the right atrium or ventricle, are eligible if they meet none of the exclusion criteria indicating haemodynamic instability, serious comorbidity or any condition mandating hospitalisation, or a familial/social environment unable to support home treatment. The first dose of rivaroxaban is given in hospital, and patients are discharged within 48 hours of presentation. Rivaroxaban is taken for at least three months. The primary outcome is symptomatic recurrent venous thromboembolism or PE-related death within three months of enrolment. Secondary outcomes include quality of life and patient satisfaction, and health care resource utilisation compared to existing data on standard-duration hospital treatment. HoT-PE is planned to analyse 1,050 enrolled patients, providing 80 % power to reject the null hypothesis that the recurrence rate of venous thromboembolism is >3 % with α≤0.05. If the hypothesis of HoT-PE is confirmed, early discharge and out-of-hospital treatment may become an attractive, potentially cost-saving option for a significant proportion of patients with acute PE. PMID:27010343

  16. The AFFORD Clinical Decision Aid To Identify Emergency Department Patients With Atrial Fibrillation At Low Risk For 30-Day Adverse Events

    PubMed Central

    Barrett, Tyler W.; Storrow, Alan B.; Jenkins, Cathy A.; Abraham, Robert L.; Liu, Dandan; Miller, Karen F.; Moser, Kelly M.; Russ, Stephan; Roden, Dan M.; Harrell, Frank E.; Darbar, Dawood

    2015-01-01

    There is wide variation in the management of emergency department (ED) patients with atrial fibrillation (AF). We aimed to derive and internally validate the first prospective, ED-based clinical decision aid to identify patients with AF at low risk for 30-day adverse events. We performed a prospective cohort study at a university-affiliated, tertiary-care, ED. Patients were enrolled from June 9, 2010 to February 28, 2013 and followed for 30 days. We enrolled a convenience sample of ED patients presenting with symptomatic AF. Candidate predictors were based on ED data available in the first two hours. The decision aid was derived using model approximation (preconditioning) followed by strong bootstrap internal validation. We utilized an ordinal outcome hierarchy defined as the incidence of the most severe adverse event within 30 days of the ED evaluation. Of 497 patients enrolled, stroke and AF-related death occurred in 13 (3%) and 4 (<1%) patients, respectively. The decision aid included the following: age, triage vitals (systolic blood pressure, temperature, respiratory rate, oxygen saturation, supplemental oxygen requirement); medical history (heart failure, home sotalol use, prior percutaneous coronary intervention, electrical cardioversion, cardiac ablation, frequency of AF symptoms); ED data (2 hour heart rate, chest radiograph results, hemoglobin, creatinine, and brain natriuretic peptide). The decision aid’s c-statistic in predicting any 30-day adverse event was 0.7 (95% CI, 0.65, 0.76). In conclusion, among ED patients with AF, AFFORD provides the first evidence based decision aid for identifying patients who are at low risk for 30-day adverse events and candidates for safe discharge. PMID:25633190

  17. Comparative value of maximal treadmill testing, exercise thallium myocardial perfusion scintigraphy and exercise radionuclide ventriculography for distinguishing high- and low-risk patients soon after acute myocardial infarction

    SciTech Connect

    Hung, J.; Goris, M.L.; Nash, E.; Kraemer, H.C.; DeBusk, R.F.; Berger, W.E.; Lew, H.

    1984-05-01

    The prognostic value of symptom-limited treadmill exercise electrocardiography, exercise thallium myocardial perfusion scintigraphy and rest and exercise radionuclide ventriculography was compared in 117 men, aged 54 +/- 9 years, tested 3 weeks after a clinically uncomplicated acute myocardial infarction (MI). During a mean follow-up period of 11.6 months, 8 men experienced ''hard'' medical events (cardiac death, nonfatal ventricular fibrillation or recurrent MI) and 14 were hospitalized for unstable angina pectoris, congestive heart failure or coronary bypass surgery (total of 22 combined events). By multivariate analysis (Cox proportional hazards model), peak treadmill work load and the change in left ventricular ejection fraction (EF) during exercise were significant (p less than 0.01) predictors of hard medical events; these 2 risk factors and recurrent ischemic chest pain in the coronary care unit were also significantly predictive (p less than 0.001) for combined events. A peak treadmill work load of 4 METs or less or a decrease in EF of 5% or more below the value at rest during submaximal effort distinguished 22 high-risk patients (20% of the study population) from 89 low-risk patients. The rate of hard medical events within 12 months was 23% (5 of 22 patients), vs 2% (2 of 89 patients) in the high- and low-risk patient subsets, respectively (p less than 0.001). Thus, in patients who underwent evaluation 3 weeks after a clinically uncomplicated MI, exercise radionuclide ventriculography contributed independent prognostic information to that provided by symptom-limited treadmill testing and was superior to exercise thallium scintigraphy for this purpose.

  18. A Comparison of Acute and Chronic Toxicity for Men With Low-Risk Prostate Cancer Treated With Intensity-Modulated Radiation Therapy or {sup 125}I Permanent Implant

    SciTech Connect

    Eade, Thomas N.; Horwitz, Eric M. Ruth, Karen; Buyyounouski, Mark K.; D'Ambrosio, David J.; Feigenberg, Steven J.; Chen, David Y.T.; Pollack, Alan

    2008-06-01

    Purpose: To compare the toxicity and biochemical outcomes of intensity-modulated radiation therapy (IMRT) and {sup 125}I transperineal permanent prostate seed implant ({sup 125}I) for patients with low-risk prostate cancer. Methods and Materials: Between 1998 and 2004, a total of 374 low-risk patients (prostate-specific antigen < 10 ng/ml, T1c-T2b, Gleason score of 6 or less, and no neoadjuvant hormones) were treated at Fox Chase Cancer Center (216 IMRT and 158 {sup 125}I patients). Median follow-up was 43 months for IMRT and 48 months for {sup 125}I. The IMRT prescription dose ranged from 74-78 Gy, and {sup 125}I prescription was 145 Gy. Acute and late gastrointestinal (GI) and genitourinary (GU) toxicity was recorded by using a modified Radiation Therapy Oncology Group scale. Freedom from biochemical failure was defined by using the Phoenix definition (prostate-specific antigen nadir + 2.0 ng/ml). Results: Patients treated by using IMRT were more likely to be older and have a higher baseline American Urological Association symptom index score, history of previous transurethral resection of the prostate, and larger prostate volumes. On multivariate analysis, IMRT was an independent predictor of lower acute and late Grade 2 or higher GU toxicity and late Grade 2 or higher GI toxicity. Three-year actuarial estimates of late Grade 2 or higher toxicity were 2.4% for GI and 3.5% for GU by using IMRT compared with 7.7% for GI and 19.2% for GU for {sup 125}I, respectively. Four-year actuarial estimates of freedom from biochemical failure were 99.5% for IMRT and 93.5% for {sup 125}I (p = 0.09). Conclusions: The IMRT and {sup 125}I produce similar outcomes, although IMRT appears to have less acute and late toxicity.

  19. School Age Effects of the Newborn Individualized Developmental Care and Assessment Program for Medically Low-Risk Preterm Infants: Preliminary Findings

    PubMed Central

    McAnulty, Gloria; Duffy, Frank H.; Kosta, Sandra; Weisenfeld, Neil I.; Warfield, Simon K.; Butler, Samantha C.; Bernstein, Jane Holmes; Zurakowski, David; Als, Heidelise

    2012-01-01

    Background: By school-age, even low-risk moderately preterm-born children show more neuro-cognitive deficits, motor impairments, academic underachievement, behavioral problems, and poor social adaptation than full-term peers. Aim: To evaluate the outcomes at school-age for moderately preterm-born children (29-33 weeks gestational age), appropriate in growth for gestational age (AGA) and medically at low-risk, randomized to Newborn Individualized Developmental Care and Assessment Program (NIDCAP) or standard care in the Newborn Intensive Care Unit. At school-age, the experimental (E) group will show better neuropsychological and neuro-electrophysiological function, as well as improved brain structure than the control (C) group. Materials and Methods: The original sample consisted of 30 moderately preterm-born infants (29 to 33 weeks), 23 (8C and 15E) of them were evaluated at 8 years of age, corrected-for-prematurity with neuropsychological, EEG spectral coherence, and diffusion tensor magnetic resonance imaging (DT-MRI) measures. Results: E-performed significantly better than C-group children on the Kaufman Assessment Battery for Children-Second Edition (KABC-II) and trended towards better scores on the Rey-Osterrieth Complex Figure Test. They also showed more mature frontal and parietal brain connectivities, and more mature fiber tracts involving the internal capsule and the cingulum. Neurobehavioral results in the newborn period successfully predicted neuropsychological functioning at 8 years corrected age. Conclusion: Moderately preterm infants cared for with the NIDCAP intervention showed improved neuropsychological and neuro-electrophysiological function as well as improved brain structure at school-age. PMID:23951557

  20. Adverse trends of cardiovascular risk factors among low risk populations (1983-1994) - a cohort study of workers and farmers in Guangzhou, China

    PubMed Central

    2011-01-01

    Background The levels and trends of cardiovascular risk factors vary greatly throughout China. We examine 10-year trends of cardiovascular risk factors (1983-1994) and the factors related to these trends among low-risk cohorts of workers and farmers in Guangzhou, China. Methods This is a cohort study of 3,131 workers and 3,493 farmers aged 25-64 years at baseline with 10 years of follow-up. We performed a longitudinal analysis to account for the aging of the cohorts and the repeated measures of the same individual. Results At baseline the prevalence of overweight (including obese) ranged from 1.0% to 11.8%, hypertension ranged from 3.8% to 10.5%, and mean serum total cholesterol (TC) ranged from 155.4 mg/dl to 187.2 mg/dl. Although prevalence of smoking declined, blood pressure levels and body mass index (BMI) increased significantly, and lipid profiles changed unfavorably during the 10-year follow-ups. The prevalence of hypertension increased from 5.0 percentage points (female farmers) to 12.3 percentage points (male farmers). Mean TC increased significantly (e.g., +22.8 mg/dl and +17.0 mg/dl in male and female farmers, respectively). In the longitudinal data analyses, increase in BMI was associated with increase in blood pressure levels and TC. Significant adverse trends of risk factors persisted after adjustment for aging, education, BMI, smoking, and alcohol intake. Conclusion Urgent action is needed to prevent and reverse the unhealthy trends occurring among these low risk Chinese workers and farmers. PMID:22168211

  1. Maternal uterine artery Doppler in the first and second trimesters as screening method for hypertensive disorders and adverse perinatal outcomes in low-risk pregnancies

    PubMed Central

    Scandiuzzi, Rosiane Maciel; Prado, Caio Antonio de Campos; Duarte, Geraldo; Quintana, Silvana Maria; da Silva Costa, Fabrício; Tonni, Gabriele; Cavalli, Ricardo de Carvalho; Marcolin, Alessandra Cristina

    2016-01-01

    Objective To assess the maternal demographic characteristics and uterine artery (UA) Doppler parameters at first and second trimesters of pregnancy as predictors for hypertensive disorders (HDs) and adverse perinatal outcomes. Methods This prospective cohort study comprised 162 singleton low-risk women undergoing routine antenatal care. The left and right UA were assessed by color and pulsed Doppler and the mean pulsatility and resistance indices as well as the presence of a bilateral protodiastolic notch were recorded at 11 to 14 and 20 to 24 weeks' gestation. Multilevel regression analysis was used to determine the effects of maternal characteristics and abnormal UA Doppler parameters on the incidence of HD, small for gestational age newborn, cesarean section rate, Apgar score <7 at 1st and 5th minute, and admission to the neonatal intensive care unit. Results Fifteen women (9.2%) developed HD. UA mean resistance index (RI), UA mean pulsatility index, and parity were independent predictors of HD. Compared to the pregnancies with a normal UA mean RI at the first and second trimesters, pregnancies with UA mean RI >95th percentile only at the first trimester showed an increased risk for HD (odds ratio, 23.25; 95% confidence interval, 3.47 to 155.73; P<0.01). Similar result was found for UA mean pulsatility index >95th percentile (odds ratio, 9.84; 95% confidence interval, 1.05 to 92.10; P=0.05). The model including maternal age, maternal and paternal ethnicity, occupation, parity and UA mean RI increased the relative risk for HD (area under receiver operating characteristics, 0.81). Conclusion A first-trimester screening combining maternal characteristics and UA Doppler parameters is useful to predict HD in a low-risk population.

  2. Home treatment of patients with low-risk pulmonary embolism with the oral factor Xa inhibitor rivaroxaban. Rationale and design of the HoT-PE Trial.

    PubMed

    Barco, Stefano; Lankeit, Mareike; Binder, Harald; Schellong, Sebastian; Christ, Michael; Beyer-Westendorf, Jan; Duerschmied, Daniel; Bauersachs, Rupert; Empen, Klaus; Held, Matthias; Schwaiblmair, Martin; Fonseca, Cândida; Jiménez, David; Becattini, Cecilia; Quitzau, Kurt; Konstantinides, Stavros

    2016-07-01

    Pulmonary embolism (PE) is a potentially life-threatening acute cardiovascular syndrome. However, more than 95 % of patients are haemodynamically stable at presentation, and among them are patients at truly low risk who may qualify for immediate or early discharge. The Home Treatment of Pulmonary Embolism (HoT-PE) study is a prospective international multicentre single-arm phase 4 management (cohort) trial aiming to determine whether home treatment of acute low-risk PE with the oral factor Xa inhibitor rivaroxaban is feasible, effective, and safe. Patients with confirmed PE, who have no right ventricular dysfunction or free floating thrombi in the right atrium or ventricle, are eligible if they meet none of the exclusion criteria indicating haemodynamic instability, serious comorbidity or any condition mandating hospitalisation, or a familial/social environment unable to support home treatment. The first dose of rivaroxaban is given in hospital, and patients are discharged within 48 hours of presentation. Rivaroxaban is taken for at least three months. The primary outcome is symptomatic recurrent venous thromboembolism or PE-related death within three months of enrolment. Secondary outcomes include quality of life and patient satisfaction, and health care resource utilisation compared to existing data on standard-duration hospital treatment. HoT-PE is planned to analyse 1,050 enrolled patients, providing 80 % power to reject the null hypothesis that the recurrence rate of venous thromboembolism is >3 % with α≤0.05. If the hypothesis of HoT-PE is confirmed, early discharge and out-of-hospital treatment may become an attractive, potentially cost-saving option for a significant proportion of patients with acute PE.

  3. Maternal uterine artery Doppler in the first and second trimesters as screening method for hypertensive disorders and adverse perinatal outcomes in low-risk pregnancies

    PubMed Central

    Scandiuzzi, Rosiane Maciel; Prado, Caio Antonio de Campos; Duarte, Geraldo; Quintana, Silvana Maria; da Silva Costa, Fabrício; Tonni, Gabriele; Cavalli, Ricardo de Carvalho; Marcolin, Alessandra Cristina

    2016-01-01

    Objective To assess the maternal demographic characteristics and uterine artery (UA) Doppler parameters at first and second trimesters of pregnancy as predictors for hypertensive disorders (HDs) and adverse perinatal outcomes. Methods This prospective cohort study comprised 162 singleton low-risk women undergoing routine antenatal care. The left and right UA were assessed by color and pulsed Doppler and the mean pulsatility and resistance indices as well as the presence of a bilateral protodiastolic notch were recorded at 11 to 14 and 20 to 24 weeks' gestation. Multilevel regression analysis was used to determine the effects of maternal characteristics and abnormal UA Doppler parameters on the incidence of HD, small for gestational age newborn, cesarean section rate, Apgar score <7 at 1st and 5th minute, and admission to the neonatal intensive care unit. Results Fifteen women (9.2%) developed HD. UA mean resistance index (RI), UA mean pulsatility index, and parity were independent predictors of HD. Compared to the pregnancies with a normal UA mean RI at the first and second trimesters, pregnancies with UA mean RI >95th percentile only at the first trimester showed an increased risk for HD (odds ratio, 23.25; 95% confidence interval, 3.47 to 155.73; P<0.01). Similar result was found for UA mean pulsatility index >95th percentile (odds ratio, 9.84; 95% confidence interval, 1.05 to 92.10; P=0.05). The model including maternal age, maternal and paternal ethnicity, occupation, parity and UA mean RI increased the relative risk for HD (area under receiver operating characteristics, 0.81). Conclusion A first-trimester screening combining maternal characteristics and UA Doppler parameters is useful to predict HD in a low-risk population. PMID:27668197

  4. CHRNA5 Risk Variant Predicts Delayed Smoking Cessation and Earlier Lung Cancer Diagnosis—A Meta-Analysis

    PubMed Central

    Hung, Rayjean J.; Baker, Timothy; Horton, Amy; Culverhouse, Rob; Saccone, Nancy; Cheng, Iona; Deng, Bo; Han, Younghun; Hansen, Helen M.; Horsman, Janet; Kim, Claire; Lutz, Sharon; Rosenberger, Albert; Aben, Katja K.; Andrew, Angeline S.; Breslau, Naomi; Chang, Shen-Chih; Dieffenbach, Aida Karina; Dienemann, Hendrik; Frederiksen, Brittni; Han, Jiali; Hatsukami, Dorothy K.; Johnson, Eric O.; Pande, Mala; Wrensch, Margaret R.; McLaughlin, John; Skaug, Vidar; van der Heijden, Henricus F.; Wampfler, Jason; Wenzlaff, Angela; Woll, Penella; Zienolddiny, Shanbeh; Bickeböller, Heike; Brenner, Hermann; Duell, Eric J.; Haugen, Aage; Heinrich, Joachim; Hokanson, John E.; Hunter, David J.; Kiemeney, Lambertus A.; Lazarus, Philip; Le Marchand, Loic; Liu, Geoffrey; Mayordomo, Jose; Risch, Angela; Schwartz, Ann G.; Teare, Dawn; Wu, Xifeng; Wiencke, John K.; Yang, Ping; Zhang, Zuo-Feng; Spitz, Margaret R.; Kraft, Peter; Amos, Christopher I.; Bierut, Laura J.

    2015-01-01

    Background: Recent meta-analyses show strong evidence of associations among genetic variants in CHRNA5 on chromosome 15q25, smoking quantity, and lung cancer. This meta-analysis tests whether the CHRNA5 variant rs16969968 predicts age of smoking cessation and age of lung cancer diagnosis. Methods: Meta-analyses examined associations between rs16969968, age of quitting smoking, and age of lung cancer diagnosis in 24 studies of European ancestry (n = 29 072). In each dataset, we used Cox regression models to evaluate the association between rs16969968 and the two primary phenotypes (age of smoking cessation among ever smokers and age of lung cancer diagnosis among lung cancer case patients) and the secondary phenotype of smoking duration. Heterogeneity across studies was assessed with the Cochran Q test. All statistical tests were two-sided. Results: The rs16969968 allele (A) was associated with a lower likelihood of smoking cessation (hazard ratio [HR] = 0.95, 95% confidence interval [CI] = 0.91 to 0.98, P = .0042), and the AA genotype was associated with a four-year delay in median age of quitting compared with the GG genotype. Among smokers with lung cancer diagnoses, the rs16969968 genotype (AA) was associated with a four-year earlier median age of diagnosis compared with the low-risk genotype (GG) (HR = 1.08, 95% CI = 1.04 to 1.12, P = 1.1*10–5). Conclusion: These data support the clinical significance of the CHRNA5 variant rs16969968. It predicts delayed smoking cessation and an earlier age of lung cancer diagnosis in this meta-analysis. Given the existing evidence that this CHRNA5 variant predicts favorable response to cessation pharmacotherapy, these findings underscore the potential clinical and public health importance of rs16969968 in CHRNA5 in relation to smoking cessation success and lung cancer risk. PMID:25873736

  5. Guidelines for investigating causality of sequence variants in human disease.

    PubMed

    MacArthur, D G; Manolio, T A; Dimmock, D P; Rehm, H L; Shendure, J; Abecasis, G R; Adams, D R; Altman, R B; Antonarakis, S E; Ashley, E A; Barrett, J C; Biesecker, L G; Conrad, D F; Cooper, G M; Cox, N J; Daly, M J; Gerstein, M B; Goldstein, D B; Hirschhorn, J N; Leal, S M; Pennacchio, L A; Stamatoyannopoulos, J A; Sunyaev, S R; Valle, D; Voight, B F; Winckler, W; Gunter, C

    2014-04-24

    The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development.

  6. New genetic variants associated with prostate cancer

    Cancer.gov

    Researchers have newly identified 23 common genetic variants -- one-letter changes in DNA known as single-nucleotide polymorphisms or SNPs -- that are associated with risk of prostate cancer. These results come from an analysis of more than 10 million SNP

  7. Cellobiohydrolase I gene and improved variants

    DOEpatents

    Adney, William S.; Decker, Stephen R.; Mc Carter, Suzanne; Baker, John O.; Nieves, Raphael; Himmel, Michael E.; Vinzant, Todd B.

    2008-05-20

    The disclosure provides a method for preparing an active exoglucanase in a heterologous host of eukaryotic origin. The method includes mutagenesis to reduce glycosylation of the exoglucanase when expressed in a heterologous host. It is further disclosed a method to produce variant cellobiohydrolase that is stable at high temperature through mutagenesis.

  8. New variant for whole pancreas grafting

    SciTech Connect

    Kootstra, G.; van Hooff, J.P.; Joerning, P.J.L.; Leunissen, K.M.; van der Linden, C.J.; Beukers, E.; Buurman, W.A.

    1987-02-01

    A new variant for whole pancreas grafting is described in which a segment of the duodenum and the spleen is included in the graft. The graft is placed extraperitoneally as in kidney transplantation. The exocrine drainage is with side-to-side anastomosis between duodenum and bladder. The spleen is irradiated to prevent the occurrence of GVHD, as is reported in splenic transplantation.

  9. Regional Phonological Variants in Louisiana Speech.

    ERIC Educational Resources Information Center

    Rubrecht, August Weston

    Based on tape recorded conversations of 28 informants in 18 Louisiana communities, this study investigated regional phonological variants in Louisiana speech. On the basis of settlement history and previous dialect studies, four regions are defined: northern Louisiana, the Florida Parishes, French Louisiana, and New Orleans. The informants are all…

  10. Normal variants of the accessory hemiazygos vein

    PubMed Central

    Blackmon, J M; Franco, A

    2011-01-01

    This short communication describes two normal variants of the accessory hemiazygous vein in a 15-year-old female. The article demonstrates that knowledge of the aberrant venous anatomy and the collateral pathway is important for the practising radiologist. PMID:21697414

  11. Truncated variants of apolipoprotein B cause hypobetalipoproteinaemia.

    PubMed Central

    Collins, D R; Knott, T J; Pease, R J; Powell, L M; Wallis, S C; Robertson, S; Pullinger, C R; Milne, R W; Marcel, Y L; Humphries, S E

    1988-01-01

    Familial hypobetalipoproteinaemia is a rare autosomal dominant disorder in which levels of apo-B-containing plasma lipoproteins are approximately half-normal in heterozygotes and virtually absent in homozygotes. Here we describe mutations of the apo-B gene that cause two different truncated variants of apo-B in unrelated individuals with hypobetalipoproteinaemia. One variant, apo-B(His1795----Met-Trp-Leu-Val-Thr-Term) is predicted to be 1799 amino acids long and arises from deletion of a single nucleotide (G) from leucine codon 1794. This protein was found at low levels in very low density and low density lipoprotein fractions in the blood. The second, shorter variant, apo-B(Arg1306----Term), is caused by mutation of a CpG dinucleotide in arginine codon 1306 converting it to a stop codon and predicting a protein of 1305 residues. The product of this allele could not be detected in the circulation. The differences in size and behaviour of these two variants compared to apo-B100 or apo-B48 point to domains that may be important for the assembly, secretion or stability of apo-B-containing lipoproteins. Images PMID:2843815

  12. New lymphogranuloma venereum Chlamydia trachomatis variant, Amsterdam.

    PubMed

    Spaargaren, Joke; Fennema, Han S A; Morré, Servaas A; de Vries, Henry J C; Coutinho, Roel A

    2005-07-01

    We retrospectively conducted a study of men who have sex with men who visited the Amsterdam, the Netherlands, sexually transmitted diseases clinic from January 2002 to December 2003 and had rectal Chlamydia trachomatis infections. We found that symptomatic (73%) as well as asymptomatic (43%) patients were infected with a new C. trachomatis LGV variant.

  13. Splicing variants of porcine synphilin-1.

    PubMed

    Larsen, Knud; Madsen, Lone Bruhn; Farajzadeh, Leila; Bendixen, Christian

    2015-09-01

    Parkinson's disease (PD), idiopathic and familial, is characterized by degradation of dopaminergic neurons and the presence of Lewy bodies (LB) in the substantia nigra. LBs contain aggregated proteins of which α-synuclein is the major component. The protein synphilin-1 interacts and colocalizes with α-synuclein in LBs. The aim of this study was to isolate and characterize porcine synphilin-1 and isoforms hereof with the future perspective to use the pig as a model for Parkinson's disease. The porcine SNCAIP cDNA was cloned by reverse transcriptase PCR. The spatial expression of SNCAIP mRNA was investigated by RNAseq. The presented work reports the molecular cloning and characterization of the porcine (Sus scrofa) synphilin-1 cDNA (SNCAIP) and three splice variants hereof. The porcine SNCAIP cDNA codes for a protein (synphilin-1) of 919 amino acids which shows a high similarity to human (90%) and to mouse (84%) synphilin-1. Three shorter transcript variants of the synphilin-1 gene were identified, all lacking one or more exons. SNCAIP transcripts were detected in most examined organs and tissues and the highest expression was found in brain tissues and lung. Conserved splicing variants and a novel splice form of synhilin-1 were found in this study. All synphilin-1 isoforms encoded by the identified transcript variants lack functional domains important for protein degradation. PMID:26101749

  14. Monomorphic adenoma, canalicular variant: report of case.

    PubMed

    Wiener, A P; Meadows, F

    1977-05-01

    A case of monomorphic adenoma, canalicular variant, has been presented. This lesion is a rare benign neoplasm most often found in the minor salivary glands of the upper lip. This appears to be the first reported case of the lesion in a non-Caucasian.

  15. Functional annotation of non-coding sequence variants

    PubMed Central

    Ritchie, Graham R. S.; Dunham, Ian; Zeggini, Eleftheria; Flicek, Paul

    2016-01-01

    Identifying functionally relevant variants against the background of ubiquitous genetic variation is a major challenge in human genetics. For variants that fall in protein-coding regions our understanding of the genetic code and splicing allow us to identify likely candidates, but interpreting variants that fall outside of genic regions is more difficult. Here we present a new tool, GWAVA, which supports prioritisation of non-coding variants by integrating a range of annotations. PMID:24487584

  16. Deregulating Low-Risk Research

    ERIC Educational Resources Information Center

    Shamoo, Adil E.

    2007-01-01

    In the past few decades, with the explosion of biotechnology and the aging of the population, the use of human subjects in research has increased significantly. The United States has done much to protect human research subjects, and no one can deny the importance of keeping them safe. But at the same time, researchers whose work poses no threat to…

  17. The importance of active surveillance, and immediate re-biopsy in low-risk prostate cancer: The largest series from Turkey

    PubMed Central

    Bayar, Göksel; Horasanlı, Kaya; Acinikli, Hüseyin; Tanrıverdi, Orhan; Dalkılıç, Ayhan; Arısan, Serdar

    2016-01-01

    Objective To evaluate long-term outcomes of active surveillance (AS) applied in low-risk prostate cancer patients, and the impact of re-biopsy results on the prediction of progression. Material and methods In our clinic, patients who had undergone AS for low-risk localized prostate cancer between the years 2005–2013 were included in the study. Our AS criteria are Gleason score ≤6, prostate-specific antigen (PSA) level <10 ng/mL, number of positive cores <3, maximum cancer involvement ratio <50% each core. Immediate re-biopsy (within 3 months) was performed to 65 patients who accepted AS. Finally, 43 patients who met re-biopsy criteria were included in the study. Prostate biopsy specimens were harvested from 12 cores under the guidance of transrectal ultrasound (TRUS). Re-biopsy was performed within 3 months (1–12 weeks). In re-biopsy, a total of 20 core biopsies were performed including the far lateral (6 cores) and transition zone (2 cores) in addition to standard 12 core biopsy. Our follow-up protocol is PSA measurement and digital rectal examination (DRE) every 3 months within the first 2 years, than every 6 months. Control biopsies was performed one year later and once upon every 3 years to patients whose PSA levels and DREs were normal at follow-up visits. More than 2 tumor invaded cores or 50% tumor in one core, and Gleason score exceeding 6 points were accepted as indications for definitive treatment. Patients were divided into two groups by re-biopsy results and compared according to the time to progression. We have done multivariate regression analysis to predict prognosis by using data on age, PSA level, and detection of tumor in re-biopsy specimens. Results Patients’ median age was 61 years and PSA level was 5 (2.7–9) ng/mL. Tumor was detected in 22 (34%) patients at re-biopsy and they underwent definitive treatment. Additionally tumor was detected in 9 patients, but active surveillance was maintained because their pathologic results met active

  18. Variant Influenza Associated with Live Animal Markets, Minnesota.

    PubMed

    Choi, M J; Morin, C A; Scheftel, J; Vetter, S M; Smith, K; Lynfield, R

    2015-08-01

    Variant influenza viruses are swine-origin influenza A viruses that cause illness in humans. Surveillance for variant influenza A viruses, including characterization of exposure settings, is important because of the potential emergence of novel influenza viruses with pandemic potential. In Minnesota, we have documented variant influenza A virus infections associated with swine exposure at live animal markets.

  19. Strategies to choose from millions of imputed sequence variants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Millions of sequence variants are known, but subsets are needed for routine genomic predictions or to include on genotyping arrays. Variant selection and imputation strategies were tested using 26 984 simulated reference bulls, of which 1 000 had 30 million sequence variants, 773 had 600 000 markers...

  20. Processing of No-Release Variants in Connected Speech

    ERIC Educational Resources Information Center

    LoCasto, Paul C.; Connine, Cynthia M.

    2011-01-01

    The cross modal repetition priming paradigm was used to investigate how potential lexically ambiguous no-release variants are processed. In particular we focus on segmental regularities that affect the variant's frequency of occurrence (voicing of the critical segment) and phonological context in which the variant occurs (status of the following…

  1. A survey of Canadian urologists’ opinions and prescribing patterns of testosterone replacement therapy in men on active surveillance for low-risk prostate cancer

    PubMed Central

    Millar, Adam C.; Elterman, Dean S.; Goldenberg, Larry; Van Asseldonk, Brandon; Curtis, Ashley; Jarvi, Keith

    2016-01-01

    Introduction: Attitudes regarding the safety of testosterone replacement therapy (TRT) in hypogonadal men with prostate cancer (PCa) have changed over the past few years with the emergence of case studies suggesting a low risk of cancer progression and a better understanding of the interaction of different levels of androgen with prostate cellular metabolism. This new view has the potential to change clinical practice. Methods: Active members of the Canadian Urological Association were surveyed about their opinions on the safety of TRT in men with low-risk PCa, as well as their current prescribing habits. Results: Of 57 responding urologists, 86% actively prescribe TRT in men with testosterone deficiency syndrome (TDS), 93% are involved in the treatment of men with PCa, and 95% offer active surveillance as a management option for low-grade/low-stage disease. Furthermore, 65% stated that they would offer TRT to men with TDS who were on active surveillance for PCa and 63% believed that TRT did not increase the risk of progression of PCa in these men. In terms of treatment methods, 96% believed TRT was safe for men who have undergone radical prostatectomy, while a smaller number felt it was safe for patients who have undergone brachytherapy (86%) or external beam radiation (84%). Despite these figures, only 35% of the surveyed physicians had ever offered TRT for men on active surveillance and only 42% actually had men in their practice who were taking testosterone while on active surveillance. Conclusions: The discrepancy between urologists’ beliefs about the safety of TRT and their clinical practice patterns may be due to multiple factors, such as hesitation in recommending treatment in real-life practice, low numbers of eligible patients, absence of screening for testosterone deficiency in patients on active surveillance, and patient preference or fears. Furthermore, the difference in perceived safety in men treated by radical prostatectomy vs. radiation therapy

  2. Superluminescent variants of marine luciferases for bioassays.

    PubMed

    Kim, Sung Bae; Suzuki, Hideyuki; Sato, Moritoshi; Tao, Hiroaki

    2011-11-15

    In this study, a rational synthesis of superluminescent variants from marine luciferases with prolonged bioluminescence has been demonstrated. A putative active site of a model marine luciferase, Gaussia princeps Luciferase (GLuc), was assigned and modified by a site-directed mutagenesis. The potent variants were found to generate up to 10 times stronger bioluminescence, emitting red shifts of up to 33 nm with natural coelenterazine than native GLuc, rendering an efficient optical signature in bioassays. The advantageous properties were demonstrated with mammalian two-hybrid assays, single-chain probes, and metastases of murine B16 melanoma in BALB/c nude mice. The unique ideas for engineering GLuc are proved to be valid even for other marine luciferases. PMID:21951281

  3. Wham: Identifying Structural Variants of Biological Consequence.

    PubMed

    Kronenberg, Zev N; Osborne, Edward J; Cone, Kelsey R; Kennedy, Brett J; Domyan, Eric T; Shapiro, Michael D; Elde, Nels C; Yandell, Mark

    2015-12-01

    Existing methods for identifying structural variants (SVs) from short read datasets are inaccurate. This complicates disease-gene identification and efforts to understand the consequences of genetic variation. In response, we have created Wham (Whole-genome Alignment Metrics) to provide a single, integrated framework for both structural variant calling and association testing, thereby bypassing many of the difficulties that currently frustrate attempts to employ SVs in association testing. Here we describe Wham, benchmark it against three other widely used SV identification tools-Lumpy, Delly and SoftSearch-and demonstrate Wham's ability to identify and associate SVs with phenotypes using data from humans, domestic pigeons, and vaccinia virus. Wham and all associated software are covered under the MIT License and can be freely downloaded from github (https://github.com/zeeev/wham), with documentation on a wiki (http://zeeev.github.io/wham/). For community support please post questions to https://www.biostars.org/.

  4. Xeroderma pigmentosum variant associated with multiple cancers.

    PubMed

    Kuwamoto, K; Miyauchi-Hashimoto, H; Isei, T; Horio, T

    1999-01-01

    A 62-year-old Japanese man with xeroderma pigmentosum (XP) variant is reported. The patient had developed at least 6 basal cell carcinomas, a squamous cell carcinoma, and a malignant melanoma on sun-exposed areas, and an atypical carcinoid on the right lung. In vivo phototesting showed a normal response. The minimal erythema dose of ultraviolet B (UVB) was not lowered and no delayed peaking of the erythema reaction was observed. His skin fibroblasts exhibited higher sensitivity to UV irradiation, but a normal level of unscheduled DNA and RNA synthesis. Cell fusions with XP group A, C, D, E, F, and G cells after UV irradiation were all complemented. Previous reports together with this case suggest that older XP variant patients have a high frequency of not only skin cancers, but also internal malignancies. PMID:10404723

  5. The Saccharomyces Genome Database Variant Viewer

    PubMed Central

    Sheppard, Travis K.; Hitz, Benjamin C.; Engel, Stacia R.; Song, Giltae; Balakrishnan, Rama; Binkley, Gail; Costanzo, Maria C.; Dalusag, Kyla S.; Demeter, Janos; Hellerstedt, Sage T.; Karra, Kalpana; Nash, Robert S.; Paskov, Kelley M.; Skrzypek, Marek S.; Weng, Shuai; Wong, Edith D.; Cherry, J. Michael

    2016-01-01

    The Saccharomyces Genome Database (SGD; http://www.yeastgenome.org) is the authoritative community resource for the Saccharomyces cerevisiae reference genome sequence and its annotation. In recent years, we have moved toward increased representation of sequence variation and allelic differences within S. cerevisiae. The publication of numerous additional genomes has motivated the creation of new tools for their annotation and analysis. Here we present the Variant Viewer: a dynamic open-source web application for the visualization of genomic and proteomic differences. Multiple sequence alignments have been constructed across high quality genome sequences from 11 different S. cerevisiae strains and stored in the SGD. The alignments and summaries are encoded in JSON and used to create a two-tiered dynamic view of the budding yeast pan-genome, available at http://www.yeastgenome.org/variant-viewer. PMID:26578556

  6. Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes.

    PubMed

    Stepniak, Beata; Kästner, Anne; Poggi, Giulia; Mitjans, Marina; Begemann, Martin; Hartmann, Annette; Van der Auwera, Sandra; Sananbenesi, Farahnaz; Krueger-Burg, Dilja; Matuszko, Gabriela; Brosi, Cornelia; Homuth, Georg; Völzke, Henry; Benseler, Fritz; Bagni, Claudia; Fischer, Utz; Dityatev, Alexander; Grabe, Hans-Jörgen; Rujescu, Dan; Fischer, Andre; Ehrenreich, Hannelore

    2015-11-26

    Fragile X syndrome (FXS) is mostly caused by a CGG triplet expansion in the fragile X mental retardation 1 gene (FMR1). Up to 60% of affected males fulfill criteria for autism spectrum disorder (ASD), making FXS the most frequent monogenetic cause of syndromic ASD. It is unknown, however, whether normal variants (independent of mutations) in the fragile X gene family (FMR1, FXR1, FXR2) and in FMR2 modulate autistic features. Here, we report an accumulation model of 8 SNPs in these genes, associated with autistic traits in a discovery sample of male patients with schizophrenia (N = 692) and three independent replicate samples: patients with schizophrenia (N = 626), patients with other psychiatric diagnoses (N = 111) and a general population sample (N = 2005). For first mechanistic insight, we contrasted microRNA expression in peripheral blood mononuclear cells of selected extreme group subjects with high- versus low-risk constellation regarding the accumulation model. Thereby, the brain-expressed miR-181 species emerged as potential "umbrella regulator", with several seed matches across the fragile X gene family and FMR2. To conclude, normal variation in these genes contributes to the continuum of autistic phenotypes.

  7. TVFMCATS. Time Variant Floating Mean Counting Algorithm

    SciTech Connect

    Huffman, R.K.

    1999-05-01

    This software was written to test a time variant floating mean counting algorithm. The algorithm was developed by Westinghouse Savannah River Company and a provisional patent has been filed on the algorithm. The test software was developed to work with the Val Tech model IVB prototype version II count rate meter hardware. The test software was used to verify the algorithm developed by WSRC could be correctly implemented with the vendor`s hardware.

  8. Time Variant Floating Mean Counting Algorithm

    SciTech Connect

    Huffman, Russell Kevin

    1999-06-03

    This software was written to test a time variant floating mean counting algorithm. The algorithm was developed by Westinghouse Savannah River Company and a provisional patent has been filed on the algorithm. The test software was developed to work with the Val Tech model IVB prototype version II count rate meter hardware. The test software was used to verify the algorithm developed by WSRC could be correctly implemented with the vendor''s hardware.

  9. Clock gene variants differentiate mood disorders.

    PubMed

    Dmitrzak-Weglarz, Monika Paulina; Pawlak, Joanna Maria; Maciukiewicz, Malgorzata; Moczko, Jerzy; Wilkosc, Monika; Leszczynska-Rodziewicz, Anna; Zaremba, Dorota; Hauser, Joanna

    2015-01-01

    Genetic variations in clock-related genes were hypothesized to be involved to in the susceptibility of mood disorders MD (both unipolar (UPD) and bipolar (BPD) disorders). In our work we investigated role of gene variants form four core period proteins: CLOCK, ARNTL, TIM and PER3. The total sample comprised from 744 mood disorders inpatients (UPD = 229, BPD = 515) and 635 healthy voluntary controls. The 42 SNPs from four genes of interest were genotyped. We used single polymorphisms, haplotypes, SNPs interactions and prediction analysis using classical statistical and machine learning methods. We observed association between two polymorphisms of CLOCK (rs1801260 and rs11932595) with BPDII and two polymorphisms of TIM (rs2291739, rs11171856) with UPD. We also detected ARNTL haplotype variant (rs1160996C/rs11022779G/rs1122780T) to be associated with increased risk of MD, BPD (both types). We established significant epistatic interaction between PER3 (rs2172563) and ARNTL (rs4146388 and rs7107287) in case of BPD. Additionally relation between PER3 (rs2172563) and CLOCK (rs1268271 and rs3805148) appeared in case of UPD. Classification and Regression Trees (C and RT) showed significant predictive value for 10 polymorphisms in all analyzed genes. However we failed to obtain model with sufficient predictive power. During analyses of sleep disturbances sample, we found carriers of homozygote variants (ARNTL: rs11022778 TT, rs1562438 TT, rs1982350 AA and PER3: rs836755 CC) showing more frequent falling asleep difficulties when compare to other genotypes carriers. Our study suggested a putative role of the CLOCK, TIM, ARNTL and PER3 and polymorphisms in MD susceptibility. In our analyses we showed association of specific gene variants with particular types of MD. We also confirmed necessity of performing separate analyzes for BPD and UPD patients. Comprehensive statistical approach is required even with individual symptoms analyses.

  10. [Lynch syndrome, Muir Torre variant: 2 cases].

    PubMed

    Castro-Mujica, María Del Carmen; Barletta-Carrillo, Claudia; Acosta-Aliaga, Marisa; Montenegro-Garreaud, Ximena

    2016-01-01

    Lynch syndrome (LS) is an autosomal-dominant inherited cancer predisposition syndrome caused by germline mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6 or PMS2). Muir-Torre syndrome (MTS) is a phenotypic variant of LS that includes a predisposition to sebaceous glands tumors and keratoacanthomas. We report two patients with MTS, with more than one LS-related cancer, skin lesions, family history of cancer andmicrosatellite instability and immunohistochemistry analysis. PMID:27131946

  11. Sex steroids and variants of gender identity.

    PubMed

    Meyer-Bahlburg, Heino F L

    2013-09-01

    This article summarizes for the practicing endocrinologist the current literature on the psychobiology of the development of gender identity and its variants in individuals with disorders of sex development (DSD) or with non-DSD transgenderism. Gender reassignment remains the treatment of choice for strong and persistent gender dysphoria in both categories, but more research is needed on the short-term and long-term effects of puberty-suppressing medications and cross-sex hormones on brain and behavior.

  12. Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants.

    PubMed

    Du, Mengmeng; Jiao, Shuo; Bien, Stephanie A; Gala, Manish; Abecasis, Goncalo; Bezieau, Stephane; Brenner, Hermann; Butterbach, Katja; Caan, Bette J; Carlson, Christopher S; Casey, Graham; Chang-Claude, Jenny; Conti, David V; Curtis, Keith R; Duggan, David; Gallinger, Steven; Haile, Robert W; Harrison, Tabitha A; Hayes, Richard B; Hoffmeister, Michael; Hopper, John L; Hudson, Thomas J; Jenkins, Mark A; Küry, Sébastien; Le Marchand, Loic; Leal, Suzanne M; Newcomb, Polly A; Nickerson, Deborah A; Potter, John D; Schoen, Robert E; Schumacher, Fredrick R; Seminara, Daniela; Slattery, Martha L; Hsu, Li; Chan, Andrew T; White, Emily; Berndt, Sonja I; Peters, Ulrike

    2016-01-01

    Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s).

  13. Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants.

    PubMed

    Du, Mengmeng; Jiao, Shuo; Bien, Stephanie A; Gala, Manish; Abecasis, Goncalo; Bezieau, Stephane; Brenner, Hermann; Butterbach, Katja; Caan, Bette J; Carlson, Christopher S; Casey, Graham; Chang-Claude, Jenny; Conti, David V; Curtis, Keith R; Duggan, David; Gallinger, Steven; Haile, Robert W; Harrison, Tabitha A; Hayes, Richard B; Hoffmeister, Michael; Hopper, John L; Hudson, Thomas J; Jenkins, Mark A; Küry, Sébastien; Le Marchand, Loic; Leal, Suzanne M; Newcomb, Polly A; Nickerson, Deborah A; Potter, John D; Schoen, Robert E; Schumacher, Fredrick R; Seminara, Daniela; Slattery, Martha L; Hsu, Li; Chan, Andrew T; White, Emily; Berndt, Sonja I; Peters, Ulrike

    2016-01-01

    Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s). PMID:27379672

  14. Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants

    PubMed Central

    Gala, Manish; Abecasis, Goncalo; Bezieau, Stephane; Brenner, Hermann; Butterbach, Katja; Caan, Bette J.; Carlson, Christopher S.; Casey, Graham; Chang-Claude, Jenny; Conti, David V.; Curtis, Keith R.; Duggan, David; Gallinger, Steven; Haile, Robert W.; Harrison, Tabitha A.; Hayes, Richard B.; Hoffmeister, Michael; Hopper, John L.; Hudson, Thomas J.; Jenkins, Mark A.; Küry, Sébastien; Le Marchand, Loic; Leal, Suzanne M.; Newcomb, Polly A.; Nickerson, Deborah A.; Potter, John D.; Schoen, Robert E.; Schumacher, Fredrick R.; Seminara, Daniela; Slattery, Martha L.; Hsu, Li; Chan, Andrew T.; White, Emily; Berndt, Sonja I.; Peters, Ulrike

    2016-01-01

    Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s). PMID:27379672

  15. Tay-Sachs disease: B1 variant.

    PubMed

    Gordon, B A; Gordon, K E; Hinton, G G; Cadera, W; Feleki, V; Bayleran, J; Hechtman, P

    1988-01-01

    This first child of non-Jewish parents had nystagmus at 4 months of age, bilateral cherry-red macular spots at 7 months of age, and hyperacusis at 8 months of age; the patient has deteriorated progressively following a clinical course typical of Tay-Sachs disease B variant. Total beta-N-acetylhexosaminidase assayed with 4-methylumbelliferyl-beta-glucosamine (4 MU GlcNAc) as substrate was within the normal range in plasma and cultured dermal fibroblasts and 2/3 the normal mean in leukocytes. The hexosaminidase A activity, assayed with the same substrate in plasma and cultured fibroblasts, approximated Tay-Sachs disease heterozygote levels; however, the activity of hexosaminidase A assayed with 4 MU Glc NAc-6-sulfate in the plasma, leukocytes, and cultured fibroblasts was less than 8, 2, and 1%, respectively of the control mean. This female infant with the B1 variant of Tay-Sachs disease demonstrated an earlier onset and more rapidly progressive course than was observed in 4 of the 5 previously reported patients with this Tay-Sachs disease variant.

  16. Orosomucoid-1 Expression in Ameloblastoma Variants.

    PubMed

    García-Muñoz, Alejandro; Bologna-Molina, Ronell; A Rodríguez, Mario; Liceága-Reyes, Rodrigo; Farfán-Morales, Jose Eduardo; Aranda-Romo, Saray; Molina-Frechero, Nelly; González-González, Rogelio

    2016-01-01

    Odontogenic tumors constitute a group of heterogeneous lesions of benign and malignant neoplasms with variable aggressiveness. Ameloblastomas are a group of benign but locally invasive neoplasms that occur in the jaws and are derived from epithelial elements of the tooth-forming apparatus. We previously described orosomucoid-1 protein expression in odontogenic myxomas. However, whether orosomucoid-1 is expressed in other odontogenic tumors remains unknown. Since orosomucoid-1 belongs to a group of acute-phase proteins and has many functions in health and disease, we identified and analyzed orosomucoid-1 expression in ameloblastoma variants and ameloblastic carcinoma using western blot and immunohistochemical techniques. Thirty cases of ameloblastoma were analyzed for orsomucoid-1; five specimens were fresh for western blot study (four benign ameloblastomas and one ameloblastic carcinoma), and 25 cases of benign ameloblastoma for immunohistochemical assays. Orosomucoid-1 was widely expressed in each tumor variant analyzed in this study, and differential orosomucoid-1 expression was observed between benign and malignant tumor. Orosomucoid-1 may play an important role in the behavior of ameloblastomas and influence the biology and development of the variants of this tumor. PMID:27386438

  17. Primary Aldosteronism and ARMC5 Variants

    PubMed Central

    Zilbermint, Mihail; Xekouki, Paraskevi; Faucz, Fabio R.; Berthon, Annabel; Gkourogianni, Alexandra; Schernthaner-Reiter, Marie Helene; Batsis, Maria; Sinaii, Ninet; Quezado, Martha M.; Merino, Maria; Hodes, Aaron; Abraham, Smita B.; Libé, Rossella; Assié, Guillaume; Espiard, Stéphanie; Drougat, Ludivine; Ragazzon, Bruno; Davis, Adam; Gebreab, Samson Y.; Neff, Ryan; Kebebew, Electron; Bertherat, Jérôme; Lodish, Maya B.

    2015-01-01

    Context: Primary aldosteronism is one of the leading causes of secondary hypertension, causing significant morbidity and mortality. A number of genetic defects have recently been identified in primary aldosteronism, whereas we identified mutations in ARMC5, a tumor-suppressor gene, in cortisol-producing primary macronodular adrenal hyperplasia. Objective: We investigated a cohort of 56 patients who were referred to the National Institutes of Health for evaluation of primary aldosteronism for ARMC5 defects. Methods: Patients underwent step-wise diagnosis, with measurement of serum aldosterone and plasma renin activity followed by imaging, saline suppression and/or oral salt loading tests, plus adrenal venous sampling. Cortisol secretion was also evaluated; unilateral or bilateral adrenalectomy was performed, if indicated. DNA, protein, and transfection studies in H295R cells were conducted by standard methods. Results: We identified 12 germline ARMC5 genetic alterations in 20 unrelated and two related individuals in our cohort (39.3%). ARMC5 sequence changes in 6 patients (10.7%) were predicted to be damaging by in silico analysis. All affected patients carrying a variant predicted to be damaging were African Americans (P = .0023). Conclusions: Germline ARMC5 variants may be associated with primary aldosteronism. Additional cohorts of patients with primary aldosteronism and metabolic syndrome, particularly African Americans, should be screened for ARMC5 sequence variants because these may underlie part of the known increased predisposition of African Americans to low renin hypertension. PMID:25822102

  18. Negative feedback buffers effects of regulatory variants

    PubMed Central

    Bader, Daniel M; Wilkening, Stefan; Lin, Gen; Tekkedil, Manu M; Dietrich, Kim; Steinmetz, Lars M; Gagneur, Julien

    2015-01-01

    Mechanisms conferring robustness against regulatory variants have been controversial. Previous studies suggested widespread buffering of RNA misexpression on protein levels during translation. We do not find evidence that translational buffering is common. Instead, we find extensive buffering at the level of RNA expression, exerted through negative feedback regulation acting in trans, which reduces the effect of regulatory variants on gene expression. Our approach is based on a novel experimental design in which allelic differential expression in a yeast hybrid strain is compared to allelic differential expression in a pool of its spores. Allelic differential expression in the hybrid is due to cis-regulatory differences only. Instead, in the pool of spores allelic differential expression is not only due to cis-regulatory differences but also due to local trans effects that include negative feedback. We found that buffering through such local trans regulation is widespread, typically compensating for about 15% of cis-regulatory effects on individual genes. Negative feedback is stronger not only for essential genes, indicating its functional relevance, but also for genes with low to middle levels of expression, for which tight regulation matters most. We suggest that negative feedback is one mechanism of Waddington's canalization, facilitating the accumulation of genetic variants that might give selective advantage in different environments. PMID:25634765

  19. UCSC Data Integrator and Variant Annotation Integrator

    PubMed Central

    Hinrichs, Angie S.; Raney, Brian J.; Speir, Matthew L.; Rhead, Brooke; Casper, Jonathan; Karolchik, Donna; Kuhn, Robert M.; Rosenbloom, Kate R.; Zweig, Ann S.; Haussler, David; Kent, W. James

    2016-01-01

    Summary: Two new tools on the UCSC Genome Browser web site provide improved ways of combining information from multiple datasets, optionally including the user's own custom track data and/or data from track hubs. The Data Integrator combines columns from multiple data tracks, showing all items from the first track along with overlapping items from the other tracks. The Variant Annotation Integrator is tailored to adding functional annotations to variant calls; it offers a more restricted set of underlying data tracks but adds predictions of each variant's consequences for any overlapping or nearby gene transcript. When available, it optionally adds additional annotations including effect prediction scores from dbNSFP for missense mutations, ENCODE regulatory summary tracks and conservation scores. Availability and implementation: The web tools are freely available at http://genome.ucsc.edu/ and the underlying database is available for download at http://hgdownload.cse.ucsc.edu/. The software (written in C and Javascript) is available from https://genome-store.ucsc.edu/ and is freely available for academic and non-profit usage; commercial users must obtain a license. Contact: angie@soe.ucsc.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:26740527

  20. Spatially variant periodic structures in electromagnetics

    PubMed Central

    Rumpf, Raymond C.; Pazos, Javier J.; Digaum, Jennefir L.; Kuebler, Stephen M.

    2015-01-01

    Spatial transforms are a popular technique for designing periodic structures that are macroscopically inhomogeneous. The structures are often required to be anisotropic, provide a magnetic response, and to have extreme values for the constitutive parameters in Maxwell's equations. Metamaterials and photonic crystals are capable of providing these, although sometimes only approximately. The problem still remains about how to generate the geometry of the final lattice when it is functionally graded, or spatially varied. This paper describes a simple numerical technique to spatially vary any periodic structure while minimizing deformations to the unit cells that would weaken or destroy the electromagnetic properties. New developments in this algorithm are disclosed that increase efficiency, improve the quality of the lattices and provide the ability to design aplanatic metasurfaces. The ability to spatially vary a lattice in this manner enables new design paradigms that are not possible using spatial transforms, three of which are discussed here. First, spatially variant self-collimating photonic crystals are shown to flow unguided waves around very tight bends using ordinary materials with low refractive index. Second, multi-mode waveguides in spatially variant band gap materials are shown to guide waves around bends without mixing power between the modes. Third, spatially variant anisotropic materials are shown to sculpt the near-field around electric components. This can be used to improve electromagnetic compatibility between components in close proximity. PMID:26217058

  1. Novel RNA variants in colorectal cancers

    PubMed Central

    Alagaratnam, Sharmini; Zhao, Sen; Nome, Torfinn; Løvf, Marthe; Bakken, Anne C.; Hektoen, Merete; Sveen, Anita; Lothe, Ragnhild A.; Skotheim, Rolf I.

    2015-01-01

    With an annual estimated incidence of 1.4 million, and a five-year survival rate of 60%, colorectal cancer (CRC) is a major clinical burden. To identify novel RNA variants in CRC, we analyzed exon-level microarray expression data from a cohort of 202 CRCs. We nominated 25 genes with increased expression of their 3′ parts in at least one cancer sample each. To efficiently investigate underlying transcript structures, we developed an approach using rapid amplification of cDNA ends followed by high throughput sequencing (RACE-seq). RACE products from the targeted genes in 23 CRC samples were pooled together and sequenced. We identified VWA2-TCF7L2, DHX35-BPIFA2 and CASZ1-MASP2 as private fusion events, and novel transcript structures for 17 of the 23 other candidate genes. The high-throughput approach facilitated identification of CRC specific RNA variants. These include a recurrent read-through fusion transcript between KLK8 and KLK7, and a splice variant of S100A2. Both of these were overrepresented in CRC tissue and cell lines from external RNA-seq datasets. PMID:26474385

  2. Orosomucoid-1 Expression in Ameloblastoma Variants

    PubMed Central

    García-Muñoz, Alejandro; Bologna-Molina, Ronell; A. Rodríguez, Mario; Liceága-Reyes, Rodrigo; Farfán-Morales, Jose Eduardo; Aranda-Romo, Saray; Molina-Frechero, Nelly; González-González, Rogelio

    2016-01-01

    Odontogenic tumors constitute a group of heterogeneous lesions of benign and malignant neoplasms with variable aggressiveness. Ameloblastomas are a group of benign but locally invasive neoplasms that occur in the jaws and are derived from epithelial elements of the tooth-forming apparatus. We previously described orosomucoid-1 protein expression in odontogenic myxomas. However, whether orosomucoid-1 is expressed in other odontogenic tumors remains unknown. Since orosomucoid-1 belongs to a group of acute-phase proteins and has many functions in health and disease, we identified and analyzed orosomucoid-1 expression in ameloblastoma variants and ameloblastic carcinoma using western blot and immunohistochemical techniques. Thirty cases of ameloblastoma were analyzed for orsomucoid-1; five specimens were fresh for western blot study (four benign ameloblastomas and one ameloblastic carcinoma), and 25 cases of benign ameloblastoma for immunohistochemical assays. Orosomucoid-1 was widely expressed in each tumor variant analyzed in this study, and differential orosomucoid-1 expression was observed between benign and malignant tumor. Orosomucoid-1 may play an important role in the behavior of ameloblastomas and influence the biology and development of the variants of this tumor. PMID:27386438

  3. Dataset of mitochondrial genome variants associated with asymptomatic atherosclerosis

    PubMed Central

    Sazonova, Margarita A.; Zhelankin, Andrey V.; Barinova, Valeria A.; Sinyov, Vasily V.; Khasanova, Zukhra B.; Postnov, Anton Y.; Sobenin, Igor A.; Bobryshev, Yuri V.; Orekhov, Alexander N.

    2016-01-01

    This dataset report is dedicated to mitochondrial genome variants associated with asymptomatic atherosclerosis. These data were obtained using the method of next generation pyrosequencing (NGPS). The whole mitochondrial genome of the sample of patients from the Moscow region was analyzed. In this article the dataset including anthropometric, biochemical and clinical parameters along with detected mtDNA variants in patients with carotid atherosclerosis and healthy individuals was presented. Among 58 of the most common homoplasmic mtDNA variants found in the observed sample, 7 variants occurred more often in patients with atherosclerosis and 16 variants occurred more often in healthy individuals. PMID:27222855

  4. Performance of Motor Sequences in Children at Heightened vs. Low Risk for ASD: A Longitudinal Study from 18 to 36 Months of Age.

    PubMed

    Focaroli, Valentina; Taffoni, Fabrizio; Parsons, Shelby M; Keller, Flavio; Iverson, Jana M

    2016-01-01

    Recent research shows that motor difficulties are a prominent component of the behavioral profile of autism spectrum disorder (ASD) and are also apparent from early in development in infants who have an older sibling with ASD (High Risk; HR). Delays have been reported for HR infants who do and who do not receive an eventual diagnosis of ASD. A growing body of prospective studies has focused on the emergence of early motor skills primarily during the first year of life. To date, however, relatively little work has examined motor skills in the second and third years. Thus, the present research was designed to investigate motor performance in object transport tasks longitudinally in HR and LR (Low Risk) children between the ages of 18 and 36 months. Participants (15 HR children and 14 LR children) were observed at 18, 24, and 36 months. Children completed two motor tasks, the Ball Task and the Block Task, each of which included two conditions that varied in terms of the precision demands of the goal action. Kinematic data were acquired via two magneto inertial sensors worn on each wrist. In the Block Task, HR children reached more slowly (i.e., mean acceleration was lower) compared to LR children. This finding is in line with growing evidence of early delays in fine motor skills in HR children and suggests that vulnerabilities in motor performance may persist into the preschool years in children at risk for ASD. PMID:27242630

  5. Performance of Motor Sequences in Children at Heightened vs. Low Risk for ASD: A Longitudinal Study from 18 to 36 Months of Age.

    PubMed

    Focaroli, Valentina; Taffoni, Fabrizio; Parsons, Shelby M; Keller, Flavio; Iverson, Jana M

    2016-01-01

    Recent research shows that motor difficulties are a prominent component of the behavioral profile of autism spectrum disorder (ASD) and are also apparent from early in development in infants who have an older sibling with ASD (High Risk; HR). Delays have been reported for HR infants who do and who do not receive an eventual diagnosis of ASD. A growing body of prospective studies has focused on the emergence of early motor skills primarily during the first year of life. To date, however, relatively little work has examined motor skills in the second and third years. Thus, the present research was designed to investigate motor performance in object transport tasks longitudinally in HR and LR (Low Risk) children between the ages of 18 and 36 months. Participants (15 HR children and 14 LR children) were observed at 18, 24, and 36 months. Children completed two motor tasks, the Ball Task and the Block Task, each of which included two conditions that varied in terms of the precision demands of the goal action. Kinematic data were acquired via two magneto inertial sensors worn on each wrist. In the Block Task, HR children reached more slowly (i.e., mean acceleration was lower) compared to LR children. This finding is in line with growing evidence of early delays in fine motor skills in HR children and suggests that vulnerabilities in motor performance may persist into the preschool years in children at risk for ASD.

  6. Clinical and cost effectiveness of a cleanser protectant lotion for treatment of perineal skin breakdown in low-risk patients with incontinence.

    PubMed

    Warshaw, Erin; Nix, Denise; Kula, Julie; Markon, Clyde Edward

    2002-06-01

    Perineal dermatitis due to urinary and/or fecal incontinence is a common problem. A multicenter, open label, phase II product evaluation was conducted to determine the effectiveness of a new cleanser protectant lotion in reducing perineal erythema and pain in patients at low-risk for perineal dermatitis and to compare the cost of this product to standard protocols of care. Nineteen elderly patients (14 male, 5 female, mean age 73.1 years) participated in the study. Average baseline scores for erythema and pain were 2.3 (+/- 0.5) and 1.5 (+/- 1.0), respectively (scale 0 to 4). After 7 days, both scores were significantly lower (mean scores 0.6 +/- 0.8 and 0.3 +/- 0.8, respectively; P < 0.01). Based on an average of 2.6 perineal episodes per day, the one-step product evaluated would cost $136 per patient/year less than standard protocols of care while reducing caregiver time (average 23 seconds per episode of care). Optimal perineal care may reduce the incidence of complications; studies to ascertain the safety and effectiveness of commonly used products and procedures are needed.

  7. Interferon lambda 1 expression in cervical cells differs between low-risk and high-risk human papillomavirus-positive women.

    PubMed

    Cannella, Fabiana; Scagnolari, Carolina; Selvaggi, Carla; Stentella, Patrizia; Recine, Nadia; Antonelli, Guido; Pierangeli, Alessandra

    2014-06-01

    Persistent infection by high-risk (HR) human papillomavirus (HPV) types is a prerequisite for progression to cancer. HR-HPVs may lead to a deregulation of innate immunity by interfering with the epithelial type I interferon (IFN) response, whereas very little is known about type III IFNs, a key component of the mucosal antiviral response. This study reports a first attempt to evaluate the activation of type III IFN genes (IFN lambda 1-3), IFN lambda receptor genes (IFN-lambdaR1 and IL10R2), and IFN-induced genes (MxA, ISG15, ISG56) in HPV-positive and HPV-negative cervical cells from 154 women attending the gynecological unit of a university hospital in Rome. Despite an increased individual variability, a coordinated expression of several IFN lambda-related genes was observed. Furthermore, IFN lambda 1 and IFN-lambdaR1 genes were expressed at higher levels in cervical cells positive to low-risk (LR) HPV compared to HR-HPV and HPV-negative cells. Consistently, ISG15 expression was significantly higher in LR-HPV-infected women than in the other groups. Moreover, IFN lambda 1 expression decreased significantly with abnormal cytological results. This study is the first to show the activation of a type III IFN response in LR-HPV-positive cervical cells and suggests that the lack of this response in HR-HPV infection may be related to lesion progression. PMID:24510368

  8. A national standard for psychosocial safety climate (PSC): PSC 41 as the benchmark for low risk of job strain and depressive symptoms.

    PubMed

    Bailey, Tessa S; Dollard, Maureen F; Richards, Penny A M

    2015-01-01

    Despite decades of research from around the world now permeating occupational health and safety (OHS) legislation and guidelines, there remains a lack of tools to guide practice. Our main goal was to establish benchmark levels of psychosocial safety climate (PSC) that would signify risk of job strain (jobs with high demands and low control) and depression in organizations. First, to justify our focus on PSC, using interview data from Australian employees matched at 2 time points 12 months apart (n = 1081), we verified PSC as a significant leading predictor of job strain and in turn depression. Next, using 2 additional data sets (n = 2097 and n = 1043) we determined benchmarks of organizational PSC (range 12-60) for low-risk (PSC at 41 or above) and high-risk (PSC at 37 or below) of employee job strain and depressive symptoms. Finally, using the newly created benchmarks we estimated the population attributable risk (PAR) and found that improving PSC in organizations to above 37 could reduce 14% of job strain and 16% of depressive symptoms in the working population. The results provide national standards that organizations and regulatory agencies can utilize to promote safer working environments and lower the risk of harm to employee mental health.

  9. Attractive Toxic Sugar Baits: Control of Mosquitoes With the Low-Risk Active Ingredient Dinotefuran and Potential Impacts on Nontarget Organisms in Morocco

    PubMed Central

    Khallaayoune, Khalid; Qualls, Whitney A.; Revay, Edita E.; Allan, Sandra A.; Arheart, Kristopher L.; Kravchenko, Vasiliy D.; Xue, Rui-De; Schlein, Yosef; Beier, John C.; Müller, Günter C.

    2014-01-01

    We evaluated the efficacy of attractive toxic sugar baits (ATSB) in the laboratory and field with the low-risk active ingredient dinotefuran against mosquito populations. Preliminary laboratory assays indicated that dinotefuran in solution with the sugar baits was ingested and resulted in high mortality of female Culex quinquefasciatus Say and Aedes aegypti Linnaeus. Field studies demonstrated >70% reduction of mosquito populations at 3 wk post-ATSB application. Nontarget feeding of seven insect orders—Hymenoptera, Lepidoptera, Coleoptera, Diptera, Hemiptera, Orthoptera, and Neuroptera—was evaluated in the field after application of attractive sugar baits (ASB) on vegetation by dissecting the guts and searching for food dye with a dissecting microscope. Nontargets were found stained with ASB 0.9% of the time when the application was applied on green nonflowering vegetation. Only two families were significantly impacted by the ASB application: Culicidae (mosquitoes) and Chironomidae (nonbiting midges) of the order Diptera. Pollinators of the other insect orders were not significantly impacted. No mortality was observed in the laboratory studies with predatory nontargets, wolf spiders or ground beetles, after feeding for 3 d on mosquitoes engorged on ATSB applied to vegetation. Overall, this novel control strategy had little impact on nontarget organisms, including pollinators and beneficial insects, and was effective at controlling mosquito populations, further supporting the development of ATSB for commercial use. PMID:24331613

  10. Performance of Motor Sequences in Children at Heightened vs. Low Risk for ASD: A Longitudinal Study from 18 to 36 Months of Age

    PubMed Central

    Focaroli, Valentina; Taffoni, Fabrizio; Parsons, Shelby M.; Keller, Flavio; Iverson, Jana M.

    2016-01-01

    Recent research shows that motor difficulties are a prominent component of the behavioral profile of autism spectrum disorder (ASD) and are also apparent from early in development in infants who have an older sibling with ASD (High Risk; HR). Delays have been reported for HR infants who do and who do not receive an eventual diagnosis of ASD. A growing body of prospective studies has focused on the emergence of early motor skills primarily during the first year of life. To date, however, relatively little work has examined motor skills in the second and third years. Thus, the present research was designed to investigate motor performance in object transport tasks longitudinally in HR and LR (Low Risk) children between the ages of 18 and 36 months. Participants (15 HR children and 14 LR children) were observed at 18, 24, and 36 months. Children completed two motor tasks, the Ball Task and the Block Task, each of which included two conditions that varied in terms of the precision demands of the goal action. Kinematic data were acquired via two magneto inertial sensors worn on each wrist. In the Block Task, HR children reached more slowly (i.e., mean acceleration was lower) compared to LR children. This finding is in line with growing evidence of early delays in fine motor skills in HR children and suggests that vulnerabilities in motor performance may persist into the preschool years in children at risk for ASD. PMID:27242630

  11. The nuclear localization of low risk HPV11 E7 protein mediated by its zinc binding domain is independent of nuclear import receptors

    SciTech Connect

    Piccioli, Zachary; McKee, Courtney H.; Leszczynski, Anna; Onder, Zeynep; Hannah, Erin C.; Mamoor, Shahan; Crosby, Lauren; Moroianu, Junona

    2010-11-10

    We investigated the nuclear import of low risk HPV11 E7 protein using 1) transfection assays in HeLa cells with EGFP fusion plasmids containing 11E7 and its domains and 2) nuclear import assays in digitonin-permeabilized HeLa cells with GST fusion proteins containing 11E7 and its domains. The EGFP-11E7 and EGFP-11cE7{sub 39-98} localized mostly to the nucleus. The GST-11E7 and GST-11cE7{sub 39-98} were imported into the nuclei in the presence of either Ran-GDP or RanG19V-GTP mutant and in the absence of nuclear import receptors. This suggests that 11E7 enters the nucleus via a Ran-dependent pathway, independent of nuclear import receptors, mediated by a nuclear localization signal located in its C-terminal domain (cNLS). This cNLS contains the zinc binding domain consisting of two copies of Cys-X-X-Cys motif. Mutagenesis of Cys residues in these motifs changed the localization of the EGFP-11cE7/-11E7 mutants to cytoplasmic, suggesting that the zinc binding domain is essential for nuclear localization of 11E7.

  12. A national standard for psychosocial safety climate (PSC): PSC 41 as the benchmark for low risk of job strain and depressive symptoms.

    PubMed

    Bailey, Tessa S; Dollard, Maureen F; Richards, Penny A M

    2015-01-01

    Despite decades of research from around the world now permeating occupational health and safety (OHS) legislation and guidelines, there remains a lack of tools to guide practice. Our main goal was to establish benchmark levels of psychosocial safety climate (PSC) that would signify risk of job strain (jobs with high demands and low control) and depression in organizations. First, to justify our focus on PSC, using interview data from Australian employees matched at 2 time points 12 months apart (n = 1081), we verified PSC as a significant leading predictor of job strain and in turn depression. Next, using 2 additional data sets (n = 2097 and n = 1043) we determined benchmarks of organizational PSC (range 12-60) for low-risk (PSC at 41 or above) and high-risk (PSC at 37 or below) of employee job strain and depressive symptoms. Finally, using the newly created benchmarks we estimated the population attributable risk (PAR) and found that improving PSC in organizations to above 37 could reduce 14% of job strain and 16% of depressive symptoms in the working population. The results provide national standards that organizations and regulatory agencies can utilize to promote safer working environments and lower the risk of harm to employee mental health. PMID:25347684

  13. Adult attachment interviews of women from low-risk, poverty, and maltreatment risk samples: comparisons between the hostile/helpless and traditional AAI coding systems.

    PubMed

    Frigerio, Alessandra; Costantino, Elisabetta; Ceppi, Elisa; Barone, Lavinia

    2013-01-01

    The main aim of this study was to investigate the correlates of a Hostile-Helpless (HH) state of mind among 67 women belonging to a community sample and two different at-risk samples matched on socio-economic indicators, including 20 women from low-SES population (poverty sample) and 15 women at risk for maltreatment being monitored by the social services for the protection of juveniles (maltreatment risk sample). The Adult Attachment Interview (AAI) protocols were reliably coded blind to the samples' group status. The rates of HH classification increased in relation to the risk status of the three samples, ranging from 9% for the low-risk sample to 60% for the maltreatment risk sample to 75% for mothers in the maltreatment risk sample who actually maltreated their infants. In terms of the traditional AAI classification system, 88% of the interviews from the maltreating mothers were classified Unresolved/Cannot Classify (38%) or Preoccupied (50%). Partial overlapping between the 2 AAI coding systems was found, and discussion concerns the relevant contributions of each AAI coding system to understanding of the intergenerational transmission of maltreatment. PMID:23724955

  14. Brain Derived Neurotrophic Factor (BDNF) levels as a possible predictor of psychopathology in healthy twins at high and low risk for affective disorder.

    PubMed

    Vinberg, Maj; Miskowiak, Kamilla; Kessing, Lars Vedel

    2014-01-01

    Brain Derived Neurotrophic Factor (BDNF) is a potential biomarker of affective disorder. However, longitudinal studies evaluating a potential predictive role of BDNF on subsequent psychopathology are lacking. The aim of this study was to investigate whether BDNF alone or in interaction with the BDNF Val66Met polymorphism predict onset of affective disorder in healthy individuals at heritable risk for affective disorder. In a high-risk study, we assessed whole blood levels of BDNF in 234 healthy monozygotic and dizygotic twins with or without a co-twin history of affective disorder (high and low risk twins, respectively). Participants were followed up longitudinally with questionnaires at 6-month intervals for mean seven years and then reassessed with a personal interview to obtain information about whether they had developed psychiatric illness. At follow-up 36 participants (15.4%) had developed psychiatric disorder. Cox regression analysis revealed that BDNF levels at baseline were not associated with onset of illness in this explorative study. Further, two-way interactions between BDNF levels and the Val66Met polymorphism or between familial risk and the Val66Met polymorphism did not predict illness onset.

  15. Codetection of Trichomonas vaginalis and Candida albicans by PCR in Urine Samples in a Low-Risk Population Attended in a Clinic First Level in Central Veracruz, Mexico

    PubMed Central

    López-Monteon, A.; Gómez-Figueroa, F. S.; Ramos-Poceros, G.; Guzmán-Gómez, D.; Ramos-Ligonio, A.

    2013-01-01

    The aim of this study is to estimate the prevalence of Trichomonas vaginalis and Candida albicans in low-risk patients treated at a first level clinic (primary health care represents the first level of contact of individuals, families, and the community with the system national health). Using a cross-sectional study in patients treated in clinical laboratory of the Sanitary District no. 7 of the city of Orizaba during the months June-July, 252 urine samples were collected for the identification of T. vaginalis and C. albicans by PCR. Furthermore, we analyzed the sociodemographic characteristics of the studied population. We observed an overall prevalence of 23.41% (95% CI 22.10–24.72) for T. vaginalis and 38.88% (95% CI 37.73–40.03) for C. albicans. There was also presence of coinfection in 14.28% (95% CI 13.10–15.46), which was associated with the presence of pain. Most of the positive cases were observed in women house-maker (80%, 95% CI 50.36–48.98). The results of this study provide evidence that the majority of positive cases observed in the studied population are presented in an asymptomatic form and usually are not associated with any risk factor. PMID:24069593

  16. Codetection of Trichomonas vaginalis and Candida albicans by PCR in urine samples in a low-risk population attended in a clinic first level in central Veracruz, Mexico.

    PubMed

    López-Monteon, A; Gómez-Figueroa, F S; Ramos-Poceros, G; Guzmán-Gómez, D; Ramos-Ligonio, A

    2013-01-01

    The aim of this study is to estimate the prevalence of Trichomonas vaginalis and Candida albicans in low-risk patients treated at a first level clinic (primary health care represents the first level of contact of individuals, families, and the community with the system national health). Using a cross-sectional study in patients treated in clinical laboratory of the Sanitary District no. 7 of the city of Orizaba during the months June-July, 252 urine samples were collected for the identification of T. vaginalis and C. albicans by PCR. Furthermore, we analyzed the sociodemographic characteristics of the studied population. We observed an overall prevalence of 23.41% (95% CI 22.10-24.72) for T. vaginalis and 38.88% (95% CI 37.73-40.03) for C. albicans. There was also presence of coinfection in 14.28% (95% CI 13.10-15.46), which was associated with the presence of pain. Most of the positive cases were observed in women house-maker (80%, 95% CI 50.36-48.98). The results of this study provide evidence that the majority of positive cases observed in the studied population are presented in an asymptomatic form and usually are not associated with any risk factor.

  17. Impact of stress and mitigating information on evaluations, attributions, affect, disciplinary choices, and expectations of compliance in mothers at high and low risk for child physical abuse.

    PubMed

    De Paúl, Joaquín; Asla, Nagore; Pérez-Albéniz, Alicia; de Cádiz, Bárbara Torres-Gómez

    2006-08-01

    The objective is to know if high-risk mothers for child physical abuse differ in their evaluations, attributions, negative affect, disciplinary choices for children's behavior, and expectations of compliance. The effect of a stressor and the introduction of mitigating information are analyzed. Forty-seven high-risk and 48 matched low-risk mothers participated in the study. Mothers' information processing and disciplinary choices were examined using six vignettes depicting a child engaging in different transgressions. A four-factor design with repeated measures on the last two factors was used. High-risk mothers reported more hostile intent, global and internal attributions, more use of power assertion discipline, and less induction. A risk group by child transgression interaction and a risk group by mitigating information interaction were found. Results support the social information-processing model of child physical abuse, which suggests that high-risk mothers process child-related information differently and use more power assertive and less inductive disciplinary techniques.

  18. Quantitative Analysis of Variant Selection for Displacive Transformations Under Stress

    NASA Astrophysics Data System (ADS)

    Kundu, Saurabh; Verma, Anil Kumar; Sharma, Vikram

    2012-07-01

    The existing variant selection models for displacive transformations are mostly qualitative in nature and attempt to predict the bulk texture using several fitting parameters. Many of these models use Kurdjumov-Sach (K-S) type orientation relationships (ORs) and ignore the phenomenological theory of martensite crystallography. So far there has not been any attempt to assess variant selection in the level of individual variants within one austenite grain. In this work, new kinds of experiments and innovative mathematical models have been developed to critically assess the variant selection phenomenon during bainite transformation under externally applied stress. Volume fractions of individual variants in a austenite grain have been calculated for the first time. Patel and Cohen's theory on variant selection has been used in a new mathematical framework. Hitherto unknown aspects of variant selection have been found, which is exciting and provides new insight into the subject.

  19. Penicillinase Studies on L-Phase Variants, G-Phase Variants, and Reverted Strains of Staphylococcus aureus.

    PubMed

    Simon, H J; Yin, E J

    1970-11-01

    L-phase variants and small colony (G-phase) variants derived from penicillinase-producing Staphylococcus aureus strains were tested for penicillinase (beta lactamase) production. A refined variation of the modified Gots test for penicillinase was used to demonstrate penicillinase synthesis. Penicillinase synthesis was reduced in L-phase variants and G-phase variants when compared to parental strains. After reversion of variants to vegetative stages had been induced, revertants were tested for production of penicillinase, coagulase, and alpha hemolysin, mannitol fermentation, and pigment production, and comparisons were made between parent and reverted vegetative forms. All revertants of G-phase variants retained penicillinase activity. Most revertants of L-phase variants showed reduction or loss of penicillinase activity. Retention of coagulase activity, alpha hemolysin production, mannitol fermentation, pigmentation, and phage type varied among revertants.

  20. Knowledge of pathologically versus clinically negative lymph nodes is associated with reduced use of radioactive iodine post-thyroidectomy for low-risk papillary thyroid cancer.

    PubMed

    Ruel, Ewa; Thomas, Samantha; Dinan, Michaela A; Perkins, Jennifer M; Roman, Sanziana A; Sosa, Julie Ann

    2016-06-01

    Cervical lymph node metastases are common in papillary thyroid cancer (PTC). Clinically negative lymph nodes confer uncertainty about true lymph node status, potentially prompting empiric postoperative radioactive iodine (RAI) administration even in low-risk patients. We examined the association of clinically (cN0) versus pathologically negative (pN0) lymph nodes with utilization of RAI for low-risk PTC. Using the National Cancer Database 1998-2011, adults with PTC who underwent total thyroidectomy for Stage I/II tumors 1-4 cm were evaluated for receipt of RAI based on cN0 versus pN0 status. Cut-point analysis was conducted to determine the number of pN0 nodes associated with the greatest decrease in the odds of receipt of RAI. Survival models and multivariate analyses predicting RAI use were conducted separately for all patients and patients <45 years. 64,980 patients met study criteria; 39,778 (61.2 %) were cN0 versus 25,202 (38.8 %) pN0. Patients with pN0 nodes were more likely to have negative surgical margins and multifocal disease (all p < 0.001). The mean negative nodes reported in surgical pathology specimens was 4; ≥5 pathologically negative lymph nodes provided the best cut-point associated with reduced RAI administration (OR 0.91, CI 0.85-0.97). After multivariable adjustment, pN0 patients with ≥5 nodes examined were less likely to receive RAI compared to cN0 patients across all ages (OR 0.89, p < 0.001) and for patients aged <45 years (0R 0.86, p = 0.001). Patients with <5 pN0 nodes did not differ in RAI use compared to cN0 controls. Unadjusted survival was improved for pN0 versus cN0 patients across all ages (p < 0.001), but not for patients <45 years (p = 0.11); adjusted survival for all ages did not differ (p = 0.13). Pathological confirmation of negative lymph nodes in patients with PTC appears to influence the decision to administer postoperative RAI if ≥5 negative lymph nodes are removed. It is possible that fewer excised

  1. Mutation update: the spectra of nebulin variants and associated myopathies.

    PubMed

    Lehtokari, Vilma-Lotta; Kiiski, Kirsi; Sandaradura, Sarah A; Laporte, Jocelyn; Repo, Pauliina; Frey, Jennifer A; Donner, Kati; Marttila, Minttu; Saunders, Carol; Barth, Peter G; den Dunnen, Johan T; Beggs, Alan H; Clarke, Nigel F; North, Kathryn N; Laing, Nigel G; Romero, Norma B; Winder, Thomas L; Pelin, Katarina; Wallgren-Pettersson, Carina

    2014-12-01

    A mutation update on the nebulin gene (NEB) is necessary because of recent developments in analysis methodology, the identification of increasing numbers and novel types of variants, and a widening in the spectrum of clinical and histological phenotypes associated with this gigantic, 183 exons containing gene. Recessive pathogenic variants in NEB are the major cause of nemaline myopathy (NM), one of the most common congenital myopathies. Moreover, pathogenic NEB variants have been identified in core-rod myopathy and in distal myopathies. In this update, we present the disease-causing variants in NEB in 159 families, 143 families with NM, and 16 families with NM-related myopathies. Eighty-eight families are presented here for the first time. We summarize 86 previously published and 126 unpublished variants identified in NEB. Furthermore, we have analyzed the NEB variants deposited in the Exome Variant Server (http://evs.gs.washington.edu/EVS/), identifying that pathogenic variants are a minor fraction of all coding variants (∼7%). This indicates that nebulin tolerates substantial changes in its amino acid sequence, providing an explanation as to why variants in such a large gene result in relatively rare disorders. Lastly, we discuss the difficulties of drawing reliable genotype-phenotype correlations in NEB-associated disease. PMID:25205138

  2. Non-coding genetic variants in human disease

    PubMed Central

    Zhang, Feng; Lupski, James R.

    2015-01-01

    Genetic variants, including single-nucleotide variants (SNVs) and copy number variants (CNVs), in the non-coding regions of the human genome can play an important role in human traits and complex diseases. Most of the genome-wide association study (GWAS) signals map to non-coding regions and potentially point to non-coding variants, whereas their functional interpretation is challenging. In this review, we discuss the human non-coding variants and their contributions to human diseases in the following four parts. (i) Functional annotations of non-coding SNPs mapped by GWAS: we discuss recent progress revealing some of the molecular mechanisms for GWAS signals affecting gene function. (ii) Technical progress in interpretation of non-coding variants: we briefly describe some of the technologies for functional annotations of non-coding variants, including the methods for genome-wide mapping of chromatin interaction, computational tools for functional predictions and the new genome editing technologies useful for dissecting potential functional consequences of non-coding variants. (iii) Non-coding CNVs in human diseases: we review our emerging understanding the role of non-coding CNVs in human disease. (iv) Compound inheritance of large genomic deletions and non-coding variants: compound inheritance at a locus consisting of coding variants plus non-coding ones is described. PMID:26152199

  3. Mutation Update: The Spectra of Nebulin Variants and Associated Myopathies

    PubMed Central

    Lehtokari, Vilma-Lotta; Kiiski, Kirsi; Sandaradura, Sarah A.; Laporte, Jocelyn; Repo, Pauliina; Frey, Jennifer A.; Donner, Kati; Marttila, Minttu; Saunders, Carol; Barth, Peter G.; den Dunnen, Johan T.; Beggs, Alan H.; Clarke, Nigel F.; North, Kathryn N.; Laing, Nigel G.; Romero, Norma B.; Winder, Thomas L.; Pelin, Katarina; Wallgren-Pettersson, Carina

    2015-01-01

    A mutation update on the nebulin gene (NEB) is necessary because of recent developments in analysis methodology, the identification of increasing numbers and novel types of variants, and a widening in the spectrum of clinical and histological phenotypes associated with this gigantic, 183 exons containing gene. Recessive pathogenic variants in NEB are the major cause of nemaline myopathy (NM), one of the most common congenital myopathies. Moreover, pathogenic NEB variants have been identified in core-rod myopathy and in distal myopathies. In this update, we present the disease-causing variants in NEB in 159 families, 143 families with NM, and 16 families with NM-related myopathies. Eighty-eight families are presented here for the first time. We summarize 86 previously published and 126 unpublished variants identified in NEB. Furthermore, we have analyzed the NEB variants deposited in the Exome Variant Server (http://evs.gs.washington.edu/EVS/), identifying that pathogenic variants are a minor fraction of all coding variants (~7%). This indicates that nebulin tolerates substantial changes in its amino acid sequence, providing an explanation as to why variants in such a large gene result in relatively rare disorders. Lastly, we discuss the difficulties of drawing reliable genotype–phenotype correlations in NEB-associated disease. PMID:25205138

  4. Usefulness of cardiac meta-iodobenzylguanidine imaging to identify patients with chronic heart failure and left ventricular ejection fraction <35% at low risk for sudden cardiac death.

    PubMed

    Kawai, Tsutomu; Yamada, Takahisa; Tamaki, Shunsuke; Morita, Takashi; Furukawa, Yoshio; Iwasaki, Yusuke; Kawasaki, Masato; Kikuchi, Atsushi; Kondo, Takumi; Takahashi, Satoshi; Ishimi, Masashi; Hakui, Hideyuki; Ozaki, Tatsuhisa; Sato, Yoshihiro; Seo, Masahiro; Sakata, Yasushi; Fukunami, Masatake

    2015-06-01

    Patients with chronic heart failure (CHF) at risk of sudden cardiac death (SCD) are often treated with implantable cardiac defibrillators (ICDs). However, current criteria for device use that is based largely on left ventricular ejection fraction (LVEF) lead to many patients receiving ICDs that never deliver therapy. It is of clinical significance to identify patients who do not require ICDs. Although cardiac I-123 meta-iodobenzylguanidine (MIBG) imaging provides prognostic information about CHF, whether it can identify patients with CHF who do not require an ICD remains unclear. We studied 81 patients with CHF and LVEF <35%, assessed by cardiac MIBG imaging at enrollment. The heart-to-mediastinal ratio (H/M) in delayed images and washout rates were divided into 6 grades from 0 to 5, according to the degree of deviation from control values. The study patients were classified into 3 groups: low (1 to 4), intermediate (5 to 7), and high (8 to 10), according to the MIBG scores defined as the sum of the H/M and washout rate scores. Sixteen patients died of SCD during a follow-up period. Patients with low MIBG score had a significantly lower risk of SCD than those with intermediate and high scores (low [n = 19], 0%; intermediate [n = 37], 19%; high [n = 25], 36%; p = 0.001). The positive predictive value of low MIBG score for identifying patients without SCD was 100%. In conclusion, the MIBG score can identify patients with CHF and LVEF <35% who have low risk of developing SCD. PMID:25851796

  5. Is there any association between National Institute of Health category IV prostatitis and prostate-specific antigen levels in patients with low-risk localized prostate cancer?

    PubMed Central

    Doluoglu, Omer Gokhan; Ceylan, Cavit; Kilinc, Fatih; Gazel, Eymen; Resorlu, Berkan; Odabas, Oner

    2016-01-01

    ABSTRACT Purpose We investigated the association between National Institute of Health category IV prostatitis and prostate-specific antigen levels in patients with low-risk localized prostate cancer. Materials and Methods The data of 440 patients who had undergone prostate biopsies due to high PSA levels and suspicious digital rectal examination findings were reviewed retrospectively. The patients were divided into two groups based on the presence of accompanying NIH IV prostatitis. The exclusion criteria were as follows: Gleason score>6, PSA level>20ng/mL, >2 positive cores, >50% cancerous tissue per biopsy, urinary tract infection, urological interventions at least 1 week previously (cystoscopy, urethral catheterization, or similar procedure), history of prostate biopsy, and history of androgen or 5-alpha reductase use. All patient's age, total PSA and free PSA levels, ratio of free to total PSA, PSA density and prostate volume were recorded. Results In total, 101 patients were included in the study. Histopathological examination revealed only PCa in 78 (77.2%) patients and PCa+NIH IV prostatitis in 23 (22.7%) patients. The median total PSA level was 7.4 (3.5–20.0) ng/mL in the PCa+NIH IV prostatitis group and 6.5 (0.6–20.0) ng/mL in the PCa group (p=0.67). The PSA level was≤10ng/mL in 60 (76.9%) patients in the PCa group and in 16 (69.6%) patients in the PCa+NIH IV prostatitis group (p=0.32). Conclusions Our study showed no statistically significant difference in PSA levels between patients with and without NIH IV prostatitis accompanying PCa. PMID:27256190

  6. Optimal Timing of Delivery among Low-Risk Women with Prior Caesarean Section: A Secondary Analysis of the WHO Multicountry Survey on Maternal and Newborn Health

    PubMed Central

    Vogel, Joshua P.; Morisaki, Naho; Pileggi-Castro, Cynthia; Ortiz-Panozo, Eduardo; Jayaratne, Kapila; Mittal, Suneeta; Ota, Erika; Souza, João Paulo; Mori, Rintaro

    2016-01-01

    Objective To investigate optimal timing of elective repeat caesarean section among low-risk pregnant women with prior caesarean section in a multicountry sample from largely low- and middle-income countries. Design Secondary analysis of a cross-sectional study. Setting Twenty-nine countries from the World Health Organization Multicountry Survey on Maternal and Newborn Health. Population 29,647 women with prior caesarean section and no pregnancy complications in their current pregnancy who delivered a term singleton (live birth and stillbirth) at gestational age 37–41 weeks by pre-labour caesarean section, intra-partum caesarean section, or vaginal birth following spontaneous onset of labour. Methods We compared the rate of short-term adverse maternal and newborn outcomes following pre-labour caesarean section at a given gestational age, to those following ongoing pregnancies beyond that gestational age. Main Outcome Measures Severe maternal outcomes, neonatal morbidity, and intra-hospital early neonatal mortality. Results Odds of neonatal morbidity and intra-hospital early neonatal mortality were 0.48 (95% confidence interval [CI] 0.39–0.60) and 0.31 (95% CI 0.16–0.58) times lower for ongoing pregnancies compared to pre-labour caesarean section at 37 weeks. We did not find any significant change in the risk of severe maternal outcomes between pre-labour caesarean section at a given gestational age and ongoing pregnancies beyond that gestational age. Conclusions Elective repeat caesarean section at 37 weeks had higher risk of neonatal morbidity and mortality compared to ongoing pregnancy, however risks at later gestational ages did not differ between groups. PMID:26866368

  7. Silver Nanoparticles Entering Soils via the Wastewater-Sludge-Soil Pathway Pose Low Risk to Plants but Elevated Cl Concentrations Increase Ag Bioavailability.

    PubMed

    Wang, Peng; Menzies, Neal W; Dennis, Paul G; Guo, Jianhua; Forstner, Christian; Sekine, Ryo; Lombi, Enzo; Kappen, Peter; Bertsch, Paul M; Kopittke, Peter M

    2016-08-01

    The widespread use of silver nanoparticles (Ag-NPs) results in their movement into wastewater treatment facilities and subsequently to agricultural soils via application of contaminated sludge. On-route, the chemical properties of Ag may change, and further alterations are possible upon entry to soil. In the present study, we examined the long-term stability and (bio)availability of Ag along the "wastewater-sludge-soil" pathway. Synchrotron-based X-ray absorption spectroscopy (XAS) revealed that ca. 99% of Ag added to the sludge reactors as either Ag-NPs or AgNO3 was retained in sludge, with ≥79% of this being transformed to Ag2S, with the majority (≥87%) remaining in this form even after introduction to soils at various pH values and Cl concentrations for up to 400 days. Diffusive gradients in thin films (DGT), chemical extraction, and plant uptake experiments indicated that the potential (bio)availability of Ag in soil was low but increased markedly in soils with elevated Cl, likely due to the formation of soluble AgClx complexes in the soil solution. Although high Cl concentrations increased the bioavailability of Ag markedly, plant growth was not reduced in any treatment. Our results indicate that Ag-NPs entering soils through the wastewater-sludge-soil pathway pose low risk to plants due to their conversion to Ag2S in the wastewater treatment process, although bioavailability may increase in saline soils or when irrigated with high-Cl water. PMID:27380126

  8. Spread of Plasmids Carrying Multiple GES Variants.

    PubMed

    Cuzon, Gaelle; Bogaerts, Pierre; Bauraing, Caroline; Huang, Te-Din; Bonnin, Rémy A; Glupczynski, Youri; Naas, Thierry

    2016-08-01

    Five GES-producing Enterobacteriaceae isolates that displayed an extended-spectrum β-lactamase (ESBL) phenotype harbored two GES variants: GES-7 ESBL and GES-6 carbapenemase. In all isolates, the two GES alleles were located on the same integron that was inserted into an 80-kb IncM1 self-conjugative plasmid. Whole-genome sequencing suggested in vivo horizontal gene transfer of the plasmid along with clonal diffusion of Enterobacter cloacae To our knowledge, this is the first description in Europe of clustered Enterobacteriaceae isolates carrying two GES β-lactamases, of which one has extended activity toward carbapenems. PMID:27216071

  9. Pitfalls and variants in pediatric chest imaging.

    PubMed

    García Asensio, D; Fernández Martín, M

    2016-05-01

    Most pitfalls in the interpretation of pediatric chest imaging are closely related with the technique used and the characteristics of pediatric patients. To obtain a quality image that will enable the correct diagnosis, it is very important to use an appropriate technique. It is important to know how technical factors influence the image and to be aware of the possible artifacts that can result from poor patient cooperation. Moreover, radiologists need to be familiar with the normal anatomy in children, with the classic radiologic findings, and with the anatomic and developmental variants to avoid misinterpreting normal findings as pathological.

  10. Gene panels to help identify subgroups at high and low risk of CHD among those randomized to antihypertensive treatment: The GenHAT Study

    PubMed Central

    Lynch, Amy I.; Eckfeldt, John H.; Davis, Barry R.; Ford, Charles E.; Boerwinkle, Eric; Leiendecker-Foster, Catherine; Arnett, Donna K.

    2012-01-01

    Objective To identify panels of genetic variants that predict treatment-related coronary heart disease (CHD) outcomes in hypertensive patients on one of four different classes of initial antihypertensive treatment. The goal was to identify subgroups of people based on their genetic profile who benefit most from a particular treatment. Methods Candidate genetic variants (n=78) were genotyped in 39,114 participants from GenHAT, ancillary to ALLHAT. ALLHAT randomized hypertensive participants (>=55 years) to one of four treatments (amlodipine, chlorthalidone, doxazosin, lisinopril). The primary outcome was fatal CHD or non-fatal MI (mean follow-up=4.9 years). A pharmacogenetic panel was derived within each of the four treatment groups. ROC curves estimated the discrimination rate between those with and without a CHD event, based on the addition of the genetic panel risk score. Results For each treatment group, we identified a panel of genetic variants that collectively improved prediction of CHD to a small but statistically significant extent. Chlorthalidone (A): NOS3, rs3918226; SELE, rs5361; ICAM1, rs1799969; AGT, rs5051; GNAS, rs7121; ROC comparison p=.004; Amlodipine (B): MMP1, rs1799750; F5, rs6025; NPPA, rs5065; PDE4D, rs6450512; MMP9, rs2274756; ROC comparison p=.006; Lisinopril (C): AGT, rs5051; PON1, rs705379; MMP12, rs652438; F12, rs1801020; GP1BA, rs6065; PDE4D, rs27653; ROC comparison p=.01; Doxazosin (D): F2, rs1799963; PAI1, rs1799768; MMP7, rs11568818; AGT, rs5051; ACE, rs4343; MMP2, rs243865; ROC comparison p=.007. Each panel was tested for a pharmacogenetic effect; panels A, B and D showed such evidence (p=.009, .006, and .001 respectively), panel C did not (p=.09). Conclusion Because each panel was associated with CHD in a specific treatment group but not the others, this research provides evidence that it may be possible to use gene panel scores as a tool to better assess antihypertensive treatment choices to reduce CHD risk in hypertensive

  11. COMT gene locus: new functional variants.

    PubMed

    Meloto, Carolina B; Segall, Samantha K; Smith, Shad; Parisien, Marc; Shabalina, Svetlana A; Rizzatti-Barbosa, Célia M; Gauthier, Josée; Tsao, Douglas; Convertino, Marino; Piltonen, Marjo H; Slade, Gary Dmitri; Fillingim, Roger B; Greenspan, Joel D; Ohrbach, Richard; Knott, Charles; Maixner, William; Zaykin, Dmitri; Dokholyan, Nikolay V; Reenilä, Ilkka; Männistö, Pekka T; Diatchenko, Luda

    2015-10-01

    Catechol-O-methyltransferase (COMT) metabolizes catecholaminergic neurotransmitters. Numerous studies have linked COMT to pivotal brain functions such as mood, cognition, response to stress, and pain. Both nociception and risk of clinical pain have been associated with COMT genetic variants, and this association was shown to be mediated through adrenergic pathways. Here, we show that association studies between COMT polymorphic markers and pain phenotypes in 2 independent cohorts identified a functional marker, rs165774, situated in the 3' untranslated region of a newfound splice variant, (a)-COMT. Sequence comparisons showed that the (a)-COMT transcript is highly conserved in primates, and deep sequencing data demonstrated that (a)-COMT is expressed across several human tissues, including the brain. In silico analyses showed that the (a)-COMT enzyme features a distinct C-terminus structure, capable of stabilizing substrates in its active site. In vitro experiments demonstrated not only that (a)-COMT is catalytically active but also that it displays unique substrate specificity, exhibiting enzymatic activity with dopamine but not epinephrine. They also established that the pain-protective A allele of rs165774 coincides with lower COMT activity, suggesting contribution to decreased pain sensitivity through increased dopaminergic rather than decreased adrenergic tone, characteristic of reference isoforms. Our results provide evidence for an essential role of the (a)-COMT isoform in nociceptive signaling and suggest that genetic variations in (a)-COMT isoforms may contribute to individual variability in pain phenotypes. PMID:26207649

  12. COMT gene locus: new functional variants

    PubMed Central

    Meloto, Carolina B.; Segall, Samantha K.; Smith, Shad; Parisien, Marc; Shabalina, Svetlana A.; Rizzatti-Barbosa, Célia M.; Gauthier, Josée; Tsao, Douglas; Convertino, Marino; Piltonen, Marjo H.; Slade, Gary Dmitri; Fillingim, Roger B.; Greenspan, Joel D.; Ohrbach, Richard; Knott, Charles; Maixner, William; Zaykin, Dmitri; Dokholyan, Nikolay V.; Reenilä, Ilkka; Männistö, Pekka T.; Diatchenko, Luda

    2015-01-01

    Abstract Catechol-O-methyltransferase (COMT) metabolizes catecholaminergic neurotransmitters. Numerous studies have linked COMT to pivotal brain functions such as mood, cognition, response to stress, and pain. Both nociception and risk of clinical pain have been associated with COMT genetic variants, and this association was shown to be mediated through adrenergic pathways. Here, we show that association studies between COMT polymorphic markers and pain phenotypes in 2 independent cohorts identified a functional marker, rs165774, situated in the 3′ untranslated region of a newfound splice variant, (a)-COMT. Sequence comparisons showed that the (a)-COMT transcript is highly conserved in primates, and deep sequencing data demonstrated that (a)-COMT is expressed across several human tissues, including the brain. In silico analyses showed that the (a)-COMT enzyme features a distinct C-terminus structure, capable of stabilizing substrates in its active site. In vitro experiments demonstrated not only that (a)-COMT is catalytically active but also that it displays unique substrate specificity, exhibiting enzymatic activity with dopamine but not epinephrine. They also established that the pain-protective A allele of rs165774 coincides with lower COMT activity, suggesting contribution to decreased pain sensitivity through increased dopaminergic rather than decreased adrenergic tone, characteristic of reference isoforms. Our results provide evidence for an essential role of the (a)-COMT isoform in nociceptive signaling and suggest that genetic variations in (a)-COMT isoforms may contribute to individual variability in pain phenotypes. PMID:26207649

  13. Genetic variants of dental plaque Methanobrevibacter oralis.

    PubMed

    Huynh, H T T; Nkamga, V D; Drancourt, M; Aboudharam, G

    2015-06-01

    Methanobrevibacter oralis is the major methanogenic archaea found in the oral cavity. It has been implicated in periodontitis, including the severe form. It is unknown whether certain M. oralis genetic variants are associated with severe periodontitis. Here, we developed multispacer sequence typing (MST) as a sequencing-based genotyping method for the assessment of M. oralis. The sequencing of four intergenic spacers from a collection of 17 dental plaque M. oralis isolates obtained from seven individuals revealed 482 genetic polymorphisms, including 401 single nucleotide polymorphisms (83.2 %), 55 deletions (11.4 %) and 26 insertions (5.4 %). Concatenation of the four spacers yielded nine genotypes, which were clustered into six groups with an index of discrimination of 0.919. One periodontitis patient may have harboured up to three genetic variants of M. oralis, revealing the previously unknown diversity of this archaea. MST will allow for the study of the dynamics of M. oralis populations, including inter-individual transmission and any correlations with the severity of periodontitis. PMID:25633825

  14. Canonical and variant histones of protozoan parasites.

    PubMed

    Dalmasso, Maria Carolina; Sullivan, William Joseph; Angel, Sergio Oscar

    2011-06-01

    Protozoan parasites have tremendously diverse lifestyles that require adaptation to a remarkable assortment of different environmental conditions. In order to complete their life cycles, protozoan parasites rely on fine-tuning gene expression. In general, protozoa use novel regulatory elements, transcription factors, and epigenetic mechanisms to regulate their transcriptomes. One of the most surprising findings includes the nature of their histones--these primitive eukaryotes lack some histones yet harbor novel histone variants of unknown function. In this review, we describe the histone components of different protozoan parasites based on literature and database searching. We summarize the key discoveries regarding histones and histone variants and their impact on chromatin regulation in protozoan parasites. In addition, we list histone genes IDs, sequences, and genomic localization of several protozoan parasites and Microsporidia histones, obtained from a thorough search of genome databases. We then compare these findings with those observed in higher eukaryotes, allowing us to highlight some novel aspects of epigenetic regulation in protists and to propose questions to be addressed in the upcoming years.

  15. [Cutaneous lymphomas: new entities and rare variants].

    PubMed

    Kempf, W; Mitteldorf, C

    2015-02-01

    Primary cutaneous lymphomas are the second most common group of extranodal non-Hodgkin lymphomas. Recently several new variants and entities have been described but have not yet become part of the World Health Organization (WHO) classification. These forms include the granulomatous form of mycosis fungoides, which is associated with a poorer prognosis, as well as indolent CD8+ lymphoproliferations on the head and at acral localizations. Within the group of cutaneous CD30+ lymphoproliferative disorders, new histological types of lymphomatoid papulosis have been identified, such as type D (CD8+ epidermotropic) and type E (angioinvasive) which simulate aggressive lymphomas. Cutaneous peripheral T-cell lymphomas are a prognostically heterogeneous group of cutaneous lymphomas. The cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma and cutaneous gamma/delta T-cell lymphoma are very aggressive neoplasms, whereas cutaneous CD4+ small to medium-sized T-cell lymphoma in its solitary or localized form represents an indolent lymphoproliferation: the terminology, histogenesis and differentiation from nodular T-cell pseudolymphoma are still a matter of debate. Among B-cell lymphomas, disorders associated with Epstein-Barr virus (EBV) are discussed focusing on EBV diffuse large B-cell lymphoma of the elderly and EBV-associated mucocutaneous ulcer. This review describes the clinical, histological and immunophenotypic features of new and rare entities and variants of cutaneous lymphomas and highlights the impact of the clinicopathological correlation in the diagnostic process.

  16. False discovery rates for rare variants from sequenced data.

    PubMed

    Capanu, Marinela; Seshan, Venkatraman E

    2015-02-01

    The detection of rare deleterious variants is the preeminent current technical challenge in statistical genetics. Sorting the deleterious from neutral variants at a disease locus is challenging because of the sparseness of the evidence for each individual variant. Hierarchical modeling and Bayesian model uncertainty are two techniques that have been shown to be promising in pinpointing individual rare variants that may be driving the association. Interpreting the results from these techniques from the perspective of multiple testing is a challenge and the goal of this article is to better understand their false discovery properties. Using simulations, we conclude that accurate false discovery control cannot be achieved in this framework unless the magnitude of the variants' risk is large and the hierarchical characteristics have high accuracy in distinguishing deleterious from neutral variants.

  17. Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants

    PubMed Central

    Romanos, Jihane; Rosén, Anna; Kumar, Vinod; Trynka, Gosia; Franke, Lude; Szperl, Agata; Gutierrez-Achury, Javier; van Diemen, Cleo C; Kanninga, Roan; Jankipersadsing, Soesma A; Steck, Andrea; Eisenbarth, Georges; van Heel, David A; Cukrowska, Bozena; Bruno, Valentina; Mazzilli, Maria Cristina; Núñez, Concepcion; Bilbao, Jose Ramon; Mearin, M Luisa; Barisani, Donatella; Rewers, Marian; Norris, Jill M; Ivarsson, Anneli; Boezen, H Marieke; Liu, Edwin; Wijmenga, Cisca

    2014-01-01

    Background The majority of coeliac disease (CD) patients are not being properly diagnosed and therefore remain untreated, leading to a greater risk of developing CD-associated complications. The major genetic risk heterodimer, HLA-DQ2 and DQ8, is already used clinically to help exclude disease. However, approximately 40% of the population carry these alleles and the majority never develop CD. Objective We explored whether CD risk prediction can be improved by adding non-HLA-susceptible variants to common HLA testing. Design We developed an average weighted genetic risk score with 10, 26 and 57 single nucleotide polymorphisms (SNP) in 2675 cases and 2815 controls and assessed the improvement in risk prediction provided by the non-HLA SNP. Moreover, we assessed the transferability of the genetic risk model with 26 non-HLA variants to a nested case–control population (n=1709) and a prospective cohort (n=1245) and then tested how well this model predicted CD outcome for 985 independent individuals. Results Adding 57 non-HLA variants to HLA testing showed a statistically significant improvement compared to scores from models based on HLA only, HLA plus 10 SNP and HLA plus 26 SNP. With 57 non-HLA variants, the area under the receiver operator characteristic curve reached 0.854 compared to 0.823 for HLA only, and 11.1% of individuals were reclassified to a more accurate risk group. We show that the risk model with HLA plus 26 SNP is useful in independent populations. Conclusions Predicting risk with 57 additional non-HLA variants improved the identification of potential CD patients. This demonstrates a possible role for combined HLA and non-HLA genetic testing in diagnostic work for CD. PMID:23704318

  18. eXtasy: variant prioritization by genomic data fusion.

    PubMed

    Sifrim, Alejandro; Popovic, Dusan; Tranchevent, Leon-Charles; Ardeshirdavani, Amin; Sakai, Ryo; Konings, Peter; Vermeesch, Joris R; Aerts, Jan; De Moor, Bart; Moreau, Yves

    2013-11-01

    Massively parallel sequencing greatly facilitates the discovery of novel disease genes causing Mendelian and oligogenic disorders. However, many mutations are present in any individual genome, and identifying which ones are disease causing remains a largely open problem. We introduce eXtasy, an approach to prioritize nonsynonymous single-nucleotide variants (nSNVs) that substantially improves prediction of disease-causing variants in exome sequencing data by integrating variant impact prediction, haploinsufficiency prediction and phenotype-specific gene prioritization.

  19. Pharmacognostical studies on Cissus quadrangularis L. variant I & II

    PubMed Central

    Austin, Anoop; Kannan, R.; Jegadeesan, M.

    2004-01-01

    The aerial parts of Cissus quadrangularis L.Variant I and II are being used therapeutically for various ailments in indigenous system of medicine. Detailed pharmacognostical studies on the aerial parts were made. Variant I and II were analysed for their physiochemical, microscopical, fluorescent, qualitative and quantitative phytochemical, TLC and HPTLC characteristics. Quantitative variations were noted among seasonal samples and between variants and the results are presented. PMID:22557140

  20. [Transferrin variants: significance and identification in paternity cases (author's transl)].

    PubMed

    Mauff, G; Doppelfeld, E; Weber, W

    1975-08-01

    Transferrin phenotypes were determined in 3380 sera of unrelated persons of the western region of Germany with 97.60 percent for TfC and 2.40 percent for Tf variants. Identification was achieved by immunochemical means or through autoradiography. Relative mobilities in some variants were measured using Tf B2C (0.7) as reference. Application of Tf variants is demonstrated in paternity cases.

  1. The power of multiplexed functional analysis of genetic variants.

    PubMed

    Gasperini, Molly; Starita, Lea; Shendure, Jay

    2016-10-01

    New technologies have recently enabled saturation mutagenesis and functional analysis of nearly all possible variants of regulatory elements or proteins of interest in single experiments. Here we discuss the past, present, and future of such multiplexed (functional) assays for variant effects (MAVEs). MAVEs provide detailed insight into sequence-function relationships, and they may prove critical for the prospective clinical interpretation of genetic variants. PMID:27583640

  2. Subtotal Gastrectomy With Billroth II Anastomosis Is Associated With a Low Risk of Ischemic Stroke in Peptic Ulcer Disease Patients: A Nationwide Population-Based Study.

    PubMed

    Chen, Chien-Hua; Lin, Cheng-Li; Kao, Chia-Hung

    2016-04-01

    Duodenal diversion can ameliorate lipid and glucose metabolism. We assessed the risk of stroke after subtotal gastrectomy with Billroth II anastomosis (SGBIIA) in peptic ulcer disease (PUD). We identified 6425 patients who received SGBIIA for PUD between 1998 and 2010 from the Taiwan National Health Insurance Research Database as the study cohort; we frequency-matched them with 25,602 randomly selected controls from the PUD population who did not receive SGBIIA according to age, sex, index year, and comorbidities including hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease, congestive heart failure, chronic kidney disease, chronic obstructive pulmonary disease (COPD), and obesity. All patients were followed until the end of 2011 to determine the incidence of stroke. The incidence of stroke was lower in patients in the SGBIIA cohort than in those in the non-SGBIIA cohort (18.9 vs 22.9 per 1000 person-years, adjusted hazard ratio [aHR] 0.80, 95% confidence interval [CI] 0.72-0.89, P < 0.001). The risk of ischemic stroke (aHR 0.77, 95% CI 0.69-0.86, P < 0.001), rather than hemorrhagic stroke (aHR 1.00, 95% CI 0.78-1.28), was lower for the SGBIIA cohort than for the non-SGBIIA cohort according to the multivariable Cox proportional hazard regression analysis. The relative risk of ischemic stroke after SGBIIA was lower in men (aHR 0.77, 95% CI 0.69-0.86) than in women (aHR 0.80, 95% CI 0.65-0.99) and in patients aged ≥65 years (aHR 0.72, 95% CI 0.63-0.81) than in those of other age groups (≤49 years, aHR 0.82, 95% CI 0.48-1.39; 50-64 years, aHR 1.01, 95% CI 0.79-1.28). The relative risk of ischemic stroke after SGBIIA was also reduced in patients with comorbidities (aHR 0.84, 5% CI 0.75-0.95) rather than in those without comorbidities (aHR 0.81, 95% CI 0.59-1.12). SGBIIA is associated with a low risk of ischemic stroke for PUD patients, and its protective effect is prominent in men, patients aged ≥65 years, and those with comorbidities.

  3. Hybrid optoelectronic neurocomputer: variants of realization

    NASA Astrophysics Data System (ADS)

    Evtikhiev, Nickolay N.; Starikov, Rostislav S.; Scherbakov, Igor B.; Gaponov, Alexandr E.; Onyky, Boris N.

    1995-04-01

    The optoelectronic devices are the most effective for realization in the form of the vector- matrix multiplier. Proposed optoelectronic neurocomputers (OENC) consist of optical vector- matrix multiplier (OVMM), random access memory (RAM) and electronic control system. There are two variants of realization. The first neurocomputer scheme includes OVMM based on MAOM -- multichannel multifrequency acousto-optic modulator (Bragg cell). MAOM is the fastest up-to-date spatial light modulator. The second neurocomputer is constructed on the basis of planar OVMM (POVMM). Vector-matrix multiplication in POVMM is executed in a very small volume. The POVMM consists of matrix of light emitting diodes and array of linear photodetectors. A special computer program `NEUROEMULATOR' was designed to learn and to test performance of neural networks. Neural networks were trained with gradient and stochastic algorithms. The paper presents results of computer simulation and hardware implementation of neural networks.

  4. A look-ahead variant of TFQMR

    SciTech Connect

    Freund, R.W.; Nachtigal, N.M.

    1994-12-31

    Recently, Freund proposed a Krylov subspace iteration, the transpose-free quasi-minimal residual method (TFQMR), for solving general nonsingular non-Hermitian linear systems. The algorithm relies on a version of the squared Lanczos process to generate the basis vectors for the underlying Krylov subspace. It then constructs iterates defined by a quasi-minimization property, which leads to a smooth and nearly monotone convergence behavior. The authors investigate a variant of TFQMR that uses look-ahead to avoid some of the problems associated with breakdowns in the underlying squared Lanczos procedure. They also present some numerical examples that illustrate the properties of the new method, as compared to the original TFQMR algorithm.

  5. Variant Creutzfeldt-Jakob Disease (vCJD)

    MedlinePlus

    ... The CDC Cancel Submit Search The CDC Variant Creutzfeldt-Jakob Disease (vCJD) Note: Javascript is disabled or is not ... gov . Recommend on Facebook Tweet Share Compartir Variant Creutzfeldt-Jakob disease (vCJD) is a prion disease that was first ...

  6. The bisection point across variants of the task

    PubMed Central

    García-Pérez, Miguel A.; Peli, Eli

    2014-01-01

    Bisection tasks are used in research on normal space and time perception and to assess the perceptual distortions accompanying neurological disorders. Several variants of the bisection task are used, which often yield inconsistent results, prompting the question of which variant is most dependable and which results are to be trusted. We addressed this question using theoretical and experimental approaches. Theoretical performance in bisection tasks is derived from a general model of psychophysical performance that includes sensory components and decisional processes. The model predicts how performance should differ across variants of the task, even when the sensory component is fixed. To test these predictions, data were collected in a within-subjects study with several variants of a spatial bisection task, including a two-response variant in which observers indicated whether a line was transected to the right or left of the midpoint, a three-response variant (which included the additional option to respond “midpoint”), and a paired-comparison variant of the three-response format. The data supported the model predictions, revealing that estimated bisection points were least dependable with the two-response variant, because this format confounds perceptual and decisional influences. Only the three-response paired-comparison format can separate out these influences. Implications for research in basic and clinical fields are discussed. PMID:24811039

  7. CBH1 homologs and variant CBH1 cellulases

    DOEpatents

    Goedegebuur, Frits; Gualfetti, Peter; Mitchinson, Colin; Neefe, Paulien

    2008-11-18

    Disclosed are a number of homologs and variants of Hypocrea jecorina Cel7A (formerly Trichoderma reesei cellobiohydrolase I or CBH1), nucleic acids encoding the same and methods for producing the same. The homologs and variant cellulases have the amino acid sequence of a glycosyl hydrolase of family 7A wherein one or more amino acid residues are substituted and/or deleted.

  8. CBH1 homologs and variant CBH1 cellulases

    DOEpatents

    Goedegebuur, Frits; Gualfetti, Peter; Mitchinson, Colin; Neefe, Paulien

    2011-05-31

    Disclosed are a number of homologs and variants of Hypocrea jecorina Cel7A (formerly Trichoderma reesei cellobiohydrolase I or CBH1), nucleic acids encoding the same and methods for producing the same. The homologs and variant cellulases have the amino acid sequence of a glycosyl hydrolase of family 7A wherein one or more amino acid residues are substituted and/or deleted.

  9. Searching for missing heritability: Designing rare variant association studies

    PubMed Central

    Zuk, Or; Schaffner, Stephen F.; Samocha, Kaitlin; Do, Ron; Hechter, Eliana; Kathiresan, Sekar; Daly, Mark J.; Neale, Benjamin M.; Sunyaev, Shamil R.; Lander, Eric S.

    2014-01-01

    Genetic studies have revealed thousands of loci predisposing to hundreds of human diseases and traits, revealing important biological pathways and defining novel therapeutic hypotheses. However, the genes discovered to date typically explain less than half of the apparent heritability. Because efforts have largely focused on common genetic variants, one hypothesis is that much of the missing heritability is due to rare genetic variants. Studies of common variants are typically referred to as genomewide association studies, whereas studies of rare variants are often simply called sequencing studies. Because they are actually closely related, we use the terms common variant association study (CVAS) and rare variant association study (RVAS). In this paper, we outline the similarities and differences between RVAS and CVAS and describe a conceptual framework for the design of RVAS. We apply the framework to address key questions about the sample sizes needed to detect association, the relative merits of testing disruptive alleles vs. missense alleles, frequency thresholds for filtering alleles, the value of predictors of the functional impact of missense alleles, the potential utility of isolated populations, the value of gene-set analysis, and the utility of de novo mutations. The optimal design depends critically on the selection coefficient against deleterious alleles and thus varies across genes. The analysis shows that common variant and rare variant studies require similarly large sample collections. In particular, a well-powered RVAS should involve discovery sets with at least 25,000 cases, together with a substantial replication set. PMID:24443550

  10. Detecting Rare Variants in Case-Parents Association Studies

    PubMed Central

    Cheng, Kuang-Fu; Chen, Jin-Hua

    2013-01-01

    Despite the success of genome-wide association studies (GWASs) in detecting common variants (minor allele frequency ≥0.05) many suggested that rare variants also contribute to the genetic architecture of diseases. Recently, researchers demonstrated that rare variants can show a strong stratification which may not be corrected by using existing methods. In this paper, we focus on a case-parents study and consider methods for testing group-wise association between multiple rare (and common) variants in a gene region and a disease. All tests depend on the numbers of transmitted mutant alleles from parents to their diseased children across variants and hence they are robust to the effect of population stratification. We use extensive simulation studies to compare the performance of four competing tests: the largest single-variant transmission disequilibrium test (TDT), multivariable test, combined TDT, and a likelihood ratio test based on a random-effects model. We find that the likelihood ratio test is most powerful in a wide range of settings and there is no negative impact to its power performance when common variants are also included in the analysis. If deleterious and protective variants are simultaneously analyzed, the likelihood ratio test was generally insensitive to the effect directionality, unless the effects are extremely inconsistent in one direction. PMID:24086332

  11. Identification of a new splice variant of BDNF in chicken

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Brain-derived neurotrophic factor (BDNF) appears to be involved in the central regulation of energy homeostasis. BDNF splicing variants were discovered in vertebrates. Results from human, mouse and rat suggest that alternative BDNF splicing variants potentially play a role in fat deposition. Using t...

  12. The personal genome browser: visualizing functions of genetic variants.

    PubMed

    Juan, Liran; Teng, Mingxiang; Zang, Tianyi; Hao, Yafeng; Wang, Zhenxing; Yan, Chengwu; Liu, Yongzhuang; Li, Jie; Zhang, Tianjiao; Wang, Yadong

    2014-07-01

    Advances in high-throughput sequencing technologies have brought us into the individual genome era. Projects such as the 1000 Genomes Project have led the individual genome sequencing to become more and more popular. How to visualize, analyse and annotate individual genomes with knowledge bases to support genome studies and personalized healthcare is still a big challenge. The Personal Genome Browser (PGB) is developed to provide comprehensive functional annotation and visualization for individual genomes based on the genetic-molecular-phenotypic model. Investigators can easily view individual genetic variants, such as single nucleotide variants (SNVs), INDELs and structural variations (SVs), as well as genomic features and phenotypes associated to the individual genetic variants. The PGB especially highlights potential functional variants using the PGB built-in method or SIFT/PolyPhen2 scores. Moreover, the functional risks of genes could be evaluated by scanning individual genetic variants on the whole genome, a chromosome, or a cytoband based on functional implications of the variants. Investigators can then navigate to high risk genes on the scanned individual genome. The PGB accepts Variant Call Format (VCF) and Genetic Variation Format (GVF) files as the input. The functional annotation of input individual genome variants can be visualized in real time by well-defined symbols and shapes. The PGB is available at http://www.pgbrowser.org/. PMID:24799434

  13. The Structural Determinants behind the Epigenetic Role of Histone Variants

    PubMed Central

    Cheema, Manjinder S.; Ausió, Juan

    2015-01-01

    Histone variants are an important part of the histone contribution to chromatin epigenetics. In this review, we describe how the known structural differences of these variants from their canonical histone counterparts impart a chromatin signature ultimately responsible for their epigenetic contribution. In terms of the core histones, H2A histone variants are major players while H3 variant CenH3, with a controversial role in the nucleosome conformation, remains the genuine epigenetic histone variant. Linker histone variants (histone H1 family) haven’t often been studied for their role in epigenetics. However, the micro-heterogeneity of the somatic canonical forms of linker histones appears to play an important role in maintaining the cell-differentiated states, while the cell cycle independent linker histone variants are involved in development. A picture starts to emerge in which histone H2A variants, in addition to their individual specific contributions to the nucleosome structure and dynamics, globally impair the accessibility of linker histones to defined chromatin locations and may have important consequences for determining different states of chromatin metabolism. PMID:26213973

  14. Selection of sequence variants to improve dairy cattle genomic predictions

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genomic prediction reliabilities improved when adding selected sequence variants from run 5 of the 1,000 bull genomes project. High density (HD) imputed genotypes for 26,970 progeny tested Holstein bulls were combined with sequence variants for 444 Holstein animals. The first test included 481,904 c...

  15. Foodborne outbreak and nonmotile Salmonella enterica variant, France.

    PubMed

    Le Hello, Simon; Brisabois, Anne; Accou-Demartin, Marie; Josse, Adeline; Marault, Muriel; Francart, Sylvie; Da Silva, Nathalie Jourdan; Weill, François-Xavier

    2012-01-01

    We report a food-related outbreak of salmonellosis in humans caused by a nonmotile variant of Salmonella enterica serotype Typhimurium in France in 2009. This nonmotile variant had been circulating in laying hens but was not considered as Typhimurium and consequently escaped European poultry flock regulations.

  16. Destabilizing interactions among [PSI(+)] and [PIN(+)] yeast prion variants.

    PubMed Central

    Bradley, Michael E; Liebman, Susan W

    2003-01-01

    The yeast Sup35 and Rnq1 proteins can exist in either the noninfectious soluble forms, [psi-] or [pin-], respectively, or the multiple infectious amyloid-like forms called [PSI+] or [PIN+] prion variants (or prion strains). It was previously shown that [PSI+] and [PIN+] prions enhance one another's de novo appearance. Here we show that specific prion variants of [PSI+] and [PIN+] disrupt each other's stable inheritance. Acquiring [PSI+] often impedes the inheritance of particular [PIN+] variants. Conversely, the presence of some [PIN+] variants impairs the inheritance of weak [PSI+] but not strong [PSI+] variants. These same [PIN+] variants generate a single-dot fluorescence pattern when a fusion of Rnq1 and green fluorescent protein is expressed. Another [PIN+] variant, which forms a distinctly different multiple-dot fluorescence pattern, does not impair [PSI+] inheritance. Thus, destabilization of prions by heterologous prions depends upon the variants involved. These findings may have implications for understanding interactions among other amyloid-forming proteins, including those associated with certain human diseases. PMID:14704158

  17. Germline Variants of Prostate Cancer in Japanese Families

    PubMed Central

    Matsui, Hiroshi; Nakaoka, Hirofumi; Ohtake, Nobuaki; Hosomichi, Kazuyoshi; Suzuki, Kazuhiro; Inoue, Ituro

    2016-01-01

    Prostate cancer (PC) is the second most common cancer in men. Family history is the major risk factor for PC. Only two susceptibility genes were identified in PC, BRCA2 and HOXB13. A comprehensive search of germline variants for patients with PC has not been reported in Japanese families. In this study, we conducted exome sequencing followed by Sanger sequencing to explore responsible germline variants in 140 Japanese patients with PC from 66 families. In addition to known susceptibility genes, BRCA2 and HOXB13, we identified TRRAP variants in a mutually exclusive manner in seven large PC families (three or four patients per family). We also found shared variants of BRCA2, HOXB13, and TRRAP from 59 additional small PC families (two patients per family). We identified two deleterious HOXB13 variants (F127C and G132E). Further exploration of the shared variants in rest of the families revealed deleterious variants of the so-called cancer genes (ATP1A1, BRIP1, FANCA, FGFR3, FLT3, HOXD11, MUTYH, PDGFRA, SMARCA4, and TCF3). The germline variant profile provides a new insight to clarify the genetic etiology and heterogeneity of PC among Japanese men. PMID:27701467

  18. Comment on the article by Vázquez and Márquez-Garcia. High-risk vs. low-risk for thrombo-embolic events: who are in the intermediate-risk group? What should be done then?

    PubMed

    Benchimol-Barbosa, Paulo Roberto; Barbosa-Filho, José

    2008-03-14

    Although high risk and low risk profile for thrombo-embolic events have been extensively and intensively investigated in multi-centre trials and described in detail in atrial fibrillation guidelines, the management of those at otherwise intermediate risk is still a 'no-one's zone'. Individual risk profile is mandatory to identify those who will benefit of anti-coagulation therapy and large-scale clinical trials are still awaited to define efficacy and efficiency profile in intermediate-risk group.

  19. Histone variants as emerging regulators of embryonic stem cell identity

    PubMed Central

    Turinetto, Valentina; Giachino, Claudia

    2015-01-01

    Dynamic regulation of chromatin structure is an important mechanism for balancing the pluripotency and cell fate decision in embryonic stem cells (ESCs). Indeed ESCs are characterized by unusual chromatin packaging, and a wide variety of chromatin regulators have been implicated in control of pluripotency and differentiation. Genome-wide maps of epigenetic factors have revealed a unique epigenetic signature in pluripotent ESCs and have contributed models to explain their plasticity. In addition to the well known epigenetic regulation through DNA methylation, histone posttranslational modifications, chromatin remodeling, and non-coding RNA, histone variants are emerging as important regulators of ESC identity. In this review, we summarize and discuss the recent progress that has highlighted the central role of histone variants in ESC pluripotency and ESC fate, focusing, in particular, on H1 variants, H2A variants H2A.X, H2A.Z and macroH2A and H3 variant H3.3. PMID:26114724

  20. Variants of RhD--current testing and clinical consequences.

    PubMed

    Daniels, Geoff

    2013-05-01

    Anti-D (-RH1) of the Rh blood group system is clinically important as it causes haemolytic transfusion reactions and haemolytic disease of the fetus and newborn. Although most people are either D+ or D-, there is a plethora of D variants, often categorized as either weak D or partial D. These two types are inadequately defined and the dichotomy is potentially misleading. DVI is the D variant most commonly associated with anti-D production and UK guidelines recommend that patients are tested with anti-D reagents that do not react with DVI. Weak D types 1, 2, and 3 are seldom, if ever, associated with alloanti-D production, so a policy recommendation would be to treat patients with those D variants as D+, to preserve D- stocks, whereas patients with all other D variants would be treated as D-. All donors with D variant red cells, including DVI, should be treated as D+.

  1. Genetic variants in Alzheimer disease - molecular and brain network approaches.

    PubMed

    Gaiteri, Chris; Mostafavi, Sara; Honey, Christopher J; De Jager, Philip L; Bennett, David A

    2016-07-01

    Genetic studies in late-onset Alzheimer disease (LOAD) are aimed at identifying core disease mechanisms and providing potential biomarkers and drug candidates to improve clinical care of AD. However, owing to the complexity of LOAD, including pathological heterogeneity and disease polygenicity, extraction of actionable guidance from LOAD genetics has been challenging. Past attempts to summarize the effects of LOAD-associated genetic variants have used pathway analysis and collections of small-scale experiments to hypothesize functional convergence across several variants. In this Review, we discuss how the study of molecular, cellular and brain networks provides additional information on the effects of LOAD-associated genetic variants. We then discuss emerging combinations of these omic data sets into multiscale models, which provide a more comprehensive representation of the effects of LOAD-associated genetic variants at multiple biophysical scales. Furthermore, we highlight the clinical potential of mechanistically coupling genetic variants and disease phenotypes with multiscale brain models. PMID:27282653

  2. Detection of rare functional variants using group ISIS.

    PubMed

    Niu, Yue S; Hao, Ning; An, Lingling

    2011-11-29

    Genome-wide association studies have been firmly established in investigations of the associations between common genetic variants and complex traits or diseases. However, a large portion of complex traits and diseases cannot be explained well by common variants. Detecting rare functional variants becomes a trend and a necessity. Because rare variants have such a small minor allele frequency (e.g., <0.05), detecting functional rare variants is challenging. Group iterative sure independence screening (ISIS), a fast group selection tool, was developed to select important genes and the single-nucleotide polymorphisms within. The performance of the group ISIS and group penalization methods is compared for detecting important genes in the Genetic Analysis Workshop 17 data. The results suggest that the group ISIS is an efficient tool to discover genes and single-nucleotide polymorphisms associated to phenotypes.

  3. The presence of prostate cancer at biopsy is predicted by a number of genetic variants.

    PubMed

    Kashyap, Aniruddh; Kluźniak, Wojciech; Wokołorczyk, Dominika; Gołąb, Adam; Sikorski, Andrzej; Słojewski, Marcin; Gliniewicz, Bartłomiej; Świtała, Jerzy; Borkowski, Tomasz; Borkowski, Andrzej; Antczak, Andrzej; Wojnar, Łukasz; Przybyła, Jacek; Sosnowski, Marek; Małkiewicz, Bartosz; Zdrojowy, Romuald; Sikorska-Radek, Paulina; Matych, Józef; Wilkosz, Jacek; Różański, Waldemar; Kiś, Jacek; Bar, Krzysztof; Bryniarski, Piotr; Paradysz, Andrzej; Jersak, Konrad; Niemirowicz, Jerzy; Słupski, Piotr; Jarzemski, Piotr; Skrzypczyk, Michał; Dobruch, Jakub; Domagała, Paweł; Piotrowski, Krzysztof; Jakubowska, Anna; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Dębniak, Tadeusz; Górski, Bohdan; Masojć, Bartłomiej; van de Wetering, Thierry; Menkiszak, Janusz; Akbari, Mohammad R; Lubiński, Jan; Narod, Steven A; Cybulski, Cezary

    2014-03-01

    Several single nucleotide polymorphisms (SNPs) have been associated with an elevated risk of prostate cancer risk. It is not established if they are useful in predicting the presence of prostate cancer at biopsy or if they can be used to define a low-risk group of men. In this study, 4,548 men underwent a prostate biopsy because of an elevated prostate specific antigen (PSA; ≥4 ng/mL) or an abnormal digital rectal examination (DRE). All men were genotyped for 11 selected SNPs. The effect of each SNP, alone and in combination, on prostate cancer prevalence was studied. Of 4,548 men: 1,834 (40.3%) were found to have cancer. A positive association with prostate cancer was seen for 5 of 11 SNPs studied (rs1800629, rs1859962, rs1447295, rs4430796, rs11228565). The cancer detection rate rose with the number of SNP risk alleles from 29% for men with no variant to 63% for men who carried seven or more risk alleles (OR = 4.2; p = 0.002). The SNP data did not improve the predictive power of clinical factors (age, PSA and DRE) for detecting prostate cancer (AUC: 0.726 vs. 0.735; p = 0.4). We were unable to define a group of men with a sufficiently low prevalence of prostate cancer that a biopsy might have been avoided. In conclusion, our data do not support the routine use of SNP polymorphisms as an adjunct test to be used on the context of prostate biopsy for Polish men with an abnormal screening test.

  4. Incorporating Non-Coding Annotations into Rare Variant Analysis

    PubMed Central

    Richardson, Tom G.; Campbell, Colin; Timpson, Nicholas J; Gaunt, Tom R.

    2016-01-01

    Background The success of collapsing methods which investigate the combined effect of rare variants on complex traits has so far been limited. The manner in which variants within a gene are selected prior to analysis has a crucial impact on this success, which has resulted in analyses conventionally filtering variants according to their consequence. This study investigates whether an alternative approach to filtering, using annotations from recently developed bioinformatics tools, can aid these types of analyses in comparison to conventional approaches. Methods & Results We conducted a candidate gene analysis using the UK10K sequence and lipids data, filtering according to functional annotations using the resource CADD (Combined Annotation-Dependent Depletion) and contrasting results with ‘nonsynonymous’ and ‘loss of function’ consequence analyses. Using CADD allowed the inclusion of potentially deleterious intronic variants, which was not possible when filtering by consequence. Overall, different filtering approaches provided similar evidence of association, although filtering according to CADD identified evidence of association between ANGPTL4 and High Density Lipoproteins (P = 0.02, N = 3,210) which was not observed in the other analyses. We also undertook genome-wide analyses to determine how filtering in this manner compared to conventional approaches for gene regions. Results suggested that filtering by annotations according to CADD, as well as other tools known as FATHMM-MKL and DANN, identified association signals not detected when filtering by variant consequence and vice versa. Conclusion Incorporating variant annotations from non-coding bioinformatics tools should prove to be a valuable asset for rare variant analyses in the future. Filtering by variant consequence is only possible in coding regions of the genome, whereas utilising non-coding bioinformatics annotations provides an opportunity to discover unknown causal variants in non

  5. A Genome-Wide Investigation of MicroRNA Expression Identifies Biologically-Meaningful MicroRNAs That Distinguish between High-Risk and Low-Risk Intraductal Papillary Mucinous Neoplasms of the Pancreas

    PubMed Central

    Permuth-Wey, Jennifer; Chen, Y. Ann; Fisher, Kate; McCarthy, Susan; Qu, Xiaotao; Lloyd, Mark C.; Kasprzak, Agnieszka; Fournier, Michelle; Williams, Vonetta L.; Ghia, Kavita M.; Yoder, Sean J.; Hall, Laura; Georgeades, Christina; Olaoye, Funmilayo; Husain, Kazim; Springett, Gregory M.; Chen, Dung-Tsa; Yeatman, Timothy; Centeno, Barbara Ann; Klapman, Jason; Coppola, Domenico; Malafa, Mokenge

    2015-01-01

    Background Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic ductal adenocarcinoma (PDAC) precursors. Differentiating between high-risk IPMNs that warrant surgical resection and low-risk IPMNs that can be monitored is a significant clinical problem, and we sought to discover a panel of mi(cro)RNAs that accurately classify IPMN risk status. Methodology/Principal Findings In a discovery phase, genome-wide miRNA expression profiling was performed on 28 surgically-resected, pathologically-confirmed IPMNs (19 high-risk, 9 low-risk) using Taqman MicroRNA Arrays. A validation phase was performed in 21 independent IPMNs (13 high-risk, 8 low-risk). We also explored associations between miRNA expression level and various clinical and pathological factors and examined genes and pathways regulated by the identified miRNAs by integrating data from bioinformatic analyses and microarray analysis of miRNA gene targets. Six miRNAs (miR-100, miR-99b, miR-99a, miR-342-3p, miR-126, miR-130a) were down-regulated in high-risk versus low-risk IPMNs and distinguished between groups (P<10−3, area underneath the curve (AUC) = 87%). The same trend was observed in the validation phase (AUC = 74%). Low miR-99b expression was associated with main pancreatic duct involvement (P = 0.021), and serum albumin levels were positively correlated with miR-99a (r = 0.52, P = 0.004) and miR-100 expression (r = 0.49, P = 0.008). Literature, validated miRNA:target gene interactions, and pathway enrichment analysis supported the candidate miRNAs as tumor suppressors and regulators of PDAC development. Microarray analysis revealed that oncogenic targets of miR-130a (ATG2B, MEOX2), miR-342-3p (DNMT1), and miR-126 (IRS-1) were up-regulated in high- versus low-risk IPMNs (P<0.10). Conclusions This pilot study highlights miRNAs that may aid in preoperative risk stratification of IPMNs and provides novel insights into miRNA-mediated progression to pancreatic malignancy. The miRNAs identified here

  6. αIIbβ3 variants defined by next-generation sequencing: Predicting variants likely to cause Glanzmann thrombasthenia

    PubMed Central

    Buitrago, Lorena; Rendon, Augusto; Liang, Yupu; Simeoni, Ilenia; Negri, Ana; Filizola, Marta; Ouwehand, Willem H.; Coller, Barry S.; Alessi, Marie-Christine; Ballmaier, Matthias; Bariana, Tadbir; Bellissimo, Daniel; Bertoli, Marta; Bray, Paul; Bury, Loredana; Carrell, Robin; Cattaneo, Marco; Collins, Peter; French, Deborah; Favier, Remi; Freson, Kathleen; Furie, Bruce; Germeshausen, Manuela; Ghevaert, Cedric; Gomez, Keith; Goodeve, Anne; Gresele, Paolo; Guerrero, Jose; Hampshire, Dan J.; Hadinnapola, Charaka; Heemskerk, Johan; Henskens, Yvonne; Hill, Marian; Hogg, Nancy; Johnsen, Jill; Kahr, Walter; Kerr, Ron; Kunishima, Shinji; Laffan, Michael; Natwani, Amit; Neerman-Arbez, Marguerite; Nurden, Paquita; Nurden, Alan; Ormiston, Mark; Othman, Maha; Ouwehand, Willem; Perry, David; Vilk, Shoshana Ravel; Reitsma, Pieter; Rondina, Matthew; Simeoni, Ilenia; Smethurst, Peter; Stephens, Jonathan; Stevenson, William; Szkotak, Artur; Turro, Ernest; Van Geet, Christel; Vries, Minka; Ward, June; Waye, John; Westbury, Sarah; Whiteheart, Sidney; Wilcox, David; Zhang, Bi

    2015-01-01

    Next-generation sequencing is transforming our understanding of human genetic variation but assessing the functional impact of novel variants presents challenges. We analyzed missense variants in the integrin αIIbβ3 receptor subunit genes ITGA2B and ITGB3 identified by whole-exome or -genome sequencing in the ThromboGenomics project, comprising ∼32,000 alleles from 16,108 individuals. We analyzed the results in comparison with 111 missense variants in these genes previously reported as being associated with Glanzmann thrombasthenia (GT), 20 associated with alloimmune thrombocytopenia, and 5 associated with aniso/macrothrombocytopenia. We identified 114 novel missense variants in ITGA2B (affecting ∼11% of the amino acids) and 68 novel missense variants in ITGB3 (affecting ∼9% of the amino acids). Of the variants, 96% had minor allele frequencies (MAF) < 0.1%, indicating their rarity. Based on sequence conservation, MAF, and location on a complete model of αIIbβ3, we selected three novel variants that affect amino acids previously associated with GT for expression in HEK293 cells. αIIb P176H and β3 C547G severely reduced αIIbβ3 expression, whereas αIIb P943A partially reduced αIIbβ3 expression and had no effect on fibrinogen binding. We used receiver operating characteristic curves of combined annotation-dependent depletion, Polyphen 2-HDIV, and sorting intolerant from tolerant to estimate the percentage of novel variants likely to be deleterious. At optimal cut-off values, which had 69–98% sensitivity in detecting GT mutations, between 27% and 71% of the novel αIIb or β3 missense variants were predicted to be deleterious. Our data have implications for understanding the evolutionary pressure on αIIbβ3 and highlight the challenges in predicting the clinical significance of novel missense variants. PMID:25827233

  7. Anatomical variant of the liver blood supply

    PubMed Central

    MASLARSKI, IVAN

    2015-01-01

    Vascular variations are significant for liver transplantations, radiological procedures, laparoscopic method of operation and for the healing of penetrating injuries, including the space close to the hepatic area. These variants are very common in the abdominal region, and their description will be useful. During a routine dissection of a 73 year old female cadaver, we found in the subhepatic region that the blood supply of the liver differed from a normal one. The difference was found in the absence of the right liver branch and the cystic artery, which normally arises from the common hepatic artery. After a detailed dissection of the superior mesenteric artery we distinguished a branchthat was routed to the right lobe of the liver. The diameter of this vessel was 3.7 mm and the length 8.2 cm. In the artery pathway, three consecutive branches were observed. The first branch was found about 2.02 cm before the portal region of the liver. The second one became visible after another millimeter and finally the artery made one little curve and became a cystic artery. PMID:26609280

  8. Variant Creutzfeldt-Jakob disease: an update.

    PubMed

    Ironside, James W

    2012-01-01

    Variant Creutzfeldt-Jakob disease (vCJD) is a novel human prion disease caused by the bovine spongiform encephalopathy agent. Most cases have occurred in the UK, with smaller numbers in 11 other countries. All definite vCJD cases have occurred in methionine homozygotes at codon 129 in the prion protein gene. Following oral infection, the vCJD agent appears to replicate in lymphoid tissues during the asymptomatic phase of the incubation period. At present, four probable cases of vCJD infection have been identified following transfusion of red blood cells from asymptomatic donors who subsequently died from vCJD. Recently, one case of likely transmission of vCJD infection by UK Factor VIII concentrates has been reported in an elderly haemophilic patient in the UK. The recent report of a blood test that may be used to detect vCJD has raised the possibility of a new way to identify infected individuals, perhaps even before the onset of clinical symptoms.

  9. Treatment of pediatric multiple sclerosis and variants.

    PubMed

    Pohl, D; Waubant, E; Banwell, B; Chabas, D; Chitnis, T; Weinstock-Guttman, B; Tenembaum, S

    2007-04-17

    Studies in adult patients with multiple sclerosis (MS) suggest significant benefit of early treatment initiation. However, there are no approved therapies for children and adolescents with MS. For adult MS, tolerability and efficacy of several immunomodulatory and immunosuppressive drugs have been demonstrated. Guidelines for the use of these MS therapies in children do not exist. Several small cohort studies of the safety and tolerability of disease-modifying therapies (DMT) in children and adolescents with MS have been recently reported. The side effects of interferon beta (IFNB) and glatiramer acetate (GA) appear to be similar to those reported by adults. The long-term tolerability and safety have yet to be established and efficacy data have yet to be studied. In view of the potential for significant long-term physical and cognitive disability in children with MS, and recent evidence that initiation of immunomodulatory therapy early in the course of MS improves long-term prognosis, an increasing number of children and adolescents with MS are being offered the DMT approved for adults. This review summarizes current knowledge of DMT in pediatric MS and experience in several centers treating pediatric MS and MS variants such as neuromyelitis optica or Devic disease, Balo concentric sclerosis, Marburg acute MS, and Schilder disease (myelinoclastic diffuse sclerosis). Finally, an overview of symptomatic MS therapies and experiences with these treatments in pediatric patients is provided. PMID:17438239

  10. Variants of human papillomavirus type 16 predispose toward persistent infection.

    PubMed

    Zhang, Lei; Liao, Hong; Yang, Binlie; Geffre, Christopher P; Zhang, Ai; Zhou, Aizhi; Cao, Huimin; Wang, Jieru; Zhang, Zhenbo; Zheng, Wenxin

    2015-01-01

    A cohort study of 292 Chinese women was conducted to determine the relationship between human papillomavirus (HPV) type 16 variants and persistent viral infection. Enrolled patients were HPV16 positive and had both normal cytology and histology. Flow-through hybridization and gene chip technology was used to identify the HPV type. A PCR sequencing assay was performed to find HPV16 E2, E6 and E7 gene variants. The associations between these variants and HPV16 persistent infection was analyzed by Fisher's exact test. It was found that the variants T178G, T350G and A442C in the E6 gene, as well as C3158A and G3248A variants in the E2 gene were associated with persistent HPV16 infection. No link was observed between E7 variants and persistent viral infection. Our findings suggest that detection of specific HPV variants would help identify patients who are at high risk for viral persistence and development of cervical neoplasia.

  11. How important are rare variants in common disease?

    PubMed

    Saint Pierre, Aude; Génin, Emmanuelle

    2014-09-01

    Genome-wide association studies have uncovered hundreds of common genetic variants involved in complex diseases. However, for most complex diseases, these common genetic variants only marginally contribute to disease susceptibility. It is now argued that rare variants located in different genes could in fact play a more important role in disease susceptibility than common variants. These rare genetic variants were not captured by genome-wide association studies using single nucleotide polymorphism-chips but with the advent of next-generation sequencing technologies, they have become detectable. It is now possible to study their contribution to common disease by resequencing samples of cases and controls or by using new genotyping exome arrays that cover rare alleles. In this review, we address the question of the contribution of rare variants in common disease by taking the examples of different diseases for which some resequencing studies have already been performed, and by summarizing the results of simulation studies conducted so far to investigate the genetic architecture of complex traits in human. So far, empirical data have not allowed the exclusion of many models except the most extreme ones involving only a small number of rare variants with large effects contributing to complex disease. To unravel the genetic architecture of complex disease, case-control data will not be sufficient, and alternative study designs need to be proposed together with methodological developments.

  12. Rare variant analysis for family-based design.

    PubMed

    De, Gourab; Yip, Wai-Ki; Ionita-Laza, Iuliana; Laird, Nan

    2013-01-01

    Genome-wide association studies have been able to identify disease associations with many common variants; however most of the estimated genetic contribution explained by these variants appears to be very modest. Rare variants are thought to have larger effect sizes compared to common SNPs but effects of rare variants cannot be tested in the GWAS setting. Here we propose a novel method to test for association of rare variants obtained by sequencing in family-based samples by collapsing the standard family-based association test (FBAT) statistic over a region of interest. We also propose a suitable weighting scheme so that low frequency SNPs that may be enriched in functional variants can be upweighted compared to common variants. Using simulations we show that the family-based methods perform at par with the population-based methods under no population stratification. By construction, family-based tests are completely robust to population stratification; we show that our proposed methods remain valid even when population stratification is present.

  13. Rare Variant Analysis for Family-Based Design

    PubMed Central

    De, Gourab; Yip, Wai-Ki; Ionita-Laza, Iuliana; Laird, Nan

    2013-01-01

    Genome-wide association studies have been able to identify disease associations with many common variants; however most of the estimated genetic contribution explained by these variants appears to be very modest. Rare variants are thought to have larger effect sizes compared to common SNPs but effects of rare variants cannot be tested in the GWAS setting. Here we propose a novel method to test for association of rare variants obtained by sequencing in family-based samples by collapsing the standard family-based association test (FBAT) statistic over a region of interest. We also propose a suitable weighting scheme so that low frequency SNPs that may be enriched in functional variants can be upweighted compared to common variants. Using simulations we show that the family-based methods perform at par with the population-based methods under no population stratification. By construction, family-based tests are completely robust to population stratification; we show that our proposed methods remain valid even when population stratification is present. PMID:23341868

  14. Robust and powerful affected sibpairtest for rare variant association

    PubMed Central

    Lin, Keng-Han; Zöllner, Sebastian

    2015-01-01

    Advances in DNA sequencing technology facilitate investigating the impact of rare variants on complex diseases. However, using a conventional case-control design, large samples are needed to capture enough rare variants to achieve sufficient power for testing the association between suspected loci and complex diseases. In such large samples, population stratification may easily cause spurious signals. One approach to overcome stratification is to use a family-based design. For rare variants, this strategy is especially appropriate, as power can be increased considerably by analyzing cases with affected relatives. We propose a novel framework for association testing in affected sibpairs by comparing the allele count of rare variants on chromosome regions shared identical by descent to the allele count of rare variants on non-shared chromosome regions, referred to as test for rare-variant association with family-based internal control (TRAFIC). This design is generally robust to population stratification as cases and controls are matched within each sibpair. We evaluate the power analytically using general model for effect size of rare variants. For the same number of genotyped people, TRAFIC shows superior power over the conventional case-control study for variants with summed risk allele frequency f < 0.05; this power advantage is even more substantial when considering allelic heterogeneity. For complex models of gene-gene interaction, this power advantage depends on the direction of interaction and overall heritability. In sum, we introduce a new method for analyzing rare variants in affected sibpairs that is robust to population stratification, and provide freely available software. PMID:25966809

  15. Human papillomavirus type-16 variants in Quechua aboriginals from Argentina.

    PubMed

    Picconi, María Alejandra; Alonio, Lidia Virginia; Sichero, Laura; Mbayed, Viviana; Villa, Luisa Lina; Gronda, Jorge; Campos, Rodolfo; Teyssié, Angélica

    2003-04-01

    Cervical carcinoma is the leading cause of cancer death in Quechua indians from Jujuy (northwestern Argentina). To determine the prevalence of HPV-16 variants, 106 HPV-16 positive cervical samples were studied, including 33 low-grade squamous intraepithelial lesions (LSIL), 28 high-grade squamous intraepithelial lesions (HSIL), 9 invasive cervical cancer (ICC), and 36 samples from women with normal colposcopy and cytology. HPV genome variability was examined in the L1 and E6 genes by PCR-hybridization. In a subset of 20 samples, a LCR fragment was also analyzed by PCR-sequencing. Most variants belonged to the European branch with subtle differences that depended on the viral gene fragment studied. Only about 10% of the specimens had non-European variants, including eight Asian-American, two Asian, and one North-American-1. E6 gene analysis revealed that 43% of the samples were identical to HPV-16 prototype, while 57% corresponded to variants. Interestingly, the majority (87%) of normal smears had HPV-16 prototype, whereas variants were detected mainly in SIL and ICC. LCR sequencing yielded 80% of variants, including 69% of European, 19% Asian-American, and 12% Asian. We identified a new variant, the Argentine Quechua-51 (AQ-51), similar to B-14 plus two additional changes: G7842-->A and A7837-->C; phylogenetic inference allocated it in the Asian-American branch. The high proportion of European variants may reflect Spanish colonial influence on these native Inca descendants. The predominance of HPV-16 variants in pathologic samples when compared to normal controls could have implications for the natural history of cervical lesions.

  16. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials

    PubMed Central

    Cholesterol Treatment Trialists' (CTT) Collaborators

    2012-01-01

    Summary Background Statins reduce LDL cholesterol and prevent vascular events, but their net effects in people at low risk of vascular events remain uncertain. Methods This meta-analysis included individual participant data from 22 trials of statin versus control (n=134 537; mean LDL cholesterol difference 1·08 mmol/L; median follow-up 4·8 years) and five trials of more versus less statin (n=39 612; difference 0·51 mmol/L; 5·1 years). Major vascular events were major coronary events (ie, non-fatal myocardial infarction or coronary death), strokes, or coronary revascularisations. Participants were separated into five categories of baseline 5-year major vascular event risk on control therapy (no statin or low-intensity statin) (<5%, ≥5% to <10%, ≥10% to <20%, ≥20% to <30%, ≥30%); in each, the rate ratio (RR) per 1·0 mmol/L LDL cholesterol reduction was estimated. Findings Reduction of LDL cholesterol with a statin reduced the risk of major vascular events (RR 0·79, 95% CI 0·77–0·81, per 1·0 mmol/L reduction), largely irrespective of age, sex, baseline LDL cholesterol or previous vascular disease, and of vascular and all-cause mortality. The proportional reduction in major vascular events was at least as big in the two lowest risk categories as in the higher risk categories (RR per 1·0 mmol/L reduction from lowest to highest risk: 0·62 [99% CI 0·47–0·81], 0·69 [99% CI 0·60–0·79], 0·79 [99% CI 0·74–0·85], 0·81 [99% CI 0·77–0·86], and 0·79 [99% CI 0·74–0·84]; trend p=0·04), which reflected significant reductions in these two lowest risk categories in major coronary events (RR 0·57, 99% CI 0·36–0·89, p=0·0012, and 0·61, 99% CI 0·50–0·74, p<0·0001) and in coronary revascularisations (RR 0·52, 99% CI 0·35–0·75, and 0·63, 99% CI 0·51–0·79; both p<0·0001). For stroke, the reduction in risk in participants with 5-year risk of major vascular events lower than 10% (RR per 1·0 mmol/L LDL cholesterol

  17. Combining Telomerase Reverse Transcriptase Genetic Variant rs2736100 with Epidemiologic Factors in the Prediction of Lung Cancer Susceptibility

    PubMed Central

    Wang, Xu; Ma, Kewei; Chi, Lumei; Cui, Jiuwei; Jin, Lina; Hu, Ji-Fan; Li, Wei

    2016-01-01

    Genetic variants from a considerable number of susceptibility loci have been identified in association with cancer risk, but their interaction with epidemiologic factors in lung cancer remains to be defined. We sought to establish a forecasting model for identifying individuals with high-risk of lung cancer by combing gene single-nucleotide polymorphisms with epidemiologic factors. Genotyping and clinical data from 500 lung cancer cases and 500 controls were used for developing the logistic regression model. We found that lung cancer was associated with telomerase reverse transcriptase (TERT) rs2736100 single-nucleotide polymorphism. The TERT rs2736100 model was still significantly associated with lung cancer risk when combined with environmental and lifestyle factors, including lower education, lower BMI, COPD history, heavy cigarettes smoking, heavy cooking emission, and dietary factors (over-consumption of meat and deficiency in fish/shrimp, vegetables, dairy products, and soybean products). These data suggest that combining TERT SNP and epidemiologic factors may be a useful approach to discriminate high and low-risk individuals for lung cancer. PMID:27162544

  18. Meta-analysis of gene-level associations for rare variants based on single-variant statistics.

    PubMed

    Hu, Yi-Juan; Berndt, Sonja I; Gustafsson, Stefan; Ganna, Andrea; Hirschhorn, Joel; North, Kari E; Ingelsson, Erik; Lin, Dan-Yu

    2013-08-01

    Meta-analysis of genome-wide association studies (GWASs) has led to the discoveries of many common variants associated with complex human diseases. There is a growing recognition that identifying "causal" rare variants also requires large-scale meta-analysis. The fact that association tests with rare variants are performed at the gene level rather than at the variant level poses unprecedented challenges in the meta-analysis. First, different studies may adopt different gene-level tests, so the results are not compatible. Second, gene-level tests require multivariate statistics (i.e., components of the test statistic and their covariance matrix), which are difficult to obtain. To overcome these challenges, we propose to perform gene-level tests for rare variants by combining the results of single-variant analysis (i.e., p values of association tests and effect estimates) from participating studies. This simple strategy is possible because of an insight that multivariate statistics can be recovered from single-variant statistics, together with the correlation matrix of the single-variant test statistics, which can be estimated from one of the participating studies or from a publicly available database. We show both theoretically and numerically that the proposed meta-analysis approach provides accurate control of the type I error and is as powerful as joint analysis of individual participant data. This approach accommodates any disease phenotype and any study design and produces all commonly used gene-level tests. An application to the GWAS summary results of the Genetic Investigation of ANthropometric Traits (GIANT) consortium reveals rare and low-frequency variants associated with human height. The relevant software is freely available. PMID:23891470

  19. Meta-analysis of Gene-Level Associations for Rare Variants Based on Single-Variant Statistics

    PubMed Central

    Hu, Yi-Juan; Berndt, Sonja I.; Gustafsson, Stefan; Ganna, Andrea; Berndt, Sonja I.; Gustafsson, Stefan; Mägi, Reedik; Ganna, Andrea; Wheeler, Eleanor; Feitosa, Mary F.; Justice, Anne E.; Monda, Keri L.; Croteau-Chonka, Damien C.; Day, Felix R.; Esko, Tõnu; Fall, Tove; Ferreira, Teresa; Gentilini, Davide; Jackson, Anne U.; Luan, Jian’an; Randall, Joshua C.; Vedantam, Sailaja; Willer, Cristen J.; Winkler, Thomas W.; Wood, Andrew R.; Workalemahu, Tsegaselassie; Hu, Yi-Juan; Lee, Sang Hong; Liang, Liming; Lin, Dan-Yu; Min, Josine L.; Neale, Benjamin M.; Thorleifsson, Gudmar; Yang, Jian; Albrecht, Eva; Amin, Najaf; Bragg-Gresham, Jennifer L.; Cadby, Gemma; den Heijer, Martin; Eklund, Niina; Fischer, Krista; Goel, Anuj; Hottenga, Jouke-Jan; Huffman, Jennifer E.; Jarick, Ivonne; Johansson, Åsa; Johnson, Toby; Kanoni, Stavroula; Kleber, Marcus E.; König, Inke R.; Kristiansson, Kati; Kutalik, Zoltán; Lamina, Claudia; Lecoeur, Cecile; Li, Guo; Mangino, Massimo; McArdle, Wendy L.; Medina-Gomez, Carolina; Müller-Nurasyid, Martina; Ngwa, Julius S.; Nolte, Ilja M.; Paternoster, Lavinia; Pechlivanis, Sonali; Perola, Markus; Peters, Marjolein J.; Preuss, Michael; Rose, Lynda M.; Shi, Jianxin; Shungin, Dmitry; Smith, Albert Vernon; Strawbridge, Rona J.; Surakka, Ida; Teumer, Alexander; Trip, Mieke D.; Tyrer, Jonathan; Van Vliet-Ostaptchouk, Jana V.; Vandenput, Liesbeth; Waite, Lindsay L.; Zhao, Jing Hua; Absher, Devin; Asselbergs, Folkert W.; Atalay, Mustafa; Attwood, Antony P.; Balmforth, Anthony J.; Basart, Hanneke; Beilby, John; Bonnycastle, Lori L.; Brambilla, Paolo; Bruinenberg, Marcel; Campbell, Harry; Chasman, Daniel I.; Chines, Peter S.; Collins, Francis S.; Connell, John M.; Cookson, William; de Faire, Ulf; de Vegt, Femmie; Dei, Mariano; Dimitriou, Maria; Edkins, Sarah; Estrada, Karol; Evans, David M.; Farrall, Martin; Ferrario, Marco M.; Ferrières, Jean; Franke, Lude; Frau, Francesca; Gejman, Pablo V.; Grallert, Harald; Grönberg, Henrik; Gudnason, Vilmundur; Hall, Alistair S.; Hall, Per; Hartikainen, Anna-Liisa; Hayward, Caroline; Heard-Costa, Nancy L.; Heath, Andrew C.; Hebebrand, Johannes; Homuth, Georg; Hu, Frank B.; Hunt, Sarah E.; Hyppönen, Elina; Iribarren, Carlos; Jacobs, Kevin B.; Jansson, John-Olov; Jula, Antti; Kähönen, Mika; Kathiresan, Sekar; Kee, Frank; Khaw, Kay-Tee; Kivimaki, Mika; Koenig, Wolfgang; Kraja, Aldi T.; Kumari, Meena; Kuulasmaa, Kari; Kuusisto, Johanna; Laitinen, Jaana H.; Lakka, Timo A.; Langenberg, Claudia; Launer, Lenore J.; Lind, Lars; Lindström, Jaana; Liu, Jianjun; Liuzzi, Antonio; Lokki, Marja-Liisa; Lorentzon, Mattias; Madden, Pamela A.; Magnusson, Patrik K.; Manunta, Paolo; Marek, Diana; März, Winfried; Leach, Irene Mateo; McKnight, Barbara; Medland, Sarah E.; Mihailov, Evelin; Milani, Lili; Montgomery, Grant W.; Mooser, Vincent; Mühleisen, Thomas W.; Munroe, Patricia B.; Musk, Arthur W.; Narisu, Narisu; Navis, Gerjan; Nicholson, George; Nohr, Ellen A.; Ong, Ken K.; Oostra, Ben A.; Palmer, Colin N.A.; Palotie, Aarno; Peden, John F.; Pedersen, Nancy; Peters, Annette; Polasek, Ozren; Pouta, Anneli; Pramstaller, Peter P.; Prokopenko, Inga; Pütter, Carolin; Radhakrishnan, Aparna; Raitakari, Olli; Rendon, Augusto; Rivadeneira, Fernando; Rudan, Igor; Saaristo, Timo E.; Sambrook, Jennifer G.; Sanders, Alan R.; Sanna, Serena; Saramies, Jouko; Schipf, Sabine; Schreiber, Stefan; Schunkert, Heribert; Shin, So-Youn; Signorini, Stefano; Sinisalo, Juha; Skrobek, Boris; Soranzo, Nicole; Stančáková, Alena; Stark, Klaus; Stephens, Jonathan C.; Stirrups, Kathleen; Stolk, Ronald P.; Stumvoll, Michael; Swift, Amy J.; Theodoraki, Eirini V.; Thorand, Barbara; Tregouet, David-Alexandre; Tremoli, Elena; Van der Klauw, Melanie M.; van Meurs, Joyce B.J.; Vermeulen, Sita H.; Viikari, Jorma; Virtamo, Jarmo; Vitart, Veronique; Waeber, Gérard; Wang, Zhaoming; Widén, Elisabeth; Wild, Sarah H.; Willemsen, Gonneke; Winkelmann, Bernhard R.; Witteman, Jacqueline C.M.; Wolffenbuttel, Bruce H.R.; Wong, Andrew; Wright, Alan F.

    2013-01-01

    Meta-analysis of genome-wide association studies (GWASs) has led to the discoveries of many common variants associated with complex human diseases. There is a growing recognition that identifying “causal” rare variants also requires large-scale meta-analysis. The fact that association tests with rare variants are performed at the gene level rather than at the variant level poses unprecedented challenges in the meta-analysis. First, different studies may adopt different gene-level tests, so the results are not compatible. Second, gene-level tests require multivariate statistics (i.e., components of the test statistic and their covariance matrix), which are difficult to obtain. To overcome these challenges, we propose to perform gene-level tests for rare variants by combining the results of single-variant analysis (i.e., p values of association tests and effect estimates) from participating studies. This simple strategy is possible because of an insight that multivariate statistics can be recovered from single-variant statistics, together with the correlation matrix of the single-variant test statistics, which can be estimated from one of the participating studies or from a publicly available database. We show both theoretically and numerically that the proposed meta-analysis approach provides accurate control of the type I error and is as powerful as joint analysis of individual participant data. This approach accommodates any disease phenotype and any study design and produces all commonly used gene-level tests. An application to the GWAS summary results of the Genetic Investigation of ANthropometric Traits (GIANT) consortium reveals rare and low-frequency variants associated with human height. The relevant software is freely available. PMID:23891470

  20. DNA repair variants and breast cancer risk.

    PubMed

    Grundy, Anne; Richardson, Harriet; Schuetz, Johanna M; Burstyn, Igor; Spinelli, John J; Brooks-Wilson, Angela; Aronson, Kristan J

    2016-05-01

    A functional DNA repair system has been identified as important in the prevention of tumour development. Previous studies have hypothesized that common polymorphisms in DNA repair genes could play a role in breast cancer risk and also identified the potential for interactions between these polymorphisms and established breast cancer risk factors such as physical activity. Associations with breast cancer risk for 99 single nucleotide polymorphisms (SNPs) from genes in ten DNA repair pathways were examined in a case-control study including both Europeans (644 cases, 809 controls) and East Asians (299 cases, 160 controls). Odds ratios in both additive and dominant genetic models were calculated separately for participants of European and East Asian ancestry using multivariate logistic regression. The impact of multiple comparisons was assessed by correcting for the false discovery rate within each DNA repair pathway. Interactions between several breast cancer risk factors and DNA repair SNPs were also evaluated. One SNP (rs3213282) in the gene XRCC1 was associated with an increased risk of breast cancer in the dominant model of inheritance following adjustment for the false discovery rate (P < 0.05), although no associations were observed for other DNA repair SNPs. Interactions of six SNPs in multiple DNA repair pathways with physical activity were evident prior to correction for FDR, following which there was support for only one of the interaction terms (P < 0.05). No consistent associations between variants in DNA repair genes and breast cancer risk or their modification by breast cancer risk factors were observed. PMID:27060854

  1. A Unique Hairy Cell Leukemia Variant.

    PubMed

    Jian, Charles; Hsia, Cyrus C

    2016-01-01

    A 65-year-old woman presented with easy bruising, left upper quadrant pain, decreased appetite, and weight loss. She had splenomegaly and lymphocytosis (lymphocyte count of 11.6 × 10(9)/l), with remarkably abnormal appearing morphology. Her hemoglobin and platelet counts were normal. Peripheral blood flow cytometry revealed a monoclonal B-cell population expressing CD11c, CD25, CD19, CD20, and CD103. An initial diagnosis of hairy cell leukemia (HCL) was made, and the patient was treated with a standard 5-day course of cladribine. However, her lymphocytosis improved transiently, with a relapse 4 months later. There was no improvement in her splenomegaly. An HCL variant (HCL-v) was considered based on her resistance to treatment with a purine nucleoside analog. A subsequent splenectomy improved symptoms. Two years after, the patient suffered a relapse and underwent 6 cycles of CHOP-R (cyclophosphamide, hydroxydaunomycin, oncovin, prednisone, and rituximab), achieving partial remission. While under observation, she progressed with lymphocytosis 6 months later and was treated with pentostatin. There was no significant improvement in her disease, and she died 8 weeks following treatment initiation. HCL-v is a clinically more aggressive mature B-cell lymphoma than HCL with worse splenomegaly, higher lymphocyte counts, and resistance to typical HCL therapy with purine nucleoside analogs. Early recognition of HCL-v in the history, physical examination, and investigations with morphology and flow cytometry is key to patient management. Further, as in our case of HCL-v, cell morphology can be distinctly atypical, with large nucleoli and extremely convoluted nuclei. The distinction between HCL and HCL-v is important as HCL-v patients require more aggressive therapy and closer follow-up. PMID:27462230

  2. A Unique Hairy Cell Leukemia Variant

    PubMed Central

    Jian, Charles; Hsia, Cyrus C.

    2016-01-01

    A 65-year-old woman presented with easy bruising, left upper quadrant pain, decreased appetite, and weight loss. She had splenomegaly and lymphocytosis (lymphocyte count of 11.6 × 109/l), with remarkably abnormal appearing morphology. Her hemoglobin and platelet counts were normal. Peripheral blood flow cytometry revealed a monoclonal B-cell population expressing CD11c, CD25, CD19, CD20, and CD103. An initial diagnosis of hairy cell leukemia (HCL) was made, and the patient was treated with a standard 5-day course of cladribine. However, her lymphocytosis improved transiently, with a relapse 4 months later. There was no improvement in her splenomegaly. An HCL variant (HCL-v) was considered based on her resistance to treatment with a purine nucleoside analog. A subsequent splenectomy improved symptoms. Two years after, the patient suffered a relapse and underwent 6 cycles of CHOP-R (cyclophosphamide, hydroxydaunomycin, oncovin, prednisone, and rituximab), achieving partial remission. While under observation, she progressed with lymphocytosis 6 months later and was treated with pentostatin. There was no significant improvement in her disease, and she died 8 weeks following treatment initiation. HCL-v is a clinically more aggressive mature B-cell lymphoma than HCL with worse splenomegaly, higher lymphocyte counts, and resistance to typical HCL therapy with purine nucleoside analogs. Early recognition of HCL-v in the history, physical examination, and investigations with morphology and flow cytometry is key to patient management. Further, as in our case of HCL-v, cell morphology can be distinctly atypical, with large nucleoli and extremely convoluted nuclei. The distinction between HCL and HCL-v is important as HCL-v patients require more aggressive therapy and closer follow-up. PMID:27462230

  3. Two variants of minimum discarded fill ordering

    SciTech Connect

    D'Azevedo, E.F. ); Forsyth, P.A.; Tang, Wei-Pai . Dept. of Computer Science)

    1991-01-01

    It is well known that the ordering of the unknowns can have a significant effect on the convergence of Preconditioned Conjugate Gradient (PCG) methods. There has been considerable experimental work on the effects of ordering for regular finite difference problems. In many cases, good results have been obtained with preconditioners based on diagonal, spiral or natural row orderings. However, for finite element problems having unstructured grids or grids generated by a local refinement approach, it is difficult to define many of the orderings for more regular problems. A recently proposed Minimum Discarded Fill (MDF) ordering technique is effective in finding high quality Incomplete LU (ILU) preconditioners, especially for problems arising from unstructured finite element grids. Testing indicates this algorithm can identify a rather complicated physical structure in an anisotropic problem and orders the unknowns in the preferred'' direction. The MDF technique may be viewed as the numerical analogue of the minimum deficiency algorithm in sparse matrix technology. At any stage of the partial elimination, the MDF technique chooses the next pivot node so as to minimize the amount of discarded fill. In this work, two efficient variants of the MDF technique are explored to produce cost-effective high-order ILU preconditioners. The Threshold MDF orderings combine MDF ideas with drop tolerance techniques to identify the sparsity pattern in the ILU preconditioners. These techniques identify an ordering that encourages fast decay of the entries in the ILU factorization. The Minimum Update Matrix (MUM) ordering technique is a simplification of the MDF ordering and is closely related to the minimum degree algorithm. The MUM ordering is especially for large problems arising from Navier-Stokes problems. Some interesting pictures of the orderings are presented using a visualization tool. 22 refs., 4 figs., 7 tabs.

  4. DNA repair variants and breast cancer risk.

    PubMed

    Grundy, Anne; Richardson, Harriet; Schuetz, Johanna M; Burstyn, Igor; Spinelli, John J; Brooks-Wilson, Angela; Aronson, Kristan J

    2016-05-01

    A functional DNA repair system has been identified as important in the prevention of tumour development. Previous studies have hypothesized that common polymorphisms in DNA repair genes could play a role in breast cancer risk and also identified the potential for interactions between these polymorphisms and established breast cancer risk factors such as physical activity. Associations with breast cancer risk for 99 single nucleotide polymorphisms (SNPs) from genes in ten DNA repair pathways were examined in a case-control study including both Europeans (644 cases, 809 controls) and East Asians (299 cases, 160 controls). Odds ratios in both additive and dominant genetic models were calculated separately for participants of European and East Asian ancestry using multivariate logistic regression. The impact of multiple comparisons was assessed by correcting for the false discovery rate within each DNA repair pathway. Interactions between several breast cancer risk factors and DNA repair SNPs were also evaluated. One SNP (rs3213282) in the gene XRCC1 was associated with an increased risk of breast cancer in the dominant model of inheritance following adjustment for the false discovery rate (P < 0.05), although no associations were observed for other DNA repair SNPs. Interactions of six SNPs in multiple DNA repair pathways with physical activity were evident prior to correction for FDR, following which there was support for only one of the interaction terms (P < 0.05). No consistent associations between variants in DNA repair genes and breast cancer risk or their modification by breast cancer risk factors were observed.

  5. Nanopore sequencing detects structural variants in cancer

    PubMed Central

    Norris, Alexis L.; Workman, Rachael E.; Fan, Yunfan; Eshleman, James R.; Timp, Winston

    2016-01-01

    ABSTRACT Despite advances in sequencing, structural variants (SVs) remain difficult to reliably detect due to the short read length (<300 bp) of 2nd generation sequencing. Not only do the reads (or paired-end reads) need to straddle a breakpoint, but repetitive elements often lead to ambiguities in the alignment of short reads. We propose to use the long-reads (up to 20 kb) possible with 3rd generation sequencing, specifically nanopore sequencing on the MinION. Nanopore sequencing relies on a similar concept to a Coulter counter, reading the DNA sequence from the change in electrical current resulting from a DNA strand being forced through a nanometer-sized pore embedded in a membrane. Though nanopore sequencing currently has a relatively high mismatch rate that precludes base substitution and small frameshift mutation detection, its accuracy is sufficient for SV detection because of its long reads. In fact, long reads in some cases may improve SV detection efficiency. We have tested nanopore sequencing to detect a series of well-characterized SVs, including large deletions, inversions, and translocations that inactivate the CDKN2A/p16 and SMAD4/DPC4 tumor suppressor genes in pancreatic cancer. Using PCR amplicon mixes, we have demonstrated that nanopore sequencing can detect large deletions, translocations and inversions at dilutions as low as 1:100, with as few as 500 reads per sample. Given the speed, small footprint, and low capital cost, nanopore sequencing could become the ideal tool for the low-level detection of cancer-associated SVs needed for molecular relapse, early detection, or therapeutic monitoring. PMID:26787508

  6. Frequency of enzyme deficiency variants in erythrocytes of newborn infants

    SciTech Connect

    Mohrenweiser, H.W.

    1981-08-01

    The frequency of enzyme deficiency variants, defined as alleles whose products are either absent or almost devoid of normal activity in erythrocytes, was determined for nine erythrocyte enzymes in some 675 newborn infants and in approximately 200 adults. Examples of this type of genetic abnormality, which in the homozygous condition are often associated with significant health consequences, were detected for seven of the nine enzymes studied. Fifteen inherited enzyme deficiency variants in 1809 determinations from adults were identified. Seven of the deficiency variants involved triosephosphate isomerase, a frequency of 0.01 in the newborn population. The average frequency of 2.4/1000 is 2 to 3 times the frequency observed for rare electrophoretic variants of erythrocyte enzymes in this same population.

  7. Genetic variant as a marker for bladder cancer therapy

    Cancer.gov

    Patients who have inherited a specific common genetic variant develop bladder cancer tumors that strongly express a protein known as prostate stem cell antigen (PSCA), which is also expressed in many pancreatic and prostate tumors, according to research a

  8. Common Gene Variants Account for Most Genetic Risk for Autism

    MedlinePlus

    ... 20, 2014 Common gene variants account for most genetic risk for autism Roles of heritability, mutations, environment ... ASD) was traced to inherited variations in the genetic code shared by many people. These and other ( ...

  9. Statistical Analysis Strategies for Association Studies Involving Rare Variants

    PubMed Central

    Bansal, Vikas; Libiger, Ondrej; Torkamani, Ali; Schork, Nicholas J.

    2013-01-01

    The limitations of genome-wide association (GWA) studies that focus on the phenotypic influence of common genetic variants have motivated human geneticists to consider the contribution of rare variants to phenotypic expression. The increasing availability of high-throughput sequencing technology has enabled studies of rare variants, but will not be sufficient for their success since appropriate analytical methods are also needed. We consider data analysis approaches to testing associations between a phenotype and collections of rare variants in a defined genomic region or set of regions. Ultimately, although a wide variety of analytical approaches exist, more work is needed to refine them and determine their properties and power in different contexts. PMID:20940738

  10. Leapfrog variants of iterative methods for linear algebra equations

    NASA Technical Reports Server (NTRS)

    Saylor, Paul E.

    1988-01-01

    Two iterative methods are considered, Richardson's method and a general second order method. For both methods, a variant of the method is derived for which only even numbered iterates are computed. The variant is called a leapfrog method. Comparisons between the conventional form of the methods and the leapfrog form are made under the assumption that the number of unknowns is large. In the case of Richardson's method, it is possible to express the final iterate in terms of only the initial approximation, a variant of the iteration called the grand-leap method. In the case of the grand-leap variant, a set of parameters is required. An algorithm is presented to compute these parameters that is related to algorithms to compute the weights and abscissas for Gaussian quadrature. General algorithms to implement the leapfrog and grand-leap methods are presented. Algorithms for the important special case of the Chebyshev method are also given.

  11. A variant of human transferrin with abnormal properties.

    PubMed Central

    Evans, R W; Williams, J; Moreton, K

    1982-01-01

    Screening of human serum samples by polyacrylamide-gel electrophoresis in the presence of 6 M-urea revealed an individual who is heterozygous for a variant transferrin. The variant transferrin is able to bind two atoms of iron, but the iron in the C-terminal binding site is bound abnormally, as judged by its spectral properties, and is dissociated from the protein on electrophoresis in the presence of 6 M-urea. The iron-free C-terminal domain of the variant protein is less stable than normal to thermal and urea denaturation. Structural changes in the variant protein have not yet been characterized. Images Fig. 1. Fig. 2. Fig. 6. Fig. 9. PMID:7082283

  12. Prevalence of Titin Truncating Variants in General Population

    PubMed Central

    Akinrinade, Oyediran; Koskenvuo, Juha W.; Alastalo, Tero-Pekka

    2015-01-01

    Background Truncating titin (TTN) mutations, especially in A-band region, represent the most common cause of dilated cardiomyopathy (DCM). Clinical interpretation of these variants can be challenging, as these variants are also present in reference populations. We carried out systematic analyses of TTN truncating variants (TTNtv) in publicly available reference populations, including, for the first time, data from Exome Aggregation Consortium (ExAC). The goal was to establish more accurate estimate of prevalence of different TTNtv to allow better clinical interpretation of these findings. Methods and Results Using data from 1000 Genomes Project, Exome Sequencing Project (ESP) and ExAC, we estimated the prevalence of TTNtv in the population. In the three population datasets, 52–54% of TTNtv were not affecting all TTN transcripts. The frequency of truncations affecting all transcripts in ExAC was 0.36% (0.32% - 0.41%, 95% CI) and 0.19% (0.16% - 0.23%, 95% CI) for those affecting the A-band. In the A-band region, the prevalences of frameshift, nonsense and essential splice site variants were 0.057%, 0.090%, and 0.047% respectively. Cga/Tga (arginine/nonsense–R/*) transitional change at CpG mutation hotspots was the most frequent type of TTN nonsense mutation accounting for 91.3% (21/23) of arginine residue nonsense mutation (R/*) at TTN A-band region. Non-essential splice-site variants had significantly lower proportion of private variants and higher proportion of low-frequency variants compared to essential splice-site variants (P = 0.01; P = 5.1 X 10−4, respectively). Conclusion A-band TTNtv are more rare in the general population than previously reported. Based on this analysis, one in 500 carries a truncation in TTN A-band suggesting the penetrance of these potentially harmful variants is still poorly understood, and some of these variants do not manifest as autosomal dominant DCM. This calls for caution when interpreting TTNtv in individuals and families

  13. The genomic signature of trait-associated variants

    PubMed Central

    2013-01-01

    Background Genome-wide association studies have identified thousands of SNP variants associated with hundreds of phenotypes. For most associations the causal variants and the molecular mechanisms underlying pathogenesis remain unknown. Exploration of the underlying functional annotations of trait-associated loci has thrown some light on their potential roles in pathogenesis. However, there are some shortcomings of the methods used to date, which may undermine efforts to prioritize variants for further analyses. Here, we introduce and apply novel methods to rigorously identify annotation classes showing enrichment or depletion of trait-associated variants taking into account the underlying associations due to co-location of different functional annotations and linkage disequilibrium. Results We assessed enrichment and depletion of variants in publicly available annotation classes such as genic regions, regulatory features, measures of conservation, and patterns of histone modifications. We used logistic regression to build a multivariate model that identified the most influential functional annotations for trait-association status of genome-wide significant variants. SNPs associated with all of the enriched annotations were 8 times more likely to be trait-associated variants than SNPs annotated with none of them. Annotations associated with chromatin state together with prior knowledge of the existence of a local expression QTL (eQTL) were the most important factors in the final logistic regression model. Surprisingly, despite the widespread use of evolutionary conservation to prioritize variants for study we find only modest enrichment of trait-associated SNPs in conserved regions. Conclusion We established odds ratios of functional annotations that are more likely to contain significantly trait-associated SNPs, for the purpose of prioritizing GWAS hits for further studies. Additionally, we estimated the relative and combined influence of the different genomic

  14. Better prediction of functional effects for sequence variants

    PubMed Central

    2015-01-01

    Elucidating the effects of naturally occurring genetic variation is one of the major challenges for personalized health and personalized medicine. Here, we introduce SNAP2, a novel neural network based classifier that improves over the state-of-the-art in distinguishing between effect and neutral variants. Our method's improved performance results from screening many potentially relevant protein features and from refining our development data sets. Cross-validated on >100k experimentally annotated variants, SNAP2 significantly outperformed other methods, attaining a two-state accuracy (effect/neutral) of 83%. SNAP2 also outperformed combinations of other methods. Performance increased for human variants but much more so for other organisms. Our method's carefully calibrated reliability index informs selection of variants for experimental follow up, with the most strongly predicted half of all effect variants predicted at over 96% accuracy. As expected, the evolutionary information from automatically generated multiple sequence alignments gave the strongest signal for the prediction. However, we also optimized our new method to perform surprisingly well even without alignments. This feature reduces prediction runtime by over two orders of magnitude, enables cross-genome comparisons, and renders our new method as the best solution for the 10-20% of sequence orphans. SNAP2 is available at: https://rostlab.org/services/snap2web Definitions used Delta, input feature that results from computing the difference feature scores for native amino acid and feature scores for variant amino acid; nsSNP, non-synoymous SNP; PMD, Protein Mutant Database; SNAP, Screening for non-acceptable polymorphisms; SNP, single nucleotide polymorphism; variant, any amino acid changing sequence variant. PMID:26110438

  15. Pelvic Lymph Node Status Assessed by 18F-Fluorodeoxyglucose Positron Emission Tomography Predicts Low-Risk Group for Distant Recurrence in Locally Advanced Cervical Cancer: A Prospective Study

    SciTech Connect

    Kang, Sokbom; Park, Jung-Yeol; Lim, Myung-Chul; Song, Yong-Joong; Park, Se-Hyun; Kim, Seok-Ki; Chung, Dae-Chul; Seo, Sang-Soo; Kim, Joo-Young; Park, Sang-Yoon

    2011-03-01

    Purpose: To develop a prediction model to identify a low-risk group for distant recurrence in patients with locally advanced cervical cancer treated by concurrent chemoradiation. Methods and Materials: Prospectively, 62 patients with locally advanced cervical cancer were recruited as a training cohort. Clinical variables and parameters obtained from positron emission tomography (PET) and magnetic resonance imaging were analyzed by logistic regression. For the test set, 54 patients were recruited independently. To identify the low-risk group, negative likelihood ratio (LR) less than 0.2 was set to be a cutoff. Results: Among the training cohort, multivariate logistic analysis revealed that advanced International Federation of Gynecology and Obstetrics (FIGO) stage and a high serum squamous cancer cell (SCC) antigen level were significant risk factors (p = 0.015 and 0.025, respectively). Using the two parameters, criteria to determine a low-risk subset for distant recurrence were postulated: (1) FIGO Stage IIB or less and (2) pretreatment SCC < 2.4 (Model A). Positive pelvic node on PET completely predicted all cases with distant recurrence and thus was considered as another prediction model (Model B). In the test cohort, although Model A did not showed diagnostic performance, Model B completely predicted all cases with distant recurrence and showed a sensitivity of 100% with negative LR of 0. Across the training and test cohort (n = 116), the false negative rate was 0 (95% confidence interval 0%-7.6%). Conclusions: Positive pelvic node on PET is a useful marker in prediction of distant recurrence in patients with locally advanced cervical cancer who are treated with concurrent chemoradiation.

  16. A retrospective comparison of androgen deprivation (AD) vs. no AD among low-risk and intermediate-risk prostate cancer patients treated with brachytherapy, external beam radiotherapy, or radical prostatectomy

    SciTech Connect

    Ciezki, Jay P. . E-mail: ciezkij@ccf.org; Klein, Eric A.; Angermeier, Kenneth; Ulchaker, James; Chehade, Nabil; Altman, Andrew; Mahadevan, Arul; Reddy, Chandana A.

    2004-12-01

    Purpose: To examine the value of androgen deprivation (AD) in the curative treatment of low- and intermediate-risk prostate cancer treated with the three major modalities: radical retropubic prostatectomy (RRP), external beam radiotherapy (EBRT), and permanent prostate implantation (PI). Methods and materials: During 1996-2001, 1668 patients with low- and intermediate-risk prostate cancer were treated at The Cleveland Clinic Foundation. Only patients with a minimum of 2 years of prostate-specific antigen follow-up were included in the analysis, and biochemical relapse-free survival (bRFS) was used as the endpoint. Patients were grouped according to treatment modality and stratified according to the use of AD. Results: The overall 5-year bRFS rate was 87.8%. The 5-year bRFS rate for low-risk patients was 89% and for intermediate-risk patients was 79%. For low-risk patients, the 5-year bRFS rates by treatment modality (without AD vs. with AD, respectively) were PI: 90% vs. 93%; EBRT: 90% vs. 93%; and RRP: 89% vs. 84%. For intermediate-risk patients, the 5-year bRFS rates by treatment modality (without AD vs. with AD, respectively) were PI: 88% vs. 82%; EBRT: 81% vs. 84%; and RRP: 75% vs. 72%. None of the comparisons within risk groups or among modalities supports an increased efficacy with the use of AD. Conclusion: Five-year bRFS rates in low-risk and intermediate-risk patients are not improved by the use of AD.

  17. Sonographic and cytopathologic correlation of papillary thyroid carcinoma variants.

    PubMed

    Lee, Ji Hyun; Shin, Jung Hee; Lee, Hyun-Woo; Oh, Young Lyun; Hahn, Soo Yeon; Ko, Eun Young

    2015-01-01

    Papillary thyroid carcinoma (PTC) is the most common thyroid cancer and constitutes more than 70% of thyroid malignancies. Although TNM staging is the most widely used parameter for determination of therapeutic plans, recent studies have suggested that different histopathologic variants of PTC can also have different clinical courses and patient prognoses. Sonographic criteria for PTC are well established and include a taller-than-wide shape, an irregular margin, microcalcifications, and marked hypoechogenicity. The role of sonography has expanded to enable the characterization of PTC variants based on their sonographic features. Tall cell and diffuse sclerosing variants appear to have more aggressive clinical courses with unfavorable prognoses, whereas the more recently described cribriform-morular and Warthin-like variants have relatively indolent clinical courses. The prognoses of patients with follicular, solid, columnar cell, and oncocytic variants are still controversial and may be similar to the prognosis of conventional PTC. Understanding the sonographic characteristics of PTC variants with clinicopathologic correlation may be helpful for suggesting an appropriate treatment plan.

  18. Generalization of Rare Variant Association Tests for Longitudinal Family Studies.

    PubMed

    Chien, Li-Chu; Hsu, Fang-Chi; Bowden, Donald W; Chiu, Yen-Feng

    2016-02-01

    Given the functional relevance of many rare variants, their identification is frequently critical for dissecting disease etiology. Functional variants are likely to be aggregated in family studies enriched with affected members, and this aggregation increases the statistical power to detect rare variants associated with a trait of interest. Longitudinal family studies provide additional information for identifying genetic and environmental factors associated with disease over time. However, methods to analyze rare variants in longitudinal family data remain fairly limited. These methods should be capable of accounting for different sources of correlations and handling large amounts of sequencing data efficiently. To identify rare variants associated with a phenotype in longitudinal family studies, we extended pedigree-based burden (BT) and kernel (KS) association tests to genetic longitudinal studies. Generalized estimating equation (GEE) approaches were used to generalize the pedigree-based BT and KS to multiple correlated phenotypes under the generalized linear model framework, adjusting for fixed effects of confounding factors. These tests accounted for complex correlations between repeated measures of the same phenotype (serial correlations) and between individuals in the same family (familial correlations). We conducted comprehensive simulation studies to compare the proposed tests with mixed-effects models and marginal models, using GEEs under various configurations. When the proposed tests were applied to data from the Diabetes Heart Study, we found exome variants of POMGNT1 and JAK1 genes were associated with type 2 diabetes. PMID:26783077

  19. Homolog-specific PCR primer design for profiling splice variants

    PubMed Central

    Srivastava, Gyan Prakash; Hanumappa, Mamatha; Kushwaha, Garima; Nguyen, Henry T.; Xu, Dong

    2011-01-01

    To study functional diversity of proteins encoded from a single gene, it is important to distinguish the expression levels among the alternatively spliced variants. A variant-specific primer pair is required to amplify each alternatively spliced variant individually. For this purpose, we developed a new feature, homolog-specific primer design (HSPD), in our high-throughput primer and probe design software tool, PRIMEGENS-v2. The algorithm uses a de novo approach to design primers without any prior information of splice variants or close homologs for an input query sequence. It not only designs primer pairs but also finds potential isoforms and homologs of the input sequence. Efficiency of this algorithm was tested for several gene families in soybean. A total of 187 primer pairs were tested under five different abiotic stress conditions with three replications at three time points. Results indicate a high success rate of primer design. Some primer pairs designed were able to amplify all splice variants of a gene. Furthermore, by utilizing combinations within the same multiplex pool, we were able to uniquely amplify a specific variant or duplicate gene. Our method can also be used to design PCR primers to specifically amplify homologs in the same gene family. PRIMEGENS-v2 is available at: http://primegens.org. PMID:21415011

  20. Five Rare β Globin Chain Hemoglobin Variants in India.

    PubMed

    Colah, Roshan B; Nadkarni, Anita; Gorakshakar, Ajit; Sawant, Pratibha; Gorivale, Manju; Mehta, Pallavi; Sawant, Madhavi; Ghosh, Kanjaksha

    2016-06-01

    Thalassemias as well as structural hemoglobin (Hb) variants are common monogenic inherited disorders of Hb in India. In this paper we describe 5 rare β-chain Hb variants identified in the Indian population on the basis of high performance liquid chromatography (HPLC). Of these 3 were identified during antenatal screening of β-thalassemia while the other 2 cases were referred to us for a diagnostic work up. These 5 Hb variants were Hb British Columbia (β CD 101 GAG → AAG), Hb Saint Louis (β CD28 CTG → CAG), Hb G Coushatta (β CD 22 GAA → GCA), Hb Pyrgos (β CD 83 GGC → GAC) and Hb Agenogi (β CD 90 GAG → AAG). Hb Saint Louis and Hb G Coushatta eluted in the HbA2 window, Hb British Columbia and Hb Agenogi eluted in the Hb C window while Hb Pyrgos eluted in an unknown window on HPLC. They were all identified by DNA sequencing. The child having Hb St. Louis had hepatosplenomegaly and anemia while the individuals with the other 4 variants were asymptomatic. Rare Hb variants are diagnostic curiosities that may be encountered by laboratories. Correct identification requires the application of more than one technique to avoid misdiagnosing them as more common variants (e.g. St. Louis and G Coushatta as E or D Iran on HPLC. Some, like G Coushatta may interfere with HPLC-based HbA1c estimation). PMID:27408413

  1. Variants Affecting Exon Skipping Contribute to Complex Traits

    PubMed Central

    Lee, Younghee; Gamazon, Eric R.; Rebman, Ellen; Lee, Yeunsook; Lee, Sanghyuk; Dolan, M. Eileen; Cox, Nancy J.; Lussier, Yves A.

    2012-01-01

    DNA variants that affect alternative splicing and the relative quantities of different gene transcripts have been shown to be risk alleles for some Mendelian diseases. However, for complex traits characterized by a low odds ratio for any single contributing variant, very few studies have investigated the contribution of splicing variants. The overarching goal of this study is to discover and characterize the role that variants affecting alternative splicing may play in the genetic etiology of complex traits, which include a significant number of the common human diseases. Specifically, we hypothesize that single nucleotide polymorphisms (SNPs) in splicing regulatory elements can be characterized in silico to identify variants affecting splicing, and that these variants may contribute to the etiology of complex diseases as well as the inter-individual variability in the ratios of alternative transcripts. We leverage high-throughput expression profiling to 1) experimentally validate our in silico predictions of skipped exons and 2) characterize the molecular role of intronic genetic variations in alternative splicing events in the context of complex human traits and diseases. We propose that intronic SNPs play a role as genetic regulators within splicing regulatory elements and show that their associated exon skipping events can affect protein domains and structure. We find that SNPs we would predict to affect exon skipping are enriched among the set of SNPs reported to be associated with complex human traits. PMID:23133393

  2. Human FABP1 T94A variant enhances cholesterol uptake.

    PubMed

    Huang, Huan; McIntosh, Avery L; Landrock, Kerstin K; Landrock, Danilo; Storey, Stephen M; Martin, Gregory G; Gupta, Shipra; Atshaves, Barbara P; Kier, Ann B; Schroeder, Friedhelm

    2015-07-01

    Although expression of the human liver fatty acid binding protein (FABP1) T94A variant alters serum lipoprotein cholesterol levels in human subjects, nothing is known whereby the variant elicits these effects. This issue was addressed by in vitro cholesterol binding assays using purified recombinant wild-type (WT) FABP1 T94T and T94A variant proteins and in cultured primary human hepatocytes expressing the FABP1 T94T (genotyped as TT) or T94A (genotyped as CC) proteins. The human FABP1 T94A variant protein had 3-fold higher cholesterol-binding affinity than the WT FABP1 T94T as shown by NBD-cholesterol fluorescence binding assays and by cholesterol isothermal titration microcalorimetry (ITC) binding assays. CC variant hepatocytes also exhibited 30% higher total FABP1 protein. HDL- and LDL-mediated NBD-cholesterol uptake was faster in CC variant than TT WT human hepatocytes. VLDL-mediated uptake of NBD-cholesterol did not differ between CC and TT human hepatocytes. The increased HDL- and LDL-mediated NBD-cholesterol uptake was not associated with any significant change in mRNA levels of SCARB1, LDLR, CETP, and LCAT encoding the key proteins in lipoprotein cholesterol uptake. Thus, the increased HDL- and LDL-mediated NBD-cholesterol uptake by CC hepatocytes may be associated with higher affinity of T94A protein for cholesterol and/or increased total T94A protein level. PMID:25732850

  3. Epigenetic reprogramming in mammalian reproduction: contribution from histone variants.

    PubMed

    Santenard, Angèle; Torres-Padilla, Maria-Elena

    2009-02-16

    Development of the mammalian embryo is, by definition, epigenetic. At the level of the nucleosome, the building block of the chromatin, changes in chromatin structure can be regulated through histone content. Apart from the canonical histones whose synthesis is restricted to S-phase, different histone variants have been identified. Histone variants can help to establish specialised chromatin regions and to regulate developmental and cell differentiation processes. While the role of histone variants has been extensively explored in differentiated cells, less is known in germ cells and embryos. Increasing lines of evidence suggest that the functions and/or properties of histone variants in embryos might be different to those in somatic cells. During reprogramming, histone variants such as H3.3 or H2A.Z are candidates to play potential important roles. We suggest that H3.3 has an important role in setting up a 'transition' signature, and provides the possibility to infer changes in chromatin architecture independent of DNA replication. This should confer flexibility during important developmental processes. The specific pathways through which H3.3 could regulate different chromatin conformations at different loci and the identification of specific proteins responsible for this deposition are an important challenge for future investigation. Lastly, the set of variants incorporated within the nucleosome can have important consequences in the regulation of epigenetic mechanisms during development. PMID:19242119

  4. Exploring the role of exposure frequency in recognizing pronunciation variants

    PubMed Central

    Pitt, Mark A.; Dilley, Laura; Tat, Michael

    2010-01-01

    Words can be pronounced in multiple ways in casual speech. Corpus analyses of the frequency with which these pronunciation variants occur (e.g., Patterson & Connine, 2001) show that typically, one pronunciation variant tends to predominate; this raises the question of whether variant recognition is aligned with exposure frequency. We explored this issue in words containing one of four phonological contexts, each of which favors one of four surface realizations of word-medial /t/: [t], [ʔ], [ɾ], or a deleted variant. The frequencies of the four realizations in all four contexts were estimated for a set of words in a production experiment. Recognition of all pronunciation variants was then measured in a lexical decision experiment. Overall, the data suggest that listeners are sensitive to variant frequency: Word classification rates closely paralleled production frequency. The exceptions to this were [t] realizations (i.e., canonical pronunciations of the words), a finding which confirms other results in the literature and indicates that factors other than exposure frequency affect word recognition. PMID:21822340

  5. Generalization of Rare Variant Association Tests for Longitudinal Family Studies.

    PubMed

    Chien, Li-Chu; Hsu, Fang-Chi; Bowden, Donald W; Chiu, Yen-Feng

    2016-02-01

    Given the functional relevance of many rare variants, their identification is frequently critical for dissecting disease etiology. Functional variants are likely to be aggregated in family studies enriched with affected members, and this aggregation increases the statistical power to detect rare variants associated with a trait of interest. Longitudinal family studies provide additional information for identifying genetic and environmental factors associated with disease over time. However, methods to analyze rare variants in longitudinal family data remain fairly limited. These methods should be capable of accounting for different sources of correlations and handling large amounts of sequencing data efficiently. To identify rare variants associated with a phenotype in longitudinal family studies, we extended pedigree-based burden (BT) and kernel (KS) association tests to genetic longitudinal studies. Generalized estimating equation (GEE) approaches were used to generalize the pedigree-based BT and KS to multiple correlated phenotypes under the generalized linear model framework, adjusting for fixed effects of confounding factors. These tests accounted for complex correlations between repeated measures of the same phenotype (serial correlations) and between individuals in the same family (familial correlations). We conducted comprehensive simulation studies to compare the proposed tests with mixed-effects models and marginal models, using GEEs under various configurations. When the proposed tests were applied to data from the Diabetes Heart Study, we found exome variants of POMGNT1 and JAK1 genes were associated with type 2 diabetes.

  6. Alternative Technical Summary Report: Electrometallurgical Treatment Variant

    SciTech Connect

    Gray, L.W.

    1995-11-30

    Immobilization is the fixation of the surplus fissile materials in an acceptable matrix such as glass or ceramics to create an environmentally benign form for disposal in a repository. In addition to the traditional characteristics required of an immobilization form to achieve isolation of the fissile material from the biosphere over geologic times, the immobilization form for the Fissile Materials Disposition Program (FMDP) must also possess the property that it is inherently as unattractive and inaccessible as the fissile material from commercial spent fuel. This latter requirement is similar to the wording of the ''spent fuel standard'' invoked in the National Academy of Sciences (NAS) study on plutonium disposition. High-level wastes (HLW) or separated cesium ({sup 137}Cs), can be added with the fissile material into the waste form to create a radiation field that increases the proliferation resistance and decreases reuse by the host nation in the following ways: (1) Plutonium will be diluted with elements that must be removed by extensive chemical processing to return it to weapons-usable purity; (2) The immobilized plutonium canisters will contain approximately 2 tonnes (2000 kg; 2.2 tons) of mass, thereby forcing the use of heavy equipment to move the canisters; (3) A gamma radiation barrier will be added to the immobilized plutonium canisters; the present concept is to add a radiation barrier that is greater than 1 Gy (100 rad) per hour at 1 m (3 ft) 30 years after fabrication; (4) These canisters will then be sealed in casks and emplaced into drifts in a federal repository where they will be monitored for 100 years before the repository is sealed. This immobilization process is shown conceptually in Figure 1. In the electrometallurgical treatment (ET) variant, plutonium-rich residues are shipped to existing Argonne National Laboratory-West (ANL-W) facilities where the plutonium is converted to plutonium chloride, dissolved in a molten salt solution, sorbed

  7. Identification of lung cancer histology-specific variants applying Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia.

    PubMed

    Brenner, Darren R; Amos, Christopher I; Brhane, Yonathan; Timofeeva, Maria N; Caporaso, Neil; Wang, Yufei; Christiani, David C; Bickeböller, Heike; Yang, Ping; Albanes, Demetrius; Stevens, Victoria L; Gapstur, Susan; McKay, James; Boffetta, Paolo; Zaridze, David; Szeszenia-Dabrowska, Neonilia; Lissowska, Jolanta; Rudnai, Peter; Fabianova, Eleonora; Mates, Dana; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Krokan, Hans E; Skorpen, Frank; Gabrielsen, Maiken E; Vatten, Lars; Njølstad, Inger; Chen, Chu; Goodman, Gary; Lathrop, Mark; Vooder, Tõnu; Välk, Kristjan; Nelis, Mari; Metspalu, Andres; Broderick, Peter; Eisen, Timothy; Wu, Xifeng; Zhang, Di; Chen, Wei; Spitz, Margaret R; Wei, Yongyue; Su, Li; Xie, Dong; She, Jun; Matsuo, Keitaro; Matsuda, Fumihiko; Ito, Hidemi; Risch, Angela; Heinrich, Joachim; Rosenberger, Albert; Muley, Thomas; Dienemann, Hendrik; Field, John K; Raji, Olaide; Chen, Ying; Gosney, John; Liloglou, Triantafillos; Davies, Michael P A; Marcus, Michael; McLaughlin, John; Orlow, Irene; Han, Younghun; Li, Yafang; Zong, Xuchen; Johansson, Mattias; Liu, Geoffrey; Tworoger, Shelley S; Le Marchand, Loic; Henderson, Brian E; Wilkens, Lynne R; Dai, Juncheng; Shen, Hongbing; Houlston, Richard S; Landi, Maria T; Brennan, Paul; Hung, Rayjean J

    2015-11-01

    Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range (0.0001> P > 5×10(-8)) are, however, still of interest for identifying causal associations. This analysis aimed to apply novel variant prioritization approaches to identify additional lung cancer variants that may not reach the GWAS level. Effects were combined across studies with a total of 33456 controls and 6756 adenocarcinoma (AC; 13 studies), 5061 squamous cell carcinoma (SCC; 12 studies) and 2216 small cell lung cancer cases (9 studies). Based on prior information such as variant physical properties and functional significance, we applied stratified false discovery rates, hierarchical modeling and Bayesian false discovery probabilities for variant prioritization. We conducted a fine mapping analysis as validation of our methods by examining top-ranking novel variants in six independent populations with a total of 3128 cases and 2966 controls. Three novel loci in the suggestive range were identified based on our Bayesian framework analyses: KCNIP4 at 4p15.2 (rs6448050, P = 4.6×10(-7)) and MTMR2 at 11q21 (rs10501831, P = 3.1×10(-6)) with SCC, as well as GAREM at 18q12.1 (rs11662168, P = 3.4×10(-7)) with AC. Use of our prioritization methods validated two of the top three loci associated with SCC (P = 1.05×10(-4) for KCNIP4, represented by rs9799795) and AC (P = 2.16×10(-4) for GAREM, represented by rs3786309) in the independent fine mapping populations. This study highlights the utility of using prior functional data for sequence variants in prioritization analyses to search for robust signals in the suggestive range. PMID:26363033

  8. Two insular regions are differentially involved in behavioral variant FTD and nonfluent/agrammatic variant PPA.

    PubMed

    Mandelli, Maria Luisa; Vitali, Paolo; Santos, Miguel; Henry, Maya; Gola, Kelly; Rosenberg, Lynne; Dronkers, Nina; Miller, Bruce; Seeley, William W; Gorno-Tempini, Maria Luisa

    2016-01-01

    The non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) and the behavioral variant frontotemporal dementia (bvFTD) are focal neurodegenerative disorders belonging to the FTD-spectrum clinical syndromes. NfvPPA is characterized by effortful speech and/or agrammatism and left frontal atrophy, while bvFTD is characterized by social-emotional dysfunction often accompanied by right-lateralized frontal damage. Despite their contrasting clinical presentations, both disorders show prominent left anterior insula atrophy. We investigated differential patterns of insular sub-region atrophy in nfvPPA and bvFTD. Based on knowledge of insular connectivity and physiology, we hypothesized that the left superior precentral region of the dorsal anterior insula (SPGI) would be more atrophic in nvfPPA due to its critical role in motor speech, whereas the ventral anterior region would be more atrophied in bvFTD reflecting its known role in social-emotional-autonomic functions. Early stage nfvPPA and bvFTD patients matched for disease severity, age, gender and education and healthy controls participated in the study. Detailed clinical history, neurological examination, neuropsychological screening evaluation, and high-resolution T1-weighted brain magnetic resonance imaging (MRI) were collected. Voxel-based morphometry (VBM) was applied to perform group comparisons across the whole brain and in bilateral insula region of interest (ROI). Correlation analyses between insular sub-region atrophy and relevant clinical features were performed. Whole brain group comparisons between nfvPPA and bvFTD showed the expected predominantly left or right anterior insular atrophy pattern. ROI analysis of bilateral insula showed that the left SPGI was significantly more atrophied in nfvPPA compared to bvFTD, while the bilateral ventral anterior and right dorsal anterior insula sub-regions were more atrophied in bvFTD than nfvPPA. Only left SPGI volume correlated with speech production

  9. Two insular regions are differentially involved in behavioral variant FTD and nonfluent/agrammatic variant PPA.

    PubMed

    Mandelli, Maria Luisa; Vitali, Paolo; Santos, Miguel; Henry, Maya; Gola, Kelly; Rosenberg, Lynne; Dronkers, Nina; Miller, Bruce; Seeley, William W; Gorno-Tempini, Maria Luisa

    2016-01-01

    The non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) and the behavioral variant frontotemporal dementia (bvFTD) are focal neurodegenerative disorders belonging to the FTD-spectrum clinical syndromes. NfvPPA is characterized by effortful speech and/or agrammatism and left frontal atrophy, while bvFTD is characterized by social-emotional dysfunction often accompanied by right-lateralized frontal damage. Despite their contrasting clinical presentations, both disorders show prominent left anterior insula atrophy. We investigated differential patterns of insular sub-region atrophy in nfvPPA and bvFTD. Based on knowledge of insular connectivity and physiology, we hypothesized that the left superior precentral region of the dorsal anterior insula (SPGI) would be more atrophic in nvfPPA due to its critical role in motor speech, whereas the ventral anterior region would be more atrophied in bvFTD reflecting its known role in social-emotional-autonomic functions. Early stage nfvPPA and bvFTD patients matched for disease severity, age, gender and education and healthy controls participated in the study. Detailed clinical history, neurological examination, neuropsychological screening evaluation, and high-resolution T1-weighted brain magnetic resonance imaging (MRI) were collected. Voxel-based morphometry (VBM) was applied to perform group comparisons across the whole brain and in bilateral insula region of interest (ROI). Correlation analyses between insular sub-region atrophy and relevant clinical features were performed. Whole brain group comparisons between nfvPPA and bvFTD showed the expected predominantly left or right anterior insular atrophy pattern. ROI analysis of bilateral insula showed that the left SPGI was significantly more atrophied in nfvPPA compared to bvFTD, while the bilateral ventral anterior and right dorsal anterior insula sub-regions were more atrophied in bvFTD than nfvPPA. Only left SPGI volume correlated with speech production

  10. Identifying Mendelian disease genes with the Variant Effect Scoring Tool

    PubMed Central

    2013-01-01

    Background Whole exome sequencing studies identify hundreds to thousands of rare protein coding variants of ambiguous significance for human health. Computational tools are needed to accelerate the identification of specific variants and genes that contribute to human disease. Results We have developed the Variant Effect Scoring Tool (VEST), a supervised machine learning-based classifier, to prioritize rare missense variants with likely involvement in human disease. The VEST classifier training set comprised ~ 45,000 disease mutations from the latest Human Gene Mutation Database release and another ~45,000 high frequency (allele frequency >1%) putatively neutral missense variants from the Exome Sequencing Project. VEST outperforms some of the most popular methods for prioritizing missense variants in carefully designed holdout benchmarking experiments (VEST ROC AUC = 0.91, PolyPhen2 ROC AUC = 0.86, SIFT4.0 ROC AUC = 0.84). VEST estimates variant score p-values against a null distribution of VEST scores for neutral variants not included in the VEST training set. These p-values can be aggregated at the gene level across multiple disease exomes to rank genes for probable disease involvement. We tested the ability of an aggregate VEST gene score to identify candidate Mendelian disease genes, based on whole-exome sequencing of a small number of disease cases. We used whole-exome data for two Mendelian disorders for which the causal gene is known. Considering only genes that contained variants in all cases, the VEST gene score ranked dihydroorotate dehydrogenase (DHODH) number 2 of 2253 genes in four cases of Miller syndrome, and myosin-3 (MYH3) number 2 of 2313 genes in three cases of Freeman Sheldon syndrome. Conclusions Our results demonstrate the potential power gain of aggregating bioinformatics variant scores into gene-level scores and the general utility of bioinformatics in assisting the search for disease genes in large-scale exome sequencing studies. VEST is

  11. Cellulase variants with improved expression, activity and stability, and use thereof

    DOEpatents

    Aehle, Wolfgang; Bott, Richard R; Bower, Benjamin; Caspi, Jonathan; Estell, David A; Goedegebuur, Frits; Hommes, Ronaldus W.J.; Kaper, Thijs; Kelemen, Bradley; Kralj, Slavko; Van Lieshout, Johan; Nikolaev, Igor; Van Stigt Thans, Sander; Wallace, Louise; Vogtentanz, Gudrun; Sandgren, Mats

    2014-03-25

    The present disclosure relates to cellulase variants. In particular the present disclosure relates to cellulase variants having improved expression, activity and/or stability. Also described are nucleic acids encoding the cellulase variants, compositions comprising the cellulase variants, and methods of use thereof.

  12. Neuroeconomic dissociation of semantic dementia and behavioural variant frontotemporal dementia.

    PubMed

    Chiong, Winston; Wood, Kristie A; Beagle, Alexander J; Hsu, Ming; Kayser, Andrew S; Miller, Bruce L; Kramer, Joel H

    2016-02-01

    Many neuropsychiatric disorders are marked by abnormal behaviour and decision-making, but prevailing diagnostic criteria for such behaviours are typically qualitative and often ambiguous. Behavioural variant frontotemporal dementia and semantic variant primary progressive aphasia (also called semantic dementia) are two clinical variants of frontotemporal dementia with overlapping but distinct anatomical substrates known to cause profound changes in decision-making. We investigated whether abnormal decision-making in these syndromes could be more precisely characterized in terms of dissociable abnormalities in patients' subjective evaluations of valence (positive versus negative outcome) and of time (present versus future outcome). We presented 28 patients with behavioural variant frontotemporal dementia, 14 patients with semantic variant primary progressive aphasia, 25 patients with Alzheimer's disease (as disease controls), and 61 healthy older control subjects with experimental tasks assaying loss aversion and delay discounting. In general linear models controlling for age, gender, education and Mini-Mental State Examination score, patients with behavioural variant frontotemporal dementia were less averse to losses than control subjects (P < 0.001), while patients with semantic variant primary progressive aphasia discounted delayed rewards more steeply than controls (P = 0.019). There was no relationship between loss aversion and delay discounting across the sample, nor in any of the subgroups. These findings suggest that abnormal behaviours in neurodegenerative disease may result from the disruption of either of two dissociable neural processes for evaluating the outcomes of action. More broadly, these findings suggest a role for computational methods to supplement traditional qualitative characterizations in the differential diagnosis of neuropsychiatric disorders. PMID:26667277

  13. Neuroeconomic dissociation of semantic dementia and behavioural variant frontotemporal dementia.

    PubMed

    Chiong, Winston; Wood, Kristie A; Beagle, Alexander J; Hsu, Ming; Kayser, Andrew S; Miller, Bruce L; Kramer, Joel H

    2016-02-01

    Many neuropsychiatric disorders are marked by abnormal behaviour and decision-making, but prevailing diagnostic criteria for such behaviours are typically qualitative and often ambiguous. Behavioural variant frontotemporal dementia and semantic variant primary progressive aphasia (also called semantic dementia) are two clinical variants of frontotemporal dementia with overlapping but distinct anatomical substrates known to cause profound changes in decision-making. We investigated whether abnormal decision-making in these syndromes could be more precisely characterized in terms of dissociable abnormalities in patients' subjective evaluations of valence (positive versus negative outcome) and of time (present versus future outcome). We presented 28 patients with behavioural variant frontotemporal dementia, 14 patients with semantic variant primary progressive aphasia, 25 patients with Alzheimer's disease (as disease controls), and 61 healthy older control subjects with experimental tasks assaying loss aversion and delay discounting. In general linear models controlling for age, gender, education and Mini-Mental State Examination score, patients with behavioural variant frontotemporal dementia were less averse to losses than control subjects (P < 0.001), while patients with semantic variant primary progressive aphasia discounted delayed rewards more steeply than controls (P = 0.019). There was no relationship between loss aversion and delay discounting across the sample, nor in any of the subgroups. These findings suggest that abnormal behaviours in neurodegenerative disease may result from the disruption of either of two dissociable neural processes for evaluating the outcomes of action. More broadly, these findings suggest a role for computational methods to supplement traditional qualitative characterizations in the differential diagnosis of neuropsychiatric disorders.

  14. Withdrawal of inhaled corticosteroids can be safe in COPD patients at low risk of exacerbation: a real-life study on the appropriateness of treatment in moderate COPD patients (OPTIMO)

    PubMed Central

    2014-01-01

    Background It has been suggested that withdrawal of inhaled corticosteroids (ICS) in COPD patients on maintenance treatment results in deterioration of symptoms, lung function and exacerbations. The aim of this real-life, prospective, multicentric study was to investigate whether withdrawal of ICS in COPD patients at low risk of exacerbation is linked to a deterioration in lung function and symptoms and to a higher frequency of exacerbations. Methods 914 COPD patients, on maintenance therapy with bronchodilators and ICS, FEV1>50% predicted, and <2 exacerbations/year were recruited. Upon decision of the primary physicians, 59% of patients continued their ICS treatment whereas in 41% of patients ICS were withdrawn and regular therapy was continued with long-acting bronchodilators mostly (91% of patients). FEV1, CAT (COPD Assessment Test), and occurrence of exacerbations were measured at the beginning (T0) and at the end (T6) of the 6 months observational period. Results 816 patients (89.3%) concluded the study. FEV1, CAT and exacerbations history were similar in the two groups (ICS and no ICS) at T0 and at T6. We did not observe any deterioration of lung function symptoms, and exacerbation rate between the two groups at T0 and T6. Conclusions We conclude that the withdrawal of ICS, in COPD patients at low risk of exacerbation, can be safe provided that patients are left on maintenance treatment with long-acting bronchodilators. PMID:25005873

  15. Connected speech production in three variants of primary progressive aphasia

    PubMed Central

    Henry, Maya L.; Besbris, Max; Ogar, Jennifer M.; Dronkers, Nina F.; Jarrold, William; Miller, Bruce L.; Gorno-Tempini, Maria Luisa

    2010-01-01

    Primary progressive aphasia is a clinical syndrome defined by progressive deficits isolated to speech and/or language, and can be classified into non-fluent, semantic and logopenic variants based on motor speech, linguistic and cognitive features. The connected speech of patients with primary progressive aphasia has often been dichotomized simply as ‘fluent’ or ‘non-fluent’, however fluency is a multidimensional construct that encompasses features such as speech rate, phrase length, articulatory agility and syntactic structure, which are not always impacted in parallel. In this study, our first objective was to improve the characterization of connected speech production in each variant of primary progressive aphasia, by quantifying speech output along a number of motor speech and linguistic dimensions simultaneously. Secondly, we aimed to determine the neuroanatomical correlates of changes along these different dimensions. We recorded, transcribed and analysed speech samples for 50 patients with primary progressive aphasia, along with neurodegenerative and normal control groups. Patients were scanned with magnetic resonance imaging, and voxel-based morphometry was used to identify regions where atrophy correlated significantly with motor speech and linguistic features. Speech samples in patients with the non-fluent variant were characterized by slow rate, distortions, syntactic errors and reduced complexity. In contrast, patients with the semantic variant exhibited normal rate and very few speech or syntactic errors, but showed increased proportions of closed class words, pronouns and verbs, and higher frequency nouns, reflecting lexical retrieval deficits. In patients with the logopenic variant, speech rate (a common proxy for fluency) was intermediate between the other two variants, but distortions and syntactic errors were less common than in the non-fluent variant, while lexical access was less impaired than in the semantic variant. Reduced speech rate

  16. Rare ADH Variant Constellations are Specific for Alcohol Dependence

    PubMed Central

    Zuo, Lingjun; Zhang, Heping; Malison, Robert T.; Li, Chiang-Shan R.; Zhang, Xiang-Yang; Wang, Fei; Lu, Lingeng; Lu, Lin; Wang, Xiaoping; Krystal, John H.; Zhang, Fengyu; Deng, Hong-Wen; Luo, Xingguang

    2013-01-01

    Aims: Some of the well-known functional alcohol dehydrogenase (ADH) gene variants (e.g. ADH1B*2, ADH1B*3 and ADH1C*2) that significantly affect the risk of alcohol dependence are rare variants in most populations. In the present study, we comprehensively examined the associations between rare ADH variants [minor allele frequency (MAF) <0.05] and alcohol dependence, with several other neuropsychiatric and neurological disorders as reference. Methods: A total of 49,358 subjects in 22 independent cohorts with 11 different neuropsychiatric and neurological disorders were analyzed, including 3 cohorts with alcohol dependence. The entire ADH gene cluster (ADH7–ADH1C–ADH1B–ADH1A–ADH6–ADH4–ADH5 at Chr4) was imputed in all samples using the same reference panels that included whole-genome sequencing data. We stringently cleaned the phenotype and genotype data to obtain a total of 870 single nucleotide polymorphisms with 0< MAF <0.05 for association analysis. Results: We found that a rare variant constellation across the entire ADH gene cluster was significantly associated with alcohol dependence in European-Americans (Fp1: simulated global P = 0.045), European-Australians (Fp5: global P = 0.027; collapsing: P = 0.038) and African-Americans (Fp5: global P = 0.050; collapsing: P = 0.038), but not with any other neuropsychiatric disease. Association signals in this region came principally from ADH6, ADH7, ADH1B and ADH1C. In particular, a rare ADH6 variant constellation showed a replicable association with alcohol dependence across these three independent cohorts. No individual rare variants were statistically significantly associated with any disease examined after group- and region-wide correction for multiple comparisons. Conclusion: We conclude that rare ADH variants are specific for alcohol dependence. The ADH gene cluster may harbor a causal variant(s) for alcohol dependence. PMID:23019235

  17. Exome arrays capture polygenic rare variant contributions to schizophrenia

    PubMed Central

    Richards, A. L.; Leonenko, G.; Walters, J. T.; Kavanagh, D. H.; Rees, E. G.; Evans, A.; Chambert, K. D.; Moran, J. L.; Goldstein, J.; Neale, B. M.; McCarroll, S. A.; Pocklington, A. J.; Holmans, P. A.; Owen, M. J.; O'Donovan, M. C.

    2016-01-01

    Schizophrenia is a highly heritable disorder. Genome-wide association studies based largely on common alleles have identified over 100 schizophrenia risk loci, but it is also evident from studies of copy number variants (CNVs) and from exome-sequencing studies that rare alleles are also involved. Full characterization of the contribution of rare alleles to the disorder awaits the deployment of sequencing technology in very large sample sizes, meanwhile, as an interim measure, exome arrays allow rare non-synonymous variants to be sampled at a fraction of the cost. In an analysis of exome array data from 13 688 individuals (5585 cases and 8103 controls) from the UK, we found that rare (minor allele frequency < 0.1%) variant association signal was enriched among genes that map to autosomal loci that are genome-wide significant (GWS) in common variant studies of schizophrenia genome-wide association study (PGWAS = 0.01) as well as gene sets known to be enriched for rare variants in sequencing studies (PRARE = 0.026). We also identified the gene-wise equivalent of GWS support for WDR88 (WD repeat-containing protein 88), a gene of unknown function (P = 6.5 × 10−7). Rare alleles represented on exome chip arrays contribute to the genetic architecture of schizophrenia, but as is the case for GWAS, very large studies are required to reveal additional susceptibility alleles for the disorder. PMID:26740555

  18. HGVS Recommendations for the Description of Sequence Variants: 2016 Update.

    PubMed

    den Dunnen, Johan T; Dalgleish, Raymond; Maglott, Donna R; Hart, Reece K; Greenblatt, Marc S; McGowan-Jordan, Jean; Roux, Anne-Francoise; Smith, Timothy; Antonarakis, Stylianos E; Taschner, Peter E M

    2016-06-01

    The consistent and unambiguous description of sequence variants is essential to report and exchange information on the analysis of a genome. In particular, DNA diagnostics critically depends on accurate and standardized description and sharing of the variants detected. The sequence variant nomenclature system proposed in 2000 by the Human Genome Variation Society has been widely adopted and has developed into an internationally accepted standard. The recommendations are currently commissioned through a Sequence Variant Description Working Group (SVD-WG) operating under the auspices of three international organizations: the Human Genome Variation Society (HGVS), the Human Variome Project (HVP), and the Human Genome Organization (HUGO). Requests for modifications and extensions go through the SVD-WG following a standard procedure including a community consultation step. Version numbers are assigned to the nomenclature system to allow users to specify the version used in their variant descriptions. Here, we present the current recommendations, HGVS version 15.11, and briefly summarize the changes that were made since the 2000 publication. Most focus has been on removing inconsistencies and tightening definitions allowing automatic data processing. An extensive version of the recommendations is available online, at http://www.HGVS.org/varnomen. PMID:26931183

  19. Identification and characterization of variant alleles at CODIS STR loci.

    PubMed

    Allor, Catherine; Einum, David D; Scarpetta, Marco

    2005-09-01

    Short tandem repeat (STR) profiles from 32,671 individuals generated by the ABI Profiler Plus and Cofiler systems were screened for variant alleles not represented within manufacturer-provided allelic ladders. A total of 85 distinct variants were identified at 12 of the 13 CODIS loci, most of which involve a truncated tetranucleotide repeat unit. Twelve novel alleles, identified at D3S1358, FGA, D18S51, D5S818, D7S820 and TPOX, were confirmed by nucleotide sequence analysis and include both insertions and deletions involving the repeat units themselves as well as DNA flanking the repeat regions. Population genetic data were collected for all variants and frequencies range from 0.0003 (many single observations) to 0.0042 (D7S820 '10.3' in North American Hispanics). In total, the variant alleles identified in this study are carried by 1.6% of the estimated 1 million individuals tested annually in the U.S. for the purposes of parentage resolution. A paternity case involving a recombination event of paternal origin is presented and demonstrates how variant alleles can significantly strengthen the genetic evidence in troublesome cases. In such instances, increased costs and turnaround time associated with additional testing may be eliminated.

  20. Canine parvovirus: the worldwide occurrence of antigenic variants.

    PubMed

    Miranda, Carla; Thompson, Gertrude

    2016-09-01

    The most important enteric virus infecting canids is canine parvovirus type 2 (CPV-2). CPV is the aetiologic agent of a contagious disease, mainly characterized by clinical gastroenteritis signs in younger dogs. CPV-2 emerged as a new virus in the late 1970s, which could infect domestic dogs, and became distributed in the global dog population within 2 years. A few years later, the virus's original type was replaced by a new genetic and antigenic variant, called CPV-2a. Around 1984 and 2000, virus variants with the single change to Asp or Glu in the VP2 residue 426 were detected (sometimes termed CPV-2b and -2c). The genetic and antigenic changes in the variants have also been correlated with changes in their host range; in particular, in the ability to replicate in cats and also host range differences in canine and other tissue culture cells. CPV-2 variants have been circulating among wild carnivores and have been well-documented in several countries around the world. Here, we have reviewed and summarized the current information about the worldwide distribution and evolution of CPV-2 variants since they emerged, as well as the host ranges they are associated with. PMID:27389721

  1. Common genetic variants influence human subcortical brain structures.

    PubMed

    Hibar, Derrek P; Stein, Jason L; Renteria, Miguel E; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S; Armstrong, Nicola J; Bernard, Manon; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brown, Andrew A; Chakravarty, M Mallar; Chen, Qiang; Ching, Christopher R K; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Olde Loohuis, Loes M; Luciano, Michelle; Macare, Christine; Mather, Karen A; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rose, Emma J; Salami, Alireza; Sämann, Philipp G; Schmaal, Lianne; Schork, Andrew J; Shin, Jean; Strike, Lachlan T; Teumer, Alexander; van Donkelaar, Marjolein M J; van Eijk, Kristel R; Walters, Raymond K; Westlye, Lars T; Whelan, Christopher D; Winkler, Anderson M; Zwiers, Marcel P; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M H; Hartberg, Cecilie B; Haukvik, Unn K; Heister, Angelien J G A M; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C M; Lopez, Lorna M; Makkinje, Remco R R; Matarin, Mar; Naber, Marlies A M; McKay, D Reese; Needham, Margaret; Nugent, Allison C; Pütz, Benno; Royle, Natalie A; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S L; van Hulzen, Kimm J E; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A; Bastin, Mark E; Brodaty, Henry; Bulayeva, Kazima B; Carless, Melanie A; Cichon, Sven; Corvin, Aiden; Curran, Joanne E; Czisch, Michael; de Zubicaray, Greig I; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Fedko, Iryna O; Ferrucci, Luigi; Foroud, Tatiana M; Fox, Peter T; Fukunaga, Masaki; Gibbs, J Raphael; Göring, Harald H H; Green, Robert C; Guelfi, Sebastian; Hansell, Narelle K; Hartman, Catharina A; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G; Heslenfeld, Dirk J; Hoekstra, Pieter J; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Liu, Xinmin; Longo, Dan L; McMahon, Katie L; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W; Mostert, Jeanette C; Mühleisen, Thomas W; Nalls, Michael A; Nichols, Thomas E; Nilsson, Lars G; Nöthen, Markus M; Ohi, Kazutaka; Olvera, Rene L; Perez-Iglesias, Rocio; Pike, G Bruce; Potkin, Steven G; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D; Rujescu, Dan; Schnell, Knut; Schofield, Peter R; Smith, Colin; Steen, Vidar M; Sussmann, Jessika E; Thalamuthu, Anbupalam; Toga, Arthur W; Traynor, Bryan J; Troncoso, Juan; Turner, Jessica A; Valdés Hernández, Maria C; van 't Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J A; van Tol, Marie-Jose; Veltman, Dick J; Wassink, Thomas H; Westman, Eric; Zielke, Ronald H; Zonderman, Alan B; Ashbrook, David G; Hager, Reinmar; Lu, Lu; McMahon, Francis J; Morris, Derek W; Williams, Robert W; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Cahn, Wiepke; Calhoun, Vince D; Cavalleri, Gianpiero L; Crespo-Facorro, Benedicto; Dale, Anders M; Davies, Gareth E; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C; Espeseth, Thomas; Gollub, Randy L; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W J H; Roffman, Joshua L; Sisodiya, Sanjay M; Smoller, Jordan W; van Bokhoven, Hans; van Haren, Neeltje E M; Völzke, Henry; Walter, Henrik; Weiner, Michael W; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A; Blangero, John; Boomsma, Dorret I; Brouwer, Rachel M; Cannon, Dara M; Cookson, Mark R; de Geus, Eco J C; Deary, Ian J; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E; Francks, Clyde; Glahn, David C; Grabe, Hans J; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E; Jönsson, Erik G; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M; Ophoff, Roel A; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S; Saykin, Andrew J; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M; Weale, Michael E; Weinberger, Daniel R; Adams, Hieab H H; Launer, Lenore J; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L; Becker, James T; Yanek, Lisa; van der Lee, Sven J; Ebling, Maritza; Fischl, Bruce; Longstreth, W T; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N; van Duijn, Cornelia M; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M Arfan; Martin, Nicholas G; Wright, Margaret J; Schumann, Gunter; Franke, Barbara; Thompson, Paul M; Medland, Sarah E

    2015-04-01

    The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

  2. Common genetic variants influence human subcortical brain structures.

    PubMed

    Hibar, Derrek P; Stein, Jason L; Renteria, Miguel E; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S; Armstrong, Nicola J; Bernard, Manon; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brown, Andrew A; Chakravarty, M Mallar; Chen, Qiang; Ching, Christopher R K; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Olde Loohuis, Loes M; Luciano, Michelle; Macare, Christine; Mather, Karen A; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rose, Emma J; Salami, Alireza; Sämann, Philipp G; Schmaal, Lianne; Schork, Andrew J; Shin, Jean; Strike, Lachlan T; Teumer, Alexander; van Donkelaar, Marjolein M J; van Eijk, Kristel R; Walters, Raymond K; Westlye, Lars T; Whelan, Christopher D; Winkler, Anderson M; Zwiers, Marcel P; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M H; Hartberg, Cecilie B; Haukvik, Unn K; Heister, Angelien J G A M; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C M; Lopez, Lorna M; Makkinje, Remco R R; Matarin, Mar; Naber, Marlies A M; McKay, D Reese; Needham, Margaret; Nugent, Allison C; Pütz, Benno; Royle, Natalie A; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S L; van Hulzen, Kimm J E; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A; Bastin, Mark E; Brodaty, Henry; Bulayeva, Kazima B; Carless, Melanie A; Cichon, Sven; Corvin, Aiden; Curran, Joanne E; Czisch, Michael; de Zubicaray, Greig I; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Fedko, Iryna O; Ferrucci, Luigi; Foroud, Tatiana M; Fox, Peter T; Fukunaga, Masaki; Gibbs, J Raphael; Göring, Harald H H; Green, Robert C; Guelfi, Sebastian; Hansell, Narelle K; Hartman, Catharina A; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G; Heslenfeld, Dirk J; Hoekstra, Pieter J; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Liu, Xinmin; Longo, Dan L; McMahon, Katie L; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W; Mostert, Jeanette C; Mühleisen, Thomas W; Nalls, Michael A; Nichols, Thomas E; Nilsson, Lars G; Nöthen, Markus M; Ohi, Kazutaka; Olvera, Rene L; Perez-Iglesias, Rocio; Pike, G Bruce; Potkin, Steven G; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D; Rujescu, Dan; Schnell, Knut; Schofield, Peter R; Smith, Colin; Steen, Vidar M; Sussmann, Jessika E; Thalamuthu, Anbupalam; Toga, Arthur W; Traynor, Bryan J; Troncoso, Juan; Turner, Jessica A; Valdés Hernández, Maria C; van 't Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J A; van Tol, Marie-Jose; Veltman, Dick J; Wassink, Thomas H; Westman, Eric; Zielke, Ronald H; Zonderman, Alan B; Ashbrook, David G; Hager, Reinmar; Lu, Lu; McMahon, Francis J; Morris, Derek W; Williams, Robert W; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Cahn, Wiepke; Calhoun, Vince D; Cavalleri, Gianpiero L; Crespo-Facorro, Benedicto; Dale, Anders M; Davies, Gareth E; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C; Espeseth, Thomas; Gollub, Randy L; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W J H; Roffman, Joshua L; Sisodiya, Sanjay M; Smoller, Jordan W; van Bokhoven, Hans; van Haren, Neeltje E M; Völzke, Henry; Walter, Henrik; Weiner, Michael W; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A; Blangero, John; Boomsma, Dorret I; Brouwer, Rachel M; Cannon, Dara M; Cookson, Mark R; de Geus, Eco J C; Deary, Ian J; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E; Francks, Clyde; Glahn, David C; Grabe, Hans J; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E; Jönsson, Erik G; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M; Ophoff, Roel A; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S; Saykin, Andrew J; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M; Weale, Michael E; Weinberger, Daniel R; Adams, Hieab H H; Launer, Lenore J; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L; Becker, James T; Yanek, Lisa; van der Lee, Sven J; Ebling, Maritza; Fischl, Bruce; Longstreth, W T; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N; van Duijn, Cornelia M; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M Arfan; Martin, Nicholas G; Wright, Margaret J; Schumann, Gunter; Franke, Barbara; Thompson, Paul M; Medland, Sarah E

    2015-04-01

    The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction. PMID:25607358

  3. De novo variants in sporadic cases of childhood onset schizophrenia

    PubMed Central

    Ambalavanan, Amirthagowri; Girard, Simon L; Ahn, Kwangmi; Zhou, Sirui; Dionne-Laporte, Alexandre; Spiegelman, Dan; Bourassa, Cynthia V; Gauthier, Julie; Hamdan, Fadi F; Xiong, Lan; Dion, Patrick A; Joober, Ridha; Rapoport, Judith; Rouleau, Guy A

    2016-01-01

    Childhood-onset schizophrenia (COS), defined by the onset of illness before age 13 years, is a rare severe neurodevelopmental disorder of unknown etiology. Recently, sequencing studies have identified rare, potentially causative de novo variants in sporadic cases of adult-onset schizophrenia and autism. In this study, we performed exome sequencing of 17 COS trios in order to test whether de novo variants could contribute to this disease. We identified 20 de novo variants in 17 COS probands, which is consistent with the de novo mutation rate reported in the adult form of the disease. Interestingly, the missense de novo variants in COS have a high likelihood for pathogenicity and were enriched for genes that are less tolerant to variants. Among the genes found disrupted in our study, SEZ6, RYR2, GPR153, GTF2IRD1, TTBK1 and ITGA6 have been previously linked to neuronal function or to psychiatric disorders, and thus may be considered as COS candidate genes. PMID:26508570

  4. [Specificities of the logopenic variant of primary progressive aphasia].

    PubMed

    Magnin, E; Teichmann, M; Martinaud, O; Moreaud, O; Ryff, I; Belliard, S; Pariente, J; Moulin, T; Vandel, P; Démonet, J-F

    2015-01-01

    The logopenic variant of primary progressive aphasia is a syndrome with neuropsychological and linguistic specificities, including phonological loop impairment for which diagnosis is currently mainly based on the exclusion of the two other variants, semantic and nonfluent/agrammatic primary progressive aphasia. The syndrome may be underdiagnosed due (1) to mild language difficulties during the early stages of the disease or (2) to being mistaken for mild cognitive impairment or Alzheimer's disease when the evaluation of episodic memory is based on verbal material and (3) finally, it is not uncommon that the disorders are attributed to psychiatric co-morbidities such as, for example, anxiety. Moreover, compared to other variants of primary progressive aphasia, brain abnormalities are different. The left temporoparietal junction is initially affected. Neuropathology and biomarkers (cerebrospinal fluid, molecular amyloid nuclear imaging) frequently reveal Alzheimer's disease. Consequently this variant of primary progressive aphasia does not fall under the traditional concept of frontotemporal lobar degeneration. These distinctive features highlight the utility of correct diagnosis, classification, and use of biomarkers to show the neuropathological processes underlying logopenic primary progressive aphasia. The logopenic variant of primary progressive aphasia is a specific form of Alzheimer's disease frequently presenting a rapid decline; specific linguistic therapies are needed. Further investigation of this syndrome is needed to refine screening, improve diagnostic criteria and better understand the epidemiology and the biological mechanisms involved.

  5. De novo variants in sporadic cases of childhood onset schizophrenia.

    PubMed

    Ambalavanan, Amirthagowri; Girard, Simon L; Ahn, Kwangmi; Zhou, Sirui; Dionne-Laporte, Alexandre; Spiegelman, Dan; Bourassa, Cynthia V; Gauthier, Julie; Hamdan, Fadi F; Xiong, Lan; Dion, Patrick A; Joober, Ridha; Rapoport, Judith; Rouleau, Guy A

    2016-06-01

    Childhood-onset schizophrenia (COS), defined by the onset of illness before age 13 years, is a rare severe neurodevelopmental disorder of unknown etiology. Recently, sequencing studies have identified rare, potentially causative de novo variants in sporadic cases of adult-onset schizophrenia and autism. In this study, we performed exome sequencing of 17 COS trios in order to test whether de novo variants could contribute to this disease. We identified 20 de novo variants in 17 COS probands, which is consistent with the de novo mutation rate reported in the adult form of the disease. Interestingly, the missense de novo variants in COS have a high likelihood for pathogenicity and were enriched for genes that are less tolerant to variants. Among the genes found disrupted in our study, SEZ6, RYR2, GPR153, GTF2IRD1, TTBK1 and ITGA6 have been previously linked to neuronal function or to psychiatric disorders, and thus may be considered as COS candidate genes. PMID:26508570

  6. Exome arrays capture polygenic rare variant contributions to schizophrenia.

    PubMed

    Richards, A L; Leonenko, G; Walters, J T; Kavanagh, D H; Rees, E G; Evans, A; Chambert, K D; Moran, J L; Goldstein, J; Neale, B M; McCarroll, S A; Pocklington, A J; Holmans, P A; Owen, M J; O'Donovan, M C

    2016-03-01

    Schizophrenia is a highly heritable disorder. Genome-wide association studies based largely on common alleles have identified over 100 schizophrenia risk loci, but it is also evident from studies of copy number variants (CNVs) and from exome-sequencing studies that rare alleles are also involved. Full characterization of the contribution of rare alleles to the disorder awaits the deployment of sequencing technology in very large sample sizes, meanwhile, as an interim measure, exome arrays allow rare non-synonymous variants to be sampled at a fraction of the cost. In an analysis of exome array data from 13 688 individuals (5585 cases and 8103 controls) from the UK, we found that rare (minor allele frequency < 0.1%) variant association signal was enriched among genes that map to autosomal loci that are genome-wide significant (GWS) in common variant studies of schizophrenia genome-wide association study (PGWAS = 0.01) as well as gene sets known to be enriched for rare variants in sequencing studies (PRARE = 0.026). We also identified the gene-wise equivalent of GWS support for WDR88 (WD repeat-containing protein 88), a gene of unknown function (P = 6.5 × 10(-7)). Rare alleles represented on exome chip arrays contribute to the genetic architecture of schizophrenia, but as is the case for GWAS, very large studies are required to reveal additional susceptibility alleles for the disorder. PMID:26740555

  7. Canine parvovirus: the worldwide occurrence of antigenic variants.

    PubMed

    Miranda, Carla; Thompson, Gertrude

    2016-09-01

    The most important enteric virus infecting canids is canine parvovirus type 2 (CPV-2). CPV is the aetiologic agent of a contagious disease, mainly characterized by clinical gastroenteritis signs in younger dogs. CPV-2 emerged as a new virus in the late 1970s, which could infect domestic dogs, and became distributed in the global dog population within 2 years. A few years later, the virus's original type was replaced by a new genetic and antigenic variant, called CPV-2a. Around 1984 and 2000, virus variants with the single change to Asp or Glu in the VP2 residue 426 were detected (sometimes termed CPV-2b and -2c). The genetic and antigenic changes in the variants have also been correlated with changes in their host range; in particular, in the ability to replicate in cats and also host range differences in canine and other tissue culture cells. CPV-2 variants have been circulating among wild carnivores and have been well-documented in several countries around the world. Here, we have reviewed and summarized the current information about the worldwide distribution and evolution of CPV-2 variants since they emerged, as well as the host ranges they are associated with.

  8. Common genetic variants influence human subcortical brain structures

    PubMed Central

    Hibar, Derrek P.; Stein, Jason L.; Renteria, Miguel E.; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S.; Armstrong, Nicola J.; Bernard, Manon; Bohlken, Marc M.; Boks, Marco P.; Bralten, Janita; Brown, Andrew A.; Chakravarty, M. Mallar; Chen, Qiang; Ching, Christopher R. K.; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L.; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J.; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H.; Olde Loohuis, Loes M.; Luciano, Michelle; Macare, Christine; Mather, Karen A.; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L.; Roiz-Santiañez, Roberto; Rose, Emma J.; Salami, Alireza; Sämann, Philipp G.; Schmaal, Lianne; Schork, Andrew J.; Shin, Jean; Strike, Lachlan T.; Teumer, Alexander; van Donkelaar, Marjolein M. J.; van Eijk, Kristel R.; Walters, Raymond K.; Westlye, Lars T.; Whelan, Christopher D.; Winkler, Anderson M.; Zwiers, Marcel P.; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M. H.; Hartberg, Cecilie B.; Haukvik, Unn K.; Heister, Angelien J. G. A. M.; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C. M.; Lopez, Lorna M.; Makkinje, Remco R. R.; Matarin, Mar; Naber, Marlies A. M.; McKay, D. Reese; Needham, Margaret; Nugent, Allison C.; Pütz, Benno; Royle, Natalie A.; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S. L.; van Hulzen, Kimm J. E.; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A.; Bastin, Mark E.; Brodaty, Henry; Bulayeva, Kazima B.; Carless, Melanie A.; Cichon, Sven; Corvin, Aiden; Curran, Joanne E.; Czisch, Michael; de Zubicaray, Greig I.; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D.; Erk, Susanne; Fedko, Iryna O.; Ferrucci, Luigi; Foroud, Tatiana M.; Fox, Peter T.; Fukunaga, Masaki; Gibbs, J. Raphael; Göring, Harald H. H.; Green, Robert C.; Guelfi, Sebastian; Hansell, Narelle K.; Hartman, Catharina A.; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G.; Heslenfeld, Dirk J.; Hoekstra, Pieter J.; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R.; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W.; Kochunov, Peter; Kwok, John B.; Lawrie, Stephen M.; Liu, Xinmin; Longo, Dan L.; McMahon, Katie L.; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W.; Mostert, Jeanette C.; Mühleisen, Thomas W.; Nalls, Michael A.; Nichols, Thomas E.; Nilsson, Lars G.; Nöthen, Markus M.; Ohi, Kazutaka; Olvera, Rene L.; Perez-Iglesias, Rocio; Pike, G. Bruce; Potkin, Steven G.; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D.; Rujescu, Dan; Schnell, Knut; Schofield, Peter R.; Smith, Colin; Steen, Vidar M.; Sussmann, Jessika E.; Thalamuthu, Anbupalam; Toga, Arthur W.; Traynor, Bryan J.; Troncoso, Juan; Turner, Jessica A.; Valdés Hernández, Maria C.; van ’t Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J. A.; van Tol, Marie-Jose; Veltman, Dick J.; Wassink, Thomas H.; Westman, Eric; Zielke, Ronald H.; Zonderman, Alan B.; Ashbrook, David G.; Hager, Reinmar; Lu, Lu; McMahon, Francis J.; Morris, Derek W.; Williams, Robert W.; Brunner, Han G.; Buckner, Randy L.; Buitelaar, Jan K.; Cahn, Wiepke; Calhoun, Vince D.; Cavalleri, Gianpiero L.; Crespo-Facorro, Benedicto; Dale, Anders M.; Davies, Gareth E.; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C.; Espeseth, Thomas; Gollub, Randy L.; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S.; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W. J. H.; Roffman, Joshua L.; Sisodiya, Sanjay M.; Smoller, Jordan W.; van Bokhoven, Hans; van Haren, Neeltje E. M.; Völzke, Henry; Walter, Henrik; Weiner, Michael W.; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A.; Blangero, John; Boomsma, Dorret I.; Brouwer, Rachel M.; Cannon, Dara M.; Cookson, Mark R.; de Geus, Eco J. C.; Deary, Ian J.; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E.; Francks, Clyde; Glahn, David C.; Grabe, Hans J.; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E.; Jönsson, Erik G.; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S.; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M.; Ophoff, Roel A.; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S.; Saykin, Andrew J.; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M.; Weale, Michael E.; Weinberger, Daniel R.; Adams, Hieab H. H.; Launer, Lenore J.; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L.; Becker, James T.; Yanek, Lisa; van der Lee, Sven J.; Ebling, Maritza; Fischl, Bruce; Longstreth, W. T.; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N.; van Duijn, Cornelia M.; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C.; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M. Arfan; Martin, Nicholas G.; Wright, Margaret J.; Schumann, Gunter; Franke, Barbara; Thompson, Paul M.; Medland, Sarah E.

    2015-01-01

    The highly complex structure of the human brain is strongly shaped by genetic influences1. Subcortical brain regions form circuits with cortical areas to coordinate movement2, learning, memory3 and motivation4, and altered circuits can lead to abnormal behaviour and disease2. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume5 and intracranial volume6. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10−33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability inhuman brain development, and may help to determine mechanisms of neuropsychiatric dysfunction. PMID:25607358

  9. [Genetic variants associated to male infertility in Mexican patients].

    PubMed

    Piña-Aguilar, Raúl Eduardo; Chima-Galán, María del Carmen; Yerena-de-vega, María de la Concepción A; Regalado-Hernández, Miguel Angel; Sánchez-Guerrero, Cecilia; García-Ortiz, Liliana; Santillán-Hernández, Yuritzi; Moreno-García, Jesús Daniel

    2013-05-01

    Recently Mexican Federation of Obstetrics and Gynecology Colleges (Federación Mexicana de Colegios de Obstetricia y Ginecologia, FEMECOG) published the Mexican guideline forthe management of male infertility, which suggests performing genetic laboratory tests as part of diagnosis and management of infertile patients and states that these should receive genetic counseling. This paper reviews the genetic approach proposed by Mexican guideline. A systematic review of medical literature was performed in Pubmed and Web of Knowledge from 1980 to 2012 in order to find reports of genetic variants associated to male infertility in Mexican patients. Also it is discussed the current knowledge of these variants, their clinical implications and finally the guidelines and recommendations for their molecular diagnosis. Most genetic variants in Mexican infertile patients are chromosome abnormalities. In relation to other variants there is only a report of Y chromosome microdeletions, repeated CAG in androgen receptor and more common mutations in CFTR, and other article reporting mutations in CFTR in patients with congenital absence of vas deferens. Little is known about the genetics of Mexican infertile patients apart from chromosome abnormalities. However, the contribution of genetics as etiology of male infertility is taking more relevance and currently the consensual management of infertile male should include the screening of genetic background. This review pretends to be a quick guide for clinicians who want to know about reports of genetic variants related to male infertility in Mexican population and how to approach their diagnosis.

  10. Assessment of functional effects of unclassified genetic variants.

    PubMed

    Couch, Fergus J; Rasmussen, Lene Juel; Hofstra, Robert; Monteiro, Alvaro N A; Greenblatt, Marc S; de Wind, Niels

    2008-11-01

    Inherited predisposition to disease is often linked to reduced activity of a disease associated gene product. Thus, quantitation of the influence of inherited variants on gene function can potentially be used to predict the disease relevance of these variants. While many disease genes have been extensively characterized at the functional level, few assays based on functional properties of the encoded proteins have been established for the purpose of predicting the contribution of rare inherited variants to disease. Much of the difficulty in establishing predictive functional assays stems from the technical complexity of the assays. However, perhaps the most challenging aspect of functional assay development for clinical testing purposes is the absolute requirement for validation of the sensitivity and specificity of the assays and the determination of positive predictive values (PPVs) and negative predictive values (NPVs) of the assays relative to a "gold standard" measure of disease predisposition. In this commentary, we provide examples of some of the functional assays under development for several cancer predisposition genes (BRCA1, BRCA2, CDKN2A, and mismatch repair [MMR] genes MLH1, MSH2, MSH6, and PMS2) and present a detailed review of the issues associated with functional assay development. We conclude that validation is paramount for all assays that will be used for clinical interpretation of inherited variants of any gene, but note that in certain circumstances information derived from incompletely validated assays may be valuable for classification of variants for clinical purposes when used to supplement data derived from other sources. PMID:18951449

  11. Variants of the melanocortin-1 receptor: do they matter clinically?

    PubMed

    Haddadeen, Ciara; Lai, Chester; Cho, Shin-Young; Healy, Eugene

    2015-01-01

    The melanocortin 1 receptor (MC1R) gene encodes for a seven-pass transmembrane receptor primarily expressed on melanocytes and melanoma cells. Single nucleotide polymorphisms (SNPs, also termed variants) in MC1R frequently cause red hair, fair skin and are associated with melanoma and keratinocyte-derived skin cancer development. Activation of wild-type (WT) MC1R in skin assists cutaneous photoprotection whereas reduced MC1R signalling, seen with MC1R variants, impairs ultraviolet radiation (UVR)-protective responses. As ancestral humans migrated out of Africa, the evolutionary advantage of MC1R variants may have related to improved cutaneous vitamin D synthesis and higher birthweight reported with certain MC1R variants. Reduced photoprotection secondary to MC1R dysfunction involves pigmentary and non-pigmentary mechanisms (reduced DNA repair, effects on cell proliferation and possibly immunological parameters), leading to clonal expansion of mutated cells within skin and subsequent carcinogenesis. Recent investigations suggest an association between MC1R genotype and vitiligo, with preliminary evidence that a MC1R agonist, [Nle4-D-Phe7]-alpha-MSH, in combination with UVB, assists repigmentation. Future development of compounds to correct defective MC1R responses secondary to MC1R variants could result in photoprotective benefits for fair-skinned individuals and reduce their skin cancer risk. PMID:25219681

  12. VCF-Miner: GUI-based application for mining variants and annotations stored in VCF files.

    PubMed

    Hart, Steven N; Duffy, Patrick; Quest, Daniel J; Hossain, Asif; Meiners, Mike A; Kocher, Jean-Pierre

    2016-03-01

    Next-generation sequencing platforms are widely used to discover variants associated with disease. The processing of sequencing data involves read alignment, variant calling, variant annotation and variant filtering. The standard file format to hold variant calls is the variant call format (VCF) file. According to the format specifications, any arbitrary annotation can be added to the VCF file for downstream processing. However, most downstream analysis programs disregard annotations already present in the VCF and re-annotate variants using the annotation provided by that particular program. This precludes investigators who have collected information on variants from literature or other sources from including these annotations in the filtering and mining of variants. We have developed VCF-Miner, a graphical user interface-based stand-alone tool, to mine variants and annotation stored in the VCF. Powered by a MongoDB database engine, VCF-Miner enables the stepwise trimming of non-relevant variants. The grouping feature implemented in VCF-Miner can be used to identify somatic variants by contrasting variants in tumor and in normal samples or to identify recessive/dominant variants in family studies. It is not limited to human data, but can also be extended to include non-diploid organisms. It also supports copy number or any other variant type supported by the VCF specification. VCF-Miner can be used on a personal computer or large institutional servers and is freely available for download from http://bioinformaticstools.mayo.edu/research/vcf-miner/. PMID:26210358

  13. VCF-Miner: GUI-based application for mining variants and annotations stored in VCF files

    PubMed Central

    Hart, Steven N.; Duffy, Patrick; Quest, Daniel J.; Hossain, Asif; Meiners, Mike A

    2016-01-01

    Next-generation sequencing platforms are widely used to discover variants associated with disease. The processing of sequencing data involves read alignment, variant calling, variant annotation and variant filtering. The standard file format to hold variant calls is the variant call format (VCF) file. According to the format specifications, any arbitrary annotation can be added to the VCF file for downstream processing. However, most downstream analysis programs disregard annotations already present in the VCF and re-annotate variants using the annotation provided by that particular program. This precludes investigators who have collected information on variants from literature or other sources from including these annotations in the filtering and mining of variants. We have developed VCF-Miner, a graphical user interface-based stand-alone tool, to mine variants and annotation stored in the VCF. Powered by a MongoDB database engine, VCF-Miner enables the stepwise trimming of non-relevant variants. The grouping feature implemented in VCF-Miner can be used to identify somatic variants by contrasting variants in tumor and in normal samples or to identify recessive/dominant variants in family studies. It is not limited to human data, but can also be extended to include non-diploid organisms. It also supports copy number or any other variant type supported by the VCF specification. VCF-Miner can be used on a personal computer or large institutional servers and is freely available for download from http://bioinformaticstools.mayo.edu/research/vcf-miner/. PMID:26210358

  14. VARIANT: Command Line, Web service and Web interface for fast and accurate functional characterization of variants found by Next-Generation Sequencing

    PubMed Central

    Medina, Ignacio; De Maria, Alejandro; Bleda, Marta; Salavert, Francisco; Alonso, Roberto; Gonzalez, Cristina Y.; Dopazo, Joaquin

    2012-01-01

    The massive use of Next-Generation Sequencing (NGS) technologies is uncovering an unexpected amount of variability. The functional characterization of such variability, particularly in the most common form of variation found, the Single Nucleotide Variants (SNVs), has become a priority that needs to be addressed in a systematic way. VARIANT (VARIant ANalyis Tool) reports information on the variants found that include consequence type and annotations taken from different databases and repositories (SNPs and variants from dbSNP and 1000 genomes, and disease-related variants from the Genome-Wide Association Study (GWAS) catalog, Online Mendelian Inheritance in Man (OMIM), Catalog of Somatic Mutations in Cancer (COSMIC) mutations, etc). VARIANT also produces a rich variety of annotations that include information on the regulatory (transcription factor or miRNA-binding sites, etc.) or structural roles, or on the selective pressures on the sites affected by the variation. This information allows extending the conventional reports beyond the coding regions and expands the knowledge on the contribution of non-coding or synonymous variants to the phenotype studied. Contrarily to other tools, VARIANT uses a remote database and operates through efficient RESTful Web Services that optimize search and transaction operations. In this way, local problems of installation, update or disk size limitations are overcome without the need of sacrifice speed (thousands of variants are processed per minute). VARIANT is available at: http://variant.bioinfo.cipf.es. PMID:22693211

  15. TREM2 variants: new keys to decipher Alzheimer disease pathogenesis.

    PubMed

    Colonna, Marco; Wang, Yaming

    2016-04-01

    Genome-wide association studies have identified rare variants of the gene that encodes triggering receptor expressed on myeloid cells 2 (TREM2) - an immune receptor that is found in brain microglia - as risk factors for non-familial Alzheimer disease (AD). Furthermore, animal studies have indicated that microglia have an important role in the brain response to amyloid-β (Aβ) plaques and that TREM2 variants may have an impact on such a function. We discuss how TREM2 may control the microglial response to Aβ and its impact on microglial senescence, as well as the interaction of TREM2 with other molecules that are encoded by gene variants associated with AD and the hypothetical consequences of the cleavage of TREM2 from the cell surface.

  16. Grinder Variant System Design and Implementation Based on Ontology

    NASA Astrophysics Data System (ADS)

    Yang, G. H.; Zhang, T. P.

    In order to improve the efficiency of product design and reuse in heterogeneous system of knowledge sharing, this paper introduced the concept of ontology into product variant design, and grinding machine design was as an example. A lot of experience and accumulated knowledge in product design was shared and reused. It is precisely to formulate ontology knowledge such as variant design features and parameter, and applied the software protégé4.3 to construct ontology model, as well as runed resoning on model data information. It developed a set of complete product intelligent system of variant design, which can effectively solve the problem of the repeated design and greatly shorten product development cycle.

  17. Albumin Naskapi variant in North American Indians and Eti Turks.

    PubMed

    Franklin, S G; Wolf, S I; Ozdemir, Y; Yüregir, G T; Isbir, T; Blumberg, B S

    1980-09-01

    Both conventional polyacrylamide gel electrophoresis and a new type of electrophoretic screening procedure indicate that the polymorphic albumin variants Naskapi, found chiefly in the Naskapi Indians of Quebec, and Mersin, found in the Eti Turks of southeastern Turkey, are molecularly identical or very similar and that the amino acid substitution site in these variants is located between residues 330 and 446. This discovery is consistent with a genetic relationship between the Eti Turks and American Indians. We also report a new variant found in the Eti Turks, albumin Adana, which migrates similarly to albumin B on conventional gels but which our new system shows to differ from the common albumin A and albumin B by a substitution between residues 549 and 585.

  18. KD4v: Comprehensible Knowledge Discovery System for Missense Variant.

    PubMed

    Luu, Tien-Dao; Rusu, Alin; Walter, Vincent; Linard, Benjamin; Poidevin, Laetitia; Ripp, Raymond; Moulinier, Luc; Muller, Jean; Raffelsberger, Wolfgang; Wicker, Nicolas; Lecompte, Odile; Thompson, Julie D; Poch, Olivier; Nguyen, Hoan

    2012-07-01

    A major challenge in the post-genomic era is a better understanding of how human genetic alterations involved in disease affect the gene products. The KD4v (Comprehensible Knowledge Discovery System for Missense Variant) server allows to characterize and predict the phenotypic effects (deleterious/neutral) of missense variants. The server provides a set of rules learned by Induction Logic Programming (ILP) on a set of missense variants described by conservation, physico-chemical, functional and 3D structure predicates. These rules are interpretable by non-expert humans and are used to accurately predict the deleterious/neutral status of an unknown mutation. The web server is available at http://decrypthon.igbmc.fr/kd4v.

  19. Massively Parallel Functional Analysis of BRCA1 RING Domain Variants

    PubMed Central

    Starita, Lea M.; Young, David L.; Islam, Muhtadi; Kitzman, Jacob O.; Gullingsrud, Justin; Hause, Ronald J.; Fowler, Douglas M.; Parvin, Jeffrey D.; Shendure, Jay; Fields, Stanley

    2015-01-01

    Interpreting variants of uncertain significance (VUS) is a central challenge in medical genetics. One approach is to experimentally measure the functional consequences of VUS, but to date this approach has been post hoc and low throughput. Here we use massively parallel assays to measure the effects of nearly 2000 missense substitutions in the RING domain of BRCA1 on its E3 ubiquitin ligase activity and its binding to the BARD1 RING domain. From the resulting scores, we generate a model to predict the capacities of full-length BRCA1 variants to support homology-directed DNA repair, the essential role of BRCA1 in tumor suppression, and show that it outperforms widely used biological-effect prediction algorithms. We envision that massively parallel functional assays may facilitate the prospective interpretation of variants observed in clinical sequencing. PMID:25823446

  20. KD4v: comprehensible knowledge discovery system for missense variant

    PubMed Central

    Luu, Tien-Dao; Rusu, Alin; Walter, Vincent; Linard, Benjamin; Poidevin, Laetitia; Ripp, Raymond; Moulinier, Luc; Muller, Jean; Raffelsberger, Wolfgang; Wicker, Nicolas; Lecompte, Odile; Thompson, Julie D.; Poch, Olivier; Nguyen, Hoan

    2012-01-01

    A major challenge in the post-genomic era is a better understanding of how human genetic alterations involved in disease affect the gene products. The KD4v (Comprehensible Knowledge Discovery System for Missense Variant) server allows to characterize and predict the phenotypic effects (deleterious/neutral) of missense variants. The server provides a set of rules learned by Induction Logic Programming (ILP) on a set of missense variants described by conservation, physico-chemical, functional and 3D structure predicates. These rules are interpretable by non-expert humans and are used to accurately predict the deleterious/neutral status of an unknown mutation. The web server is available at http://decrypthon.igbmc.fr/kd4v. PMID:22641855

  1. Arylsulfatase A: Relationship of genotype to variant electrophoretic properties

    SciTech Connect

    Park, D.S.; Poretz, R.D.; Ricketts, M.H.; Manowitz, P.

    1996-04-01

    Previous work has shown that specific electrophoretic variants of arylsulfatase A occur more frequently among alcoholic patients than among psychiatric and normal controls. The present study sequenced the gene for two of these electrophoretic variants, IIIa and IIIb. Both contain an A-to-G transition corresponding to substitution of Asn{sub 350} by Ser, with the resulting loss of an N -glycosylation site. The difference in electrophoretic mobility of their gene products is due to a mutation in the IIIb gene resulting in the replacement of Arg{sub 496} by His. Evidence is presented that individuals posessing either of two other electrophoretic variants, Va and Vb, are heterozygous for a normal ASA allele and either a IIIa or IIIb allele, respectively. Thus, the relationship between the phenotype of the electrophoretic banding patterns, IIIa, IIIb, Va, and Vb, and their corresponding genotypes has been elucidated. 18 refs., 5 figs., 1 tab.

  2. Scripps Genome ADVISER: Annotation and Distributed Variant Interpretation SERver

    PubMed Central

    Pham, Phillip H.; Shipman, William J.; Erikson, Galina A.; Schork, Nicholas J.; Torkamani, Ali

    2015-01-01

    Interpretation of human genomes is a major challenge. We present the Scripps Genome ADVISER (SG-ADVISER) suite, which aims to fill the gap between data generation and genome interpretation by performing holistic, in-depth, annotations and functional predictions on all variant types and effects. The SG-ADVISER suite includes a de-identification tool, a variant annotation web-server, and a user interface for inheritance and annotation-based filtration. SG-ADVISER allows users with no bioinformatics expertise to manipulate large volumes of variant data with ease – without the need to download large reference databases, install software, or use a command line interface. SG-ADVISER is freely available at genomics.scripps.edu/ADVISER. PMID:25706643

  3. Sequencing Structural Variants in Cancer for Precision Therapeutics.

    PubMed

    Macintyre, Geoff; Ylstra, Bauke; Brenton, James D

    2016-09-01

    The identification of mutations that guide therapy selection for patients with cancer is now routine in many clinical centres. The majority of assays used for solid tumour profiling use DNA sequencing to interrogate somatic point mutations because they are relatively easy to identify and interpret. Many cancers, however, including high-grade serous ovarian, oesophageal, and small-cell lung cancer, are driven by somatic structural variants that are not measured by these assays. Therefore, there is currently an unmet need for clinical assays that can cheaply and rapidly profile structural variants in solid tumours. In this review we survey the landscape of 'actionable' structural variants in cancer and identify promising detection strategies based on massively-parallel sequencing. PMID:27478068

  4. Human AZU-1 gene, variants thereof and expressed gene products

    DOEpatents

    Chen, Huei-Mei; Bissell, Mina

    2004-06-22

    A human AZU-1 gene, mutants, variants and fragments thereof. Protein products encoded by the AZU-1 gene and homologs encoded by the variants of AZU-1 gene acting as tumor suppressors or markers of malignancy progression and tumorigenicity reversion. Identification, isolation and characterization of AZU-1 and AZU-2 genes localized to a tumor suppressive locus at chromosome 10q26, highly expressed in nonmalignant and premalignant cells derived from a human breast tumor progression model. A recombinant full length protein sequences encoded by the AZU-1 gene and nucleotide sequences of AZU-1 and AZU-2 genes and variant and fragments thereof. Monoclonal or polyclonal antibodies specific to AZU-1, AZU-2 encoded protein and to AZU-1, or AZU-2 encoded protein homologs.

  5. Fire Usage and Ancient Hominin Detoxification Genes: Protective Ancestral Variants Dominate While Additional Derived Risk Variants Appear in Modern Humans

    PubMed Central

    Alink, Gerrit M.; Scherjon, Fulco; MacDonald, Katharine; Smith, Alison C.; Nijveen, Harm; Roebroeks, Wil

    2016-01-01

    Studies of the defence capacity of ancient hominins against toxic substances may contribute importantly to the reconstruction of their niche, including their diets and use of fire. Fire usage implies frequent exposure to hazardous compounds from smoke and heated food, known to affect general health and fertility, probably resulting in genetic selection for improved detoxification. To investigate whether such genetic selection occurred, we investigated the alleles in Neanderthals, Denisovans and modern humans at gene polymorphisms well-known to be relevant from modern human epidemiological studies of habitual tobacco smoke exposure and mechanistic evidence. We compared these with the alleles in chimpanzees and gorillas. Neanderthal and Denisovan hominins predominantly possess gene variants conferring increased resistance to these toxic compounds. Surprisingly, we observed the same in chimpanzees and gorillas, implying that less efficient variants are derived and mainly evolved in modern humans. Less efficient variants are observable from the first early Upper Palaeolithic hunter-gatherers onwards. While not clarifying the deep history of fire use, our results highlight the long-term stability of the genes under consideration despite major changes in the hominin dietary niche. Specifically for detoxification gene variants characterised as deleterious by epidemiological studies, our results confirm the predominantly recent appearance reported for deleterious human gene variants, suggesting substantial impact of recent human population history, including pre-Holocene expansions. PMID:27655273

  6. DNA-based identification of novel bovine casein gene variants.

    PubMed

    Gallinat, J L; Qanbari, S; Drögemüller, C; Pimentel, E C G; Thaller, G; Tetens, J

    2013-01-01

    In cattle, at least 39 variants of the 4 casein proteins (α(S1)-, β-, α(S2)- and κ-casein) have been described to date. Many of these variants are known to affect milk-production traits, cheese-processing properties, and the nutritive value of milk. They also provide valuable information for phylogenetic studies. So far, the majority of studies exploring the genetic variability of bovine caseins considered European taurine cattle breeds and were carried out at the protein level by electrophoretic techniques. This only allows the identification of variants that, due to amino acid exchanges, differ in their electric charge, molecular weight, or isoelectric point. In this study, the open reading frames of the casein genes CSN1S1, CSN2, CSN1S2, and CSN3 of 356 animals belonging to 14 taurine and 3 indicine cattle breeds were sequenced. With this approach, we identified 23 alleles, including 5 new DNA sequence variants, with a predicted effect on the protein sequence. The new variants were only found in indicine breeds and in one local Iranian breed, which has been phenotypically classified as a taurine breed. A multidimensional scaling approach based on available SNP chip data, however, revealed an admixture of taurine and indicine populations in this breed as well as in the local Iranian breed Golpayegani. Specific indicine casein alleles were also identified in a few European taurine breeds, indicating the introgression of indicine breeds into these populations. This study shows the existence of substantial undiscovered genetic variability of bovine casein loci, especially in indicine cattle breeds. The identification of new variants is a valuable tool for phylogenetic studies and investigations into the evolution of the milk protein genes.

  7. Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients.

    PubMed

    Sadovnick, A Dessa; Traboulsee, Anthony L; Bernales, Cecily Q; Ross, Jay P; Forwell, Amanda L; Yee, Irene M; Guillot-Noel, Lena; Fontaine, Bertrand; Cournu-Rebeix, Isabelle; Alcina, Antonio; Fedetz, Maria; Izquierdo, Guillermo; Matesanz, Fuencisla; Hilven, Kelly; Dubois, Bénédicte; Goris, An; Astobiza, Ianire; Alloza, Iraide; Antigüedad, Alfredo; Vandenbroeck, Koen; Akkad, Denis A; Aktas, Orhan; Blaschke, Paul; Buttmann, Mathias; Chan, Andrew; Epplen, Joerg T; Gerdes, Lisa-Ann; Kroner, Antje; Kubisch, Christian; Kümpfel, Tania; Lohse, Peter; Rieckmann, Peter; Zettl, Uwe K; Zipp, Frauke; Bertram, Lars; Lill, Christina M; Fernandez, Oscar; Urbaneja, Patricia; Leyva, Laura; Alvarez-Cermeño, Jose Carlos; Arroyo, Rafael; Garagorri, Aroa M; García-Martínez, Angel; Villar, Luisa M; Urcelay, Elena; Malhotra, Sunny; Montalban, Xavier; Comabella, Manuel; Berger, Thomas; Fazekas, Franz; Reindl, Markus; Schmied, Mascha C; Zimprich, Alexander; Vilariño-Güell, Carles

    2016-01-01

    Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93-1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility. PMID:27194806

  8. Classification of BRCA1 missense variants of unknown clinical significance

    PubMed Central

    Phelan, C; Dapic, V; Tice, B; Favis, R; Kwan, E; Barany, F; Manoukian, S; Radice, P; van der Luijt, R B; van Nesselrooij, B P M; Chenevix-Trench, G; kConFab; Caldes, T; de La Hoya, M; Lindquist, S; Tavtigian, S; Goldgar, D; Borg, A; Narod, S; Monteiro, A

    2005-01-01

    Background: BRCA1 is a tumour suppressor with pleiotropic actions. Germline mutations in BRCA1 are responsible for a large proportion of breast–ovarian cancer families. Several missense variants have been identified throughout the gene but because of lack of information about their impact on the function of BRCA1, predictive testing is not always informative. Classification of missense variants into deleterious/high risk or neutral/low clinical significance is essential to identify individuals at risk. Objective: To investigate a panel of missense variants. Methods and results: The panel was investigated in a comprehensive framework that included (1) a functional assay based on transcription activation; (2) segregation analysis and a method of using incomplete pedigree data to calculate the odds of causality; (3) a method based on interspecific sequence variation. It was shown that the transcriptional activation assay could be used as a test to characterise mutations in the carboxy-terminus region of BRCA1 encompassing residues 1396–1863. Thirteen missense variants (H1402Y, L1407P, H1421Y, S1512I, M1628T, M1628V, T1685I, G1706A, T1720A, A1752P, G1788V, V1809F, and W1837R) were specifically investigated. Conclusions: While individual classification schemes for BRCA1 alleles still present limitations, a combination of several methods provides a more powerful way of identifying variants that are causally linked to a high risk of breast and ovarian cancer. The framework presented here brings these variants nearer to clinical applicability. PMID:15689452

  9. Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients.

    PubMed

    Sadovnick, A Dessa; Traboulsee, Anthony L; Bernales, Cecily Q; Ross, Jay P; Forwell, Amanda L; Yee, Irene M; Guillot-Noel, Lena; Fontaine, Bertrand; Cournu-Rebeix, Isabelle; Alcina, Antonio; Fedetz, Maria; Izquierdo, Guillermo; Matesanz, Fuencisla; Hilven, Kelly; Dubois, Bénédicte; Goris, An; Astobiza, Ianire; Alloza, Iraide; Antigüedad, Alfredo; Vandenbroeck, Koen; Akkad, Denis A; Aktas, Orhan; Blaschke, Paul; Buttmann, Mathias; Chan, Andrew; Epplen, Joerg T; Gerdes, Lisa-Ann; Kroner, Antje; Kubisch, Christian; Kümpfel, Tania; Lohse, Peter; Rieckmann, Peter; Zettl, Uwe K; Zipp, Frauke; Bertram, Lars; Lill, Christina M; Fernandez, Oscar; Urbaneja, Patricia; Leyva, Laura; Alvarez-Cermeño, Jose Carlos; Arroyo, Rafael; Garagorri, Aroa M; García-Martínez, Angel; Villar, Luisa M; Urcelay, Elena; Malhotra, Sunny; Montalban, Xavier; Comabella, Manuel; Berger, Thomas; Fazekas, Franz; Reindl, Markus; Schmied, Mascha C; Zimprich, Alexander; Vilariño-Güell, Carles

    2016-07-07

    Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93-1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.

  10. Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients

    PubMed Central

    Sadovnick, A. Dessa; Traboulsee, Anthony L.; Bernales, Cecily Q.; Ross, Jay P.; Forwell, Amanda L.; Yee, Irene M.; Guillot-Noel, Lena; Fontaine, Bertrand; Cournu-Rebeix, Isabelle; Alcina, Antonio; Fedetz, Maria; Izquierdo, Guillermo; Matesanz, Fuencisla; Hilven, Kelly; Dubois, Bénédicte; Goris, An; Astobiza, Ianire; Alloza, Iraide; Antigüedad, Alfredo; Vandenbroeck, Koen; Akkad, Denis A.; Aktas, Orhan; Blaschke, Paul; Buttmann, Mathias; Chan, Andrew; Epplen, Joerg T.; Gerdes, Lisa-Ann; Kroner, Antje; Kubisch, Christian; Kümpfel, Tania; Lohse, Peter; Rieckmann, Peter; Zettl, Uwe K.; Zipp, Frauke; Bertram, Lars; Lill, Christina M; Fernandez, Oscar; Urbaneja, Patricia; Leyva, Laura; Alvarez-Cermeño, Jose Carlos; Arroyo, Rafael; Garagorri, Aroa M.; García-Martínez, Angel; Villar, Luisa M.; Urcelay, Elena; Malhotra, Sunny; Montalban, Xavier; Comabella, Manuel; Berger, Thomas; Fazekas, Franz; Reindl, Markus; Schmied, Mascha C.; Zimprich, Alexander; Vilariño-Güell, Carles

    2016-01-01

    Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93–1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility. PMID:27194806

  11. Crystallographic variant selection in {alpha}-{beta} brass

    SciTech Connect

    Stanford, N.; Bate, P.S. . E-mail: pete.bate@man.ac.uk

    2005-02-01

    The transformation texture of {alpha}/{beta} brass with a diffusional Widmanstaetten {alpha} growth morphology has been investigated. Electron micrographs and electron backscattered diffraction was used to determine that the orientation relationship between the {beta} phase and the {alpha} associated with nucleation at {beta} grain boundaries was 44.3 deg <1 1 6>. Crystallographic variant selection was observed across those prior {beta}/{beta} grain boundaries, but this has little effect on the transformation texture due to the crystal symmetry. The effect of the crystallographic variant selection on texture is further weakened by nucleation of diffusional transformed {alpha} in the grain interior.

  12. Protective variant for hippocampal atrophy identified by whole exome sequencing.

    PubMed

    Nho, Kwangsik; Kim, Sungeun; Risacher, Shannon L; Shen, Li; Corneveaux, Jason J; Swaminathan, Shanker; Lin, Hai; Ramanan, Vijay K; Liu, Yunlong; Foroud, Tatiana M; Inlow, Mark H; Siniard, Ashley L; Reiman, Rebecca A; Aisen, Paul S; Petersen, Ronald C; Green, Robert C; Jack, Clifford R; Weiner, Michael W; Baldwin, Clinton T; Lunetta, Kathryn L; Farrer, Lindsay A; Furney, Simon J; Lovestone, Simon; Simmons, Andrew; Mecocci, Patrizia; Vellas, Bruno; Tsolaki, Magda; Kloszewska, Iwona; Soininen, Hilkka; McDonald, Brenna C; Farlow, Martin R; Ghetti, Bernardino; Huentelman, Matthew J; Saykin, Andrew J

    2015-03-01

    We used whole-exome sequencing to identify variants other than APOE associated with the rate of hippocampal atrophy in amnestic mild cognitive impairment. An in-silico predicted missense variant in REST (rs3796529) was found exclusively in subjects with slow hippocampal volume loss and validated using unbiased whole-brain analysis and meta-analysis across 5 independent cohorts. REST is a master regulator of neurogenesis and neuronal differentiation that has not been previously implicated in Alzheimer's disease. These findings nominate REST and its functional pathways as protective and illustrate the potential of combining next-generation sequencing with neuroimaging to discover novel disease mechanisms and potential therapeutic targets. PMID:25559091

  13. Reducing Communication in Algebraic Multigrid Using Additive Variants

    SciTech Connect

    Vassilevski, Panayot S.; Yang, Ulrike Meier

    2014-02-12

    Algebraic multigrid (AMG) has proven to be an effective scalable solver on many high performance computers. However, its increasing communication complexity on coarser levels has shown to seriously impact its performance on computers with high communication cost. Moreover, additive AMG variants provide not only increased parallelism as well as decreased numbers of messages per cycle but also generally exhibit slower convergence. Here we present various new additive variants with convergence rates that are significantly improved compared to the classical additive algebraic multigrid method and investigate their potential for decreased communication, and improved communication-computation overlap, features that are essential for good performance on future exascale architectures.

  14. A rare anatomic variant of the superior glenohumeral ligament.

    PubMed

    Pradhan, R L; Itoi, E; Watanabe, W; Yamada, S; Nagasawa, H; Shimizu, T; Wakabayashi, I; Sato, K

    2001-01-01

    The attachment of the superior glenohumeral ligament (SGHL) to the upper pole of the glenoid is variable and 3 types have been described. We report an anatomic variant of SGHL attachment to the upper pole of the glenoid that has not heretofore been reported in the literature. In this case, the SGHL overrode the biceps origin, continued to the superior labrum posteriorly, and had no attachment to the middle glenohumeral ligament or the anterior labrum. This variant was detected during routine arthroscopic examination undertaken before surgery on a rotator cuff tear.

  15. Mechanisms underlying structural variant formation in genomic disorders